Inside the FDA’s Quiet Move to Weaken Drug Approval Standards

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<p>The Food and Drug Administration (FDA) is preparing to reduce the default number of <a href="https://medshadow.org/about-fda-drug-development-process-risk-of-side-effects/">clinical trials</a> it will require to approve new drugs, a shift confirmed by FDA Commissioner Marty Makary <a href="https://www.statnews.com/2025/12/04/fda-considers-single-clinical-trial-for-new-product-approvals/?utm_campaign=morning_rounds&utm_medium=email&_hsenc=p2ANqtz-9Vt7vRFBy4LkKEkMi9Ye9qwyrstqIbjsOS5IFxvtQ3FqyKgIyc2e5vxuXJRntxddGUhQqcvBp9MtmlonRpgTjsK1bU5A&_hsmi=392913829&utm_content=392913829&utm_source=hs_email">in an interview with <em>STAT News</em></a>. The decision could allow drugmakers to pursue FDA approval with just one pivotal trial, instead of multiple studies that together are typically required to demonstrate safety and efficacy.</p>
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<p>The FDA <a href="https://www.statnews.com/2025/12/04/fda-considers-single-clinical-trial-for-new-product-approvals/?utm_campaign=morning_rounds&utm_medium=email&_hsenc=p2ANqtz-9Vt7vRFBy4LkKEkMi9Ye9qwyrstqIbjsOS5IFxvtQ3FqyKgIyc2e5vxuXJRntxddGUhQqcvBp9MtmlonRpgTjsK1bU5A&_hsmi=392913829&utm_content=392913829&utm_source=hs_email">noted </a>that the policy changes could take effect within three to six months, but offered very little insight into the process behind the decision or how the FDA plans to operationalize it.</p>
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<p>“For the most part, it's not clear to me why the announcement is coming out in the way that it's coming out,” says <a href="https://medicine.yale.edu/profile/joseph-ross/">Joseph Ross, M.D.</a>, a professor of medicine and public health who researches issues concerning pharmaceutical regulations at Yale School of Medicine. “The FDA has a very clear and structured process for proposing new policy that involves establishing draft guidance, working with experts, and putting it out for public comment before finalizing that guidance. This idea of just telling everybody that the standards have changed is not the way policy is typically made.” </p>
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<h2 class="wp-block-heading">A Long Trend Toward Looser Drug Approval Standards</h2>
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<p>For decades, the <a href="https://onlinelibrary.wiley.com/doi/10.1002/pst.2262">FDA’s standard for market approval</a> has been for drugmakers to demonstrate the effectiveness of their products through substantial evidence from at least two adequate and well-controlled studies, typically phase 3 clinical trials. In its <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-clinical-evidence-effectiveness-human-drug-and-biological-products">1998 clinical trial guidelines</a>, the agency stated, “a single clinical experimental finding of efficacy, unsupported by other independent evidence, has not usually been considered adequate scientific support for a conclusion of effectiveness.” According to the guidelines, reasons for this inadequacy include systematic biases that may skew the study’s conclusions, positive results generated by chance, or outright scientific fraud.</p>
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<p>Yet there has always been room for exceptions. Under the <a href="https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-administration-modernization-act-fdama-1997">FDA Modernization Act of 1997</a> — an act largely designed to increase efficiency at the agency — the FDA noted it would allow approval of a drug based on just one trial “if [the agency] determines, based on relevant science, that<a href="https://www.law.cornell.edu/definitions/uscode.php?width=840&height=800&iframe=true&def_id=21-USC-3076010-174133500&term_occur=999&term_src="> </a>data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness.” </p>
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<p>Additionally, in 2014, the FDA put together four <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics">programs</a> designed to speed the review of new drugs developed for serious and life-threatening conditions. These programs include:</p>
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<li>Fast-track designation (which eases parts of the review process) </li>
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<li>Breakthrough therapy designation (which accelerates evaluation for treatments showing early signs of effectiveness) </li>
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<li>Priority review designation (which shortens the agency’s decision window by several months)</li>
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<li>Accelerated approval (which allows drugs to reach the market faster if they have convincing <a href="https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure">surrogate endpoints</a> — lab tests or other interim indicators that stand in for actual clinical outcomes — when evaluating new therapies)</li>
