Category: 3. Business

  • Johnson & Johnson Statement on the Auτonomy Study

    TITUSVILLE, N.J., November 21, 2025 – The Auτonomy proof-of-concept study was a first-of-its-kind precision approach to evaluating targeted intervention in early Alzheimer’s disease. Following a scheduled review that determined posdinemab did not achieve statistical significance in slowing clinical decline, the Auτonomy study will be discontinued.

    The initial findings underscore the deep complexity of the disease, and together with the forthcoming analyses, will offer valuable insights that will shape ongoing and future research as the understanding of Alzheimer’s biology evolves. A full evaluation of the data will be shared with the scientific community in due course.

    For nearly three decades, Johnson & Johnson has made meaningful progress to advance scientific understanding of Alzheimer’s disease. We remain committed to transforming the future of Alzheimer’s care and confident in our pioneering pipeline of therapies to treat the broad spectrum of disease. We extend our deepest gratitude to the patients, caregivers, investigators, and clinical trial site teams who participated in the Auτonomy trial.


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  • Hyundai IONIQ 9 Named “EV of the Year” by the Hispanic Motor Press

    Hyundai IONIQ 9 Named “EV of the Year” by the Hispanic Motor Press

    The award was presented by the Hispanic Motor Press at the 2025 Los Angeles Auto Show’s AutoMobility LA media days, where the top vehicles were chosen by a distinguished jury panel of Hispanic automotive journalists, content creators, and industry experts. Hyundai’s IONIQ 9 stood out among finalists for its three-row versatility, innovative EV technology, advanced safety features, and family-friendly appeal — making it the clear choice for this coveted title.

    “We are incredibly honored to receive the ‘EV of the Year’ award from the Hispanic Motor Press,” said Claudia Marquez, COO, Hyundai Motor America. “This recognition reflects our commitment to delivering electric vehicles that prioritize safety, convenience, and innovation for families, aligned with the priorities of the Hispanic community. The IONIQ 9 brings long-range capability, ultra-fast charging, and a spacious, tech-forward interior, making EV ownership effortless and rewarding.”

    “This is the electric vehicle today’s Hispanic families have been waiting for,” said Ricardo Rodriguez-Long, founder and president, Hispanic Motor Press. “The IONIQ 9 offers generous interior space for every passenger, quiet and confident performance, and the latest driver-assistance and connectivity features. Built on a proven EV platform with quick-recharge capability, it delivers real-world practicality with the refinement and value our community expects.”

    Hispanic Motor Press Awards
    The Hispanic Motor Press Awards is the premier U.S. Hispanic awards program for the Latino community to educate and help pre-select the best vehicle options in the market. The jury panel is comprised of an independent group of national Hispanic automotive journalists, content creators, and influencers who assess vehicles while considering key purchase drivers for Hispanic families in quality, reliability, style, safety, technology, and value. The annual awards include the Hispanic scholarship program for communications, automotive, and technology college students.

    Hyundai Motor America
    Hyundai Motor America offers U.S. consumers a technology-rich lineup of cars, SUVs, and electrified vehicles, while supporting Hyundai Motor Company’s Progress for Humanity vision. Hyundai has significant operations in the U.S., including its North American headquarters in California, the Hyundai Motor Manufacturing Alabama assembly plant, the all-new Hyundai Motor Group Metaplant America, and several cutting-edge R&D facilities. These operations, combined with those of Hyundai’s 850 independent dealers, contribute $20.1 billion annually and 190,000 jobs to the U.S. economy, according to a published economic impact report. For more information, visit www.hyundainews.com.

    Hyundai Motor America on Twitter | YouTube | Facebook | Instagram | LinkedIn | TikTok

    SOURCE Hyundai Motor America


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  • SEC SolarWinds Dismissal: Shifting Cyber Enforcement Risks

    The outcome caps a long-running and closely watched legal dispute that began with sweeping fraud and controls allegations tied to SolarWinds’ statements about its cybersecurity practices and its disclosures following the breach of its flagship Orion software platform in 2020. The dismissal comes amid a broader recalibration of enforcement priorities in the new administration, including the SEC’s announcement earlier this year that it will focus on public issuer “fraudulent disclosure” relating to cybersecurity—signaling a pivot away from actions based on more nuanced allegations of disclosure deficiencies. The SEC’s decision to abandon the SolarWinds case altogether is the most pointed example yet of that shift.

    The SEC’s dismissal may bring a sigh of relief to many companies and CISOs who were concerned about the chilling effect the case could have on the work of security teams to proactively identify vulnerabilities and gaps in cyber programs. However, public companies must still proceed carefully when making public statements about their security programs. In the wake of a cyber incident, any number of federal, state, or international regulators, as well as courts and litigants, may scrutinize and seize upon a company’s cybersecurity disclosures as evidence of negligence or worse. This includes the SEC, which, in late 2023, issued new requirements for companies to disclose material cyber risks and incidents to investors. Accordingly, effective governance around drafting and vetting cybersecurity statements and disclosures remains critical.

    I. Dispute Background

    The SolarWinds lawsuit arose out of the 2020 supply-chain attack, widely attributed to the Russian Foreign Intelligence Service, in which the threat actors inserted malicious code into an Orion software update, allowing potential access to thousands of SolarWinds customers. Prior to and after its 2018 IPO, SolarWinds had published a “Security Statement” on its website describing its cybersecurity practices, including its password policies, access controls, secure development lifecycle practices, and use of the NIST Cybersecurity Framework. SolarWinds had also disclosed to investors that its systems were “vulnerable” to threats from nation-state actors. Once it discovered the attack in December 2020, SolarWinds filed a Form 8-K with the SEC and publicly disclosed the incident while continuing its investigation and remediation efforts.

    In October 2023, the SEC brought an enforcement action against SolarWinds and Brown in federal court, alleging the defendants defrauded investors by overstating SolarWinds’ cybersecurity practices and understating known risks. First, the amended complaint alleged SolarWinds and Brown violated the Securities Act and Exchange Act by making materially false and misleading statements in the company’s Security Statement posted on its website, in SEC registration statements, in press releases, blog posts, and podcasts. Second, the complaint alleged that SolarWinds violated reporting provisions by filing materially misleading cybersecurity risk disclosures in pre-incident public filings, and by issuing an incomplete December 2020 Form 8-K in which SolarWinds presented its understanding of the attack. Third, the SEC alleged that SolarWinds failed to devise and maintain adequate internal accounting controls under Section 13(b)(2)(B) of the Exchange Act, and it further alleged that Brown aided and abetted these violations. Finally, the agency claimed SolarWinds violated the requirements under Rule 13a-15(a) to maintain proper disclosure controls and procedures to escalate incidents to management. This case marked the first time the SEC brought a cybersecurity enforcement action against an individual CISO, and the first time it asserted accounting control claims based on technical cybersecurity failings. 

    II. 2024 Partial Dismissal

    On July 18, 2024, U.S. District Judge Paul A. Engelmayer of the Southern District of New York issued a 107 page opinion dismissing most of the SEC’s claims. The court rejected the claims alleging false and misleading statements made in press releases, blog posts, and podcasts, finding them to be only “non-actionable corporate puffery.” It also rejected the allegations concerning the post-incident disclosures, emphasizing that they must be read in context of an unfolding investigation and that the SEC’s arguments relied on the benefit of hindsight. The court dismissed the SEC’s novel internal accounting controls claims, holding that such controls are about assuring the integrity of the company’s financial transactions, not detecting or preventing cybersecurity deficiencies in source code or network environments. Finally, the court dismissed the Rule 13a 15(a) disclosure controls claim, finding that the existence of two misclassified incidents did not amount to “systemic deficiencies” in SolarWinds’ disclosure controls and procedures.

    The only claims that were allowed to proceed concerned the representations in the website Security Statement about access controls and password protection policies. The court drew a line between “corporate puffery” and actionable statements and held that the Security Statement was publicly accessible and part of the “total mix of information” SolarWinds provided to the public, and that the SEC sufficiently pled SolarWinds’ practices materially diverged from its statements. 

    III. 2025 Summary Judgment Proceedings

    Following the court’s 2024 ruling, SolarWinds and Brown moved for summary judgment in April 2025. Signaling another shift in SolarWinds’ favor, the SEC acknowledged in a Joint Statement of Undisputed Facts that, during the relevant period, SolarWinds did implement practices described in its Security Statement, including use of the NIST Cybersecurity Framework; role based access provisioning; enforcement of password complexity; and secure development lifecycle measures such as vulnerability testing, regression testing, penetration testing, and product security assessments.

    IV. 2025 Settlement and Final Dismissal

    On July 2, 2025, prior to any ruling on summary judgment, the SEC, SolarWinds, and Brown jointly notified Judge Engelmayer that they had reached a settlement in principle. The court stayed proceedings to allow the parties to finalize the settlement paperwork. The anticipated settlement, however, did not materialize. Instead, on November 20, 2025, the parties filed a Joint Stipulation to Dismiss, in which the SEC agreed to dismiss the remaining claims against SolarWinds and Brown with prejudice without any settlement conditions (other than a waiver of potential claims against the SEC and the United States arising from the litigation).

    V. The Next Chapter: What to Take Away from SolarWinds

    The dismissal indicates a shift in the SEC’s enforcement approach—one that narrows, but does not eliminate, risk for public companies. For now, it appears the Commission is moving toward a “back to basics” approach, focusing on egregious misstatements and material misrepresentations resulting in investor harm. Even as the SEC refocuses on more traditional fraud theories, companies remain exposed to liability and scrutiny across multiple fronts, including expanding and disparate regulatory regimes, as well as private litigation that mines public statements and incident reporting for inconsistencies or omissions.

    1. Regulatory and litigation risk remains high

    While the SEC may pare back enforcement, this does not mean that other regulators will follow suit. Sector-specific regulators and state regulators, for example, have been increasingly active in cyber enforcement and may fill the void. Global companies also face a growing array of international regulators that scrutinize cyber incidents with data privacy, critical infrastructure, and operational resilience impacts. 

    In addition to regulatory enforcement, private litigation remains active. Securities class actions are common following high profile cyber incidents, particularly when public disclosures are contested. Indeed, plaintiffs’ firms are quick to file derivative suits alleging oversight failures and consumer class actions under consumer protection laws are frequent when cyber incidents are made public. 

    Of course, courts and regulators evaluate these issues case by case. The record in SolarWinds turned on specific facts, many of which ended up more favorable to SolarWinds following discovery than the SEC had initially alleged. And while Judge Engelmayer agreed with several of SolarWinds’ key arguments related to its conduct and statements at issue, that is not to say that another court would reach the same outcome. One or two slightly different takes on the statements or actions that were in question could have swung the pendulum in the opposite direction. 

    Regardless of the outcome in this case, companies should continue to concentrate on the quality and accuracy of cybersecurity disclosures, the robustness of governance and controls supporting those disclosures, and the documentation that demonstrates reasonable, risk aligned practices. In particular, companies should ensure incident materiality determinations are well documented, cross channel communications are consistent, and governance processes tie public statements to verified technical facts.

    2. Securities disclosure requirements have expanded

    The disclosures at issue in SolarWinds took place before the SEC adopted its new rule on Cybersecurity Risk Management, Strategy, Governance, and Incident Disclosure by Public Companies (the “Cyber Rules”). Since December 2023, the Cyber Rules have imposed new requirements for timely Form 8 K reporting of material incidents and added detailed requirements for disclosures of cyber risk management and governance in annual reports. Companies should be diligent in ensuring that their disclosures and public statements made today are in line with what the company has put into place. Even if the SEC declines to bring an enforcement action based on alleged disclosure deficiencies where there is no investor harm, the new triggering requirements and the expanded disclosures under the Cyber Rules heighten the risk that those statements, or the failure to make those statements, will be used against companies by private litigants and other regulators.

    3. Executives are not off the hook.

    The SolarWinds case raised concerns that CISOs could be subject to a low bar for personal liability. With the dismissal, companies may wonder whether individual executive exposure for cyber failures remains a serious risk. While the threshold for individual CISO enforcement risk may now be higher in the securities context, senior leaders may still be targeted in cases involving alleged misrepresentations, negligence, or failures in oversight that result in consumer or market harm.

    Indeed, the expectation environment for CISOs and other senior leaders continues to intensify. Regulators increasingly expect sophisticated boards and executive teams to focus not only on the existence of cybersecurity programs, but on their specificity, execution quality, and alignment with risk standards. This includes probing “ground truth” technical measures like vulnerability management, identity and access controls, incident response readiness, logging and monitoring sufficiency, and third party risk management—and assessing whether responsible individuals exercised appropriate oversight.

    In short, while one case may reduce immediate headline risk, it may not meaningfully change the direction of the broader legal and regulatory landscape. Executives with cybersecurity oversight should continue to assume heightened scrutiny, ensure governance around risk prioritization and resourcing, and demonstrate reasonableness regarding technical controls and external statements.

    4. Enforcement will vary by impact. 

    SEC enforcement is certainly not one-size-fits-all. Even given the SEC’s refocused priorities, enforcement could vary across companies and sectors. Factors such as inherent cyber risk, size, sophistication, and market impact may influence enforcement. Sectors that are more likely to suffer or inflict greater impact from significant operational disruptions, such as financial institutions, providers of pervasive technology services, or critical infrastructure, may be scrutinized more heavily. In other words, the greater the potential harm to shareholders or the market generally, the greater SEC scrutiny the company is likely to face.

    5. Enforcement priorities could shift again.

    Agency priorities often change from administration to administration, and the pendulum could swing back again. Companies should assume that shifts in enforcement emphasis are temporary and continue to anchor cyber governance in well-supported risk management practices that can withstand regulatory and judicial scrutiny. 

    VI. Final Takeaway

    The SEC’s decision to dismiss its remaining claims against SolarWinds reflects a narrowing of one enforcement path but still leaves intact significant exposure possibilities, including more traditional securities actions, parallel regulatory regimes, and private litigation. The most durable mitigation is disciplined governance: aligning public statements with verified technical reality, document materiality and incident response judgments, and sustain reasonable, risk based controls. Those steps remain the foundation for withstanding scrutiny from investors, courts, and regulators—regardless of shifting enforcement cycles. 

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  • Wealth management firms to pay $25.5 million to settle employees’ class action

    Wealth management firms to pay $25.5 million to settle employees’ class action

    WASHINGTON, Nov 21 (Reuters) – A group of major asset and wealth management firms has agreed to pay $25.5 million to resolve claims in U.S. court that they conspired to restrict job mobility and suppress wages for thousands of financial professionals.

    Lawyers for the employees on Thursday asked, opens new tab a federal judge in Kansas to grant final approval of the settlement.

    Sign up here.

    The nationwide accord covers more than 4,400 current and former employees who worked for companies including Mariner Wealth Advisors and American Century Companies between 2012 and 2020. The plaintiffs sued last year , alleging the companies violated antitrust law by agreeing not to recruit or hire each other’s workers.

    American Century and another defendant, Montage Investments, previously reached non-prosecution agreements with the U.S. Justice Department over related allegations, according to the filing.

    In a statement, American Century said it was pleased to resolve the workers’ lawsuit in Kansas and “remains committed to fair and honest competition in compliance with all laws and regulations.”

    A lawyer for Mariner Wealth and Montage did not immediately respond to a request for comment, and neither did lead attorneys for the plaintiffs.

    The asset and wealth management firms denied any wrongdoing.

    The plaintiffs said the Mariner defendants have about $65.9 billion in assets under management and the American Century defendants manage about $230 billion in assets.

    The plaintiffs said the settlement offers significant and immediate relief and avoids the risk and costs of continuing litigation.

    Settlement payments will be based on factors including length of employment, the court papers showed.

    Lawyers for the plaintiffs estimated an average payout of about $3,700 per person. Eligible employees will receive payments automatically.

    The settlement also said the plaintiffs’ lawyers will ask for up to one-third of the fund for legal fees, or about $8.5 million.

    The case is Jakob Tobler et al v. 1248 Holdings LLC, U.S. District Court for the District of Kansas, No. 2:24-cv-02068-EFM-GEB.

    For plaintiffs: George Hanson of Stueve Siegel Hanson, and Rowdy Meeks of Rowdy Meeks Legal Group

    For Mariner: Jonathan King of DLA Piper

    For American Century: John Schmidtlein of Williams & Connolly

    Read more:

    US naval shipbuilders seek Supreme Court review in engineers’ pay case
    US judge approves pizza chain Papa John’s ‘no poach’ antitrust settlement
    US poultry producers sued by growers over hiring and pay
    Pharmacy residents accuse US hospitals of wage-fixing in new lawsuit

    Reporting by Mike Scarcella

    Our Standards: The Thomson Reuters Trust Principles., opens new tab

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  • China controls this key resource AI needs – threatening stocks and the U.S. economy

    China controls this key resource AI needs – threatening stocks and the U.S. economy

    By Kristina Hooper

    AI relies on rare-earth elements to grow its infrastructure – and the U.S. relies on AI to grow GDP

    Capital spending on AI has been a key driver of U.S. stock market returns and continues to exceed expectations, comprising a large portion of S&P 500 SPX capital expenditures.

    Jason Furman, a Harvard University economics professor, calculated that 92% of total U.S. GDP growth for the first half of 2025 could be attributed to AI spending. Without AI-related data-center construction, he reported, GDP growth would have been an anemic 0.1% on an annualized basis.

    Given so much riding on the AI capex boom, it’s important to consider what could derail U.S. economic growth and the U.S. stock market

    One major risk is access to rare earth elements. Limited rare-earth access could present the U.S. with challenges similar to what it faced in the 1970s from its dependence on oil.

    Rare-earth elements are used extensively in artificial intelligence, including disk drives, cooling servers and especially semiconductor fabrication. Artificial intelligence has enormous computational and memory demands, which is why high-capacity, high-performance semiconductors are the linchpin of the AI build-out. Rare earths are also integral for national security – used in radar, lasers and satellite systems.

    From the 1960s to the 1990s, the U.S. was the leader in rare-earth elements production. In 1995, two decisions were made that had far-ranging consequences, dramatically changing the trajectory of U.S. leadership in rare earth elements.

    First, the U.S. approved China’s purchase of U.S. rare-earth magnet company Magnequench from General Motors, thereby acquiring a highly advanced technology that arguably would have taken many years to develop.

    Second, China applied to join the World Trade Organization, ultimately enabling it to sell its rare-earth elements to a global market. China was able to sell at a lower cost than the U.S., contributing to the closure of the U.S. mining company that produced rare earth elements, MP Materials Corp. (MP), in 2002.

    MP Materials was reopened for national defense use in 2017. U.S. production has since ramped up, with rare-earth production reaching 45,000 tons in 2024 – yet that’s still less than one-sixth of China’s production.

    Yet the U.S. Department of Defense’s lofty goal of meeting defense-related demand for light- and heavy rare earths by 2027 may not be achieved, given America’s rare-earth mining and processing limitations. Even if it is, significant commercial demand, including the enormous AI build-out, will not be met.

    China controls the supply

    China controls around 70% of the world’s rare earth resource output and about 90% of the world’s rare earth processing capabilities. Access to rare-earth elements has been a key bargaining chip in U.S. trade negotiations with China.

    As a result, the U.S. has been increasing efforts to diversify its rare-earths supply and gain reliable and adequate exposure to these elements through its allies. Australia and Canada, for instance, have significant rare-earth resources that can help support America’s rare-earth element needs.

    New technologies may also lessen or eliminate the need for rare-earth elements in various uses and make rare-earth element recycling more efficient (currently, just 1% of rare-earth elements are recycled). In addition, U.S. government policies can discourage or at least disincentivize demand for rare earth element-intensive products such as electric vehicles, as the Trump administration has done by eliminating EV tax credits.

    Rare earth element independence should be as high a priority for the U.S. as energy independence was 50 years ago. Until there’s a viable alternative to the China-dominated rare-earth supply chain, AI capital spending – and both the U.S. economy and stock market – are vulnerable. Accordingly, stock investors should pay attention to trade deals and policymakers’ comments, and consider supply-chain risks when evaluating AI-related investments.

    Kristina Hooper is chief market strategist at Man Group, which manages alternative investments. The opinions expressed are her own.

    More: Big Tech is spending on power for AI – whether Washington functions or not

    Also read: AI has real problems. The smart money is investing in the companies solving them now.

    -Kristina Hooper

    This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

    (END) Dow Jones Newswires

    11-21-25 1619ET

    Copyright (c) 2025 Dow Jones & Company, Inc.

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  • FDA Approves KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), Each with Padcev® (enfortumab vedotin-ejfv), as Perioperative Treatment for Adults with Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

    Represents the first PD-1 inhibitor plus ADC regimens for this patient population


    Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) in combination with Padcev® (enfortumab vedotin-ejfv), as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, for the treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. These approvals represent the first PD-1 inhibitor plus ADC regimens for this patient population.

    These approvals are based on data from the Phase 3 KEYNOTE-905 trial (also known as EV-303), which was conducted in collaboration with Pfizer and Astellas. Results, which were presented at the recent European Society for Medical Oncology (ESMO) Congress, showed that after a median follow-up of 25.6 months, KEYTRUDA plus Padcev, as perioperative treatment, demonstrated a statistically significant 60% reduction in the risk of event-free survival (EFS) events versus surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy (HR=0.40 [95% CI, 0.28-0.57]; p<0.0001; 48/170 [28%] versus 95/174 [55%]; median EFS not reached [NR] [95% CI, 37.3-NR] versus 15.7 months [95% CI, 10.3-20.5]). KEYTRUDA plus Padcev also demonstrated a statistically significant 50% improvement in overall survival (OS) versus surgery alone (HR=0.50 [95% CI, 0.33-0.74]; p=0.0002; 38/170 [22%] versus 68/174 [39%]; median OS NR [95% CI, NR-NR] vs 41.7 [95% CI, 31.8-NR]). The trial demonstrated a statistically significant difference in pathologic complete response (pCR) rate (57.1% [95% CI: 49.3, 64.6] vs. 8.6% [95% CI: 4.9, 13.8]; p<0.0001). The effectiveness of KEYTRUDA QLEX for its approved indications has been established based upon evidence from the adequate and well-controlled studies conducted with KEYTRUDA and additional data from MK-3475A-D77 comparing the pharmacokinetic, efficacy, and safety profiles of KEYTRUDA QLEX and KEYTRUDA.

    KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA or KEYTRUDA QLEX, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, other transplant (including corneal graft) rejection. Additionally, fatal and other serious complications can occur in patients who receive allogenic hematopoietic stem cell transplantation (HSCT) before or after treatment. Consider the benefit vs risks for these patients. Treatment of patients with multiple myeloma with a PD-1/PD-L1-blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials due to the potential for increased mortality. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA or KEYTRUDA QLEX. Based on the severity of the adverse reaction, KEYTRUDA and KEYTRUDA QLEX should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA and KEYTRUDA QLEX can also cause severe or life-threatening infusion-related reactions. Based on their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

    “Pembrolizumab plus enfortumab vedotin is poised to address a critical unmet need,” said Dr. Matthew Galsky, Lillian and Howard Stratton Professor of Medicine, Director of Genitourinary Medical Oncology, Mount Sinai Tisch Cancer Center, and KEYNOTE-905 study investigator. “Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin. These approvals, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades.”

    “Our company’s ongoing commitment to putting patients at the center of finding new innovations in cancer care has made the introduction of these new options a reality for patients who are truly in need,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “Moreover, we are honored to provide these patients who previously had only one option — surgery — with a choice to receive their immunotherapy either intravenously or subcutaneously.”

    Study design and additional data supporting the approval

    KEYNOTE-905, also known as EV-303, is an open-label, randomized, multi-arm, controlled Phase 3 trial (ClinicalTrials.gov, NCT03924895) evaluating perioperative KEYTRUDA, with or without Padcev, versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. The trial enrolled 344 patients who were randomized 1:1 to receive either:

    • Neoadjuvant KEYTRUDA 200 mg over 30 minutes as an intravenous infusion on Day 1 and enfortumab vedotin 1.25 mg/kg as an intravenous infusion on Days 1 and 8 of each 21 day cycle for 3 cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg over 30 minutes on Day 1 of each 21 day cycle for 14 cycles and adjuvant enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21 day cycle for 6 cycles (n=170).
    • Immediate radical cystectomy (RC) and pelvic lymph node dissection (PLND) alone (n=174).

    Treatment continued until completion of study medications, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase, or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within 5 weeks prior to RC and PLND, and at 6 weeks post radical cystectomy. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to 2 years, and every 24 weeks thereafter.

    A total of 149 (88%) patients in the KEYTRUDA in combination with enfortumab vedotin arm and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND.

    The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.

    The major efficacy outcome measure of this trial was EFS defined as the time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death. OS and pCR rate as assessed by blinded independent pathology review were additional efficacy outcome measures.

    For the 167 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 1.4 months (range: 1 day to 2.7 months) and the median number of cycles of KEYTRUDA was 3 (range: 1 to 3) out of the planned 3 cycles in the neoadjuvant phase. For the 96 patients who received KEYTRUDA in the adjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 8.5 months (range: 1 day to 12.9 months) and the median number of cycles of KEYTRUDA was 12 (range: 1 to 14) out of the planned 14 cycles in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of KEYTRUDA was 5 (range: 1, 17) out of the planned 17 cycles.

    In KEYNOTE-905, the most common adverse reactions (≥20%) occurring in cisplatin-ineligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin (n =167) were rash (54%), pruritus (47%), fatigue (47%), peripheral neuropathy (39%), alopecia (35%), dysgeusia (35%), diarrhea (34%), constipation (28%), decreased appetite (28%), nausea (26%), urinary tract infection (24%), dry eye (21%), and weight loss (20%).

    In the neoadjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 27% (n=167) of patients; the most frequent (≥2%) were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients; the most frequent (>1%) were rash (2.4%, including generalized exfoliative dermatitis), increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each).

    Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin and underwent radical cystectomy, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions.

    In the adjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 43% (n=100); the most frequent (≥2%) were urinary tract infection (8%); acute kidney injury and pyelonephritis (5% each); urosepsis (4%); and hypokalemia, intestinal obstruction, and sepsis (2% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 28% of patients; the most frequent (>1%) were diarrhea (5%), peripheral neuropathy, acute kidney injury, and pneumonitis (2% each).

    About KEYTRUDA® (pembrolizumab) injection, 100 mg

    KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

    Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

    About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use

    KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL).

    Selected KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) Indications in the U.S.

    Urothelial Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma:

    • who are not eligible for any platinum-containing chemotherapy, or
    • who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

    KEYTRUDA and KEYTRUDA QLEX in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, are each indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

    See additional selected KEYTRUDA and KEYTRUDA QLEX indications in the U.S. after the Selected Important Safety Information.

    Selected Important Safety Information for KEYTRUDA and KEYTRUDA QLEX

    Contraindications

    KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients.

    Severe and Fatal Immune-Mediated Adverse Reactions

    KEYTRUDA and KEYTRUDA QLEX are monoclonal antibodies that belong to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

    Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA or KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

    Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA and KEYTRUDA QLEX require interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

    Immune-Mediated Pneumonitis

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions.

    Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

    Immune-Mediated Colitis

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

    Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%) and Grade 2 (0.4%) adverse reactions.

    Hepatotoxicity and Immune-Mediated Hepatitis

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions.

    KEYTRUDA With Axitinib or KEYTRUDA QLEX With Axitinib

    KEYTRUDA and KEYTRUDA QLEX, when either is used in combination with axitinib, can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib or KEYTRUDA QLEX and axitinib, and consider administering corticosteroids as needed.

    With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

    Immune-Mediated Endocrinopathies

    Adrenal Insufficiency

    KEYTRUDA and KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions.

    Hypophysitis

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA,

    including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

    Thyroid Disorders

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity.

    Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

    Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

    Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%).

    Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

    Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Type 1 DM occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy.

    Immune-Mediated Nephritis With Renal Dysfunction

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated nephritis.

    Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

    Immune-Mediated Dermatologic Adverse Reactions

    KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity.

    Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%) and Grade 3 (0.8%) adverse reactions.

    Other Immune-Mediated Adverse Reactions

    The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA, KEYTRUDA QLEX, or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis (2.8%), duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

    Hypersensitivity and Infusion- or Administration-Related Reactions

    KEYTRUDA and KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. With KEYTRUDA and KEYTRUDA QLEX, monitor for signs and symptoms of infusion- and administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion-related reactions have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Hypersensitivity and administration related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX in combination with platinum doublet chemotherapy, including Grade 2 (2.8%). Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate systemic reactions. For severe or life-threatening systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX.

    Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

    Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

    Increased Mortality in Patients With Multiple Myeloma

    In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

    Embryofetal Toxicity

    Based on their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA or KEYTRUDA QLEX and advise them to use effective contraception during treatment and for 4 months after the last dose.

    Adverse Reactions

    In study MK-3475A-D77, when KEYTRUDA QLEX was administered with chemotherapy in metastatic non–small cell lung cancer (NSCLC), serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%). KEYTRUDA QLEX was permanently discontinued due to an adverse reaction in 16% of 251 patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis. Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase. The most common adverse reactions (≥20%) were nausea (25%), fatigue (25%), and musculoskeletal pain (21%).

    In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

    In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

    In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

    In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

    In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

    In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

    In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

    In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy.

    The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy or chemoradiotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain.

    In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

    Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%).

    In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%).

    Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

    Adverse reactions observed in KEYNOTE-483 were generally similar to those occurring in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy.

    In KEYNOTE-689, the most common adverse reactions (≥20%) in patients receiving KEYTRUDA were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%).

    In the neoadjuvant phase of KEYNOTE-689, of the 361 patients who received at least one dose of single agent KEYTRUDA, 11% experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients, including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%).

    Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4%, patient decision in 3%, adverse reactions in 1.4%, physician’s decision in 1.1%, unresectable tumor in 0.6%, loss of follow-up in 0.3%, and use of non-study anti-cancer therapy in 0.3%.

    Of the 323 KEYTRUDA-treated patients who received surgery following the neoadjuvant phase, 1.2% experienced delay of surgery (defined as on-study surgery occurring ≥9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions, and 2.8% did not receive adjuvant treatment due to adverse reactions.

    In the adjuvant phase of KEYNOTE-689, of the 255 patients who received at least one dose of KEYTRUDA, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% of patients, including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%), and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis, and death not otherwise specified.

    In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

    In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

    In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

    In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%).

    In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

    In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

    In KEYNOTE-905, the most common adverse reactions (≥20%) occurring in cisplatin-ineligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin (n =167) were rash (54%), pruritus (47%), fatigue (47%), peripheral neuropathy (39%), alopecia (35%), dysgeusia (35%), diarrhea (34%), constipation (28%), decreased appetite (28%), nausea (26%), urinary tract infection (24%), dry eye (21%), and weight loss (20%).

    In the neoadjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 27% (n=167) of patients; the most frequent (≥2%) were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients; the most frequent (>1%) were rash (2.4%, including generalized exfoliative dermatitis), increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each).

    Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin and underwent radical cystectomy, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions.

    In the adjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 43% (n=100); the most frequent (≥2%) were urinary tract infection (8%); acute kidney injury and pyelonephritis (5% each); urosepsis (4%); and hypokalemia, intestinal obstruction, and sepsis (2% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 28% of patients; the most frequent (>1%) were diarrhea (5%), peripheral neuropathy, acute kidney injury, and pneumonitis (2% each).

    In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

    Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

    In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

    In KEYNOTE-811, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%).

    In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%).

    In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

    Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

    In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 294 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients; those ≥1% included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (51%), urinary tract infection (35%), vomiting (34%), fatigue (28%), hypothyroidism (23%), constipation (20%), weight loss (19%), decreased appetite (18%), pyrexia (14%), abdominal pain and hyperthyroidism (13% each), dysuria and rash (12% each), back and pelvic pain (11% each), and COVID-19 (10%).

    In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

    KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%).

    For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

    For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

    In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

    In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%).

    In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

    In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

    In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

    In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

    In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4).

    Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

    Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

    In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

    In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

    Lactation

    Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose.

    Pediatric Use

    In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months).

    The safety and effectiveness of KEYTRUDA QLEX for the treatment of pediatric patients 12 years and older who weigh greater than 40 kg have been established for:

    • Stage IIB, IIC, or III melanoma following complete resection
    • Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors
    • Recurrent locally advanced or metastatic Merkel cell carcinoma

    Use of KEYTRUDA QLEX in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults and additional pharmacokinetic and safety data for KEYTRUDA in pediatric patients 12 years and older. Pembrolizumab exposures in pediatric patients 12 years and older who weigh greater than 40 kg are predicted to be within range of those observed in adults at the same dosage.

    The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma (stage IIB, IIC, or III melanoma following complete resection in pediatric patients 12 and older), MCC, and MSI-H or dMMR cancer.

    Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients.

    The safety and effectiveness of KEYTRUDA QLEX have not been established in pediatric patients younger than 12 years of age for the treatment of melanoma, MCC, and MSI-H or dMMR cancer.

    The safety and effectiveness of KEYTRUDA and KEYTRUDA QLEX have not been established in pediatric patients for other approved indications shown.

    Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%).

    Geriatric Use

    Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older.

    Of the 167 patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin, 37% (n=61) were 65-74 years and 46% (n=77) were 75 years or older. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 12% in patients 75 years or older.

    Additional Selected KEYTRUDA and KEYTRUDA QLEX Indications in the U.S.

    Melanoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic melanoma.

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with stage IIB, IIC, or III melanoma following complete resection.

    Non-Small Cell Lung Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, for the first-line treatment of adult patients with metastatic squamous NSCLC.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

    • stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
    • metastatic.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA or KEYTRUDA QLEX.

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

    Malignant Pleural Mesothelioma

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM).

    Head and Neck Squamous Cell Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent.

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with platinum and fluorouracil (FU), for the first-line treatment of adult patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

    Microsatellite Instability-High or Mismatch Repair Deficient Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older.

    Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.

    Gastric Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

    Esophageal Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

    • in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with tumors that express PD-L1 (CPS ≥1), or
    • as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

    Cervical Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemoradiotherapy (CRT), for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 III-IVA).

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

    KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

    Hepatocellular Carcinoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1–containing regimen.

    Biliary Tract Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).

    Merkel Cell Carcinoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older.

    Renal Cell Carcinoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with axitinib, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) at intermediate high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

    Endometrial Carcinoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and paclitaxel, followed by KEYTRUDA or KEYTRUDA QLEX as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

    KEYTRUDA and KEYTRUDA QLEX, as a single agent, are each indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

    Cutaneous Squamous Cell Carcinoma

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

    Triple-Negative Breast Cancer

    KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then each continued as a single agent as adjuvant treatment after surgery.

    KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

    About the Merck Access Program for KEYTRUDA

    At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com/.

    About Merck’s Patient Support Program for KEYTRUDA

    Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com/.

    Merck’s focus on cancer

    Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.

    About Merck

    At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

    Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA

    This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

    Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovation products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

    The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

    Please see Prescribing Information for KEYTRUDA (pembrolizumab) at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

    Please see Prescribing Information for KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_pi.pdf and Medication Guide for KEYTRUDA QLEX at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_mg.pdf


    Source: Merck & Co., Inc., Rahway, NJ, USA


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  • Journal of Medical Internet Research

    Journal of Medical Internet Research

    Digital health technologies (DHTs), encompassing a wide array of tools from mHealth apps and telemedicine to artificial intelligence, hold transformative potential for health care worldwide [,]. By expanding access to care, enhancing patient engagement, and improving the efficiency of diagnostic and treatment pathways, these technologies offer significant opportunities to build more accessible, affordable, and equitable health systems [-]. The World Health Organization defines digital health as “the field of knowledge and practice associated with the development and use of digital technologies to improve health.” [] This broad concept includes not only established eHealth domains but also emerging areas such as big data analytics and the Internet of Things, reflecting its integral role in modern health care.

    However, the benefits of digital health are not universally realized and are not distributed equally []. Factors such as digital literacy, access to devices and internet, socioeconomic status, cultural relevance, and community context influence who benefits from digital health solutions [,]. In fact, digital literacy and internet connectivity have been termed “super social determinants of health” because of their foundational influence on all other determinants of health in the digital age []. The rapid digitization of health care may widen health disparities if solutions are not developed with these determinants in mind []. Growing evidence suggests that the digital transformation in health care may exacerbate existing health inequities, creating new barriers for marginalized populations including persons with disabilities, patients of racial or ethnic minority groups, those with limited language proficiency, and people with low socioeconomic status [-].

    Previous research on the digital divide and health care access for vulnerable groups has illuminated various forms of exclusion, such as the inaccessibility of health websites and mobile apps, often due to a lack of distinguishable button features, inaccessible content, or the absence of assistive technology integration [,]. For individuals with blindness specifically, existing literature frequently points to significant challenges in interacting with visually-oriented digital environments []. Crucially, much of this prior research tends to homogenize the experiences of vulnerable populations [], overlooking the nuanced realities and varying adaptive capacities within specific subgroups. This oversight means that while broad challenges are identified, the potential for certain segments of vulnerable communities to navigate and even leverage digital tools remains underexplored.

    Within this context, educated and digitally literate young adults with blindness represent a critically overlooked and underexplored subgroup. For the purpose of this study, we define our participant cohort as follows: “young adults” refers to individuals aged 18 to 30 years [], a generation broadly considered digitally native; “educated” refers to individuals who have received or are currently pursuing higher education (including associate’s, Bachelor’s, Master’s, or doctoral degrees); and “blindness” is defined according to the World Health Organization criteria of a presenting visual acuity of less than 3/60 in the better eye []. This cohort embodies a central paradox: they are a digitally native generation, often exhibiting a greater willingness and capacity to adopt new technologies and engage in digital transformation through exploratory learning. The proliferation of smartphones equipped with assistive features like screen readers and voice assistants theoretically holds significant promise for enhancing their independence. However, their entire digital experience is mediated by these assistive technologies, rendering them uniquely vulnerable to design and usability flaws in mainstream applications. The existing literature, by not adequately differentiating within the community with blindness, fails to capture the unique dynamic of empowerment and exclusion experienced by this specific subgroup. This study addresses the critical gap by proposing that a segment of high-literacy individuals with blindness, through personal effort and adaptive strategies, can indeed mitigate some impacts of the digital divide, a nuanced perspective often underestimated in studies that generalize vulnerabilities. Understanding this internal heterogeneity is paramount for developing genuinely effective and equitable digital health solutions.

    China offers a uniquely relevant context for exploring these complex issues. It boasts one of the worlds largest internet user bases, exceeding 1.1 billion individuals as of 2024 [], with extensive access to a variety of internet-based services, including health care []. Concurrently, China is home to one of the largest populations with disabilities in the world, including nearly 10 million who are blind [], a significant proportion of whom are young. While some studies in China have identified health care barriers for visually impaired individuals, such as difficulties with registration, navigation, and understanding treatment processes [], the majority of empirical studies on digital health access have tended to focus on older adults or persons with disabilities in general. These studies offer valuable broad overviews but often do not provide in-depth insights into the specific experiences of educated young adults with blindness navigating both empowerment and exclusion in a rapidly digitizing health care system. The unique combination of a highly developed digital infrastructure and a large young population with blindness in China provides invaluable insights into how accessibility challenges persist and manifest even amid advanced technological environments, underscoring the urgency for inclusive design.

    To address this gap, this qualitative study aims to comprehensively explore the lived experiences of educated and digitally literate young adults with blindness in China as they access health care services in the digital age. A qualitative methodology is uniquely suited to capture the rich, in-depth narratives of these interactions, uncovering the nuanced facilitators and barriers that quantitative methods might miss. This nuanced understanding of their lived experiences with the digital health ecosystem can inform policy developments and improve clinical practices in promoting digital health equity.

    Study Design

    We used a qualitative design to gain an in-depth understanding of how educated and digitally literate young adults with blindness navigate health care access with the assistance of DHTs. This approach was chosen to capture the rich, subjective lived experiences and perceptions of participants, offering deep insights into how they interpret their personal encounters, construct their realities, and attribute meaning to their experiences within a rapidly digitizing health care ecosystem []. A qualitative methodology is particularly appropriate for exploring complex social phenomena where individual perspectives are central to uncovering the underlying dynamics of empowerment and exclusion. This study adheres to the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines () [].

    Participants and Recruitment

    Participants

    This study focused on educated young adults with blindness who actively use smartphones and digital platforms to access health care services. Participants were selected based on the following inclusion and exclusion criteria ().

    Textbox 1. Inclusion and exclusion criteria.

    Inclusion criteria

    • Citizens and residents of China
    • Mandarin speakers
    • Young adults aged 16 to 36 years
    • Higher education (associate’s degree, Bachelor’s degree, or higher)
    • Capable of independently operating at least 1 digital device (eg, smartphone or computer)
    • Individuals with blindness (presenting visual acuity worse than 3/60 in the better eye, based on World Health Organization standards [])

    Exclusion criteria

    • No experience seeking health care services within the past 2 years
    • Unwilling to participate or unable to clearly articulate their experiences
    • Failure to meet any of the defined inclusion criteria
    Recruitment and Sample Size

    A purposive snowball sampling approach was used to recruit participants. Initially, participants were selected from online communities and social media platforms serving people with blindness in China. Initial recruitment was facilitated by author CC (who is also a highly educated adult with blindness), who posted the study invitation in several WeChat groups dedicated to information exchange and community building among the population with blindness. Interested and eligible individuals were then contacted directly by the author for screening. Following their interview, initial participants were asked to refer peers in their network who also met the study criteria, thus generating the subsequent snowball sample.

    A total of 12 participants were recruited for this study. In qualitative research, the sample size was determined by the principle of data saturation, not statistical generalizability. This approach is supported by findings from Guest et al [], which indicate that 12 interviews are often sufficient to reach thematic saturation in a relatively homogeneous sample. Our analysis showed a similar pattern: over 70% of themes were identified within the first 6 interviews, and the primary core themes were established by the 10th interview. To confirm saturation, 2 additional interviews were conducted, which yielded no new core themes. Therefore, the final sample of 12 participants was considered sufficient for a comprehensive analysis.

    Data Collection

    Semistructured interviews were conducted in Mandarin Chinese during September 2024 by 1 author (JZ), a female PhD student trained in qualitative research methods. The interviewer had no prior relationship with the participants, which helped minimize biases and address potential ethical concerns. All interviews were carried out remotely using the Tencent Meeting (Tencent Technology Co Ltd) videoconferencing platform. Tencent Meeting was selected due to the necessity for remote data collection during the COVID-19 outbreak and its status as a mainstream, accessible, and free online conferencing tool widely used in mainland China [,]. This ensured both the safety of participants and researchers and provided a familiar and convenient platform for our digitally literate participants with blindness. Before the interviews, participants were provided with detailed information about the study’s purpose, procedures, and the expected time commitment.

    A topic guide with open-ended questions () was used during interviews to ensure comprehensive coverage of relevant topics and allow participants to freely elaborate on their experiences. Follow-up questions were posed as needed to clarify responses and gather more detailed information on participants’ perspectives. The interview questions were developed by reviewing the existing literature and absorbing expert opinions. To ensure validity, the guide was pretested by 2 educated adults with blindness (who were not included in the final sample) and revised based on their feedback. Participants were initially asked to share their personal background and how they became blind. Subsequently, they were prompted to describe their past and present experiences in accessing health care services, while the third part focused on the perceived benefits and challenges of using digital tools, including how such technologies empowered or hindered their access to health care. Follow-up questions were tailored to participants’ responses to encourage deeper elaboration. Finally, participants were invited to share any additional thoughts or address overlooked aspects before concluding the interview. The interviewer took field notes during the interviews to supplement the data and highlight key moments []. A total of 12 interviews were conducted, with durations ranging from 35 to 90 minutes (mean 55.0, SD 18.5). All interviews were audio-recorded with participants’ permission, transcribed verbatim, and checked by participants.

    Ethical Considerations

    This study received ethical approval from the Peking University Institutional Review Board (IRB00001052-22097). Due to the participants’ blindness, a verbal informed consent process was meticulously followed. Before each interview, participants were thoroughly informed about the study’s purpose, procedures, their right to withdraw at any time without penalty, the voluntary nature of their participation, and the measures taken to ensure confidentiality. Oral consent was obtained after ensuring that participants fully understood all aspects of the study, and this consent was audio-recorded as part of the interview. To protect the privacy and confidentiality of participants, strict measures were implemented. All data collected, including interview transcripts and audio recordings, were anonymized immediately upon transcription by removing direct identifiers such as names, specific locations, or any other potentially identifying information. Pseudonyms were assigned to participants to ensure their anonymity in all research outputs. All data were stored securely on password-protected university servers accessible only to the research team. Participants received compensation ranging from 60 to 100 RMB (US $8.40 to $14.00) for their time and participation. We confirm that no images or other materials that could identify individual participants are included in this paper or any supplementary materials. All procedures involving human subjects were conducted in accordance with the ethical standards of the institutional and national research committee and with the Helsinki Declaration.

