FDA’s Drug Review Gold Standard
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FDA’s Drug Review Gold Standard

Brownstein Client Alert, Nov. 22, 2024

Robert F. Kennedy Jr., President-elect Trump’s nominee for secretary of health and human services, has said one of his mandates from the president-elect is to return agencies to the gold standard of scientific review. This alert summarizes what the FDA’s gold standard for human drug (and biologic) review is and what “returning” to it might mean.

 

The evolution of the standard

Initially, in 1906, Congress had provided for no premarket review of drugs. By 1938, Congress required the premarket review of drug safety. Years later, in 1962, after thalidomide use in Europe caused severe birth defects, Congress required that the Food and Drug Administration (FDA) could only approve drugs if “safe and effective” as demonstrated by “substantial evidence.” This dual standard—safe and effective and substantial evidence, coupled with FDA’s practice of reviewing and analyzing submitted data itself, without relying solely on the drug sponsor’s presentation and analysis of the data—is the FDA’s gold standard of drug review.

FDA understands “safe and effective” to mean the benefit of the drug exceeds its risks. “Substantial evidence” is defined to mean “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.” A 1985 FDA regulation (21 CFR 314.126) describes the characteristics of an “adequate and well-controlled” study. For example, it describes five types of controls, such as using a placebo control arm, a no treatment control arm, and an historical control (comparison to adequately documented natural history of the disease or condition the drug is intended to treat).

 

Accelerated Approval

In 1992, in response to the need for treatments for AIDS, FDA issued a regulation (21 CFR 314.510) permitting the accelerated approval of a drug for a serious or life-threatening disease if substantial evidence demonstrated that the drug has “an effect on a surrogate endpoint that is reasonably likely ... to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity,” with a requirement that clinical benefit be verified and described post-approval. This approach “accelerates” approval because the clinical trials that measure effect on a surrogate endpoint or clinical endpoint short of survival or irreversible morbidity are shorter than the trials needed to measure clinical benefit. Congress codified this approach in 1997, revised it in 2012, and reformed the post-approval study requirement in 2023 (in the face of some drug sponsors not completing or beginning required post-approval studies in a timely manner and FDA not withdrawing such drugs). The accelerated approval approach successfully led to several therapies for HIV infection, making a deadly disease a chronic one if consistently treated. FDA has since used accelerated approval to approve drugs for many different serious diseases, most notably cancers and many rare diseases, and most of these drugs have demonstrated clinical benefit post-approval.

 

One Clinical Study 

Also in 1997, Congress amended the “substantial evidence” standard to allow FDA to consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to be substantial evidence if FDA “determines, based on relevant science, ... the data and evidence are sufficient to establish effectiveness.”

Congress has repeatedly upheld the “substantial evidence” standard; for example, in 2012 and 2017. At the same time, FDA, with congressional support, has begun efforts to understand how innovations like adaptive clinical trial designs, real-world evidence and data captured by “digital apps” may be used to evaluate drugs and support the “substantial evidence” standard. For example, as scientific understanding of the genetic and molecular basis for rare diseases has advanced and allowed for the development of more therapies for rare diseases, FDA has increasingly used “natural history” studies, including using real-world evidence such as from digital apps, of these diseases as the external “control” in single-arm clinical trials (i.e., trials in which each participant receives the study drug and no participant is randomized to a control intervention or placebo).

 

Exceptions to the standard

There are statutory and practical exceptions to the drug review standard. In 2004, Congress established emergency use authorization, which permits FDA to authorize (rather than approve) for emergency use a drug (or device) that does not meet the approval standard if it is needed to address a domestic, military or public health emergency, and “based on the totality of scientific evidence ... it is reasonable to believe that ... the product may be effective.” FDA used this authority to authorize the COVID-19 vaccines as well as COVID-19 treatments and tests.

FDA also permits the distribution and use of unapproved versions (typically imported or compounded drugs) of approved drugs when the approved drugs are in shortage. On a much smaller scale, FDA has permitted patients to use drugs under an investigational drug exemption (IND) to address serious unmet needs of small patient populations. For example, FDA has used this approach when a drug would not be safe for a larger, related patient population (because benefit does not exceed risk) but the safety risk is acceptable in a smaller population that has no alternative, effective treatments; this approach assures that patients in the larger, related population cannot access a drug that would not be safe for them.