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<p>And if the goal is to reduce barriers to investigational drugs, the FDA has also built out pathways like the <a href="https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/right-try">Right To Try Act</a> and <a href="https://www.fda.gov/news-events/public-health-focus/expanded-access">Expanded Access</a> that let people obtain medications while they're still in trials.</p>
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<p>But while expedited approvals were always meant to be exceptions in the process of novel drug rollout, they have <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2764603">steadily become the norm</a>: Since 2020, and without much fanfare, the <a href="https://www.agencyiq.com/blog/analysis-the-majority-of-novel-drugs-approved-by-fda-rely-on-evidence-from-a-single-pivotal-trial/?utm_source=chatgpt.com">median number of pivotal trials for <em>all</em> new drug approvals</a> has dropped from two to one. </p>
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<p>But while expedited approvals were always meant to be exceptions in the process of novel drug rollout, they have <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2764603">steadily become the norm</a>: Since 2020, and without much fanfare, the <a href="https://www.agencyiq.com/blog/analysis-the-majority-of-novel-drugs-approved-by-fda-rely-on-evidence-from-a-single-pivotal-trial/?utm_source=chatgpt.com">median number of pivotal trials for <em>all</em> new drug approvals</a> has dropped from two to one. </p>
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<p>“The FDA has been drifting in this direction for quite a long time now,” says <a href="https://med.stanford.edu/profiles/robert-kaplan">Robert Kaplan, Ph.D.</a>, a health policy researcher at Stanford Clinical Excellence Research Center and a former associate director of the National Institutes of Health. </p>
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<p>Dr. Kaplan and his colleagues have been tracking what they call a steady decline in clinical evidence requirements. They point to a major shift in 2016, when <a href="https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act">the 21st Century Cures Act</a> encouraged the FDA to rely more heavily on <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC10398162/">validated surrogate endpoints (</a>for example, a reduction in blood pressure may be used as a proxy for a lower risk of heart attack). The Act was supported by more than 1,300 lobbyists, the majority of whom <a href="https://www.statnews.com/2016/12/05/21st-century-cures-act-winners-losers/">reportedly worked for pharmaceutical companies</a>. The intent was to make it easier and faster to demonstrate a drug’s safety and effectiveness, <a href="https://www.fda.gov/files/medical%20devices/published/The-Least-Burdensome-Provisions-of-the-FDA-Modernization-Act-of-1997--Concept-and-Principles---Final-Guidance-for-FDA-and-Industry.pdf">further lowering the evidentiary bar</a> for approval.</p>
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<p>“The Cures Act was a piece of legislation that was very much supported by industry, and with the justification that we needed to get products to people much more rapidly,” Dr. Kaplan explains. “But what happened with the 21st Century Cures Act, in my opinion, very much loosened the standards. And I think that that has been problematic.”</p>
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<p>In 2022, lawmakers introduced the <a href="https://www.congress.gov/bill/117th-congress/house-bill/6000">21st Century Cures 2.0 bill</a>, an updated package building on the 2016 legislation, which aimed to further streamline the drug-approval process. Among its provisions is a plan to <a href="https://pubmed.ncbi.nlm.nih.gov/36762462/">phase out mandatory animal testing</a> in certain cases. The measure, however, has not advanced as a standalone bill.</p>
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<h2 class="wp-block-heading">Why Assurances of ‘Confirmatory Evidence’ Leave Room for Skepticism</h2>
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<p>With the agency’s recent announcement of an official shift toward fewer trials and a lowered burden of regulations, the safety and efficacy of new drugs increasingly hinge on the strength of the confirmatory evidence supporting them. Such <a href="https://www.fda.gov/media/172166/download">evidence </a>can include real-world data drawn from electronic health records, explanations of a drug’s mechanism of action, and findings from related or similar therapies (the types of confirmatory evidence that can complement a single trial result can be found in the FDA’s 2023 <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical">draft guidance</a>).</p>
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<p>In a Dec. 3 interview with <em>STAT</em>, Makary said, “You can achieve the same statistical power with one trial as you would with two trials when it’s designed and controlled appropriately.” </p>