    Data Analysis

    This study used thematic analysis, a flexible and powerful method for systematically generating robust findings by “identifying, analyzing, and reporting patterns (themes) within data” []. Following the inductive qualitative thematic analysis approach outlined by Braun and Clarke [,], our data analysis encompassed 3 phases: reading, coding, and theming, informed by practical thematic analysis guidelines [].

    The reading phase commenced with the transcription of recorded interviews by 1 author (JZ), which were subsequently verified by the participants. The translated interview transcripts were then imported into the qualitative data analysis software MAXQDA 24 (VERBI GmbH) to facilitate the analytical process. During this phase, the researchers achieved extensive familiarization with the data through repeated readings.

    The coding phase began with initial code development and involved a systematic and iterative process. One researcher (JZ) initiated the process by assigning descriptive codes line-by-line to segments of the interview transcripts using MAXQDA 24. These codes were generated inductively, emerging organically from a close reading of the text. They represented specific concepts, ideas, or experiences directly relevant to the study’s objectives, aiming to capture the richness of participants’ perspectives in their own words. To ensure academic rigor and reliability, a second researcher (CS) independently analyzed 30% of the uncoded interview transcripts, generating her own list of key themes without any influence from JZ. After this blind coding process, the codes were discussed and compared among all authors. Code definitions were refined, and a shared codebook was developed. This iterative process involved reviewing and revising codes, merging similar concepts, and resolving discrepancies, ultimately ensuring a comprehensive and aligned approach to the remaining data [].

    The theming phase involved synthesizing these refined codes into broader, overarching themes that addressed the research questions [,]. Throughout the entire data analysis process, particular attention was paid to the concept of data saturation. Discussions regarding saturation began during the initial reading phase and continued iteratively throughout coding and theming to ensure that no new information was emerging and that the themes were well-developed and grounded in the data.

    Participants’ Characteristics

    A total of 12 educated and digitally literate young participants with blindness were included in this qualitative study (). The average age was 25.4 (SD 2.2) years, more than half were female (7/12, 58%), and most experienced blindness from an early age (9/12, 75%; aged <6 y). Reflecting the inclusion criteria, all participants were currently pursuing or had completed higher education: 17% (2/12) held junior college degrees, while 83% (10/12) had completed or were pursuing Bachelor’s degrees or higher. In terms of occupation, 58% (7/12) were employed, with the remaining 42% (5/12) being students or unemployed. Half of the participants (6/12, 50%) resided in first-tier cities, with the remaining half evenly distributed between new first-tier or second-tier and third-tier or below cities (3/12, 25% each). The most common reasons for seeking health care were acute conditions and injury treatment (6/12, 50%), followed by chronic and skin conditions (4/12, 33%).

    Table 1. Demographic information of educated young adults with blindness (N=12).
    Characteristics Value
    Age (y), mean (SD) 25.4 (2.2)
    Sex, n (%)
     Male 5 (42)
     Female 7 (58)
    Age of blindness onset (y), n (%)
     Congenital or early onset (0‐5) 9 (75)
     Acquired (>6) 3 (25)
    Education, n (%)
     Junior college 2 (17)
     Bachelor’s degree or higher (completed or in-progress) 10 (83)
    Occupation, n (%)
     Employed 7 (58)
     Students or unemployed 5 (42)
    Residence (city tier), n (%)
     First-tier 6 (50)
     New first-tier or second-tier 3 (25)
     Third-tier and below 3 (25)
    Primary health care visits, n (%)
     Acute conditions and injury treatment 6 (50)
     Chronic and skin conditions 4 (33)
     General check-ups 1 (8)
     Gynecological care 1 (8)

    Overarching Category: Experiences of Empowerment but Exclusion in Digital Health Care

    Participants’ experiences navigating health care in the digital age were rich and multifaceted, consistently revealing a complex dynamic of both empowerment and exclusion. Our thematic analysis yielded 7 key themes, which are presented under 2 overarching categories: empowerment (reflecting how digital technologies enhance autonomy and access), and exclusion (highlighting persistent barriers and unmet potentials in digital health care; ).

    Table 2. Overview of themes.
    Overarching category and theme Summary of key points identified
    Empowerment

    Digital platforms empowering self-management and health care access
    DHTs enabled participants to independently book appointments, reducing wait times and enhancing efficiency. These platforms also provided diverse and comprehensive health information, fostering self-advocacy and proactive health management.
    Digital platforms empowering for finding medical visit companions DHTs facilitated the discovery of medical companions, improving access to services and fostering a sense of independent navigation. This assistance provided both physical navigation and emotional support during hospital visits.
    Exclusion
    Inaccessible online appointment systems Online appointment systems often lacked inclusive booking options and featured cluttered interfaces not optimized for screen readers, limiting access for individuals with blindness despite the general shift to digital platforms.
    Inaccessible health care environments and information formats The absence of accessible interfaces on self-service machines (eg, for check-in, payment, and prescription pickup) and the lack of accessible formats for written materials (eg, laboratory reports) created significant barriers within hospital environments.
    Lack of provider competencies in respecting patient autonomy Provider assumptions of digital incompetence led to communication being directed at sighted companions, undermining patient autonomy and reinforcing stereotypes, despite patients’ digital literacy.
    Data privacy and security concerns The increased digitalization of health services heightened concerns over data breaches, making privacy harder to maintain. Complex interfaces and the use of voice-based assistive tools in public settings further complicated privacy management.
    Challenges related to the quality and consistency of online companion support While enabling, reliance on online platforms for companions introduced specific challenges related to the inconsistent quality and limited capabilities of support, often lacking emotional connection and accountability.

    aDHT: digital health technology.

    Empowerment: Digital Technologies Fostering Access

    Digital Platforms Empowering Self-Management and Health Care Access

    All 12 participants in this study demonstrated a high level of digital engagement, routinely using smartphones and screen reader technology to overcome accessibility challenges in daily life, extending their digital practices into areas such as information seeking, learning, and social interaction. The most frequently used applications include WeChat, Rednote (xiaohongshu in Chinese), TikTok (Douyin in Chinese), Bilibili, and Xianyu, which are popular platforms in China for social networking, content sharing, and e-commerce. This digital proficiency directly translated into enhanced health care engagement.

    Participants reported using digital platforms to access health care services and information, including managing appointments and consulting health-related content online. In participants’ views, digital platforms offer two key advantages: (1) they provide a wealth of diverse and comprehensive information, surpassing traditional word-of-mouth referrals; and (2) they enable users to access this information with temporal and spatial flexibility, offering greater convenience compared to time- and location-bound methods. This enhanced access to information did more than improve convenience; it facilitated a fundamental shift from passive reliance on others to proactive self-advocacy. Participants perceived this newfound ability to independently seek out and act on information as a powerful form of self-expression and a significant gain in personal freedom. For instance, one participant described how digital platforms enabled her to proactively seek mental health support tailored to her needs:

    I posted on Rednote saying that I am blind and looking for a psychiatrist who does not discriminate against me, and I received several responses from supportive individuals. This made me feel that I no longer need constant attention from my parents or those around me, as I can proactively seek information and help online.
    [Participant ZX, female, 22 years]

    For those with acquired vision loss (ie, vision loss that occurs after birth due to accidents, disease, or other environmental influences), the internet served as a crucial lifeline to rebuild life trajectories. As formal medical guidance on rehabilitation was often lacking, online patient communities and peer networks are usually the last resort of comfort:

    Doctors usually just said, ‘there’s no treatment,’ and offered little else. It was other patients—people I met online or in hospitals—who told me about schools for the blind, massage training, or what assistive devices to get.
    [Participant CT, male, 30]

    Compared to traditional hospital appointment scheduling that requires in-person visits, online appointment scheduling systems have greatly improved health care access by allowing patients to register remotely via hospital WeChat Official Accounts (inside WeChat). Real-time updates offer patients more control over scheduling, allowing them to easily find alternative hospitals with available appointments.

    Now, all tertiary hospitals have fully implemented online appointment systems, which is more convenient for blind people like us who could frequently use smartphones. I always make appointments through the hospital’s WeChat Official Account before seeing a doctor.
    [Participant ML, female, 27 years]

    Digital Platforms Empowering for Finding Medical Visit Companions

    Hospital visits without assistance posed significant challenges for individuals with blindness, sometimes leading to delays in seeking necessary health care. For people with blindness without family or friends nearby, digital platforms offer a potential solution by connecting them with volunteer networks or organizations providing paid medical visit companions (MVCs). All participants reported benefits when receiving assistance from MVCs, as the presence of a companion alleviated anxieties and provided a sense of security throughout their hospital journey.

    In the past, I would often delay medical visits because I felt overwhelmed by the hospital environment and often leave the hospital feeling that I had not addressed all my concerns, simply because I was too anxious to ask questions. When I was in Hangzhou, I began using Xianyu around one year ago to find companions. Over the past year, I have used this service a few times to arrange for someone to accompany me during medical appointments. I searched for keywords like ‘medical visit companions services’ and found options where individuals offered accompaniment services. They took me from home to the hospital and back, with charges from 30 to 80 yuan per hour. Having someone with me allows me to ask the right questions and make sure my issues are resolved.
    [Participant RL, male, 26 years]

    These insights highlight the empowering role that MVCs play in fostering both physical navigation and emotional support, making it easier for individuals with blindness to take charge of their health care. Through the combination of technological access and personal support, participants can be more engaged with their health care providers, which significantly improves health care seeking experience and their health outcomes.

    Exclusion: Persistent Barriers and Unmet Potentials in Digital Health Care

    Inaccessible Online Appointment Systems

    A significant challenge reported by participants was how the shift to digital platforms, while offering convenience, simultaneously erected new and formidable barriers. This dual reality was aptly summarized by a participant who noted:

    Online registration/payment has made things more convenient, but there’s still a lot that’s not working.
    [Participant HY, female, 24 years]

    This gap was particularly evident where digital platforms, despite offering convenience, featured designs that created new exclusionary hurdles. For instance, many hospital WeChat Official Accounts, while the primary channel for online appointments, presented cluttered interfaces with complex layouts and images not optimized for screen readers. This poor usability hindered navigation and undermined informed decision-making, as 1 participant explained:

    Each hospital has its own WeChat Official Account, and they differ from one another. The interface is complex, and the buttons are not designed with focus settings. This inaccessibility prevents me from accessing relevant information, thereby impacting my healthcare decision-making.
    [Participant CY, female, 24 years]

    Inaccessible Health Care Environments and Information Formats

    Participants reported that complex hospital environments remain highly challenging to navigate. Standardized accessibility features—such as Braille indicators in elevators, poorly designed tactile paths, and the lack of auditory cues in key areas—are commonly not available yet. More critically, the increasing digitalization within hospitals often introduced new barriers or failed to mitigate existing physical ones.

    For example, written materials such as laboratory reports, discharge records, and prescriptions are printed on paper without accessible formats like Braille or large print, making it difficult to understand and hindering patients with blindness from accessing vital information about their diagnosis and treatment. One participant expressed frustration:

    Even when I get my laboratory report and discharge record, they’re just regular paper printouts with no way for me to read them independently. I feel like I’m missing out on important information, and it’s frustrating.
    [Participant NX, female, 24 years]

    Moreover, hospitals are increasingly relying on touchscreen-based self-service machines for tasks like registration, payment, and report retrieval, which are often inaccessible to people with blindness due to the lack of screen reader compatibility. A participant reflected on this challenge:

    These machines have no screen reader compatibility, so I always need someone to briefly help me retrieve my reports.
    [Participant ZY, male, 26 years]

    Lack of Provider Competencies in Respecting Patients’ Autonomy

    Many participants indicated the lack of provider competencies in respecting their autonomy, the challenge that gained particular salience within the increasingly digitized health care landscape. Specifically, a pervasive issue identified was the default assumption among many health care providers that patients with blindness lack digital literacy or the ability to independently engage with digital platforms. In an age where digital tools are designed to empower patients with greater access to information and enhanced self-management capabilities, the lack of corresponding adaptation or improvement in provider communication creates a jarring and disempowering contrast. Consequently, while most health care providers display positive attitudes, they often lack the necessary skills to effectively engage with patients who are blind. This knowledge gap can lead to communication barriers, undermining the autonomy that technology aims to support. In extreme cases, some health care staff seem to view patients with blindness as objects of curiosity rather than patients in need of medical care. A participant summed up such experiences:

    Sometimes doctors ask irrelevant questions, like ‘Can you talk?’ or ‘Can you hear?’ as if they are observing an unfamiliar species instead of treating a patient. These kinds of questions only reinforce the communication barriers and make me feel like I’m not being taken seriously as a person in need of medical care, but rather as an object of curiosity.
    [Participant RL, male, 26 years]

    This lack of provider competencies is also reflected in the fact that health care providers often address the sighted companion instead of the patient with blindness during visits, despite the patient’s digital literacy and capacity for self-advocacy. Participants reported frequent occurrences where providers directed questions and communication to the companion, assuming they were unable to independently communicate or make decisions. One participant noted:

    Whenever I have a companion, the doctor naturally chooses to speak to them instead of me. Even after repeatedly reminding the doctors that I am the patient and should be the one answering questions, they still act as if I am incapable of engaging in a normal conversation. It’s frustrating and undermines my autonomy.
    [Participant ML, female, 27 years]

    Data Privacy and Security Concerns

    In the digital age, concerns regarding data privacy and information security are exacerbated for individuals with blindness, who often rely on assistive technologies and other forms of support in accessing health care. These vulnerabilities are not limited to physical interactions with medical staff but extend to broader digital infrastructures, including health platforms, mobile apps, and the public environments where these technologies are used.

    Participants consistently expressed difficulties in independently navigating privacy settings or understanding consent-related information embedded within digital health applications. Complex interfaces, inaccessible terms of service, and a lack of screen reader-compatible designs hinder the ability of these individuals to make informed choices. As a participant noted:

    Sometimes I just agree to everything because I can’t really read the privacy policy with the screen reader. The text layout is all over the place, and I’m not even sure what I’m consenting to.
    [Participant WQ, female, 27 years]

    Moreover, the use of voice-based assistive tools in public or semipublic settings presents distinct privacy risks. Given that these tools often verbalize sensitive health information, individuals in proximity may inadvertently overhear confidential data. This issue is further complicated by the involvement of MVCs, who assist with tasks such as navigating digital platforms, completing forms, or managing payments. While such assistance is often essential, it can inadvertently compromise the individuals’ sense of privacy and control. As 1 participant expressed:

    Having a companion can be helpful, but sometimes I still prefer to visit alone because there are certain things I don’t want others to know. Even if I ask the volunteer to keep the information confidential and not disclose it, I still don’t feel comfortable because they have to help with payments and other tasks, and I end up feeling like I have no privacy.
    [Participant CT, male, 30 years]

    Challenges Related to the Quality and Consistency of Online Companion Support

    While digital platforms offered new avenues for finding companions, this also introduced specific challenges related to the quality and consistency of support. Participants expressed concerns about the inconsistent experience and limited capabilities among MVCs, particularly regarding mobility assistance and understanding patient needs. Digital platforms often facilitated one-time interactions that lacked emotional connection and accountability, leading to varied and sometimes unreliable support:

    That volunteer is in such a rush to finish his task and go home that he barely listens to what I need. There were times when I had to repeat myself multiple times just to get basic assistance.
    [Participant YN, female, 27 years]

    In summary, the findings highlight a complex and often contradictory landscape for educated and digitally literate young people with blindness accessing health care in the digital age. While digital platforms offer significant opportunities for empowerment in areas like appointment booking and companion support, these benefits are consistently counterbalanced by pervasive challenges such as inaccessible interfaces, systemic gaps in provider competence, and exacerbated privacy concerns. This dual reality of simultaneous empowerment and exclusion underscores the heterogeneous nature of the digital divide within vulnerable populations.

    Principal Findings

    To the best of our knowledge, this qualitative study is the first to specifically explore the health care experiences of educated and digitally literate young people with blindness in China within the context of the rapidly evolving digital health landscape. Our findings reveal an “empowered but excluded” dynamic, a paradox that vividly illustrates the lived reality of young people with blindness as a digitally native yet vulnerable generation. On one hand, participants demonstrated that DHTs and online platforms served as valuable tools, empowering them in self-managing their health conditions, proactively accessing health care information, and efficiently finding MVCs. On the other hand, this potential for digital empowerment and enhanced independence was significantly undermined by persistent and systemic barriers. These included reduced offline access to essential services, inaccessible digital and physical health care interfaces, a pervasive lack of provider competencies in respecting patients’ autonomy within a digital context, and heightened concerns regarding data privacy and security exacerbated by digital interactions.

    Comparison With Prior Work: Empowerment

    Our findings corroborate existing literature on the empowering potential of DHTs for individuals with visual impairments. Participants’ ability to effectively use online platforms for appointment booking and to access a wealth of diverse and comprehensive health information aligns with previous research highlighting improved self-management and enhanced health literacy through digital tools [-]. The increased autonomy and freedom participants reported, stemming from their capacity to proactively seek information and support, resonates with the broader discourse on patient empowerment in the digital age [-]. This study extends these insights by specifically demonstrating how educated individuals with blindness, through their active engagement with screen reader technology and other digital tools, convert these opportunities into tangible benefits, challenging simplistic narratives of universal exclusion. The use of online patient communities and peer networks to fill gaps in formal medical guidance, particularly for those with acquired vision loss, further underscores the internet’s role as a crucial lifeline and a source of social support.

    A distinctive contribution of this study is the exploration of digital platforms for finding MVCs. While the importance of companions for individuals with blindness in navigating health care is well-documented [], the use of online platforms (such as Xianyu in China) to locate and coordinate such support represents an innovative, user-driven adaptation. This strategy allows for greater independence in arranging assistance, improving the overall health care–seeking experience, an area previously underexplored in digital health literature.

    Comparison With Prior Work: Exclusion

    Despite the empowering potential of DHTs, our participants’ experiences reveal a profound exclusion shaped by persistent technological disaffordances, provider interactions that often disregard patient autonomy, and digital privacy concerns, which collectively hinder their independent and equitable health care engagement. Our findings align with prior research showing that many digital health platforms remain largely inaccessible to users with blindness and low vision [,]. This inaccessibility manifests in specific barriers, including websites that fail to meet accessibility standards, visual-centric data displays, and complex interfaces that do not accommodate screen readers or alternative input methods [-]. These limitations are not just technical oversights but reflect a broader systemic neglect of the needs of people with disabilities in the design and development process.

    Furthermore, our study highlights how the interaction between digital and nondigital environments can amplify existing inequalities. Beyond technological inaccessibility, participants frequently encountered health care providers who failed to recognize and respect their autonomy. This finding is consistent with previous research which shows that health care providers may hold stereotypes or paternalistic assumptions about persons who are blind, leading to exclusionary communication practices and undermining patient-centered care [,]. Our study adds to this discourse by illustrating how relational autonomy—a framework that emphasizes the importance of direct, respectful communication and the clinician-patient relationship as central to support patients’ identities and capabilities [-]. When providers fail to engage patients with blindness as active participants in their care, it not only erodes trust but also reinforces structural inequities [,].

    Finally, our findings align with previous research showing that digital privacy poses unique challenges for users with blindness, extending beyond standard concerns about data breaches. When using visual assistance technologies or sharing sensitive data, they may be unable to independently verify what information is being disclosed [,]. This complexity of privacy for users with blindness is tightly interwoven with issues of accessibility, autonomy, and trust. Our study’s contribution lies in showing the compounded effect of these factors on young individuals with blindness in China, revealing that digital empowerment is fragile and easily overridden by systematic barriers within the health care environment.

    Implications for Practice and Policy

    To address the systematic barriers identified in this study and improve the health care experiences of young people with blindness, we propose the following feasible policy and practical implications.

    First, developers and policymakers must enforce adherence to established accessibility standards. For web-based platforms, this includes the Web Content Accessibility Guidelines []. However, as health care services increasingly migrate to mobile apps, it is equally critical to incorporate mobile-specific accessibility guidelines, such as Apple’s Human Interface Guidelines for accessibility []. Research shows that compliance is often partial; therefore, involving users with disabilities directly in a co-design process is critical for identifying specific needs, such as intuitive navigation, accessible onboarding, and the use of clear language [].

    Second, medical education and professional training must be enhanced. Evidence shows that structured communication skills training improves health care professionals’ self-efficacy and performance, leading to more effective and empathetic patient interactions. To address the biases reported by our participants, these training programs must include strategies to help providers recognize and mitigate unconscious bias related to disability, incorporating the perspectives of marginalized patient groups into the training design [-].

    Thirdly, robust and accessible privacy controls are needed. Individuals with blindness require privacy information and controls that are both accessible and understandable, emphasizing the need for clear, multi-modal communication and cross-platform compatibility in privacy tools. The development and implementation of accessible authentication methods, such as Braille passwords or universally usable verification tools, should be prioritized.

    Finally, it is crucial to empower young individuals with blindness by building their capacity for self-determination. Organizations led by and for individuals with blindness play a pivotal role in this process by equipping them with self-advocacy and daily living skills []. In the Chinese context, while organizations like the China Disabled Persons’ Federation provide foundational services [], nongovernmental organizations such as the Golden Cane, the Beijing Hongdandan Cultural Service Center, and the One Plus One Disability Charity Group are vital in promoting rights advocacy and independent living skills [-]. A notable gap remains in dedicated health care navigation training programs that integrate digital literacy for e-health services. Closing this gap is essential to ensure young blind individuals in China can fully leverage digital health advancements.

