Tag Archives: PDUFA

Public Comment PDUFA VII Commitment Letter (Docket #FDA-2021-N-0891) From the National Center for Health Research

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 dz@center4research.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

Testimony of Diana Zuckerman, PhD, President of the National Center for Health Research at the FDA PDUFA Meeting, September 28, 2021

I’m Dr. Diana Zuckerman, president of the National Center for Health Research, a patient-centered and consumer-oriented public health think tank.  Our Center is very involved in FDA issues pertaining to the safety and efficacy of medical products, and I appreciate the opportunity to share my views today. 

PDUFA performance measures have focused on speed, but in addition PDUFA performance measures should evaluate whether patients are protected from ineffective or unsafe products being approved!  As Commissioner, Peggy Hamburg said innovation needs to mean products are better, not just new.  The performance goals we’ve heard about today fall short, because they emphasize speed and ease of approval, not on the quality of the outcome of FDA reviews or of the outcome for the patients using these products.  

PDUFA have resulted in more and faster approvals, but not all those approvals have helped patients, and some have seriously harmed them.

Premarket performance should also include evaluations of the percentage of applications that were rejected or withdrawn because there was a lack of evidence proving safety or efficacy.  And the specific reasons why they were rejected or withdrawn.

When post-market surveillance works, it should sometimes result in FDA warnings, recalls, or withdrawals.  FDA should provide the percentage of these for 5 years post approval and the reasons for those actions.

Performance should also include the percentage of products approved based on at least two well-designed studies providing solid scientific evidence.  As someone trained in epidemiology, I love big data, but since most applications are for new products not yet on the market, clinical trials will still be the best data available.  We want to know how many approvals were based on at least two phase 3 randomized, controlled trials demonstrating robust evidence of safety and efficacy and favorable benefit-risk profiles.

Performance should also be based on the percentage of approved products for which FDA mandated post-marketing studies and the percentage where those obligations were fulfilled – started and ended on time, conducted as required, and whether they did or did not confirm safety and efficacy.  As you know, FDA recently had a meeting on widely used cancer drugs that were approved for certain indications through accelerated approval but failed to provide data confirming that they worked for those types of cancer.  And yet the indications remained approved for years after it was obvious they did not work.  Those delays are harmful to patients and should be considered a performance goal worthy of user fee support.  

A newly published study indicates that too often a rejected application is subsequently resubmitted and approved when FDA ignores their own criticisms of the original application, even when those criticisms remain valid.  The controversial approval of Aduhelm is just the most salient example of that.

 Specific Changes to Commitment Letter

I have a general concern about the Commitment letter, because it changes policies that should be publicly debated by Congress and should include input from patient, consumer and public health advocates as part of any negotiations. Policies should not be negotiated behind closed doors at meetings that exclude those important perspectives.  

I have time to recommend 5 specific changes to the Commitment letter:

  1.   I was glad to hear about FDA’s new efforts to include patient preferences and involvement. The Commitment letter should specify that these activities should always include harmed patients, not just patients recruited by industry, who are often patients desperate for treatment.  All patient perspectives are important, we all are concerned about patients who urgently need a treatment that works, but harmed patients have too often been excluded from FDA meetings and committees.
  2.   Voluntary REMS strategies are rarely proven to work. The REMS program needs a complete overhaul or REMS should be avoided. Instead, most safety concerns should be resolved before products are approved. A good example is the REMS for prescription opioids, which FDA learned was not working. Few doctors took the voluntary training, fewer finished the voluntary training, and even those who were trained did not learn all the important issues that were included.
  3.   The letter should implement the National Academies’ public health framework for regulatory oversight of opioids.
  4.   In-person manufacturing inspections remain the most effective way to determine problems. We all understand that remote inspections were needed during the pandemic, but the Commitment letter should specify that remote inspections should be the exception.
  5.   User fees should fund independent, objective studies to assess and quantify the harms that resulted or were avoided due to approval decisions.

And I will just add one other issue, since enhancements to the Sentinel program were discussed earlier in this meeting.  I have been a strong supporter of the Sentinel post-market surveillance program, but it has been in place for years and cost an enormous amount of money.  So, it was distressing to hear this morning that the FDA is still trying to figure out how to use those data so that they can provide usable information about safety and efficacy.

In conclusion, those of us who respect and admire the FDA know how important it is as a public health agency. We must make sure that industry user fees do not interfere with that essential mission. When performance goals and the Commitment letter are made behind closed doors, it is difficult for the public to have confidence that the FDA is a public health agency.