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<p>And while new guidelines may be put in place to ensure that requiring only a single trial does not compromise a new product’s quality, some remain skeptical. A 2025 <a href="https://journals.sagepub.com/doi/10.1177/17407745251376620">study</a> led by Dr. Ross found that fewer than 20% of new drugs approved on a single pivotal trial from 2015 to 2023 were supported by any confirmatory evidence of effectiveness. “That means 80% of the time, we had no idea how the approval based on a single pivotal trial was being made,” he says.</p>
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<p>A 2025 <a href="https://journals.sagepub.com/doi/10.1177/17407745251376620">study</a> led by Dr. Ross found that fewer than 20% of new drugs approved on a single pivotal trial from 2015 to 2023 were supported by any confirmatory evidence of effectiveness. “That means 80% of the time, we had no idea how the approval based on a single pivotal trial was being made,” he says.</p>
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<p>There is also the risk of selective reporting with a single trial, says Dr. Kaplan. “If we do 20 trials, we expect one of those to have a statistically significant result by chance.” That scenario, he says, could create a strong incentive not to report unfavorable results. </p>
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<p>This kind of selective reporting can mean patients are exposed to drugs whose real risks haven’t been fully identified. A 2022 <a href="https://link.springer.com/article/10.1186/s13023-021-02166-9">study</a> found that almost 70% of FDA-approved drugs for rare diseases — which already undergo <a href="https://doi.org/10.1093/haschl/qxaf057">significantly fewer trials</a> — later required safety-related labeling changes, signaling risks that hadn’t been recognized at the time of approval. About 15% of those updates involved severe side effects.</p>
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<p>And while expedited approval can be useful, there is little data to <a href="https://jamanetwork.com/journals/jama/fullarticle/2817337">prove its benefit</a> in patients’ lives. One <a href="https://jamanetwork.com/journals/jama/fullarticle/2817337">review</a> of cancer drugs granted accelerated approval between 2013 and 2017 found that more than 40% failed to demonstrate gains in either survival or quality of life.</p>
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<p>And as for the impact of the new single-trial strategy on overall drug safety, “it will take some time to discover that,” notes Dr. Kaplan. </p>
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<h2 class="wp-block-heading">A Split Standard: Less Evidence for Drugs, More Expectations for Vaccines</h2>
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<p>Industry leaders have weighed in on Makary’s statement with mixed feelings. Some <a href="https://www.linkedin.com/posts/dalderman_fda-biotech-makary-activity-7402339656257916928-Y5JF/?utm_source=share&utm_medium=member_ios&rcm=ACoAAAJOdSkBrNHvtk_NGsCjogquWXfKnwRJ1LI">celebrated the reduced cost and duration</a> to get products to market, while others cautioned that the shift puts a <a href="https://www.linkedin.com/pulse/big-shift-fda-one-pivotal-trial-default-most-new-drug-shekhar-khawas-kd8vc/?trackingId=x6L7yqwXRKOcjgnp4Ym%2Biw%3D%3D">heavier burden on clinical study design</a>. Del Smith, Ph.D., CEO and co-founder of Acclinate, a digital health company that uses data to identify underrepresented populations in healthcare, <a href="https://www.linkedin.com/feed/update/urn:li:activity:7402753012189929472/">wrote</a> on LinkedIn, “In a two-trial world, you had a margin for error. In a “one-shot” world, you don’t.”</p>
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<p>The FDA’s move to ease evidence requirements for new drugs stands in stark contrast to the agency’s <a href="https://www.biocentury.com/article/657740">recent stance on vaccines</a>. In a <a href="https://www.nejm.org/doi/full/10.1056/NEJMp2517497">letter</a> published <em>in the New England Journal of Medicine</em>, twelve former FDA commissioners criticized the agency’s plan to subject vaccines to a higher and more subjective approval bar, such as demanding randomized controlled trials that are costly and time-consuming. Their concern with the new oversight is that it will impede the agency’s ability to keep up with the evolution of viruses and bacteria, and ultimately “disadvantage the people the FDA exists to protect, including millions of Americans at high risk from serious infections.”</p>
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<p>Ultimately, loosening the criteria for drug approval means patients and clinicians will have fewer data to inform clinical decisions, notes Dr. Ross, who worries, "we're going to be less certain about whether a drug is effective and safe when they are approved for use."</p>
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<p>MedShadow has reached out to the FDA for comments and will continue to monitor any updates from the agency. </p>
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