    Strengths, Limitations, and Future Research

    This study’s primary strength lies in its novel contribution to understanding the health care experiences of a previously overlooked subgroup: young, educated individuals with blindness in China. By focusing on this specific demographic, our research offers three key contributions. First, it challenges the homogeneous view of vulnerable groups by demonstrating that high-literacy individuals possess unique capabilities and face distinct challenges within the digital ecosystem. Second, it introduces and evidences the “empowered but excluded” paradox, providing a nuanced theoretical framework that moves beyond a simple narrative of digital exclusion. It shows that empowerment and exclusion are not mutually exclusive but coexist, shaped by the interplay between individual agency and systemic barriers. Third, this framework helps distinguish which challenges can be mitigated through individual effort and digital literacy versus those that require fundamental changes in policy, technology design, and clinical practice. The qualitative depth provides rich, contextualized insights that explain how and why these dynamics manifest, laying the groundwork for tailored interventions.

    This study has several limitations. As a qualitative study, the findings are based on a small sample of 12 educated young individuals with blindness in China and may not be generalizable to other age groups, cultural contexts, or countries with different health care and digital infrastructures. The recruitment strategy may have introduced selection bias, potentially attracting participants with more pronounced positive or negative experiences with DHTs. Furthermore, participant recall bias might have influenced their accounts of past health care experiences. Despite these limitations, this study offers rich, contextualized insights into the lived experiences of a typically underrepresented group in digital health research. Future research should explore these issues with larger, more diverse samples, potentially using quantitative or mixed-methods approaches to assess the prevalence of the themes identified and to evaluate the effectiveness of interventions aimed at improving health care accessibility and autonomy for people with blindness in the digital age. Comparative studies across different socioeconomic and cultural settings would also be beneficial.

    Conclusions

    This study explored how educated young adults with blindness in China navigate health care in the digital age, revealing an “empowered but excluded” dynamic. The potential for digital empowerment and enhanced independence, though present, is consistently curtailed by systematic barriers including inaccessible technologies, provider practices that limit patient autonomy, and privacy vulnerabilities. To bridge this gap, our findings underscore the necessity of a multifaceted approach: enhancing technological accessibility through robust standards adherence and inclusive co-design processes; improving health care provider competencies in patient-centered care via targeted training; and empowering young individuals with blindness by building their capacity for self-determination. Implementing these integrated strategies is vital for realizing equitable health care access and true independence for this digitally native yet vulnerable generation.

    The authors would like to express our sincere gratitude to all the participants for their courage and openness in sharing their experiences, and to the key informants for contributing their valuable perspectives.

    This work was supported by the National Natural Science Foundation of China (grant number 72442021) and the University of Chinese Academy of Social Sciences Innovation Fund (grant number 2025-KY-077). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    The data supporting this study are available upon reasonable request from the corresponding author.

    All authors contributed to the paper and approved the final submitted version.

    None declared.

    Edited by Alicia Stone, Amaryllis Mavragani; submitted 24.Jun.2025; peer-reviewed by Kabelo Leonard Mauco, Soyoung Choi; final revised version received 22.Oct.2025; accepted 23.Oct.2025; published 21.Nov.2025.

    © Junling Zhao, Can Su, Xiji Zhu, Cong Cai, Wei Liu, Xiaochen Ma. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.Nov.2025.

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research (ISSN 1438-8871), is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

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    Journal of Medical Internet Research

    Age-related macular degeneration (AMD) is a progressive retinal disorder affecting millions of people worldwide []. In its advanced stages, characterized by neovascularization and geographic atrophy (GA), it can lead to significant vision loss, although symptoms may be subtle during the early and intermediate phases []. The Classification of Atrophy Meetings group has defined atrophy lesion development as incomplete retinal pigment epithelium (RPE) and outer retinal atrophy and complete RPE and outer retinal atrophy (cRORA) based on imaging methods []. GA, also known as cRORA, is the endpoint of dry AMD and is characterized by the loss of photoreceptors, RPE, and choriocapillaris [,]. With the advent of 2 approved therapies for GA secondary to AMD in 2023, namely pegcetacoplan (Syfovre) [] and avacincaptad pegol [], the treatment of GA represents a significant breakthrough. However, the effectiveness of these therapies relies heavily on early detection and the ability to monitor treatment response—a significant unmet need in current clinical practice. The recent approval of complement inhibitors underscores the necessity for precise, reproducible, and practical tools to not only identify GA at its earliest stages but also to objectively track morphological changes over time, thereby evaluating therapeutic efficacy [,]. Artificial intelligence (AI) is uniquely positioned to address this gap by enabling precise, reproducible, and automated quantification of GA progression and treatment response using noninvasive imaging modalities []. Unlike conventional methods that rely on subjective and time-consuming manual assessments, AI algorithms can detect subtle subclinical changes in retinal structures—such as photoreceptor integrity loss, RPE atrophy, and hyperreflective foci—long before they become clinically apparent. Thus, AI-based retinal imaging offers a critical foundation for early detection and timely intervention in GA.

    Various imaging techniques, both invasive and noninvasive, can directly visualize GA lesions. Invasive methods, such as fluorescence angiography, often result in a poor patient experience and entail high costs due to pupil dilation and sodium fluorescein injection. While it remains the gold standard for assessing neovascular AMD and offers significant diagnostic insights for retinal vascular diseases, in most cases, noninvasive fundus images are used for GA diagnosis and management []. Color fundus photography (CFP), fundus autofluorescence (FAF), and near-infrared reflectance (NIR) are based on 2D images, which can generally produce results to quantify the atrophic area but fail to identify the retinal structure axially []. Compared with fundus imaging, optical coherence tomography (OCT) provides high-resolution, noninvasive 3D images of retinal structures for macular assessment. In addition, conventional B-scan (axial direction) OCT images can be integrated with en-face scans, facilitating the identification of atrophy borders similar to FAF [,]. Nonetheless, manual labeling is tedious, time-consuming, and impractical in a clinical setup []. There is an urgent and unmet need for early detection and management of GA using retinal image modalities. Recent advancements in AI, especially deep learning (DL), present a promising opportunity for enhancing GA detection, classification, segmentation, quantification, and prediction.

    In the 1950s, AI referred to computer systems capable of performing complex tasks that historically only a human could do. So what is AI? How is it used in medicine today? And what may it do in the future? AI refers to the theory and development of computer systems capable of performing tasks that historically required human intelligence, such as recognizing speech, making decisions, and identifying patterns. AI is an umbrella term that encompasses a wide variety of technologies, including machine learning (ML) and DL []. ML is a subfield of AI that uses algorithms trained on datasets to create self-learning models capable of predicting outcomes and classifying information without human intervention []. ML refers to the general use of algorithms and data to create autonomous or semiautonomous machines. DL, meanwhile, is a subset of ML that layers algorithms into “neural networks” with 3 or more layers. Thus, it somewhat resembles the human brain, enabling machines to perform increasingly complex tasks []. DL algorithms generally have high and clinically acceptable diagnostic accuracy across different areas (ophthalmology, respiratory, breast cancer, etc) in radiology []. Within ophthalmology, DL algorithms showed reliable performance for detecting multiple findings in macular-centered retinal fundus images []. Therefore, automatic GA segmentation plays a vital role in the diagnosis and management of advanced AMD and its application in the clinical setting.

    Given the rapid evolution of AI applications in ophthalmology and the growing clinical importance of GA, this study aimed to systematically review the current evidence on AI-based approaches for the detection and management of GA secondary to dry AMD using noninvasive imaging modalities. We aimed to evaluate diagnostic accuracy relative to reference standards and examine methodological challenges to inform the design of future research and clinical implementation.

    Protocol and Registration

    Before starting this systematic review and meta-analysis, we registered a protocol on the PROSPERO website. This review adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and PRISMA-DTA (PRISMA of Diagnostic Test Accuracy) checklists [,].

    Eligibility Criteria

    We included studies using AI algorithms to detect, classify, identify, segment, quantify, or predict GA secondary to AMD from CFP, OCT, OCT angiography, FAF, or NIR. The data were from participants, with or without symptoms, who were diagnosed with GA (or cRORA) secondary to nonexudative AMD. Study designs were not restricted; multicenter or single-center, prospective or retrospective, post hoc analysis, clinical study, or model development studies were all accepted. Eyes with neovascular complications or macular atrophy from causes other than AMD, any previous anti-vascular endothelial growth factor treatment, any confounding retinopathy, or poor image quality were excluded.

    Electronic Search Strategy

    Two consecutive searches were conducted on PubMed, Embase, Web of Science, Scopus, Cochrane Library, and CINAHL. Because this review required the extraction of baseline data and items, considering the completeness of the data, we did not conduct any in press or print source searches and excluded conference proceedings and similar materials. The initial search was completed from the date of entry to December 1, 2024; the updated search, from December 1, 2024, to October 5, 2025. We used a search strategy for patient (GA) and index tests (AI and retinal images) that had been used in previous Cochrane Review without any search peer review process []. There were no restrictions on the date of publication. The language was limited to English. In , detailed search strategies for each database are provided. During this process, no filters were used. During the search process, we adhered to the PRISMA-S (Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension) reporting guidelines [].

    Selection Process

    All relevant literature was imported into EndNote (version 20; Clarivate Analytics) software, and literature screening was conducted independently by 2 researchers (NS and JL) who specialize in ophthalmology. Duplicates were removed from the software, and the titles and abstracts of the literature were reviewed to identify those relevant to the topic. Finally, the full texts were downloaded and examined, leading to the selection of literature that met the inclusion criteria. In cases of inconsistencies in the final inclusion decisions made by the 2 researchers, a third professional (LL) was consulted to resolve the dispute.

    Data Collection Process

    Using standardized data items, the data were extracted independently from the included studies by 2 researchers (NS and JL). A third review author (LL) confirmed or adjudicated any discrepancies through group discussion. We retrieved the following data items: (1) study characteristics (author, year, study design, region, and theme), (2) dataset characteristics (databases, source of databases, training/validation/testing ratio, patient number, number of images or volumes, scan number, mean age, clinical registration number, and model evaluation method), (3) image and algorithm characteristics (devices, metrics, image modality, image resolution, and AI algorithms), (4) performance metrics (outcomes, performance of models, ground truth, and performance of the ophthalmologists), and (5) main results. All the information was retrieved from the main text and the tables provided in . Therefore, we did not seek additional data by contacting the authors or experts. In some studies, the authors reported multiple sets of performance data based on a subset of a single dataset. For example, they may have reported results such as sensitivity, specificity, accuracy, and so forth, conducted on the cross-validation set, the test set, or the development set. We referred to the relevant literature to select the optimal set of test performance results []. However, when the primary study provided performance results based on a single test, the development dataset was used to train the AI model, and an external validation set ultimately was used to determine the performance of the optimal model. We extracted the external validation set performance data [].

    Risk of Bias and Application

    We worked in pairs to assess the risk of bias and the applicability of the studies, which involved detection, classification, identification, segmentation, and quantification using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-AI [] and the modified QUADAS-2 tool [], while predictive studies used the Prediction Model Risk of Bias Assessment Tool (PROBAST) [].

    In the current context, QUADAS-AI has not yet established a complete specification of items. Therefore, we referenced the examples provided by QUASAS-AI and the published literature to compile the revised QUADAS-AI items, which included 4 domains and 9 leading questions (Table S4 in ). The PROBAST tool comprises participants, predictors, outcomes, and analysis, containing 20 signaling questions across 4 domains (Table S5 in ). We also evaluated the applicability of the study based on the leading or signaling questions in the first 3 domains. A study with “yes” answers to all index questions was considered to have a low risk of bias. If the answer to any of the informational questions was “no,” there was a potential for bias, leading the authors to rate the risk of bias as high. “Indeterminate” grades were applied when detailed content was not provided in the literature, making it difficult for the evaluator to reach a judgment. They were used only when the reported data were insufficient. Throughout the process, disagreements between the 2 reviewers (NS and JL) were resolved by consulting the senior reviewer (LL).

    Data Synthesis

    As very few studies reported the number of true positives, true negatives, false positives, and false negatives, we restricted the quantitative analysis to determine the diagnostic accuracy of AI as a triaging tool for GA secondary to nonexudative AMD. However, a meta-analysis was not performed due to significant methodological heterogeneity across studies, arising from diverse AI architectures, imaging modalities, outcome metrics, and validation protocols. Instead, a systematic review was performed to qualitatively summarize performance trends. This approach allowed for a comprehensive evaluation of the AI capabilities in the detection and management of GA via noninvasive images.

    Study Selection

    A total of 979 records related to the topic of this systematic review were searched across 6 different databases using a combination of subject terms and free-text terms. After removing duplicates, 335 records remained and were examined for titles and abstracts. Excluding studies not relevant to the research topic resulted in 200 reports. The full texts were then downloaded and reviewed in detail based on the eligibility criteria for the studies. In the final qualitative analysis, 41 studies were included. Of these, 10 focusing on GA diagnosis, 20 on GA assessment and progression, and 11 on GA prediction. presents the detailed flow diagram of the literature selection.

    Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for literature selection. GA: geographic atrophy.

    AI in Detecting the Presence of GA

    Ten of the 41 included studies focused on AI-based detection of GA using noninvasive retinal images (Table S1 in ). As listed in , the studies were published from 2018 to 2025. Four of the studies [-] focused on model development, 3 [-] were retrospective studies, and 3 [-] were prospective studies (1 multicenter cohort study, 1 multicenter and low-interventional clinical study, and 1 clinical study). Geographically, half were from the United States, with others from Israel, Italy, Switzerland, Germany, and a multicenter European collaboration. The studies addressed several detection-related tasks: 5 focused solely on GA detection [-,,], 2 covered detection and classification [,], and others integrated detection with quantification or segmentation [,,].

    Table 1. Characteristics of studies evaluating artificial intelligence (AI) models for geographic atrophy (GA) detection using noninvasive retinal imaging.
    Author Study design Region Purpose of the study Source of datasets Number of patients Number of images or scans Model evaluation method Image modality (image resolution) AI algorithms Outcomes Performance of models
    Fineberg et al [] Retrospective cohort study Israel (Petah Tikva) Detection and classification (GA) Rabin Medical Center 113 659 10-fold cross-validation NIR (640*640 pixels) CNNs: ResNet50, EfficientNetB0, ViT_B_16, and YOLOv8 variants. ACC, P, SEN, SPE, F1, IoU, and DSC
    • GA classification:
      EfficientNetB0: ACC=0.9148; P=0.9204; SEN=0.9233; SPE=1.0; F1=0.9147.
    • ResNet50: ACC=0.8815; P=.8933; SEN=0.8917; SPE=0.9833; F1=0.8812.
    • ViT_B_16: ACC=0.963; P=.9632; SEN=0.9667; SPE=1.0; F1=0.9629.
    • GA detection: YOLOv8-Large: SEN=0.91; P=0.91; IoU=0.84; DSC=0.88.
    Kalra et al [] Retrospective clinical study United States (Cleveland) Detection, quantification, and segmentation (presence of GA and pixel-wise GA area measurement) the Cole Eye Institute of the Cleveland Clinic 341 900 triple-fold cross-validation SD-OCT (256*256 pixels) CNN: U-Net F1, ACC, P, R, SEN, and SPE
    • GA detection- ACC=0.91, SEN=0.86, SPE=0.94, F1=0.87.
    • GA segmentation: ACC=0.96, SEN=0.95, SPE=0.93, F1=0.82.
    Derradji et al [] Retrospective clinical study Switzerland (Lausanne) Detection and segmentation (RORA) An existing image database of the Medical Retina Department at Jules-Gonin Eye Hospital 57 62 5-fold cross-validation SD-OCT (NR) CNN: U-Net SEN, DSC, P, and Kappa
    • Grader 1: DSC: mean 0.881 (SD 0.074); Precision: mean 0.928 (SD 0.054); SEN: mean 0.850 (SD 0.119); Kappa: mean 0.846 (SD 0.072).
    • Grader 2: DSC: mean 0.844 (SD 0.076); Precision: mean 0.799 (SD 0.133); SEN: mean 0.915 (SD 0.064); Kappa: mean 0.800 (SD 0.082).
    de Vente et al [] Prospective multicenter and low-interventional clinical study (including cross-sectional and longitudinal study part) 20 sites in 7 European countries Detection and quantification (cRORA) The MACUSTAR Study Cohort 168 143 (ZEISS); 167 (Spectrails) NR SD-OCT (512*650 pixels) CNN: U-Net SEN, SPE, PPV, NPV, and Kappa
    • ZEISS: SEN=0.6; SPE=0.964; PPV=0.375; NPV=0.985.
    • Spectralis: SEN=0.625; SPE=0.974; PPV=0.714; NPV=0.961.
    Sarao et al [] Prospective clinical study Italy (Udine) Detection (presence of GA) the Istituto Europeo di Microchirurgia Oculare (IEMO) study 180 540 NR CFP (NR) CNN: Efficientnet_b2 SEN, SPE, ACC, F1, R, AUROC, and AUPRC
    • SEN: 100% (95%CI 83.2%-100%); SPE=97.5% (95% CI 86.8%-99.9%); ACC=98.4%; F1=0.976; R=1; AUROC=0.988 (95% CI 0.918-1); AUPRC=0.952 (95%CI 0.719-0.994).
    Keenan et al [] Multicenter and prospective cohort study United States (Maryland) Detection (presence of GA) Age-Related Eye Disease Study (AREDS) dataset 4582 59,812 5-fold cross-validation CFP (512 pixels) CNN: inception v3 ACC, SEN, SPE, P, AUC, and Kappa
    • ACC=0.965 (95% CI 0.959-0.971); Kappa=0.611 (95% CI 0.533-0.689); SEN=0.692 (95% CI 0.560-0.825); SPE=0.978 (95% CI 0.970-0.985); Precision=0.584 (95% CI 0.491-0.676).
    Yao et al [] Model development and evaluation United States (California) Detection (presence of nGA) the Early Stages of AMD (LEAD) study 140 1884 5-fold cross-validation SD-OCT (512*496 pixels) CNN: ResNet18 SEN, SPE, ACC, P, and F1
    • SEN=0.76 (95% CI 0.67-0.84); SPE=0.98 (95% CI 0.96-0.99); PRE=0.73 (95% CI 0.54-0.89); ACC=0.97 (95% CI 0.95-0.98); F1=0.74 (95% CI 0.61-0.84).
    Chiang et al [] Model development United States (California) Detection (complete retinal pigment epithelial and outer retinal atrophy (cRORA) in eyes with AMD) University of Pennsylvania, University of Miami, and Case Western Reserve University; (2) Doheny Image Reading Research Laboratory, Doheny-UCLA (University of California Los Angeles Eye Centers) 71 (training); 649 (testing #1); 60 (testing #2) 188 (training); 1117 (testing #1) 5-fold cross-validation SD-OCT (256*256 pixels) CNN: ResNet18 SEN, SPE, PPV, NPV, AUROC, and AUPRC
    • SEN=0.909 (95% CI 0.778-1.000); SPE=0.553 (95% CI 0.394-0.703); PPV=0.541 (95% CI 0.375-0.707); NPV=0.913 (95% CI 0.778-1.000); AUROC=0.84 (95% CI 0.75-0.94); AUPRC=0.82 (95% CI 0.70-0.93).
    Elsawy et al [] Model development United States (Maryland) Detection (explain decision making and compare methods) The Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT study from Devers Eye Institute, Emory Eye Center, Duke Eye Center, and the National Eye Institute 311 1284 scans 10-fold cross-validation SD-OCT (128*128 or 224* pixels) 3D CNN: deep-GA-Net ACC, P, R, F1, Kappa, AUROC, and AUPRC
    • ACC=0.93 (95% CI 0.92-0.94); Precision=0.90 (95% CI 0.88-0.91); Recall=0.90 (95% CI 0.89-0.92); F1 score=0.90 (95% CI 0.89-0.91); Kappa=0.80 (95% CI 0.77-0.83); AUROC=0.94 (95% CI 0.93-0.95); AUPRC=0.91 (95% CI 0.90-0.93).
    Treder et al [] Model development Germany (Muenster) Detection and classification (GA) Public database: ImageNet 400 (training); 60 (test set) 400 (training); 60 (test set) NR FAF (NR) Deep CNN: self-learning algorithm SEN, SPE, and ACC
    • Probability score: mean 0.981 (SD 0.048); SEN=100%; SPE=100%; ACC=100%.

    aAI: artificial intelligence.

    bACC: accuracy.

    cAUPRC: area under the precision-recall curve.

    dCNN: convolutional neural network.

    eCFP: color fundus photography.

    fcRORA: complete retinal pigment epithelium and outer retinal atrophy.

    gDSC: dice similarity coefficient.

    hFAF: fundus autofluorescence.

    iIoU: intersection over union.

    jNR: not reported.

    kOCT: optical coherence tomography.

    lPPV: positive predictive value.

    mP: precision.

    nR: recall.

    oSD-OCT: spectral domain OCT.

    pSEN: sensitivity.

    qSPE: specificity.

    rAUROC: area under the receiver operating characteristic curve.

    sAMD: age-related macular degeneration.

    tNPV: negative predictive value.

    Dataset configurations varied: 6 studies used training, validation, and test sets [-,,]; 3 used only training and test sets [,,]; and 1 included a tuning set []. Collectively, these studies involved at least 7132 participants, with ages ranging from 50 to 85 years. Three studies were registered with ClinicalTrials.gov (NCT00734487, NCT01790802, and NCT03349801) [,,]. Cross-validation methods included 5-fold (40% of studies) [,,,], 10-fold (20%) [,], and triple-fold (10%) []; 30% did not report validation details.

    Spectral-domain (SD)–OCT was the most frequently used imaging modality (6/10 of studies) [-,,,], followed by CFP (2/10) [,], and FAF or NIR (2/10 each) [,]. Most studies applied image preprocessing techniques—such as size standardization, orientation adjustment, intensity normalization, and noise reduction—to improve model performance. DL-based algorithms for GA detection have been developed for multiple image modalities. For example, Derradji et al [] trained a convolutional neural networks (CNNs), U-Net, to predict atrophic signs in the retina, based on the EfficientNet-b3 architecture. Kalra et al [] and de Vente et al [] also trained a DL model based on U-Net. Yao et al [] applied 3D OCT scans with ResNet18 pretrained on the ImageNet dataset, and Chiang et al [] developed CNN (ResNet18) to improve computational efficiency. Elsawy et al [] proposed Deep-GA-Net, a 3D backbone CNN with a 3D loss-based attention layer, and evaluated the effectiveness of using attention layers. Sarao et al [] used a deep CNN, the EfficientNet_b2 model, which was pretrained on the ImageNet dataset and is well-known for its high efficiency and small size. Keenan et al [] established their model using Inception v3, while Treder et al [] performed a deep CNN, a self-learning algorithm, processing input data with FAF images.

