On Friday, May 27, the Senate Committee on Health, Education, Labor and Pensions (HELP) released the latest version of its must-pass Food and Drug Administration (FDA) user fee reauthorization bill, one week after the House Energy & Commerce Committee unanimously voted its version out of committee. Both chambers’ bills include a range of provisions beyond those strictly necessary to reauthorize the FDA’s fee system for its approval of drugs, medical devices, generic drugs, and biosimilars; the Senate’s version, clocking in at over 400 pages of legislative text, is more ambitious at present, including a wide range of reforms to the regulation of cosmetic products, dietary supplements, and diagnostic tests. Differences remain to be worked out between the chambers.
In this post, I review key provisions in the newly released bills and consider their implications for FDA. The user fee programs were last reauthorized in 2017 and are set to expire unless Congress reauthorizes them again by the end of September 2022, the start of the new fiscal year.
Areas Of Agreement Between The Bills
Reauthorizing The User Fee Programs And Other Initiatives
Both bills reauthorize the suite of user fees branded drug, generic drug, biosimilar, and medical device companies must pay the agency for review of their products. Both bills appear to move forward with the fee levels that were negotiated between FDA and industry groups prior to their release, though there had been some delays (and associated Congressional criticism) over the medical device reauthorization.
Both bills also include an additional set of program reauthorizations, including the Best Pharmaceuticals for Children program, a series of orphan drug grants, certain third-party medical device inspections, and others. Although the form of these reauthorizations is largely the same, there are some differences between them. As one example, the House’s reauthorization of the Critical Path public-private partnership program increases its level of funding from $6 million annually to $10 million annually (see Sec. 711), while the Senate’s reauthorization of the program maintains its existing level of funding.
Accelerated Approval Reforms
Both bills include a set of reforms to FDA’s accelerated approval process, which enables the agency to approve drugs for serious conditions on the basis of evidence regarding surrogate endpoints that are “reasonably likely” to predict a clinical benefit, rather than on the basis of demonstrated clinical benefits themselves. In exchange, drug manufacturers typically must complete post-approval trials to confirm those clinical benefits, or FDA may withdraw their product from the market. Recently, the accelerated approval program has been increasingly criticized over the relatively weak incentives it provides manufacturers to actually complete those follow-on clinical trials, as well as FDA’s ability (or inability) to withdraw products from the market when manufacturers delay follow-on trials or when those trials fail to demonstrate a clinical benefit.
Several examples of these criticisms have been the subject of public scrutiny. When approving Exondys 51 for the treatment of Duchenne muscular dystrophy in September 2016, FDA requested that its confirmatory trial be completed by November 2020. But the trial did not begin on schedule, and results are not expected until 2026. Makena, first approved in 2011 for the treatment of recurrent preterm birth, was unable to demonstrate the expected clinical benefit in its confirmatory trial in 2019. But despite an October 2020 recommendation by FDA to remove the drug from the market, it remains available today, and FDA has yet to even hold a hearing (expected this fall) on the subject.
In the oncology context, perhaps in response to increasing public pressure of the program, 13 indications were removed from the market in 2021 alone, although just seven accelerated approval indications had been removed from the market in the program’s entire operation prior to that point. This is to say nothing of FDA’s June 2021 approval of Aduhelm using the accelerated approval pathway over the objections of its nearly unanimous advisory committee, in which Biogen was given nearly nine years to submit the report regarding its follow-on clinical trials to the agency.
FDA had specifically asked legislators to change the program to address some of these issues. First, the agency asked for greater authority to ensure that confirmatory trials are completed in a timely fashion, including where possible that such trials be underway at the time of approval. Second, FDA asked for clarity and greater authority regarding its procedures for withdrawing accelerated approval indications. FDA Center for Drug Evaluation and Research Director Dr. Patrizia Cavazzoni noted at a Senate HELP hearing: “Right now the expedited withdrawal path is anything but expedited. It can take up to 2 years and require lots of resources and lots of administrative burden.”
Both the House and Senate bills include elements of these ideas, though they are weaker than the versions included in the Accelerated Approval Integrity Act of 2022, sponsored by House Energy & Commerce Chairman Frank Pallone (D-NJ). Both bills require earlier design of confirmatory trials and enable FDA to require that trials be underway at the time of approval. However, both also contemplate that the post-approval studies may be “augmented or supported by real world evidence.” There are concerns that relying on evidence other than randomized controlled trials may compromise the agency’s “gold standard” for demonstrating evidence of efficacy.
Both bills also alter the existing statutory expedited withdrawal standard, though at this time it is not clear how beneficial the changes will be to FDA. Currently, the statute states only that FDA may use “expedited procedures (as prescribed by the Secretary in regulations which shall include an opportunity for an informal hearing)” to withdraw an approval under particular circumstances. Although this requires the agency to hold an informal hearing, it otherwise provides the agency with significant discretion in determining its expedited withdrawal procedures.
Both bills replace this provision with a longer list of specific procedural requirements before FDA can withdraw an accelerated approval. Because this proposed list does not include an informal hearing, as is currently required, it may ultimately prove to be less burdensome than the current statutory requirements. However, it does require FDA to hold an advisory committee meeting if the sponsor requests it, in addition to other agency meetings and opportunities for public comments, and as a result it may ultimately be similarly burdensome or even more so, as it limits FDA’s existing procedural discretion. Neither bill adopts Chairman Pallone’s “automatic withdrawal” proposal, which would have made it significantly easier for the agency to respond to recalcitrant manufacturers.
