Food and Drug Administration Dockets Management Staff (HFA-305)
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
August 13, 2025
National Center for Health Research Comments on the Reauthorization of
The Prescription Drug User Fee Act [Docket No. FDA-2025-N-0816]
The National Center for Health Research appreciates the opportunity to share our views on needed improvements to the PDUFA negotiation process and policies for PDUFA VIII. We are a nonprofit think tank that scrutinizes the safety and effectiveness of medical products and the policies that affect the U.S. healthcare system. We do not accept funding from companies that make those products or entities with a financial interest in our work.
We wish that Congress provided sufficient appropriations for FDA’s essential work, and our president is a founding board member of the Alliance for a Stronger FDA, which includes industry and nonprofit leaders who work tirelessly to improve those appropriations. However, we know that the agency needs user fees to get safe and effective medical products to market in a timely manner. User fees are vital to ensure that reviewers have subject matter expertise, institutional knowledge, adequate time, and uninterrupted access to the FDA library with peer-reviewed research, among other scientific resources. The agency also needs the staff and resources to revise indications and labeling as needed and to remove products from the market that are not proven to be safe or effective.
Unfortunately, user fees have mainly supported faster reviews and more frequent meetings between the FDA and sponsors to address concerns about their applications. That is not what’s most important for most patients. Most patients’ greatest concern is to have access to safe and effective medical products to treat, maintain, and promote their health. Our own research shows, for example, that many years after FDA approved cancer drugs on the basis of surrogate endpoints, only one of the 18 drugs was proven to save lives or improve patients’ quality of life.[1] It is important to note that our research confirmed and provided several years of follow-up data to a study of now-CBER director Dr. Vinay Prasad.
As a way of showing the FDA’s renewed commitment to transparency, we strongly urge that patients and healthcare professionals will be represented at PDUFA user fee negotiations. At a minimum, they deserve to watch the negotiations virtually if they are not permitted to actively participate. In the past, minutes of the negotiation meetings have been too vague to be informative, which has prevented key stakeholders from providing effective input.
Previous PDUFA Commitment letters have focused on performance goals for meetings and timelines for premarket reviews. These goals benefit industry, and may indirectly benefit patients, but are not patient-centered, and not focused on the public health mission of the FDA or the quality of drugs or biologics, because they do not focus on safety or efficacy.
We strongly urge the agency to include performance goals with metrics on quality post-market surveillance including confirmatory studies with clinically meaningful outcomes. This is especially important when drugs are approved based on data from short-term studies with a small sample size or based on surrogate endpoints instead of measures of how a patient feels, functions, or how long they live.
For example, user fees should be used to support for FDA staff and resources needed for essential work other than reviews of new drugs and biologics, especially for work that benefits companies as well as patients. These include:
- Confirmatory trials required for products granted accelerated approval
- Post-market studies required for products approved based on surrogate endpoints or short-term preliminary data, or to follow-up on worrisome adverse event reports or unexpected findings from independently funded studies or testing
- Inspections of manufacturing facilities and related work caused by problematic findings or failed inspections, since those are also required to ensure that companies can sell their products and that the products being manufactured are safe and effective.
To ensure that PDUFA makes CDER and CBER function more effectively, patient advocates, public health researchers, and professionals without industry ties need representation during negotiations to ensure there are performance goals that directly benefit patients and consumers as well as the overall functioning of these important Centers.
To regain the public trust in the FDA, PDUFA needs to show that user fees will focus more on ensuring that drugs are safe and effective in ways that matter to patients. Speed should be secondary, because when drugs are ineffective or unsafe, patients lose confidence in their doctors and the FDA. That is not good for our country and will not help achieve our mutual goal of healthier adults and children.
PDUFA Commitment Letter
We’ve reviewed the 71-page PDUFA VII Commitment letter and were very disappointed at how infrequently any mention was made of the importance of FDA’s role ensuring that the drugs the agency is newly approving or previously approved are safe or effective. There was more mention of “regulatory flexibility” aimed at making the regulatory process less stringent for the companies it regulates, than there was to ensuring that the benefits of newly approved drugs or previously approved drugs outweigh the risks for the American public.
Section K: Enhancing Regulatory Science and Expediting Drug Development
As an example of how safety and efficacy were rarely mentioned, we will briefly examine Section K of the PDUFA VII Commitment Letter. This section describes what FDA should do “to advance the use of biomarkers and pharmacogenomics, enhancing communications between FDA and sponsors during drug development, and advancing the development of drugs for rare diseases” to ensure that “new and innovative products are developed and available to patients in a timely manner.“
This section of the Commitment Letter describes numerous steps required of the FDA to facilitate approvals, with no mention of ensuring solid scientific evidence of safety or efficacy. In PDUFA VIII, any such programs should include clear instructions that evidence from two well-designed studies is still the cornerstone of FDA approval, as well as the importance of clinically meaningful outcomes and statistical significance.