 

Returning to the gold standard

FDA, with congressional endorsement, exercises the gold standard with flexibility to address public health challenges and make use of innovations in study design and practice. Yet there are critics of FDA’s approach who lament the use of accelerated approval, one clinical trial and confirmatory evidence, and emergency use authorizations, all of which are discretionary decisions by the FDA or the secretary of HHS. What, then, do President-elect Trump and HHS secretary nominee Kennedy mean by returning FDA’s review of drugs to the gold standard?

It could mean stepping back from the use of innovations like adaptive trial designs, real-world evidence and digital apps, which could make the development of innovative drugs more expensive, more challenging and slower. It could mean always requiring at least two randomized controlled trials or limiting the use of one study and confirmatory evidence, which would make bringing drugs such as rare disease therapies to market slower, more challenging and more expensive. It could mean abandoning, or reducing, the use of the accelerated approval mechanism that FDA introduced in response to AIDS, as Kennedy has expressed skepticism that HIV causes AIDS. It could mean abandoning emergency use authorizations, as Kennedy has longstanding, public concerns with the COVID-19 vaccines.

Presumably, it does not mean doing away with the safety and effectiveness standard altogether, though doing so would comport with a couple of Kennedy’s views: First, his deep antipathy to the current model of drug development, which relies on patents and exclusivities to fund the studies needed for FDA approval. Second, his support of products and uses that lack evidentiary support at the gold standard level, such as chelation therapy and stem cells.

Or, as FDA’s approvals and non-approvals of some drugs are controversial, it could be that Kennedy takes issue with specific FDA approval actions and will seek to review them going forward. The FDA’s statutory authorities are vested in the secretary of HHS. Those authorities are delegated to the commissioner of food and drugs (and then from the commissioner to the leaders of responsible offices across the FDA), but Kennedy could revise the delegation to reserve his ability to review and make drug approval decisions himself, with or without FDA review. This prospect raises concerns: Would drug approvals halt (it would be impossible for Kennedy to do it himself)? Would Kennedy’s review delay approvals of drugs after FDA review? Would he disapprove drugs that FDA concluded it would approve? Would he approve drugs that FDA concludes it would not approve?

Reducing or eliminating use of single clinical trials and confirmatory evidence, or use of the accelerated approval pathway, would increase the cost and time necessary to bring many drugs to market, especially rare disease therapies. Secretarial review of FDA approvals, or the possibility of such review, would increase the risk involved in seeking to develop a drug. Each of these changes would reduce or discount the potential return on investment of developing a drug and would mean that some drugs would not be pursued for development. The size of these effects is hard to estimate. Suffice it to say, some patients would be denied access to drugs that could improve, perhaps significantly, their lives.

 

Next Steps

The issues raised here are significant for both patients awaiting new treatments and for the industry developing those drugs. We expect that the Senate will raise these issues to Kennedy as he moves through the confirmation process. He is expected to appear before both the Senate Finance and Senate Health, Education, Labor and Pensions committees before his nomination will be considered by the full Senate. We will monitor the process and report further if clarity is gained on any of these questions.


THIS DOCUMENT IS INTENDED TO PROVIDE YOU WITH GENERAL INFORMATION REGARDING THE EFFECTS OF RFK JR. FOLLOWING THROUGH WITH HIS PROMISE TO RESTORE THE GOLDEN STANDARD OF MEDICAL APPROVAL. THE CONTENTS OF THIS DOCUMENT ARE NOT INTENDED TO PROVIDE SPECIFIC LEGAL ADVICE. IF YOU HAVE ANY QUESTIONS ABOUT THE CONTENTS OF THIS DOCUMENT OR IF YOU NEED LEGAL ADVICE AS TO AN ISSUE, PLEASE CONTACT THE ATTORNEYS LISTED OR YOUR REGULAR BROWNSTEIN HYATT FARBER SCHRECK, LLP ATTORNEY. THIS COMMUNICATION MAY BE CONSIDERED ADVERTISING IN SOME JURISDICTIONS.

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