The Senate bill does include one interesting difference from the House’s version: the creation of an “intra-agency coordinating council” to “ensure the consistent and appropriate use of accelerated approval” across the agency. It is possible to imagine this council having some important policy effects – given the large number of recent withdrawals of oncology indications, it certainly appears as if the Oncology Center of Excellence is responding to criticism of the program and working to ensure trials are completed as required, and that Center’s insights might be helpful. It is likely relevant to note that the bill specifically states that the council is to include “[a]t least 3 directors of review division overseeing products approved under accelerated approval, including at least one director of a review division within the Office of Neuroscience.” The Office of Neuroscience oversaw the approvals of both Exondys 51 and Aduhelm.
Prioritizing Different Areas For Reform
Beyond the expected reauthorizations and accelerated approval reforms, the bills largely select different areas of focus for reform, with the House bill focusing on diversity in clinical trials and the Senate version on reforms to cosmetics, dietary supplements, and diagnostics. Both include non-overlapping provisions to promote competition in various markets. To be clear, there are not conflicting proposals in the two bills—the House and Senate versions do not include significantly different proposals to reform dietary supplement regulation, for example. But there are important proposals in each bill that are absent in the other. The lack of substantially conflicting proposals suggests that a conference process between the chambers might be easier than if there were substantial disagreements, though that remains to be seen.
Improving Diversity In Clinical Trials
The House bill includes a number of provisions with the goal of improving the diversity of patients enrolled in clinical trials. The bill requires sponsors to submit “diversity action plans,” including the “sponsor’s goals for enrollment” in the trial and “how the sponsor intends to meet such goals.” Other provisions require FDA to submit reports on these action plans, and to hold public workshops on the topic of enhancing trial diversity.
These provisions include elements of some but not all of the bills on this topic that had been discussed before the Energy & Commerce Committee in a March hearing. Some of those bills were specific to the neurology or Alzheimer’s context, perhaps inspired by the lack of diversity in the trials for Biogen’s Aduhelm. Despite the fact that Black and Hispanic patients are more likely to have Alzheimer’s than are white patients, white patients were vastly overrepresented in the relevant trials, with the initial trials including only 0.6 percent Black participants and 3 percent Hispanic participants, a figure that rose only slightly in the pivotal trials. In practice, these initiatives will create opportunities for improved evidence development but also challenges for FDA, including on the enforcement front.
The Senate bill includes a set of reforms to cosmetics regulation that appear to be modeled significantly after a 2018 discussion draft on the topic. The bill imposes a series of new requirements on cosmetics manufacturers, including requiring them to register both products and facilities with FDA and to label their products with particular information. FDA will establish good manufacturing practice regulations, as it has for other types of medical products. The agency is given the authority to require a recall of a cosmetic product in certain circumstances, including if use or exposure to the product “will cause serious adverse health consequences or death.”
The 1994 Dietary Supplement Health and Education Act provided FDA with some authority over dietary supplements, but it did not require companies to register each of their products with FDA or provide the agency with other information about their products. As a result, because FDA does not necessarily have a full picture of what products are on the market, it is difficult for the agency to enforce the regulatory authority that it does have, especially given the size of the industry (estimated at over $50 billion in the United States alone). The Senate bill now requires dietary supplement companies to list their products with FDA, which should improve the agency’s ability to identify and enforce its consumer protection provisions.
The Senate bill also includes the Verifying Accurate Leading-edge IVCT Development (VALID) Act, providing the agency with greater authority to regulate laboratory-developed tests, those that are “designed, manufactured and used within a single laboratory.” In 1976, the agency began exercising its enforcement discretion as it relates to these tests, but as the character of these tests and their clinical use changed over time, concerns arose that the agency’s enforcement discretion strategy could be putting patients at risk. During the Obama Administration, FDA attempted to create a risk-based regulatory structure for laboratory-developed tests, but it ultimately did not finalize that approach. Fundamentally, the VALID Act provides for regulation of these tests based on the level of risk associated with them, similar to the agency’s existing system for regulating other medical devices. If it becomes law, this will be the culmination of a years-long (even decades-long) effort by the agency to regulate these tests. The extensive brackets that were present in the previous version of the Senate’s bill are now gone, suggesting that many remaining issues have been worked out, but additional topics of discussion may remain.
Promoting Competition In Drug Markets
One area on which there is agreement on the goal but perhaps a lack of consensus as to strategy is promoting competition. Many different challenges to generic entry have been noted, and in response, Congress has developed a number of bills to address the topic. Both bills include provisions which seem to be motivated by the goal of promoting drug competition (or of discouraging potentially anti-competitive behaviors), though the provisions included in the current bills only touch on a limited number of the overall issues that have been identified. But the relevant provisions do not overlap, as with the previous aspects of the bills. The House bill includes provisions (Sections 601 and 602) designed to simplify the generic approval process in certain types of cases, and another (Section 811) intended to reverse the impact of a recent court decision that could have had an anticompetitive effect regarding orphan drug development. The Senate bill includes provisions on the biologics side (Sections 503 and 504), regarding exclusivity for interchangeable biosimilar products, and providing some increased transparency to Purple Book listings.
The user fee bills include a range of other provisions, though they are unlikely to create substantial obstacles to the reauthorization’s passage. Further, if the proposed Cures 2.0 package moves forward, there may be additional opportunities for FDA-related reforms later this year. The process of reconciliation between the chambers will be an important one to watch, though, to determine whether all of the new elements survive into the final bill.
I receive research funding from Arnold Ventures to study the interaction of the accelerated approval program and state Medicaid reimbursement.