The Commitment Letter for PDUFA VIII should specify ways to increase safety and efficacy information that is publicly available and easy-to-understand, to reduce the burden on patients and providers that need to make potentially life-saving or life-threatening decisions regarding medical treatments.
For example, in #2 of Section K of the PDUFA VII Commitment Letter, entitled “Ensuring Sustained Success of Breakthrough Therapy Program,” the following addition in blue to the existing wording (in black) would have made it clear in PDUFA VII (and for information about the Breakthrough Program in a PDUFA VIII Commitment Letter) that, in addition to speedy review, the benefits of each approved Breakthrough drug should outweigh the risks:
Both FDA and the regulated industry are committed to ensuring the expedited development and review of innovative therapies for serious or life-threatening diseases or conditions by investing additional resources into the breakthrough therapy program to ensure that the therapies are proven to have benefits that outweigh the risks.
Another example is #3 in that same section in the PDUFA VII Commitment Letter, entitled “Early Consultation on the Use of New Surrogate Endpoints.” The description should have made it clear that the FDA must agree to the use of a surrogate endpoint in order to use it as a primary endpoint. This could have been clear (for PDUFA VII and in future descriptions of surrogate endpoints in PDUFA VIII) with the edits to the current wording (in black) which is in blue below:
Requests to engage with FDA on this topic will be considered a Type C meeting request. The purpose of this meeting is to discuss the feasibility of the surrogate as a primary endpoint and identify any gaps in knowledge and how they might be addressed. The outcome of this meeting may require further investigation by the sponsor and discussion and will require agreement with the agency before the surrogate endpoint could be used as the primary basis for product approval.
Our next example is #4, entitled “Advancing Development of Drugs for Rare Diseases.“ This current wording (in black) for PDUFA VII requires additional wording (in blue) to make it clear that evidence is important for treatment for rare diseases. This wording would have improved this section in the PDUFA VII Commitment Letter and in future information about regulating treatments for rare diseases in a PDUFA VIII Commitment Letter.
“FDA will continue to include information on rare disease approvals in its annual reports on innovative drug approvals, including utilization of expedited programs and regulatory flexibility and including metrics that indicate that approvals are based on convincing evidence that the drug or biologic has clinically meaningful benefits that outweigh the risks, and appropriate comparative metrics to non-rare disease approvals.
To support the advancement of rare disease treatments, FDA will establish a pilot program for supporting efficacy endpoint development for drugs that treat rare diseases by offering additional engagement opportunities with the Agency to sponsors of development programs that meet specific criteria. This pilot program will be strengthened to provide greater assurance that the endpoints indicate clinically meaningful benefits.
Section L. Enhancing Regulatory Decision Tools to Support Drug Development and Review
The first item in this section is entitled “Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision-Making.” We appreciate the FDA’s ongoing efforts to be more patient-centered, but we agree with the numerous patient groups who report that the FDA rarely shows interest in patients who ask the agency to help reduce harm to patients caused by taking drugs for approved or off-label indications. Many patients involved in these FDA efforts were recruited by industry and trained to support industry priorities, particularly getting drugs to market as quickly as possible. Too often these patients focus on anecdotal evidence based on their own experience, without understanding scientific standards or the benefits of controlled clinical trials or clinical endpoints rather than surrogate endpoints. Their views are important but need to be balanced by including patients with different priorities and the perspectives that comes from being harmed by FDA-approved prescribed drugs.
Section M. Enhancement and Modernization of the FDA Drug Safety System
This section is especially important to patients’ health and safety. Unfortunately, “modernization” in PDUFA VII included the goal of reducing or eliminating REMS and on maintaining Sentinel, rather than improving either of these programs.
We agree that PDUFA VIII fees should support REMS and Sentinel again, but specific improvements are needed to make REMS more effective, rather than to eliminate ones that were designed to safeguard patients.
