October 28, 2021
The National Center for Health Research (NCHR) appreciates the opportunity to provide public comments on the PDUFA VII Commitment letter, and to express our substantial concerns with the overall process, some of the content of the letter, and performance goals that should have been made in the letter, but were not.
The Prescription Drug User Fee Authorization (PDUFA) negotiation between the Food and Drug Administration (FDA) and pharmaceutical industry is unlike regulatory processes at other federal agencies. The typical process is more transparent, and includes meaningful stakeholder engagement and feedback from the public. The fact that the very industries being regulated by the FDA meet behind closed doors with FDA staff to negotiate a Commitment Letter, with no members of the public allowed to even be in the room, raises important questions about why industry has more say in FDA policies and practices than other Stakeholders.
The Commitment letter submitted for public comment is even more problematic than usual because it includes numerous policy/regulatory changes that would normally be determined by Congress, not by a negotiation between regulated industry and a federal agency. Policy/regulatory changes should be deleted from the Commitment Letter.
The remainder of this comment will focus on performance goals.
As a public health think tank, NCHR has supported user fees as a way to improve resources for the FDA. However, we have repeatedly expressed concerns that the performance goals being negotiated by the FDA and industry are focused largely on the speed of the review and approval process, as well as industry’s access to FDA staff, with no explicit metrics to measure the safety and effectiveness of the drugs that are being reviewed and approved. We support performance goals that enable companies to communicate with the FDA early in the drug approval process. However, the emphasis on speed has resulted in too little attention to whether the drugs have clinically meaningful benefits for different populations of patients that outweigh the risks to those patients.
One of our concerns pertaining to the performance goals is the lack of FDA oversight regarding whether commitments to diversity that companies made to the FDA are met in the studies used as the basis of approval or post-market studies. When there are too few older patients and racial minorities to conduct subgroup analyses, as is often the case, it has been impossible to draw conclusions about the safety and efficacy of these drugs across the different patient populations.
Another major issue missing from performance goals is that the emphasis on various expedited review pathways has resulted in FDA making approval decisions based on only one pivotal study, and often based on a surrogate endpoint or biomarker rather than a clinical outcome that is meaningful to patients, such as overall survival. When post-market confirmatory trials are required, they are not monitored closely by the FDA; as a result, years pass before the studies are either abandoned or completed, often with much smaller, less diverse study populations and higher loss to follow-up than was “required.” For example, in 2021, we learned that several cancer drugs had been found to be ineffective in confirmatory trials, many years after they had been approved for several specific indications under an accelerated pathway. A study recently published in JAMA Internal Medicine reported that these ineffective indications cost Medicare more than half a billion dollars.1 Another example of potential harms from a questionable review is the recent FDA approval of Aduhelm for Alzheimer’s patients.2 This drug was originally approved for all Alzheimer’s patients based on a questionable biomarker studied only in patients with mild Alzheimer’s and the FDA allowed the company 9 years to complete a confirmatory study. Fortunately, the agency responded to public outrage by changing the approval to only mild Alzheimer’s, since those were the only patients that had been studied. Unfortunately, the company still has 9 years to confirm that the drug is effective, and, in the meantime, other pharmaceutical companies are racing to submit applications based on the same flawed biomarkers. These are just two examples of why enforcement of timely and comprehensive post-market surveillance requirements should be required as essential performance goals. The current version of the Commitment Letter does not do so.
User fees have been used previously to generously support the Sentinel program’s post-market surveillance system; however, the impact of that system is not explained to the general public. FDA should notify Congress and the public about how many drugs have been removed from the market due to Sentinel data, the number and type of label revisions that resulted, and how adverse events found through Sentinel did or did not differ for drugs approved under various review pathways. The number of years that specific products were on the market before Sentinel reported the need for label revisions or removal from the market should also be calculated and widely reported as part of the performance goals.
User fees should also be used to improve communication with patients and caretakers, including older adults, people with disabilities, people who are not fluent in English, and those with limited literacy skills. Information provided by the FDA should include different formats and videos and virtual meetings should have the option for closed-captioning and American Sign Language translation.
In conclusion, we believe that the Commitment Letter should delete policy/regulatory proposals and do more to ensure the safety of patients and consumers and the scientific integrity of the drug review process using the types of metrics we have suggested as part of the performance goals. We appreciate the efforts of the agency to work toward those ends, but when patients, consumers and other stakeholders are excluded from the PDUFA negotiations, their priorities are excluded. We urge the Biden Administration to improve the PDUFA VII Commitment Letter in the ways described in this comment.
For more information, please contact Dr. Diana Zuckerman at firstname.lastname@example.org.
1 Shahzad M, Naci H, Wagner AK. Estimated Medicare Spending on Cancer Drug Indications with a Confirmed Lack of Clinical Benefit after US Food and Drug Administration Accelerated Approval. JAMA Intern Med. Published online October 18, 2021. doi:10.1001/jamainternmed.2021.5989
2 FDA Grants Accelerated Approval for Alzheimer’s Drug, June 07, 202. 1https://www.fda.gov/news-events/press announcements/fda-grants-accelerated-approval-alzheimers-drug