    A total of 14 performance sets were extracted from the 10 studies. Key metrics included sensitivity, specificity, accuracy, positive predictive value, negative predictive value, intersection over union, area under the receiver operating characteristic curve, area under the precision-recall curve, F1-score, precision, recall, Kappa, and dice similarity coefficient. Six OCT-based studies showed that DL models could detect GA with high accuracy, comparable to human graders [-,,,]. Two studies using CFP also reported strong performance [,], while FAF- and NIR-based approaches demonstrated excellent repeatability and reliability [,].

    We conducted a thorough evaluation of the 10 diagnostic studies’ methodological quality for the “participant selection,” “index test,” “reference standard,” and “flow and timing” domains at the study level (). None of the studies had an overall low or unclear risk of bias; instead, every study had a high risk of bias in at least 1 of the 4 domains. Regarding “patient selection,” only 4 studies [,,,] described the eligibility criteria; the rest did not report them. One study [] used an open dataset (ImageNet) and did not include a test set. The small sample size of 4 studies [,,,] may have resulted in overfitting. In addition, 3 studies [,,] did not report image formats and resolutions. Five studies [,,-] had a high risk of bias in participant selection because the included participants were not only GA secondary to dry AMD but also had other unrelated diseases. Regarding the “Index test,” only 1 algorithm was externally validated using a different dataset []; all other items were evaluated as low risk.

    Table 2. Methodological quality and applicability assessment for studies on geographic atrophy (GA) detection using the revised Quality Assessment of Diagnostic Accuracy Studies–Artificial Intelligence (QUADAS-AI).
    Study Risk of bias Concerns regarding applicability
    Patient selection Index test Reference standard Flow and timing Patient selection Index test Reference standard
    Chiang et al [] High risk Low risk Low risk Low risk Low risk Low risk Low risk
    Elsawy et al [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    Kalra et al [] High risk High risk Low risk Low risk High risk Low risk Low risk
    Keenan et al [] High risk High risk Low risk Low risk High risk Low risk Low risk
    Sarao et al [] High risk High risk Low risk Low risk High risk Low risk Low risk
    Yao et al [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    Treder et al [] High risk High risk Low risk Low risk High risk Low risk Low risk
    Vente et al [] High risk High risk Low risk Low risk High risk Low risk Low risk
    Derradji et al [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    Fineberg et al [] High risk High risk Low risk Low risk Low risk Low risk Low risk

    AI in GA Assessment and Progression

    Twenty studies explored AI for GA assessment and progression using noninvasive imaging, published between 2019 and 2025 (Table S2 in ). As shown in , these studies covered 11 segmentation [,,-], 2 algorithm optimization [,], 3 AMD progression classification [-], and 3 combined tasks such as identification, segmentation, and quantification [-]. One study focused solely on GA quantification []. Retrospective analyses accounted for 9 studies [,,,,,,,,], while 7 were model development [,-,,,], and the remainder were prospective [,], comparative [], or cross-sectional []. Geographically, contributions came from China (6/20), the United States (7/20), the United Kingdom (2/20), Australia (2/20), France (1/20), Israel (1/20), and Austria (1/20).

    Table 3. Characteristics of studies evaluating artificial intelligence (AI) models for geographic atrophy (GA) assessment and progression using noninvasive retinal imaging.
    Author Study design Region Purpose of the study Source of datasets Number of patients Number of images or scans Model evaluation method Image modality (Image resolution) AI algorithms Outcomes Performance of models
    Pramil et al [] Retrospective review of images United States (Boston) Segmentation (GA lesions) The “SWAGGER” cohort of the non-Exudative Age-Related Macular Degeneration (from New England Eye Center at Tufts Medical Center) 90 126 5-fold cross-validation SS-OCT (500*500 pixels) CNN: U-Net SEN, SPE, and DICE
    • SEN=0.95; SPE=0.91; DSC (vs G1): mean 0.92 (SD 0.11); DSC (vs G2): mean 0.91 (SD 0.12).
    Siraz et al [] Retrospective comparative study United States (North Carolina) Classification (central and noncentral GA) Atrium Health Wake Forest Baptist 104 355 NR SD-OCT (224*224 pixels) CNNs: ResNet50, MobileNetV2, and ViT-B/16 AUROC, F1, and ACC
    • ResNet50: AUROC: mean 0.545 (SD 0.004), F1: mean 0.431 (SD 0.00); ACC: mean 0.756 (SD 0.00).
    • MobileNetV2: AUROC: mean 0.521 (SD 0.016), F1: mean 0.432 (SD 0.002); ACC: mean 0.756 (SD 0.00).
    • ViT-B/16: AUROC: mean 0.718 (SD 0.002), F1: mean 0.602 (SD 0.004); ACC: mean 0.780 (SD 0.005).
    Arslan et al [] Retrospective cohort clinical study Australia (Victoria) Segmentation (GA lesion area) The Center for Eye Research Australia or a private ophthalmology practice diagnosed with GA 51 702 5-fold cross-validation FAF (768*768 or 1536*1536 pixels) CNN: U-Net DSC, DSC loss, SEN, SPE, MAE, ACC, R, and P
    • DSC: mean 0.9780 (SD 0.0124); DSC loss: mean 0.0220 (SD 0.0041); SEN: mean 0.9903 (SD 0.0041); SPE: mean 0.7498 (SD 0.0955); MAE: mean 0.0376 (SD 0.0184); ACC: mean 0.9774 (SD 0.0090); P: mean 9837 (SD 0.0116).
    Hu et al [] Retrospective clinical study China (Shenyang) Classification (dry AMD progression phases) Shenyang Aier Eye Hospital 338 3401 5-fold cross-validation SD-OCT (NR) CNNs: EfficientNetV2, DenseNet169, Xception, and ResNet50NF ACC, SEN, SPE, F1, Macro-f1, and Kappa
    • ACC=97.31%; SEN=89.25%; SPE=98.80%; F1=91.21%; Macro-f1=92.08%; Kappa=95.45%.
    Spaide et al [] Retrospective analysis and model comparison United States (Washington) Segmentation (GA lesion area) The SWAGGER cohort from the New England Eye Center at Tufts Medical Center 87 126 scans 5-fold cross-validation SS-OCT (NR) CNN: U-Net DSC
    • UNet-1: 0.82 (95% CI 0.78-0.86).
    • UNet-Avg: 0.88 (95% CI 0.85-0.91).
    • UNet-Drop: 0.90 (95% CI 0.87-0.93).
    Vogl et al [] Retrospective analysis Austria (Vienna) Identification (GA progression after pegcetacoplan treatment) The FILLY trial 156 NR NR SD-OCT (512*512 pixels) CNN: U-Net LPR
    • Compared with sham treatment, monthly: −28% (−42.8 to −9.4).
    • Every other month: −23.9% (−40.2 to −3.0).
    Szeskin et al [] Retrospective analysis Israel (Jerusalem) Identification, quantification (GA lesion) Datasets D1 and D2 from the Hadassah University Medical Center D1: 18; D2: 16 NR 4-fold cross-validation SD-OCT (496*1024 pixels and 496*1536 pixels) CNN: the custom column classification CNN AUROC, P, R, and F1
    • AUROC=0.970; (Segment) P: mean 0.84 (SD 0.11); R: mean 0.94 (SD 0.03); (Lesion) P: mean 0.72 (SD 0.03); R: mean 0.91 (SD 0.18).
    Spaide et al [] Retrospective analysis United States (California) Segmentation (GA lesion area) Proxima A and B Proxima A: 154; Proxima B: 183 Proxima A: 497; Proxima B: 940 NR FAF, NIR (768 *768 pixels) Multimodal DL: U-Net; YNet DSC and r2
    • (G1-Ynet)DSC: mean 0.92 (SD 0.09).
    • (G1-Unet)DSC: mean 0.90 (SD 0.09).
    • (G2-Ynet)DSC: mean 0.91 (SD 0.09).
    • (G2-Unet)DSC: mean 0.90 (SD 0.09).
    • (Ynet) r2: 0.981.
    • (Unet) r2: 0.959.
    AI-khersan et al [] Retrospective analysis United States (Texas) Segmentation (GA) The Retina Consultants of Texas and Retina Vitreous Associates 33; 326 367; 348 5-fold cross-validation SD-OCT (512*496pixels; 200*1024pixels) CNN: 3D-to-2D U-Net DSC and r2
    • For Spectralis data, DSC=0.826; r2=0.906.
    • For Cirrus data, DSC=0.824; r2=0.883.
    Chu et al [] Prospective study United States (Washington) Identification, segmentation, and quantification (GA) The University of Miami 70; 20; 25 NR NR SS-OCT (512*512 pixels) CNN: U-Net DSC, SEN, and SPE
    • DSC: mean 0.940 (SD 0.032). SEN=100%; SPE: 100%.
    Merle et al [] Prospective observational study Australia (Victoria) Quantification (GA) The Center for Eye Research Australia 50 NR NR SD-OCT; FAF (NR) CNN: U-Net Spearman correlation coefficient and SEN
    • (OCT-automatically) Spearman correlation coefficient=0.85 (95% CI 0.71-0.91); SEN=0.59.
    Yang et al [] Model development China (Shenyang) Classification (stage of dry AMD progression) Shenyang Aier Excellence Eye Hospital 1310 16,384 3-fold cross-validation SD-OCT (NR) CNNs: ResNet50, EfficientNetB4, MobileNetV3, Xception ACC, SEN, SPE, and F1
    • ACC(GA): ResNet50=92.35%; EfficientNetB4=93.85%; MobileNetV3=89.64%; Xception=91.16%.
    • ACC (nascent GA): ResNet50=91.56%; EfficientNetB4=89.66%; MobileNetV3=89.43%; Xception=85.22%.
    Ji et al [] Model development China (Nanjing) Segmentation (GA lesion area) Dataset1 and dataset2 8; 54 NR NR SD-OCT (224*224 pixels) Weakly supervised multitask learning: Mirrored X-Net DSC, IoU, AAD, and CC
    • DSC: mean 0.862 (SD 0.080); IoU: mean 0.765 (SD 0.119); AAD: mean 0.090 (SD 0.090); CC: 0.992.
    Ma et al [] Model development China (Jinan) Segmentation (GA lesion area) Dataset1 and dataset2 62 NR 5-fold cross-validation SD-OCT (224*224 pixels) Weakly supervised model: VGG16 DSC, OR, AAD, CC, and AUROC
    • DSC: mean 0.847 (SD 0.087); OR: mean 0.744 (SD 0.126); AAD: mean 0.150 (SD 0.149); CC: 0.969; AUROC: 0.933.
    Royer et al [] Model development France (Issy-Les-Moulineaux) Segmentation (GA lesion area) the Clinical Imaging Center of the Quinze-Vingts Hospital 18 328 8 different random combinations of 12 series to train the model and 6 for the tests NIR (256*256 pixels) Unsupervised neural networks: W-net F1, P, and R
    • F1: mean 0.87 (SD 0.07); P: mean 0.90 (SD 0.07); R: mean 0.85 (SD 0.11).
    Xu et al [] Model development China (Jinan) Segmentation (GA lesion area) dataset1 and dataset2 8 (test I); 56 (test II) 55 (dataset1); 56 (dataset2) NR SD-OCT (1024*512*128pixels; 1024*200*200pixels) Self-learning algorithm OR, AAD, and CC
    • OR: mean 84.48% (SD 11.98%); AAD: mean 11.09% (SD 13.61%); CC: 0.9948.
    Zhang et al [] Model development United Kingdom (London) Segmentation and quantification (GA) The FILLY study 200 984 NR SD-OCT (NR) CNN: U-Net DSC, ICC, ACC, SEN, SPE, and F1
    • Approach 1: ACC=0.91 (95% CI 0.89-0.93); F1=0.94 (95% CI 0.92-0.96); SEN=0.99 (95% CI 0.97-1.00); SPE=0.54 (95% CI 0.47-0.61); DSC: mean 0.92 (SD 0.14); ICC=0.94.
    • Approach 2: ACC=0.94 (95% CI 0.92-0.96); F1=0.96 (95% CI 0.94-0.98); SEN=0.98 (95% CI 0.96-1.00); SPE=0.76 (95% CI 0.70-0.82); DSC: mean 0.89 (SD 0.18); ICC: 0.91.
    Liu et al [] Model development China (Wuhan) Segmentation (GA) Wuhan Aier Eye Hospital; the public dataset OCTA500 300 2923 5-fold cross-validation SD-OCT (512*512 pixels) Self-learning algorithm (dual-branch image projection network) Jaccard index, DSC, ACC, P, and R
    • DSC: mean 7.03 (SD 2.73); Jaccard index: mean 80.96 (SD 4.29); ACC: mean 91.84 (SD 2.13); P: mean 87.12 (SD 2.34); R: mean 86.56 (SD 2.92).
    Williamson et al [] Cross-sectional study United Kingdom (London) Segmentation (GA lesion area) INSIGHT Health Data Research Hub at Moorfields Eye Hospital 9875 (OCT); 81 (FAF) NR NR 3D-OCT; FAF (512*512 pixels) Self-learning algorithm PPV
    Safai et al [] Comparative analysis United States (Wisconsin) Identification (the best AI framework for segmentation of GA) AREDS2 study; the GlaxoSmithKline (GSK) study 271(AREDS2); 100(GSK) 601 (AREDS2); 156 (GSK) 5-fold cross-validation FAF (512*512 pixels) CNNs: UNet, FPN, PSPNet, EfficientNet, ResNet, VGG, mViT CC and DSC
    • FPN_EfficientNet: CC=0.98, DSC=0.931.
    • FPN_CCesNet: CC=0.98, DSC=0.902.
    • FPN_VGG: CC=0.98, DSC=0.934.
    • FPN_mViT: CC=0.99, DSC=0.939.
    • UNet_EfficientNet: CC=0.98, DSC=0.924.
    • UNet_CCesNet: CC=0.97, DSC=0.930.
    • UNet_VGG: CC=0.97, DSC=0.896; UNet_mViT: CC=0.99, DSC=0.938.
    • PSPNet_EfficientNet: CC=0.93, DSC=0.890.
    • PSPNet_CCesNet: CC=0.87, DSC=0.877.
    • PSPNet_VGG: CC=0.95, DSC=0.900.
    • PSPNet_mViT: CC=0.98, DSC=0.889.

    aSS-OCT: swept-source OCT.

    bCNN: convolutional neural network.

    cSEN: sensitivity.

    dSPE: specificity.

    eDSC: dice similarity coefficient.

    fNR: not reported.

    gSD-OCT: spectral domain OCT.

    hAUROC: area under the receiver operating characteristic curve.

    iACC: accuracy.

    jCGA: central geographic atrophy.

    kNCGA: noncentral geographic atrophy.

    lFAF: fundus autofluorescence.

    mMAE: mean absolute error.

    nR: recall.

    oP: precision.

    pAMD: age-related macular degeneration.

    qLPR: local progression rate.

    rNIR: near-infrared reflectance.

    sDL: deep learning.

    tr2: Pearson correlation coefficient.

    uOCT: optical coherence tomography.

    vIoU: intersection over union.

    wAAD: absolute area difference.

    xCC: correlation coefficient.

    yOR: overlap ratio.

    zICC: intraclass coefficient.

    aaPPV: positive predictive value.

    abAREDS2: Age-Related Eye Disease Study 2.

    acFPN: Feature Pyramid Network.

    adVGG: Visual Geometry Group.

    aemViT: Mix Vision Transformer.

    Dataset configurations varied: 9 out of 20 studies used training, validation, and test sets [,,-,-]; 11 studies used training and test sets [,,-,]; 2 studies used training and validation sets [,]; 1 study comprised training, tuning, and internal validation sets []; and 2 studies did not specify [,]. Across studies, at least 14,064 participants provided image data for analysis. Less than half of the studies (9/20, 45%) provided demographic information, with the average age of participants ranging from 55 to 94 years. Six studies were registered with ClinicalTrials.gov (NCT01342926, NCT02503332, NCT02479386, NCT02399072, and NCT04469140 [,,,,,]). To assess the generalization ability of the DL model, cross-validation methods included 5-fold (8/20 studies [,,,-,]), 4-fold (1/20 study []), 3-fold (1/20 study []), and other approaches (1/20 study []). Nine studies did not report validation specifics.

    Multiple imaging modalities supported GA assessment: spectral domain optical coherence tomography (SD-OCT) was most common, followed by swept-source OCT (SS-OCT), 3D-OCT, FAF, and NIR. Preprocessing techniques were widely applied to standardize images and improve model performance. Algorithm architectures varied, with U-Net being the most frequently used. Other approaches included custom CNNs, self-learning algorithms, weakly supervised models, and multimodal networks. For example, Hu et al [] trained the DL models (ResNet-50, Xception, DenseNet169, and EfficientNetV2), evaluating them on a single fold of the validation dataset, with all F1-scores exceeding 90%. Yang [] proposed an ensemble DL architecture that integrated 4 different CNNs, including ResNet50, EfficientNetB4, MobileNetV3, and Xception, to classify dry AMD progression stages. GA lesions on FAF were automatically segmented using multimodal DL networks (U-Net and Y-Net) fed with FAF and NIR images []. In contrast to the multimodal algorithms mentioned above (ie, the examples of DL models), Safai [] investigated 3 distinct segmentation architectures along with 4 commonly used encoders, resulting in 12 different AI model combinations to determine the optimal AI framework for GA segmentation on FAF images.

    From 20 studies, 42 performance sets were collected. Common metrics included correlation coefficient, mean absolute error, Spearman correlation coefficient, intraclass coefficient, overlap ratio, Pearson correlation coefficient (r2), Kappa, specificity (SPE), sensitivity (SEN), accuracy, positive predictive value (PPV), F1-score, P, R, intersection over union, and dice similarity coefficient (DSC). Regarding the segmentation, classification, identification, and quantification of GA in SD-OCT, 12 studies demonstrated performance comparable to that of clinical experts [,,,,,-,,]. AI was also capable of efficiently detecting, segmenting, and measuring GA in SS-OCT, 3D-OCT, and FAF images, according to 4 studies [,,,]. AI for GA segmentation in FAF and NIR images, with clinical data showing good segmentation performance [,,].

    We performed a comprehensive assessment of the methodological quality of 16 GA assessment and progression studies encompassing 4 domains (). Only 8 studies detailed the eligibility criteria in the “patient selection” category, while the others had not been published. Three of the studies [-] lacked complete datasets, and 3 others [,,] had small datasets or limited volumes of data. In addition, 3 studies [,,] failed to provide information on image formats or resolutions. Two studies [,] were ranked as high risk regarding patient selection since the participants included other types of dry AMD (drusen, nascent GA). In terms of applicability, 18 studies were classified as low risk, while 2 were deemed high risk concerning patient selection. Concerning the “Index test,” only 3 algorithms underwent external validation with a different dataset [,,]. All other items were evaluated as low risk.

    Table 4. Methodological quality and applicability summary of geographic atrophy (GA) assessment and progression studies using revised Quality Assessment of Diagnostic Accuracy Studies–Artificial Intelligence (QUAUAS-AI).
    Study Risk of bias Concerns regarding applicability
    Patient selection Index test Reference standard Flow and timing Patient selection Index test Reference standard
    M Hu [] High risk High risk Low risk Low risk High risk Low risk Low risk
    JK Yang [] High risk High risk Low risk Low risk High risk Low risk Low risk
    A Safai [] Low risk Low risk Low risk Low risk Low risk Low risk Low risk
    WD Vogl [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    A Szeskin [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    ZD Chu [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    ZX Ji [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    X Ma [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    C Royer [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    T Spaide [] High risk Low risk Low risk Low risk Low risk Low risk Low risk
    T Spaide [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    DJ Williamson [] Low risk High risk Low risk Low risk Low risk Low risk Low risk
    RB Xu [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    J Arslan [] Low risk High risk Low risk Low risk Low risk Low risk Low risk
    V Pramil [] Low risk High risk Low risk Low risk Low risk Low risk Low risk
    GY Zhang [] High risk Low risk Low risk Low risk Low risk Low risk Low risk
    DA Merle [] High risk High risk Low risk Low risk Low risk Low risk Low risk
    H AI-khersan [] Low risk High risk Low risk Low risk Low risk Low risk Low risk
    S Siraz [] Low risk High risk Low risk Low risk Low risk Low risk Low risk
    XM Liu [] High risk High risk Low risk Low risk Low risk Low risk Low risk

    AI in Predicting GA Lesion Area and Progression

    Eleven studies used AI for predicting GA lesion growth and progression using noninvasive imaging (Table S3 in ). These studies were published between 2021 and 2025, with some information provided in . The study designs consisted of 6 retrospective studies [-], 2 model development studies [,], 2 post hoc analyses [,], and 1 clinical evaluation of a DL algorithm []. Participants or images came from various regions: 6 studies were based in the United States [,-,], 3 in Australia [-], 1 in Switzerland [], and another involving multiple centers in China and the United States []. Research aims focused on GA growth prediction [,,-,,], combined prediction and evaluation of lesion features [], treatment response assessment [], and integrated segmentation-prediction tasks [,].