REMS
For example, FDA required a REMS program to train physicians who prescribe opioids, with the goal of reducing the opioid epidemic by reducing inappropriate prescribing. That REMS underwent several changes after it was initiated in 2012. As early as 2017, there was clear evidence that most physicians did not undergo the brief online REMS training that was required to be offered, and that many of those who started the training did not complete it or answer all key questions correctly.[2] Despite those shortcomings, in 2020, the FDA announced that “the central component” of the REMS was still a voluntary continuing education (CE) program “for all health care providers, including nurses and pharmacists, who are involved in the management of patients with pain (in addition to doctors and others who prescribe these products).” The companies were required to offer the training through accredited CE providers, but the REMS does not require health professionals to take the training. Although Congress passed a law in 2023 that requires that physicians registered with the DEA take an 8 hour training on opioids, the physicians do need to get a passing grade on a test based on the training.[3] PDUFA VIII should be used to strengthen the REMS to either require health professionals to pass a test to show knowledge of key information needed to safely prescribe opioids, or FDA should work with medical societies or other entities who have the authority to do so. We also point out the conflict of interest of the FDA having the companies that sell opioids to be responsible for the training and for evaluating the effectiveness of the training.
Sentinel System
The Sentinel System was launched in 2008, with the goal of being an early warning system that could identify risks years earlier than would otherwise occur, by analyzing information from health records of millions of patients. Sentinel has resulted in several changes in risk information included in drug labeling, but the impact seems relatively modest considering the cost and scope of the program.
PDUFA VIII should include performance goals that quantify and specify how Sentinel should be used to provide additional information about risks on labels and to what extent it has resulted in changes to indications as more information becomes available about the risks of specific drugs and biologics. The enormous Sentinel “real world” datasets can be used to evaluate various adverse events on popular and less widely used drugs and to compare the safety of drugs used by similar patients for the same indication. Sentinel can provide evidence of benefits when different treatments for the same indication are compared, but since it is based on real world evidence, the benefits of drugs cannot be compared to a placebo. Sentinel has the data to make such comparisons possible, but it is not known how often that has been used. PDUFA VIII should require metrics on how user fees help Sentinel meet these types of important performance goals.
Other PDUFA Issues
We have provided just a few examples of the specific ways that the PDUFA VIII Commitment letter should specify the types of performance goals and program expectations that will help patients, consumers, and health professionals make better informed decisions about FDA-approved drugs and biologics. PDUFA VII was too focused on making it easier to get drugs and biologics to market quickly and not focused enough on making sure “innovative” treatments were more beneficial to patients than previously approved treatments, or compared to no treatments at all.
We also want to express our concerns about the “non-user fee” spending trigger. The PDUFA statute outlines that if spending of appropriated funds for FDA reviewer salaries and expenses falls below inflation-adjusted 1997 levels, the agency must refund user fees. The intent of this clause was to ensure that user fees are used to supplement congressional funding but not replace it. However, given the dramatic downsizing of FDA staff this year, there is a risk that these “trigger” levels of non-user fee spending will not be met and could result in the agency refunding user fees regardless of how well the performance goals stipulated by industry. This would have a catastrophic impact on the agency’s ability to review prescription drugs effectively and ensure that they are safe and effective.
We are also concerned that whenever the Congress is unable to agree on appropriations levels and the government shuts down as a result, staff paid by user fees are the only ones who are allowed to work. That is just one of many reasons that user fees should support safeguards as well as reviews of new drugs and biologics.
We also ask that the FDA to be transparent about the cost of artificial intelligence (AI) in the review of drug applications. FDA expects that AI can reduce review time, but since AI sometimes makes up information or citations, human reviewers will still need to review any information that AI provides. It is not clear whether AI is funded by non-user fee appropriated funds as a reviewer salary or an expense. Historically, AI models at the agency have been designed and managed by third-party consultants. It is likely that review queries would come at a cost to the agency, and we ask that FDA be transparent about that. This funding distinction is important because an increased use of AI in the review process, in tandem to fewer FDA staff, could lead to a spending gap that influences user fees.
In conclusion, there are many ways that PDUFA VIII can provide great benefits to patients and our healthcare system, in addition to benefits to industry. The U.S. taxpayers deserve to have their needs met with the help of user fees, since they are the ones who purchase the drugs and biologics that are approved by the FDA.
We would be glad to discuss our concerns or answer any questions and can be reached at info@center4research.org.
References
[1] Rupp, T., & Zuckerman, D. (2017). Quality of Life, Overall Survival, and Costs of Cancer Drugs Approved Based on Surrogate Endpoints. JAMA internal medicine, 177(2), 276–277. https://doi.org/10.1001/jamainternmed.2016.7761
[2] Cepeda, M.S., Coplan P.M., Kopper N.W. et al .ER/LA Opioid Analgesics REMD: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes, Pain Medicine, 18:1, 78–85. https://doi.org/10.1093/pm/pnw129
[3] U.S. FDA, Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) https://www.fda.gov/drugs/information-drug-class/opioid-analgesic-risk-evaluation-and-mitigation-strategy-rems