    Table 5. Characteristics of studies evaluating artificial intelligence (AI) models for geographic atrophy (GA) prediction using noninvasive retinal imaging.
    Author Study design Region Purpose of the study Source of datasets Number of patients Number of images or scans or cubes Model evaluation method Image modality (resolution) AI algorithms Outcomes Performance of models
    Gigon et al [] Retrospective monocentric study Switzerland (Lausanne) Prediction (RORA progression) Jules Gonin Eye Hospital 119 NR NR SD-OCT (384*384 pixels) CNN: EfficientNet-b3 DSC
    • 0-6 months: 0.84
    • 6-12 months: 0.84
    • >12 months: 0.89
    Dow et al [] Retrospective cohort study United States (Atlanta, Georgia, Portland, Oregon, North Carolina; Maryland, Raleigh, Morrisville, Cary); United Kingdom (Durham, South Durham) Prediction (iAMD to GA within 1 year) 3 independent datasets from AREDS2 and a tertiary referral center and associated satellites 316; 53; 48 1085; 53; 48 5-fold cross-validation SD-OCT (512 *1000 pixels) CNN: Inception v3 SEN, SPE, PPV, NPV, ACC
    • SEN: 0.91 (95% CI 0.74-0.98); SPE: 0.80 (95% CI 0.63-0.91); PPV: 0.78 (95% CI 0.70-0.85); NPV: 0.92 (95% CI 0.90-0.95); ACC: 0.85 (95% CI 0.87-0.91)
    Cluceru et al [] Retrospective clinical study; observation study United States (California) Prediction and evaluation (GA growth rate and GA features related to shape and size) The lampalizumab phase 3 clinical trials and an accompanying observational study 1041; 255 NR 5-fold cross-validation FAF (384 * 384 pixels) CNN: VGG16 r2
    • Full FAF images: 0.44 (95% CI 0.36-0.49)
    • Rim only: 0.37 (95% CI 0.35-0.4)
    • Lesion only: 0.34 (95% CI 0.31-0.36)
    • Background only: 0.3 (95% CI 0.27-0.33)
    • Mask only: 0.27 (95% CI 0.24-0.29)
    Anegondi et al [] Retrospective clinical study; observation study United States (California) Prediction and prognosis (GA lesion area and GA growth rate after lampalizumab treatment) The lampalizumab phase 3 clinical trials and an accompanying observational study 1279; 443; 106; 169 NR 5-fold cross-validation SD-OCT, FAF (512*512 pixels) CNN: Inception v3 r2 GA prediction:

    • FAF-only: 0.98 (95% CI 0.97‐0.99)
    • OCT-only: 0.91 (95% CI 0.87‐0.95),
    • Multimodal: 0.94 (95% CI 0.92‐0.96).

    GA growth rate:

    • FAF-only: 0.65 (95% CI 0.52‐0.75),
    • OCT-only: 0.36 (95% CI 0.29‐0.43),
    • Multimodal: 0.47 (95% CI 0.40‐0.54)
    Salvi et al [] Retrospective analysis United States (California) Prediction (the 1 year region of growth of GA lesions) The following lampalizumab clinical trials and prospective observational studies 597 NR NR FAF (768*768 pixels or 1536*1536 pixels) CNN: U-Net P, R, DSC, r2 Whole lesion:

    • P: mean 0.70 (SD 0.12); R: mean 0.73 (SD 0.12); DSC: mean 0.70 (SD 0.09); r2: 0.79
    Yoshida [] Retrospective analysis United States (California) Prediction (GA progression) Three prospective clinical trials 1219; 442 NR 5-fold cross-validation 3D OCT (496*1024*49 voxels) CNNs: (1) en-face intensity maps; (2) SLIVER-net; (3) a 3D CNN; and (4) en-face layer thickness and between-layer intensity maps from a segmentation model r2
    • GA lesion area: En-face intensity map: 0.91; SLIVER-net: 0.83; 3D DenseNet: 0.90; OCT EZ and RPE thickness map: 0.90;
    • GA growth rate: En-face intensity map: 0.33; SLIVER-net: 0.33; 3D DenseNet: 0.35; OCT EZ and RPE thickness map: 0.35.
    GS Reiter [] Post hoc analysis Austria (Vienna) Prediction (GA lesions progression) the phase II randomized controlled trial FILLY 134 268 scans 5-fold cross-validation FAF, NIR, SD-OCT (NR) CNN: PSC-UNet ACC, Kappa, concordance index
    • ACC: 0.48; Kappa: 0.23; concordance index: 0.69
    J Mai [] Post hoc analysis Austria (Vienna) Segmentation, quantification, and prediction (GA lesion and progression) The phase 2 FILLY clinical trial and the Medical University of Vienna (MUV) 113; 100 226; 967 5-fold cross-validation SD-OCT, FAF (768*768 and 1536*1536 pixels) CNN: U-Net DSC, Hausdorff distance, ICC
    • MUV: DSC: mean 0.86 (SD 0.12); Hausdorff distance: mean 0.54 (SD 0.45);
    • FILLY: DSC: mean 0.91 (SD 0.05); Hausdorff distance: mean 0.38 (SD 0.40)
    YH Zhang [] Model development China (Nanjing); United States (California) Prediction (GA growth) The Byers Eye Institute of Stanford University; the Jiangsu Provincial People’s Hospital 22; 3 86 cubes; 33 cubes Leave-one-out cross-validation SD-OCT (178*270 pixels) Recurrent neural network: the bi-directional long-short term memory network; CNN: 3D-UNet DSC, CC
    • Scenario I: DSC: 0.86; CC: 0.83;
    • Scenario II: DSC: 0.89; CC: 0.84;
    • Scenario III: DSC: 0.89; CC: 0.86;
    • Scenario IV: DSC: 0.92; CC: 0.88;
    • Scenario V: DSC: 0.88; CC: 0.85;
    • Scenario VI: DSC: 0.90; CC: 0.86
    SX Wang [] Model development United States (California) Segmentation and prediction (GA lesion area and GA progression) The University of California—Los Angeles 147 NR 8-fold cross-validation SD-OCT, FAF (512*512 pixels) CNN: U-Net SEN, SPE, ACC, OR
    • ACC: 0.95; SEN: 0.60; SPE: 0.96; OR: 0.65
    J Mai [] Clinical evaluation of a DL-based algorithm Austria (Vienna) Prediction (GA lesions progression) The Medical University of Vienna 100 967 5-fold cross-validation SD-OCT, FAF (NR) CNN: PSC-UNet DSC, MAE, and r2
    • 0-1 year: DSC: mean 0.25 (SD 0.16); MAE: mean 0.13 (SD 0.11)
    • 1-2 years: DSC: mean 0.38 (SD 0.20); MAE: mean 0.25 (SD 0.24);
    • 2-3 years: DSC: mean 0.38 (SD 0.21); MAE: mean 0.35 (SD 0.34);
    • >3 years: DSC: mean 0.37 (SD 0.23); MAE: mean 0.72 (SD 0.48)

    aRORA: retinal pigment epithelial and outer retinal atrophy.

    bNR: not reported.

    cOCT: optical coherence tomography.

    dCNN: convolutional neural network.

    eDSC: dice similarity coefficient.

    fAMD: age-related macular degeneration.

    gAREDS2: Age-Related Eye Disease Study 2.

    hSEN: sensitivity.

    iSPE: specificity.

    jPPV: positive predictive value.

    kNPV: negative predictive value.

    lACC: accuracy.

    mFAF: fundus autofluorescence.

    nr2: Pearson correlation coefficient.

    oP: precision.

    pR: recall.

    qEZ: ellipsoid zone.

    rRPE: retinal pigment epithelium.

    sNIR: near-infrared reflectance.

    tICC: intraclass coefficient.

    uCC: correlation coefficient.

    vOR: overlap ratio.

    wMAE: mean absolute error.

    Dataset structures varied: 3 out of 11 studies used training-validation-test splits [,,]; 2 out of 11 studies used training-test sets [,]; 3 out of 11 studies used training-validation sets [,,]; and the rest adopted development–holdout [,] or development-holdout-independent test configurations []. In total, 6706 participants were included across studies. Fewer than half of the studies (4/11, 36.4%) reported demographic information, with mean age ranges spanning from 74 to 83 years [,,,]. Six studies [-,,] were ethically approved and registered on ClinicalTrials.gov under the following identifiers: NCT02503332, NCT02247479, NCT02247531, NCT02479386, NCT01229215, and NCT02399072. The DL model’s generalizability was assessed using leave-one-out cross-validation in 1 study [], 5-fold cross-validation in 7 studies [,,,,-], and 8-fold cross-validation in 1 study []. The remaining 2 studies [,] did not specify the cross-validation methodology.

    Studies used 3D-OCT, SD-OCT, NIR, and FAF images, primarily sourced from Heidelberg, Zeiss, and Bioptigen devices. While most reported image metrics, 2 studies did not specify resolution details [,]. Commonly used DL architectures included Inception v3 [,], PSC-UNet [,], U-Net [,,], EfficientNet-b3 [], and VGG16 []. In addition, some studies introduced novel approaches, such as en-face intensity maps, SLIVER-net, 3D CNN, and a recurrent neural network, for improved GA progression forecasting.

    According to various image modalities, datasets, and follow-up durations, we gathered 31 sets of performance data from 11 studies. The performance metrics included the Hausdorff distance, concordance index, overlap, SEN, SPE, accuracy, mean absolute error, Kappa, DSC, P, PPV, R, r2, and negative predictive value. The findings for a single image modality (3D-OCT, SD-OCT, or FAF) demonstrated the development of DL algorithms to predict GA growth rate and progression with excellent performance characteristics comparable to trained experts [-,-]. Multimodal approaches combining FAF, NIR, and SD-OCT further showed feasibility for individualized lesion growth prediction and localization [,-].

    In this systematic review, we used the PROBAST tool to rigorously evaluate prediction models across 4 domains, addressing 20 signaling questions for each paper reviewed. Within the “participants” domain, all studies used appropriate data sources; however, only 6 studies [-,,] clearly outlined their inclusion and exclusion criteria for participants, leaving the others unclear. In terms of “predictors,” these were defined and evaluated similarly for all participants, having no connection to outcome data and being available at baseline. All studies evaluated “yes” to the questions on outcome measurement methods, definitions, interference factors, and measurement time intervals. Concerning “analysis,” Dow [] and Zhang [] applied a small dataset with an insufficient number of participants. While Zhang performed internal validation, the lack of external validation notably limits the model’s generalizability, which was constructed with bi-directional long-short term memory networks and CNN frameworks. Two studies by Salvi [] and Yoshida [] lacked independent and external validation. Gigon [] failed to explicitly mention missing data handling, complex problems, and model overfitting. Conversely, all other items were evaluated as low risk, and the applications of the studies were universally ranked as low risk (Table S1 in ).

    Principal Findings

    This systematic review evaluated the performance of AI, particularly DL algorithms, in detecting and managing GA secondary to dry AMD using noninvasive imaging modalities. Our findings demonstrate that AI models exhibit strong capabilities in accurately detecting, segmenting, quantifying, and predicting GA progression from OCT, FAF, CFP, and NIR imaging, achieving diagnostic accuracy comparable to that of human experts. However, this review also identified several methodological challenges, such as limited sample sizes, inconsistent annotation standards, and a general lack of external validation, which may hinder the clinical generalizability and practical application of these models. Despite these limitations, AI-based tools show significant potential for future use by both specialists and nonspecialists in primary and specialty care settings.

    AI in Detecting GA With OCT, FAF, NIR, and CFP Images

    Ten studies published between 2018 and 2025 were included, involving at least 7132 participants aged 50 to 85 years. Half of the studies were conducted in the United States, while others originated from European countries. SD-OCT was the most frequently used imaging modality (6/10 studies), followed by CFP (2/10 studies), NIR (1/10 studies), and FAF (1/10 studies). Image preprocessing techniques, such as standardization of size, orientation, and intensity, as well as noise reduction, were consistently applied to enhance model stability and training efficiency. However, 3 studies did not report critical image parameters, such as resolution, potentially limiting reproducibility. DL-based algorithms, including CNNs, were the primary methodologies used for GA detection. Cross-validation techniques, such as 5-fold and 10-fold methods, were used in half of the studies to assess model robustness, though 3 studies did not report validation strategies. AI, particularly DL algorithms, holds significant promise for the detection of GA using noninvasive imaging modalities. OCT, CFP, NIR, and FAF each demonstrated robust diagnostic potential, with performance metrics rivaling or exceeding human expertise.

    AI for GA Management With OCT, FAF, and NIR Images

    A total of 20 studies (14,064 participants) were published between 2019 and 2025, focusing on themes such as GA segmentation, classification, quantification, and progression prediction. The research designs and geographic regions are diverse. The studies included retrospective analysis (9/20), model development (7/20), and prospective, comparative, or cross-sectional studies (4/20). Significant contributions came from China (6/20) and the United States (7/20), with additional studies from the United Kingdom (2/20), Australia (2/20), France (1/20), Israel (1/20), and Austria (1/20). The studies used a variety of imaging modalities to assess GA, including SD-OCT, FAF, NIR, SS-OCT, and 3D-OCT. DL algorithms demonstrated remarkable performance in GA management tasks. U-Net was the most commonly used architecture. Multimodal approaches combined FAF and NIR images with DL networks to improve segmentation accuracy. Performance metrics, such as DSC, Kappa, SEN, SPE, and accuracy, consistently showed strong diagnostic accuracy, with several studies achieving performance comparable to clinical experts.

    Eleven studies with 6706 participants, published between 2021 and 2025, concentrated on the application of AI for predicting and segmenting GA lesions, as well as their growth and progression. The methodologies were diverse, including retrospective studies, model development studies, post hoc analyses, and clinical algorithm assessment. Participants or images were gathered from regions such as the United States, Australia, Switzerland, and various centers in China and the United States, ensuring broad geographic representation. Demographic information was reported in fewer than half of the studies, with a mean age ranging from 74 to 83 years. Imaging modalities, such as 3D-OCT, SD-OCT, NIR, and FAF, were obtained from devices including Bioptigen, Heidelberg Spectralis HRA+OCT, and Cirrus OCT. While the image preprocessing parameters were consistent across most studies, some did not specify image resolution. Multiview CNN architectures and advanced frameworks, such as the bi-directional long-short term memory networks, were used. DL algorithms exhibited excellent predictive capabilities, with multimodal approaches enabling individualized GA lesion growth prediction.

    Noninvasive Image Analysis Techniques for GA

    GA, a late-stage form of dry AMD, is marked by the irreversible loss of photoreceptors, RPE, and choriocapillaris [,]. The application of noninvasive imaging modalities has revolutionized the detection and management of GA. A comparative summary of AI performance across these modalities is provided in Table S2 in . CFP serves as a standard initial assessment tool, useful for screening and early detection. It identifies GA lesions as visible underlying choroidal vessels and well-defined regions of RPE hypopigmentation []. FAF imaging using a blue excitation wavelength (488 nm) visualizes metabolic changes at the level of photoreceptor or RPE complex and is practical in assessing GA lesion size and progression with hypo-autofluorescence []. In contrast to nonatrophic areas, GA lesions on NIR (787-820 nm, longer than FAF) typically appear brighter and less harmful to the eye []. In addition, NIR can help detect the boundaries of foveal lesions, where image contrast is lower on FAF []. Recently, the Classification of Atrophy Meeting group recommended that atrophy in both patients with and those without neovascular AMD be defined based on specific drusen characteristics and other anatomical features, and it is most easily characterized by OCT [,]. OCT stands out as the gold standard for GA detection and classification, providing high-resolution, cross-sectional, and en face images of the retina and choroid. SD-OCT is widely used in research and clinical trials, offering precise measurement of GA area and growth rates, while SS-OCT and 3D-OCT offer superior structural insights and potential for AI-driven automation [,,]. Despite the higher cost and technical complexity of advanced OCT technologies, their detailed GA assessment capabilities make them indispensable tools in both clinical practice and research. Furthermore, OCT provides volumetric (3D) structural data, unlike the 2D en face projections of FAF, CFP, and NIR. It allows AI to learn not just the surface appearance of atrophy but also the cross-sectional structure alterations that define and precede GA []. As technology advances, the integration of AI and further developments in imaging techniques are expected to enhance the utility of these modalities, overcoming current limitations and expanding their applications in ophthalmology.

    Advantages and Challenges of AI Architectures in Clinical Workflow

    AI addresses critical limitations of traditional GA monitoring, such as labor-intensive manual grading and intergrader variability []. Therefore, automated algorithms enable rapid, standardized analysis of large fundus image datasets, reducing clinician workload and enhancing reproducibility []. Furthermore, our review revealed a clear trend in the choice of model architectures tailored to specific clinical tasks. A critical analysis of these architectures is provided in Table S3 in . Interestingly, with the advancement of AI algorithm architectures, numerous studies have emerged that use these technologies to identify atrophy caused by various retinal diseases and to evaluate treatment outcomes through image analysis. Miere et al [] pretrained a DL-based classifier to automatically distinguish GA from atrophy secondary to inherited retinal diseases on FAF according to etiology, using 2 approaches (a trained and validated method and a 10-fold cross-validation method), achieving good accuracy and excellent area under the receiver operating characteristic (AUROC) values. In addition, a study examined the association between treatment and changes in photoreceptor lamina thickness in patients with GA secondary to AMD. The effect of pegcetacoplan on photoreceptors in OCT was supported by this post hoc analysis, which demonstrated that treatment with the drug was linked with reduced outer retinal thinning []. Similarly, DL-based OCT image analysis assessed the therapeutic effectiveness of complement component 3 inhibition in delaying GA progression, with findings indicating decreased photoreceptor thinning and loss []. Recent studies demonstrating the application of AI algorithms in imaging further validate their potential as reliable supplements to human expertise in the diagnosis and management of GA.

    Technical Challenges and Limitations

    Despite the promising advancements in AI for GA detection and management, several technical challenges and limitations persist. A significant limitation of OCT-based AI models is their difficulty in distinguishing GA secondary to AMD from other forms of retinal atrophy; thus, the findings may not generalize to broader AMD cases or other retinal diseases, which limits their clinical applicability. In addition, images from different OCT devices show significant variability and imprecision, not offering good enough data acquisition []. Another major challenge is the variability in algorithm performance caused by differences in training data, image acquisition protocols, and disease definitions. These differences reduce reproducibility and limit practical deployment. For instance, the absence of standardized reporting in AI studies can result in discrepancies when interpreting results and hinder comparisons between different models. Moreover, despite the high-performance metrics (eg, SEN, SPE, DSC>0.85, and AUROC>0.95) reported by many studies, methodological limitations remain. All diagnostic studies included in this review were assessed as high risk in at least 1 domain (10/10), only 1 GA assessment study (1/20) was evaluated as low risk across all domains, and several prediction studies (7/11) were ranked as high or unclear risk in at least 1 domain, primarily due to small or nonrepresentative datasets and a lack of detailed reporting on image preprocessing and external validation. These methodological shortcomings may lead to an overestimation of AI model performance and reduced overall robustness, thereby decreasing the generalizability of the findings and limiting confidence in their real-world applicability. Future studies should prioritize the use of larger, more diverse datasets and implement rigorous validation frameworks to enhance performance metrics (including detection, segmentation, quantification, and prediction accuracy) and conduct prospective, multicenter validation studies to improve clinical applicability and generalizability. Furthermore, adherence to established reporting guidelines for AI studies (such as the Standards for Reporting Diagnostic Accuracy-AI and Checklist for Artificial Intelligence in Medical Imaging [,]) would improve comprehension and transparency, allow for more meaningful comparisons between systems, and facilitate meta-analyses.

    Real-World Implications and Research Contributions

    Overall, despite some limitations, AI is constantly evolving and holds great potential for transformation in the health care sector []. AI has the potential to accelerate existing forms of medical analysis; however, its algorithms require further testing to be fully trusted. Clinically, AI-based automated tools show strong potential to facilitate early detection, precise quantification, progression, and prediction of GA, thereby reducing the burden on retinal specialists and improving diagnostic consistency. Furthermore, DL algorithms have demonstrated effectiveness in identifying retinal image features associated with cognitive decline, dementia, Parkinson disease, and cardiovascular risk factors []. These findings indicate that AI-based retinal images hold promise for transforming primary care and systemic disease management. Although most AI applications remain in the validation phase, the integration of AI with multimodal imaging, novel biomarkers, and emerging therapeutics holds promise for transforming clinical management paradigms in GA and advancing personalized medicine. Future efforts should focus on developing standardized datasets, improving algorithmic generalizability, and conducting real-world validation studies to fully integrate AI into routine ophthalmic practice.

    Conclusion

    AI, especially DL-based algorithms, holds considerable promise for the detection and management of GA secondary to dry AMD, with performance comparable to trained experts. This systematic review synthesizes and critically appraises the current evidence, highlighting that AI’s capabilities extend across GA management—from initial detection and precise segmentation to the forecasting of lesion progression, which informs future research directions. Meanwhile, with the development of C5 inhibitors, AI-based noninvasive fundus image analysis is expected to detect, identify, and monitor GA at an early stage, thereby increasing the window of opportunity in the future. AI has strong potential to augment and streamline clinical workflows by offering automated, reproducible analysis that can assist clinicians in managing large volumes of imaging data; however, more studies are needed to further validate its effectiveness, repeatability, and accuracy.

    The authors declared that artificial intelligence (AI) or AI-assisted technologies were not used in the writing process of this manuscript.

    This research was funded by the Central High-Level Traditional Chinese Medicine Hospital Project of the Eye Hospital, China Academy of Chinese Medical Sciences (grant no GSP5-82); the National Natural Science Foundation of China (grant no 82274589); the Science and Technology Innovation Project, China Academy of Chinese Medical Sciences (grant no CI2023C008YG); the Institute-level Research Launch Fund of the Eye Hospital, China Academy of Chinese Medical Sciences (grant no kxy-202402); and the Special Project for the Director of the Business Research Office (grant no 2020YJSZX-2).

    All data generated or analyzed during this study are included in this published article and its multimedia appendix files.

    None declared.

    Edited by Amaryllis Mavragani, Stefano Brini; submitted 26.Jul.2025; peer-reviewed by Jiale Zhang, Xiaolong Liang; final revised version received 11.Oct.2025; accepted 11.Oct.2025; published 21.Nov.2025.

    © Nannan Shi, Jiaxian Li, Mengqiu Shang, Weidao Zhang, Kai Xu, Yamin Li, Lina Liang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.Nov.2025.

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research (ISSN 1438-8871), is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

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  • Journal of Medical Internet Research

    Journal of Medical Internet Research

    Digital Interventions in Youth Mental Health

    Despite having the greatest level of need, young adults have the worst access to timely and quality mental health care []. Both before and after the COVID-19 pandemic, there is robust evidence that demand for youth mental health support significantly outstrips availability in both the health care and education systems []. In the context of a sharp rise in help-seeking, digital health interventions (mental health supports that are delivered via web-based or mobile-based platforms) offer enormous potential to improve outcomes, to widen access, and to meet the increasing demand on mental health services.

    Several meta-analyses have been conducted on digital interventions (mostly focused on cognitive behavioral therapy [CBT] or “third-wave” cognitive interventions) that address depression and anxiety in young adults. An umbrella review by Harith and colleagues [] found evidence to support the use of digital interventions, but noted that effectiveness was greatly dependent on the delivery format and the mental health problem targeted. Furthermore, Harith et al [] noted that despite young people (as “digital natives”) frequently expressing a preference for the internet as a source of seeking health-related information to address or solve health problems, engagement with and adherence to digital health interventions is often suboptimal.

    Moderated Online Social Therapy

    One approach to improving mental health recovery in young adults is Moderated Online Social Therapy (MOST) []. MOST was initially developed as a digital mental health platform to provide a low-intensity, cost-effective, and engaging approach to prolonging the benefits of specialized Early Intervention for Psychosis (EIP) services []. MOST has shown benefits in terms of return to education and employment among participants, decreased need for emergency care, and has shown to be cost-effective from both the health care sector and societal perspective []. MOST has since been trialed in young adults in single-arm studies of help-seeking young people aged between 16 and 25 years in Australia [] and the Netherlands [], and in young people with depression [], social anxiety [], at high risk of psychosis [], at increased risk of suicide [], with borderline personality disorders [], and in a large-scale national study of young adults in Australia [], with small to large benefits observed for social function and symptom severity. As a digital intervention, MOST consists of both evidence-based online therapy content supported by therapist contact and a Facebook-style community supported and moderated by peer support workers. Evidence of the acceptability of MOST for young people has been reported in a number of studies, including in young people with social anxiety [], emerging mental health issues [], and psychosis [].

    The design and therapeutic content of MOST is strongly influenced by self-determination theory [], an empirically supported theory of motivation, which focuses on the processes and social environments that facilitate or hamper social functioning. In terms of engagement and adherence, MOST differs from other “self-help” style digital interventions by providing access to therapeutic content online that is supported by access to a therapist. It is further supplemented by social supports, including peer support and an online community. Providing these face-to-face supports is likely to improve engagement, which is identified as a major barrier to the use of digital interventions [,,].

    Student Mental Health

    In many European countries, young adults remain in some form of education until their early twenties. Based on the figures published in 2022 by the Organisation for Economic Co-operation and Development, 54% of 18‐ to 24-year-old young adults are in some form of third-level education, rising to 59% in Europe, and up to 63% in Ireland []. According to a 2018 World Health Organization study of ~14,000 students from across 8 countries, approximately one in three screened positive for at least one common DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) anxiety, mood, or substance disorder []. Similarly, Sheldon et al [], in a meta-analysis of third-level students, reported a pooled prevalence of depression at 25% and suicide-related outcomes at 14%. Taken together, these data suggest that education settings such as universities and colleges represent a key location for the development and delivery of mental health interventions. As noted above, however, access to young adult mental health services is often limited, and particularly so in university mental health services, where a student may at best have access to short-term (1-4) sessions of counseling. In this context, MOST may provide a means to supplement existing 1:1 therapy in a scalable and cost-effective manner.

    Objectives

    The purpose of this study was to provide information about the feasibility of conducting a randomized trial of MOST in young people who recently attended a university counseling service, along with preliminary data regarding the efficacy of MOST for the purpose of a definitive randomized controlled trial. This study was carried out as part of a funded program of research entitled “Improving Psychosocial Supports in Youth Mental Health” (the PSYcHE program).

    Ethical Considerations

    This study was approved by the Galway Clinical Research Ethics Committee, Merlin Park Hospital, Galway, Ireland (reference CA2468). All participants provided informed written consent, and protocols were put in place for the proposed management of vulnerable individuals in the study. Participants were reimbursed €25 (approximately US $29) for each assessment (see below). The ethics application also detailed General Data Protection Regulation (GDPR) considerations including the pseudonymization of data and data management practices to ensure the privacy of participants. The trial was registered with ISRCTN (number 15520701).

    Setting and Inclusion Criteria

    We conducted this prospective, assessor-blind, randomized controlled pilot study at the student counseling service of the University of Galway, Ireland, which serves just over 18,000 students. We aimed to include students who attended the service with persistent mental health difficulties of at least 12 months in duration. The rationale for this was to focus on a more homogeneous sample of young people seeking help for mental health difficulties rather than more transient difficulties causing distress. Inclusion criteria were being aged between 18 and 35 years, self-reporting mental health difficulties of longer than 1 year in duration, being clinically stable, and having the ability to give consent. Clinical stability in this context was determined by the referring counselor. A participant was considered eligible for MOST based on the criteria that the participant was finishing their attendance at the counseling service and no longer required the 1:1 counseling support they had been receiving. Exclusion criteria were a history of organic impairment (including IQ<70), a history of head injury with loss of consciousness >5-minute duration, and substance abuse in the preceding month.

    Referrals to the study were made electronically by the student counselor toward the end of the participant’s short-term 1:1 counseling sessions (~4 sessions were provided). Once the referral was received, a research assistant completed the informed consent procedure, after which an initial screening was conducted. Following screening against inclusion and exclusion criteria, eligible participants were enrolled into the study and completed a baseline assessment. See for a breakdown of recruitment across the study period.

    Randomization and Masking

    Procedure

    Following baseline assessment, participants were randomly allocated to their treatment group. Randomization was implemented using Sealed Envelope [] at a rate of 2:1 intervention versus control. A block design approach was taken to account for gender, with 6 participants per block. Research assessors (master’s level psychology research assistants) were masked to group allocation. Participants were informed about their trial allocation by a research assistant who was independent from the research assessors and whose role was to “onboard” participants onto the MOST intervention platform. To ensure that assessors remained blind to treatment status, research assessors were asked to guess the treatment arm of the participant following each assessment. Assessors correctly guessed intervention status only 39% of the time (12/31 guesses made; χ2=2.62, P=.11), suggesting that assessors were in fact blinded to status.

    Intervention Group
    Overview

    For those randomized to the MOST arm, an onboarding process was completed, during which participants were registered with the platform and given a guided tour. MOST has been described elsewhere [,,]. In brief, participation in the platform consisted of (1) engaging with a therapy “journey”; psychotherapeutic content automatically tailored for each participant based on their response to a questionnaire completed as part of the onboarding, further discussion below, (2) support with participation on the therapy journey from a therapist in the form of fortnightly ~15-minute video or telephone calls, (3) a community wall, see below, and (4) peer support for engagement in the community wall in the form of fortnightly ~30-minute video or telephone calls. Clinical and peer support workers followed established protocols provided by the MOST platform developers. Clinicians and peer support workers also met with the study principal investigator, as a group, on a monthly basis. During these meetings, engagement with each participant was reviewed and assessed according to the therapist and peer support manuals.

    Therapy Journey

    The Therapy Journey took the form of interactive online therapy modules (focusing on anxiety, social anxiety, depression, and social interaction) based on third-wave CBT and primarily targeting social functioning by, for example, fostering self-efficacy (identifying personal strengths based on the strengths-based framework), positive emotions and subjective well-being (eg, practicing mindfulness and self-compassion), or positive connections with others (eg, focusing on empathy skills). Participants’ engagement and application of this content in daily life is supported by 5 activity types: comics, reflective actions, actions, talking points, and pages. Comics are illustrated multipaneled narratives that bring therapeutic concepts to life via recurring characters, reflective actions are prompts for reflection, actions suggest a practical step (eg, behavioral experiment), talking points prompt young people and peer workers to post their thoughts and reactions to the content, and pages summarize each track and provide psychoeducation. Users have the option to save activities to a “toolkit,” so they have an accessible, personalized, and labeled bank of strategies when needed.

    Community Interaction

    The MOST community took the form of an online social network to foster social support. Participants are encouraged to communicate with one another and with peer and expert moderators. This is in order to foster a sense of connection as well as combat loneliness and self-stigma []. The community includes a “feed” page that allows participants to post text, images, and links to be read and responded to by other members of the community. This feed is only available to others on the MOST platform and is moderated by clinicians and led by peer-support workers with lived experience and informed by the evidence-based problem-solving framework []. A further feature of MOST is an online group function, referred to as “Talk it Out,” which enables users to nominate issues (eg, “how to break through shyness and make new friends?”), which are discussed in moderated groups through structured problem-solving phases (eg, brainstorming, pros and cons, and wrap-up).

    Control Group

    Those randomized to the control arm of the study continued to receive care as usual. As participants entered the trial after attending the student counseling service, they were free to seek help from usual supports both internal and external to the university (student medical services, etc). However, control participants were not provided additional supports through the trial, and in a majority of cases, were not receiving other therapeutic intervention during the period assessed. Control participants could be onboarded to MOST following their 26-week assessment.

    Outcomes Assessed

    As a pilot study, our main outcome metrics related to the feasibility of the trial included the number of participants recruited, their engagement with the treatment, and their retention at the follow-up assessment period. In addition, we also aimed to establish the feasibility of our primary and secondary outcome measures, along with some indication of treatment effect estimates that might be expected for these measures, to inform power calculations for a full trial.

    Outcome measures were administered to participants in both groups by assessors blinded to intervention allocation at baseline, 12 weeks, and 26 weeks. Participants were reimbursed €25 (approximately US $29) for their time for each assessment. The overarching aim of the PSYcHE research program under which this study was carried out was to improve psychosocial function. As such, our main outcome variable was social and occupational function. As described in detail previously [], identifying suitable measures of social and occupational function is complex, agreeing with the adage that simple measures are not accurate and accurate measures are not simple. As a result, for the purposes of this study, we included two separate measures of social and occupational function. The first was the Social and Occupational Functioning Assessment Scale (SOFAS) [], an interviewer-rated global assessment of social and occupational function. The second measure was the Time Use Survey (TUS) [], an interviewer-rated assessment of constructive economic activity and structured activity.

    Given that improved social and functional outcomes may relate changes in cognitive and social cognitive function (a hypothesis of the broader PSYcHE program), two measures of cognitive and social cognitive function were included—the Weschler Logical Memory task [], which is a brief measure of verbal episodic memory, and the Reading the Mind in the Eyes Test (RMET) [], which is a brief measure of social cognition, measuring theory of mind.

    In terms of clinical variables, we initially intended to assess the feasibility of loneliness, as measured by the UCLA (University of California, Los Angeles) Loneliness Scale []. However, studies published soon after the start of the trial, both of MOST and of other digital interventions, indicated that some of the largest effects might be observed on measures of anxiety, mood, and distress (eg, [,,]). Consequently, the trial protocol was amended after 6 months to also include additional clinical measures. That is, a measure of anxiety (Generalized Anxiety Disorder-7; GAD-7) [] and of depression (Patient Health Questionnaire-9; PHQ-9) []. These were therefore available for 51 of the 74 participants, 32 in the intervention arm and 19 in the control arm.

    Intervention Engagement Data

    Engagement data were extracted from the MOST platform once participants had completed 26 weeks on the platform. Data extracted included time spent, in minutes, working through therapeutic content as well as the number of therapeutic content activities completed, community activity (posts, comments, and reactions on the community wall), and texts and calls with therapists and peer support workers. The number of weeks spent engaging with the intervention was also calculated for each participant. Engagement was estimated as the combined total number of weeks that each participant logged into the MOST platform and moved beyond the homepage, or engaged in a call with their assigned therapist or peer support worker.

    Evidence around engagement with digital mental health interventions, including definitions of engagement and thresholds for engagement, is inconsistent and varied depending on the type of digital intervention, the participants involved, and the context in which the intervention is implemented [-]. As previous studies have measured engagement in different ways, leading to uncertainty about what engagement could be expected, we did not set an a priori indicator of engagement. In the absence of an agreed-upon measurement of engagement, we adopted a pragmatic approach informed by adherence literature as well as rates of engagement in previous digital interventions [-]. As such, we defined engagement as active use of one or more aspects of the MOST intervention and applied the following thresholds: We considered minimal engagement as >20%, partial engagement as 50%, and full engagement as >80%. For a 26-week trial, 20% engagement approximates to engagement for 5 or more weeks, and 50% as engagement for more than 12 weeks.

    Statistical Analysis

    Formal sample size calculations were not performed for this pilot study. Instead, the target sample size was based on recruitment of an adequate sample size for a pilot study conducted for the purposes of establishing parameters for a definitive study. Previous guidance on sample size estimation for pilot studies [,] has suggested a minimum of 60 participants as an adequate sample. A period of 36 months was initially proposed as a timeframe to recruit participants into the trial. This was based on funding, and also allowing for the fact that the majority of students were on campus for ~7 months of the year. As such, we sought to recruit a minimum average of 3 students per university term month, approximately 20 students per year of the trial.

    To assess differences between groups, analyses of covariance (ANCOVAs) were carried out to obtain adjusted mean differences between groups with a 95% CI, while accounting for baseline variables. Effect sizes were also calculated by taking the β coefficients of the treatment arm from the ANCOVAs and dividing them by the pooled baseline SD for each measure, respectively. The analysis plan did not include reporting of P values; this was based on recommendations that, as pilot studies are not fully powered, interpretation of results should be done with caution and the analysis should be designed to inform future trials rather than hypothesis testing []. Effect sizes were reported using the standard cutoffs of small (d=0.2), medium (d=0.5), and large (d=0.8) []. All analyses were completed at the end of the last follow-up assessments and were based on the intention-to-treat population. Analyses were carried out between the intervention and control groups as well as between participants who engaged for 5 or more weeks (minimum threshold for engagement) and the control participants. Analyses were conducted using SPSS v29 (IBM Inc).

    Recruitment and Sample Description

    Recruitment

    Our initial target was to recruit 60 participants over a 36-month period, representing a recruitment rate of 20 participants per year. We expected that most of the recruitment would occur during the 7 months of term time, such that we would be required to recruit ~3.3 participants per month of term (semester) time (~1.67 participants per calendar month) to achieve this target. The actual number of participants recruited was 74 over the 44 months (extended by 8 months due to the COVID pandemic) between April 2021 and December 2024 (see for the CONSORT [Consolidated Standards of Reporting Trials] participant flowchart []). In terms of the university semester, this equates to ~3.1 participants recruited for each month of term time or ~1.68 participants per calendar month (see for recruitment numbers by month).

    Figure 1. Participant recruitment and retention. MOST: Moderated Online Social Therapy.
    Sample Description

    A demographic and clinical description of the sample is provided in . The sample had a mean age of 22.69 years (SD=5.34) and 72% (53/74) identified as female. Nearly 68% (50/74) of the sample lived in shared accommodation, while 24% (18/74) continued to live at home. Predictably, for a sample recruited from a student cohort, all but 2 participants were in full- or part-time education at the time of baseline assessment, with those 2 participants having just left education since initial contact.

    Table 1. Demographic and clinical description of the sample at baseline assessment.
    Intervention group (n=47) Control group (n=27)
    Age (years), mean (SD) 22.77 (6.12) 22.56 (3.71)
    Gender (male:female:genderflux:other) 12:32:1:2 5:21:0:1
    Current education status, n (%)
     Not in education 1 (2) 1 (4)
     Part time 2 (4) 3 (11)
     Full time 44 (94) 23 (85)
    Accommodation, n (%)
     Lives with parents 13 (28) 5 (19)
     Lives with others 30 (64) 20 (74)
     Lives alone 1 (2) 1 (4)
    Presenting problem (self-report), n (%)
     Anxiety 20 (43) 13 (48)
     Mood 10 (21) 7 (26)
     Academic 6 (13) 5 (19)
     Relational 4 (9) 1 (4)
     Behavioral 3 (6) 0 (0)
     Other 4 (9) 1 (4)
    Duration of difficulties (months), mean (SD) 44.45 (40.66) 52.33 (44.83)
    Clinical measures, mean (SD)
     GAD-7 11.12 (4.77) 11.63 (4.93)
     UCLA Loneliness Scale 47.96 (11.3) 48.04 (10.33)
     PHQ-9 12.32 (5.06) 13.63 (5.11)
    Risk of alcohol and drug dependency, mean (SD)
     AUDIT 7.29 (6.38) 7 (4.53)
     DUDIT 2.26 (4.62) 2.67 (4.53)
    Predicted general cognitive ability, mean (SD)
     TOPF 104.16 (8.72) 104.93 (6.63)

    aGAD-7: Generalized Anxiety Disorder-7.

    bUCLA: University of California, Los Angeles.

    cPHQ-9: Patient Health Questionnaire-9.

    dAUDIT: Alcohol Use Disorders Identification Test.

    en=45.

    fDUDIT: Drug Use Disorders Identification Test.

    gn=46.

    hTOPF: Test of Premorbid Functioning.

    In terms of duration of mental health difficulties, reflecting the inclusion criteria of experiencing difficulties for at least 12 months, participants subjectively reported duration of difficulties as ranging from 12 to 165 months (13.8 years) in the intervention arm and 12‐192 months (16 years) in the control arm. The most commonly self-reported difficulties were anxiety (33/74, 45%), mood (17/74, 23%), academic difficulties (11/74, 15%), and relationship difficulties (5/74, 7%). In terms of alcohol use—measured by the Alcohol Use Disorders Identification Test (AUDIT) []—59% (44/74) were classified as “low risk,” 30% (22/74) as “low risk” or “increasing risk,” and 7% (5/74) as “possibly dependent” on alcohol. In terms of drug use—measured by the Drug Use Disorders Identification Test (DUDIT) []—all participants were estimated as “probably not” substance dependent and none as probably heavily dependent.

    In terms of randomization, which was set at 2:1 intervention to control, 47 (64%) of the 74 participants were assigned to the intervention arm of the study. No randomization errors were identified during the trial period.

    Rates of Retention and Engagement

    Retention

    This was defined as the percentage of participants who completed outcome measures at 12 and 26 weeks. Our initial target for retention was 75% at 12 and 26 weeks, with a threshold target of 70% required to proceed to a full randomized controlled trial without amendment of the study. In terms of actual retention rates in the study, 12-week assessments were collected for 52 (70%) of the 74 participants, representing 30 (64%) of the 47 intervention participants and 22 (81%) of the 27 participants in the control arm. Twenty-six-week assessments were available for 49 (66%) out of the 74 participants. This represented 28 (60%) of the intervention group and 21 (78%) of the control group. In summary, this reflects an overall dropout rate of 30% at 12-week follow-up, increasing marginally to 34% at 26 weeks.

    Rates of Engagement

    As described above, engagement was captured in terms of discrete activities on MOST (see ) and then categorized in terms of number of weeks of engagement in the intervention. Participants were categorized according to their level of engagement using the following thresholds: minimal engagement ≥5 weeks, 20% of the intervention period; partial engagement ≥12 weeks, 50% of the intervention period; and full engagement ≥21 weeks, 80% of the intervention period. Of the 47 participants in the intervention arm, we observed that 38 (81%) engaged with the program for 5 or more weeks, 39 (83%) were engaged in the first 12 weeks, and 35 (74%) continued to engage beyond 12 weeks (see ). Finally, to allow future comparison with other studies of MOST and other digital interventions, engagement was also recorded and summarized in terms of min-max; median and mean for total activity time; number of therapy journey activities completed; community posts made, commented on, or reacted to; and number of calls with the therapist and peer support worker. These are provided in .

    Outcome Measures

    shows the group means and SDs, adjusted mean differences, and the effect sizes for those differences between the intervention group and the control group for all outcome measures. shows the same descriptive values for participants from the intervention group who had a minimum of 20% engagement on MOST, compared to the control group.

    Table 2. Comparison of outcome data for full sample.
    Intervention group Control group Adjusted mean difference (95% CI) Effect size (d)
       Participants, n Mean (SD) Participants, n Mean (SD)
    Primary outcome measures
     Social and occupational function
      SOFAS
       0 weeks 47 79.38(8.26) 27 77.89 (8.86)
       12 weeks 29 81.48 (9.83) 22 78.45 (10.82) –2.36 (–8 to 3.27) –0.28
       26 weeks 24 82.79 (10.26) 21 83.52 (7.7) 1.08 (–4.09 to 6.25) 0.13
      TUS constructive economic activity
       0 weeks 47 43.77 (19.13) 27 45.3 (29.52)
       12 weeks 30 36.42 (15.26) 22 48.32 (32.04) 10.86 (–1.66 to 23.37) 0.47
       26 weeks 28 38.18 (19.52) 21 42.85 (14.91) 4.36 (–6.06 to 14.78) 0.19
      TUS structured activity
       0 weeks 47 53.62 (19.33) 27 53.67 (28.23)
       12 weeks 30 46.23 (16.08) 22 59.63 (31.38) 12.74 (0.66 to 24.83) 0.56
       26 weeks 28 47.91 (21.43) 21 52.49 (16.09) 4.13 (–7.08 to 15.34) 0.18
    Secondary outcome measures
     Cognitive and social cognitive function
      RMET
       0 weeks 47 27.19 (4.3) 27 27.11 (3.48)
       12 weeks 30 27.1 (4.36) 22 25 (4.16) –0.93 (–2.67 to 0.81) –0.23
       26 weeks 28 28.21 (4.3) 21 27.48 (3.49) –0.11 (–1.98 to 1.76) –0.03
      Logical memory
       0 weeks 47 9.38 (2.89) 27 8.78 (3.06)
       12 weeks 17 8.82 (2.7) 16 8.81 (2.4) 0.02 (–1.34 to 1.38) 0.01
       26 weeks 28 9.54 (2.91) 21 8.86 (3.29) –0.69 (–2.12 to 0.75) –0.23
     Clinical measures
      UCLA Loneliness Scale
       0 weeks 46 47.96 (11.3) 26 48.04 (10.33)
       12 weeks 30 45.23 (13) 22 44.14 (12.73) –3.43 (–9.55 to 2.69) –0.31
       26 weeks 28 40.14 (13.23) 21 42.48 (12.38) –1.44 (–7.64 to 4.77) –0.13
      PHQ-9
       0 weeks 31 12.32 (5.06) 19 13.63 (5.11)
       12 weeks 20 10 (6.1) 19 10.05 (4.89) –1.72 (–5.46 to 2.02) –0.34
       26 weeks 21 8.9 (5.8) 18 9.83 (3.7) 0.54 (–2.92 to 4) 0.11
      GAD-7
       0 weeks 32 11.12 (4.77) 19 11.63 (4.93)
       12 weeks 20 9.6 (6.2) 19 9.32 (4.77) –2.36 (–5.58 to 0.85) –0.50
       26 weeks 21 8.1 (5.32) 18 8.28 (5.07) 1.08 (–2.64 to 4.81) 0.23

    aSOFAS: Social and Occupational Functioning Assessment Scale.

    bNot applicable.

    cTUS: Time Use Survey.

    dRMET: Reading the Mind in the Eyes Test.

    eWeschler logical memory task.

    fUCLA: University of California, Los Angeles.

    gPHQ-9: Patient Health Questionnaire-9.

    hGAD-7: Generalized Anxiety Disorder-7.

    Table 3. Comparison of outcome data between participants who engaged for a minimum of 5 weeks and control participants.
    Intervention group (>5 weeks engagement) Control group Adjusted mean difference (95% CI) Effect size (d)
       Participants, n Mean (SD) Participants, n Mean (SD)
    Primary outcome measures
     Social and occupational function
      SOFAS
       0 weeks 38 79.5 (8.3) 27 77.89 (8.86)
       12 weeks 27 81.22 (10.05) 22 78.45 (10.82) –2.16 (–7.96 to 3.64) –0.25
       26 weeks 22 81.82 (10.15) 21 83.52 (7.7) 1.91 (–3.34 to 7.16) 0.22
      TUS constructive economic activity
       0 weeks 38 46.27 (19.91) 27 45.3 (29.52)
       12 weeks 28 35.6 (15.41) 22 48.32 (32.04) 11.76 (–1.12 to 24.64) 0.49
       26 weeks 26 37.36 (20.04) 21 42.85 (14.91) 5.18 (–5.56 to 15.92) 0.21
      TUS structured activity
       0 weeks 38 55.74 (19.82) 27 53.67 (28.23)
       12 weeks 28 45.7 (16.36) 22 59.63 (31.38) 13.24 (0.73 to 25.75) 0.56
       26 weeks 26 46.58 (21.41) 21 52.49 (16.09) 5.41 (–5.89 to 16.72) 0.23
    Secondary outcome measures
     Cognitive and social cognitive function
      RMET
       0 weeks 38 27.39 (4.48) 27 27.11 (3.48)
       12 weeks 28 27.21 (4.48) 22 25 (4.16) –0.87 (–2.66 to 0.93) –0.21
       26 weeks 26 28.08 (4.35) 21 27.48 (3.49) 0.13 (–1.79 to 2.04) 0.03
      Logical memory
       0 weeks 38 9.39 (3.12) 27 8.78 (3.06)
       12 weeks 16 8.75 (2.77) 16 8.81 (2.4) 0.1 (–1.29 to 1.5) 0.03
       26 weeks 26 9.58 (2.97) 21 8.86 (3.29) –0.7 (–2.18 to 0.78) –0.23
     Clinical measures
      UCLA Loneliness Scale
       0 weeks 37 48.41 (11.72) 26 48.04 (10.33)
       12 weeks 28 46.32 (12.67) 22 44.14 (12.73) –4.4 (–10.51 to 1.72) –0.40
       26 weeks 26 40.54 (13.47) 21 42.48 (12.38) –1.23 (–7.58 to 5.11) –0.11
      PHQ-9
       0 weeks 25 12.88 (5.15) 19 13.63 (5.11)
       12 weeks 19 10.32 (6.09) 19 10.05 (4.89) –2.23 (–5.94 to 1.47) –0.44
       26 weeks 19 9.05 (6.07) 18 9.83 (3.7) 0.38 (–3.29 to 4.05) 0.07
      GAD-7
       0 weeks 26 11.58 (4.47) 19 11.63 (4.93)
       12 weeks 19 9.53 (6.38) 19 9.32 (4.77) –2.13 (–5.32 to 1.06) –0.47
       26 weeks 19 8.37 (5.47) 18 8.28 (5.07) 1.1 (–2.83 to 5.03) 0.24

    aSOFAS: Social and Occupational Functioning Assessment Scale.

    bNot applicable.

    cTUS: Time Use Survey.

    dRMET: Reading the Mind in the Eyes Test.

    eWeschler logical memory task.

    fUCLA: University of California, Los Angeles.

    gPHQ-9: Patient Health Questionnaire-9.

    hGAD-7: Generalized Anxiety Disorder-7.

    Primary Outcome Measures: Social and Occupational Functioning

    No difficulties were encountered in administering the SOFAS. In terms of group comparisons, there was a small effect on SOFAS scores at 12 weeks for those allocated to MOST (d=−0.28), with an equivalent effect size (d=−0.25) observed when only those who engaged for more than 5 of the 26 weeks (ie, >20%) were included in the intervention arm. Of note, there was no evidence of an effect of MOST on the SOFAS when measured at 26 weeks for either the full intervention group or for those who were at least minimally engaged.

    Two issues emerged in the administration of the TUS. The first of these was COVID-19 related. Across the first 18 months of the recruitment period, time use was significantly altered by restrictions imposed due to the pandemic. The second was the issue of tracking activity over 6 months when students’ activity differed significantly depending on when they were in college during the semester, or during the holiday period between semesters. Consequently, the changes in TUS scores were problematic to interpret in terms of the size of the effect of the intervention.

    Secondary Outcome Measures
    Cognitive and Social Cognitive Assessment

    As widely used cognitive measures, no difficulties were observed in administering either the logical memory task or the RMET. A small effect was observed on the RMET task at 12 weeks for both the intervention group (d=−0.23) and when only those who had at least minimally engaged were assessed (d=−0.21). No effect was observed on the declarative memory scale at 12 weeks. While a small effect at 26 weeks was observed in the full group (d=−0.23), this was not consistent between the full and the >20% engaged group.

    Clinical Functioning

    As already noted, the trial protocol was amended after 6 months to also include the GAD-7 and PHQ-9, which were therefore available for 51 of the 74 participants, 32 in the intervention arm and 19 in the control arm. Across the clinical measures, small to medium effects in favor of the intervention arm were observed at 12 weeks, with effect sizes of d=−0.5 for the GAD-7, d=−0.34 for the PHQ-9, and d=−0.31 for the Loneliness Scale. Comparable effect sizes were observed in the full intervention arm and when only those with >20% engagement were used in the comparison. Again, as with other effect sizes favoring the intervention arm, these effects were not observed at 26 weeks.

    Overview of Findings

    This trial investigates the feasibility of conducting a randomized controlled trial of a moderated online intervention in a university setting. The intervention included online tailored mental health content with support from a therapist and peer-to-peer social mentoring and networking with the aim of improving mental health and social functioning. Based on recruitment at a single site, we achieved our recruitment target of 1.67 participants per month (~3.1 participants per semester month). Retention in the trial was 70% (52/74) at 12 weeks, reducing to 66% (49/74) at 26 weeks. For the intervention group, when engagement was measured in terms of participation in at least one component of the intervention (therapy journey, therapist contact, community wall participation, or peer support contact), 81% (38/47) of the intervention group engaged for 5 or more weeks of the trial (equivalent to at least 20% of the maximum 26 weeks for which the intervention was available to participants).

    While the study was not adequately powered to test for differences between intervention and control groups, calculation of effect sizes associated with mean differences between the intervention group and the control arm indicated a small benefit favoring the intervention group (d=0.28) for the SOFAS measure of social and occupational functioning (but not the TUS). Similar small effects were observed for the secondary cognitive variables of memory function and social cognitive function. Finally, slightly larger (positive) effects were observed on the clinical measures available (d=−0.5 for GAD-7, d=−0.34 for PHQ-9, and d=−0.31 for the Loneliness Scale). Across each of these primary and secondary measures, the effect sizes observed at 12 weeks were similar when either the full intervention group or only those with at least minimal engagement (5 or more weeks) were compared to the control group. However, these effect sizes reduced to less than d=0.1 at 26 weeks.

    Progression to a Full Trial

    As noted above, rates of recruitment were as originally planned, and no difficulties were encountered with randomization procedures and completion of outcome measures (except for the TUS, discussed further below). Retention rates in the trial of 70% (52/74) at 12 weeks were marginally lower than the criteria of 75%, indicating that fewer participants (n=4) were retained than expected. Our criteria of 75% was based on Alvarez-Jimenez et al’s [] original study in patients with early psychosis. As such, this may have been unrealistic for a student population given that previous studies of MOST in a similar sample reported a retention rate of 59% [].

    Outcome Measures Used

    From the point of view of measurement of outcomes, our primary outcome was social and occupational functioning. Social and occupational function is difficult to measure accurately at the best of times []. Additionally, our study coincided with the COVID-19 pandemic, which significantly impacted social and occupational function and time use for many participants during the study. Furthermore, given the student experience of moving between the routine of term time and the social and occupational upheaval associated with the winter and summer breaks, intervention-related changes in functioning were difficult to track accurately. While observer-rated measurement using the SOFAS was able to detect the same level of effects as observed on cognitive and clinical measures, time use did not appear to be a sensitive or reliable measure of change in function. On this basis, other measures of social function might be considered to index change in this domain in a future trial. Qualitative feedback from participants would also be useful to give insight into how social function could best be captured in this sample.

    Among the measures recorded in the study, the largest effect observed was on the GAD-7, a measure of generalized anxiety (d=−0.5). While this was not a primary outcome measure in the trial, measures of anxiety (and mood) are the measures most closely related to the therapy content of MOST given that much of the MOST therapy journeys focus on anxiety, social anxiety, or mood []. It might be expected, therefore, that the largest effects might be observed on these more proximal outcome measures.

    A noticeable difference in the effect sizes can be observed across time points, with some benefits associated with participating in the intervention arm at 12 weeks and not appearing at 26 weeks. In the Alvarez-Jimenez et al [] psychosis sample, no difference in social functioning was apparent between groups at follow-up, whereas a difference in the odds of enrolling in education or finding employment was observed. Given the near full college enrollment in our sample (as a study of students), we were obviously unlikely to see the same educational or occupational benefits. In the Van Doorn et al [] study, the significant difference in social and occupational function, as measured by the SOFAS, did persist at 26 weeks. However, that study represented a single-group design investigating changes within the intervention group over time, as opposed to between-group differences. In this study, it is unlikely that these differences between 12 and 26 weeks are explained by engagement attrition, as most of the attrition occurred in the initial couple of weeks, with 83% (39/47) engaged for at least 5 weeks and 74% (35/47) engaged beyond 12 weeks. Instead, the reduced effect at 26 weeks appears to have reflected the improved scores of the control group at 26 weeks, as indexed by the SOFAS, the social cognitive, and clinical measures. Finally, implementing MOST after participants have attended counseling sessions represents a step-down approach designed to maintain positive treatment gains begun in the initial treatment received [,]. The findings at 12 weeks suggest that this maintenance of gains was achieved in this study. However, the length of the intervention and the level of engagement needed to continue improvement warrant further investigation. This is discussed below.

    Strengths, Limitations, and Future Directions

    The purpose of a pilot study is to identify potential difficulties and avoid these prior to commencing a full trial. In terms of strengths, several aspects of the methodology for evaluating the use of MOST in a young adult student sample were supported in this study, including the feasibility of recruitment and retention, randomization, and a majority of the assessments used at each time point. In terms of the weaknesses of our methodology, we have already noted the difficulty with measuring social and occupational function. Specifically, the TUS might not be a suitable measure for use in a student population. We have also noted that the largest effect sizes for MOST are likely to be observed on clinical outcome measures that relate more directly to the intervention. As previously outlined, the addition of some of the clinical measures came after the trial had begun, and thus, data were missing for some participants. While the rationale for the inclusion of these variables is sound (see outcomes used in other MOST trials as well as digital interventions in this context [,,]), and the results are promising, further evidence is needed to examine the impact of MOST on these outcomes.

    We also note that the dropout rate was slightly higher in the intervention arm compared to the control arm. This is likely to reflect, in part, the time demands of participating in the various components of MOST. One unanswered question following this study is how long students should be expected to participate. As noted in , there were clear significant differences between participants in terms of their interest or willingness to remain involved across the 26 weeks that MOST was offered. While, as noted, the vast majority remained active for more than 5 weeks, the median number of months of involvement was 5 months (mean 4.32, SD 1.95). This information should inform expectations for involvement in the full trial.

    In terms of the implementation of the intervention, fidelity checklists were not used in this trial. A future evaluation of MOST in this context would benefit from adopting a fidelity procedure to ensure consistency in the delivery of the intervention. Such a checklist is being adopted by Mangelsdorf et al [] in their recently begun trial of MOST for young people with depressive symptoms.

    In line with best practice in randomized trials, this study examined the feasibility of comparing participants using MOST with care-as-usual participants. While this approach in a future full trial will be vital for investigating the effectiveness of MOST, it would also be useful to compare MOST to other existing digital mental health interventions. Given the rise in interest in digital interventions both generally and in the university context (see [,]), such a comparison would give insight both to the comparative effectiveness of MOST and would allow for further exploration of attrition rates in MOST, as well as barriers and facilitators to engagement.

    As reported above, 72% (53/74) of the sample identified as female. Literature around the prevalence of mental health difficulties and around help-seeking in young people indicates that more females present with and seek help for mental health difficulties at university than males [,]. However, this overrepresentation of females in the sample limits the generalizability of the results and should be addressed in future studies of MOST.

    Other limitations in this study include potential self-selection bias in terms of participation in the intervention and completion of assessments. As noted in the participant flowchart (), 13 young people declined to participate in MOST, and attrition in the assessments was higher than in the intervention itself, with 39 participants continuing to engage with MOST at 12 weeks, but only 30 opting to complete assessments at this time. It was also outside the scope of this study to report on findings beyond 26 weeks. Further follow-up with participants would not only inform a future trial but would also give insight in terms of the long-term efficacy of MOST. Finally, this trial was impacted by the COVID-19 pandemic. As mentioned, this had an impact on the social and occupational functioning of participants. Furthermore, some assessments took place online due to restrictions, and the pandemic may have had an impact on engagement with MOST, with participants potentially engaging differently than they might have otherwise. Further examination of engagement with MOST is thus warranted.

    Conclusions

    Based on the recruitment, retention, and engagement rates observed, this pilot feasibility study provides evidence for the feasibility of a full randomized controlled trial of MOST with a young adult population. Moreover, the effect sizes favoring the intervention arm are consistent with previous studies, suggesting that MOST may be a potentially beneficial support for youth mental health in the context of further education. This study also highlights important factors that need to be addressed in a full study, such as including measures of anxiety and depression as potentially primary outcome variables, of selecting sensitive measures of social function, and of ensuring sustained engagement in the intervention.

    The authors would like to thank Dillon O’Reilly, Niamh O’Brien, Matthew Toher, Kyra Renaud, Lorcan O’Connor, and Jack Brody for their contributions to the completion of the trial, and to Talissa Walsh, Cathal Ó’Curraoin, and Sophie Mahon for their assistance with trial assessments. Our thanks to Prof Molly Byrne for ongoing advice on trial methodologies. Our thanks to study participants, clinicians, and the Youth Advisory Panel (YAP) for their participation and input. We are grateful to the Moderated Online Social Therapy (MOST) program developers and to the funders of this study. Generative artificial intelligence was not used in this study or in the generation of this manuscript.

    This work was funded by the Irish Health Research Board as part of the Research Leader Award entitled the PSYcHE program to GD (RL-20-‐07). MA-J was supported by an Investigator Grant (APP1177235) from the National Health and Medical Research Council and a Dame Kate Campbell Fellowship from the University of Melbourne. The funder of the study (the Health Research Board, Ireland) had no role in study design, data collection, data analysis, data interpretation, or writing of the report. GD had full access to all the data in the study and had final responsibility for the decision to submit for publication.

    The full protocol, in addition to datasets and statistical code generated during the study, will be available from the corresponding author on reasonable request.

    GD and JMC originated the conception and design of the study. GD, MDOR, SMH, EF, TB, and CH led the trial, and GD, MDOR, and SMH completed the analysis and interpretation of data. All authors reviewed and approved the manuscript.

    MA-J was involved with the development of the Moderated Online Social Therapy (MOST) program but not involved with supervising any of the assessment procedures or data analysis.

    Edited by Javad Sarvestan; submitted 10.Mar.2025; peer-reviewed by Adeleke Adekola, Ali Al-Asadi, Diana Gyimah; final revised version received 13.Jun.2025; accepted 16.Jun.2025; published 21.Nov.2025.

    © Maeve Dwan-O’Reilly, Sophie Mae Harrington, Conor Gavin, Emmet Godfrey, Megan Cowman, Christina Gleeson, Anna O’Mahony-Sinnott, James McCormack, Emma Frawley, Tom Burke, Karen O’Connor, Max Birchwood, Caroline Heary, Mario Alvarez-Jimenez, Gary Donohoe. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.Nov.2025.

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research (ISSN 1438-8871), is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

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  • Why trouble for the biggest foreign buyer of U.S. debt could ripple through America’s bond market

    Why trouble for the biggest foreign buyer of U.S. debt could ripple through America’s bond market

    By Vivien Lou Chen

    Developments in Japan are creating a risk that investors in the U.S. Treasury market may one day pull the rug out by keeping more of their savings at home

    Why turmoil around Japan’s new government could wash up in U.S. financial markets.

    Recent developments overseas have the potential to complicate the White House’s agenda to bring down borrowing costs, while heightening competition for investors in the U.S. and Japanese bond markets.

    Aggressive fiscal-stimulus efforts by the cabinet of Japan’s first female prime minister, Sanae Takaichi, have created a spike in long-dated yields of Japanese government bonds and further weakness in the yen (USDJPY) in the past few weeks. It’s a situation that is being likened to the September-October 2022 crisis in the U.K., which stemmed from a crisis in confidence over a package of unfunded tax cuts proposed by then-Prime Minister Liz Truss’s government.

    Read: Liz Truss redux? Simultaneous drop for Japanese currency and bonds draws eerie parallels

    The U.S. needs to manage the cost of interest payments given a more than $38 trillion national debt, and this is a primary motivation for why the Trump administration wants to bring down long-term Treasury yields. Last week, Treasury Secretary Scott Bessent said in a speech in New York that the U.S. is making substantial progress in keeping most market-based rates down. He also said the 10-year “term premium,” or additional compensation demanded by investors to hold the long-dated maturity, is basically unchanged. Longer-duration yields matter because they provide a peg for borrowing rates used by U.S. households, businesses and the government.

    Developments in Japan are now creating the risk that U.S. yields could rise alongside Japan’s yields. This week, Japanese government-bond yields hit their highest levels in almost two decades, with the country’s 10-year rate BX:TMBMKJP-10Y spiking above 1.78% to its highest level in more than 17 years. The 40-year yield BX:TMBMKJP-40Y climbed to an all-time high just above 3.7%.

    In the U.S., 2- BX:TMUBMUSD02Y and 10-year yields BX:TMUBMUSD10Y finished Friday’s session at the lowest levels of the past three weeks, at 3.51% and almost 4.06% respectively. The 30-year U.S. yield BX:TMUBMUSD30Y fell to 4.71% or lowest level since Nov. 13.

    There’s a risk now that U.S. yields may not fall as much as they otherwise might after factoring in market-implied expectations for a series of interest-rate cuts by the Federal Reserve into 2026.

    Japan’s large U.S. footprint

    Treasury yields are not going to necessarily follow rates on Japanese government bonds higher “on a one-for-one basis,” but there might be a limit on how low they can go, said Adam Turnquist, chief technical strategist at LPL Financial. He added that the impact of Japanese developments on the U.S. bond market could take years to play out, but “we care now because of the direction Japan’s policy is going in” and the possibility that this impact might occur even sooner.

    Some of the catalysts that usually tend to push Treasury yields lower, such as any commentary from U.S. monetary policymakers that suggests the Fed might be inclined to cut rates, “might be muted because of the increased value of foreign debt,” Turnquist added.

    U.S. government debt rallied for a second day on Friday, pushing yields lower, after New York Fed President John Williams said there is room to cut interest rates in the near term.

    All three major U.S. stock indexes DJIA SPX COMP closed higher Friday, but notched sharp weekly losses, as investors attempted to calm doubts over the artificial-intelligence trade.

    The troubling spike in yields on Japanese government bonds hasn’t fully spilled over into the U.S. bond market yet, but it remains a risk. “A repeat of the Truss episode is what people are afraid of,” said Marc Chandler, chief market strategist and managing director at Bannockburn Capital Markets.

    Concerns about Japan gained added significance on Friday, when Takaichi’s cabinet approved a 21.3 trillion yen (or roughly $140 billion) economic stimulus package, which Reuters described as lavish. The amount of new spending being injected into the country’s economy from a supplementary budget, much of which is not repurposed from existing funds, is 17.7 trillion yen ($112 billion).

    Anxiety over Takaichi’s stimulus efforts has resulted in a Japanese yen that has weakened against its major peers and fallen to a 10-month low ahead of Friday’s session, and in a spike in the country’s long-dated yields. Yields on 30-year BX:TMBMKJP-30Y Japanese government debt have risen this month to 3.33%.

    Japan is the biggest foreign holder of Treasurys, with a roughly 13% share, according to the most recent data from the U.S. Treasury Department, and the concern is that the country’s investors might one day pull the rug by keeping more of their savings at home.

    Bond-auction anxiety

    Earlier in the week, a weak 20-year auction in Japan was cited as one reason why U.S. Treasury yields were a touch lower in early New York trading, which means that demand for U.S. government paper remained in place. Global investors are often incentivized to move their money based on which country offers the highest yields and best overall value.

    “The conventional wisdom is that as yields rise in Japan, the Japanese are more likely to keep their savings at home rather than export it,” Chandler said. “The Japanese have been buyers of Treasurys and U.S. stocks, and if they decide to keep their money at home, those U.S. markets could lose a bid.”

    For now, Japanese investors, which include insurers and pension funds, appear to be continuing to export their savings by buying more foreign government debt like Treasurys. Data from the U.S. Treasury Department shows that as of September, Japanese investors held just under $1.19 trillion in Treasurys, a number which has been climbing every month this year and is up from about $1.06 trillion last December.

    One reason for this is the exchange rate. The yen has depreciated against almost every major currency this year. Japanese investors have been buying U.S. Treasurys because they can diversify against the yen, which is the weakest of the G-10 currencies on an unhedged basis, according to Chandler.

    If concerns about the Takaichi government’s stimulus efforts translate into even higher yields in Japan, this could incentivize local investors to keep more of their savings at home, but might also mean rising yields for countries like the U.S.

    -Vivien Lou Chen

    This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

    (END) Dow Jones Newswires

    11-21-25 1609ET

    Copyright (c) 2025 Dow Jones & Company, Inc.

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