Tag Archives: Drugs

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

Policy, Testimony & Briefings, , ,

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

NCHR Statement Regarding Cancer Drugs that Failed to Confirm Efficacy after Accelerated Approval

Policy, Testimony & Briefings, , ,

April 29, 2021

I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  Today I’m speaking from my perspective as a scientist who left Harvard more than 30 years ago to come to Washington D.C. to work in the House of Representatives. I worked as a Congressional investigator for the Subcommittee that conducted oversight over all of HHS, and that’s when I first learned about the laws and regulations governing the FDA.  I was responsible for several oversight hearings that attracted enormous media attention, because we found that patients had been harmed when the FDA was not following the law pertaining to FDA approval.

The law is very clear:  Drugs and biologics must be proven safe and effective, and that’s defined as having benefits that outweigh the risks for most patients.  FDA’s memoranda that were provided to this Committee for this meeting and for each of these indications over these last 3 days have made it clear that the data do not support that.  This Advisory Committee has looked at the data, seen reasons for optimism when looking at nonsignificant trends, and recommended that the FDA keep drugs on the market that don’t meet the standard specified by law.  That’s your right to do that, since you are advising the FDA based on your perspectives, experiences, and interpretations of the data.

I want to thank the FDA scientists who carefully analyzed the data and presented their findings.  You did a great job.  I’m here to urge the FDA to follow in your footsteps and follow the law and rescind approval for these indications until the companies complete randomized clinical trials that prove that the benefits outweigh the risks. I especially want to thank Dr. Pazdur for explaining how the FDA’s Expanded Access program can fill in the gaps for patients who need access to these drugs.  The companies agreed to complete confirmatory trials as part of the accelerated approval of their drugs, and I strongly urge the FDA to hold them to it.

All of these companies are leaders in their field and absolutely capable of conducting the research needed to prove whether or not their drugs have benefits that outweigh the risks for the exact specific indications they were previously approved for.  The companies also have the ability to make expanded access quick and easy.  Let’s face it, if they don’t have the expertise and resources to do the studies and help with expanded access, who does?  If the data don’t confirm the initial accelerated approval, the companies should work with the FDA to design trials to narrow the indication to figure out which are the patients most likely to be helped and which are the ones most likely to be harmed.

Hahn Defends Using Less ‘Robust’ Data During COVID, But Critics Contend It Has Gone Too Far

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Sarah Karlin-Smith, Informa Pharma Intelligence: June 04, 2020

[…]

Anecdotes Are Not Data Sets

The regulatory flexibility touted by Hahn was embraced to some degree by even some of the agency’s most notable critics, who agreed that the nature of the COVID-19 pandemic should allow for a different pace of decision making than under normal circumstances. However, they said they were concerned that FDA is misusing such flexibility, particularly when it came to the emergency use authorization (EUA) for hydroxychloroquine and chloroquine.

“I agree with Dr. Hahn that in emergency situations it makes sense to move quickly and change course quickly if the evidence is different from what was hoped for. But the only justification for making [hydroxychloroquine] immediately widely available was that President Trump had ‘a good feeling about it,” said Diana Zuckerman, president of the National Center for Health Research.

The EUA was granted based on laboratory data and anecdotal clinical reports. (Also see “FDA’s Emergency Use Authorization for Malaria Drugs Could Hinder Trials of Other COVID-19 Treatments” – Pink Sheet, 30 Mar, 2020.)

Zuckerman described this not as datasets but as anecdotal evidence. “Scientists don’t call anecdotal evidence datasets. As any scientist can tell you, the plural of anecdote is ‘anecdotes’ not ‘data,”” Zuckerman said.

In an emergency situation “making decisions on the fly and using the best data that you have is inevitable,” but the agency should follow certain principles when it does this, said Aaron Kesselheim, the director of the Program on Regulation, Therapeutics and Law at Harvard Medical School and Brigham and Women’s Hospital.

Kesselheim’s third principle was that the FDA should revisit or revise these decisions just as quickly as they made them when new information emerges. He said the FDA has done a good job in some circumstances of adhering to these principles and done less well in others.

As Hahn mentioned in his speech, the agency has reversed some of its early EUAs for COVID-19 tests. (Also see “FDA Yanks Potentially Faulty COVID-19 Antibody Tests – And More May Be On The Chopping Block” – Medtech Insight, 22 May, 2020.)

[…]

Read the full article here.

Medical Professors are Supposed to Share Their Outside Income With the University of California. But Many Don’t.

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Annie Waldman, ProPublica, December 6, 2019

For nearly two decades, Dr. Neal Hermanowicz has led the movement disorders program at the University of California’s Irvine campus, where he earns more than $380,000 a year in salary and bonuses. The widely respected expert on Parkinson’s and Huntington’s diseases adds to his income by consulting for drug companies.

Since 2014, 11 pharmaceutical companies have paid him a total of at least $588,000 for consulting, speaking and honoraria, according to federal data. For example, he has received more than $225,000 in speaking and consulting fees from San Diego-based Acadia Pharmaceuticals, manufacturer of a controversial drug for Parkinson’s-related psychosis. In 2017, he was the company’s highest-paid physician consultant in the U.S. That year, he prescribed the drug more than 180 times, costing patients or their insurers more than $445,000.

Under University of California rules aimed at discouraging excessive moonlighting, Hermanowicz should not only have reported his outside income to UC Irvine; he should also have turned over more than $200,000 to the school from 2016 to 2018, according to UC Irvine policies. His academic department would then have decided how much to keep and how much to return to him. That didn’t happen. From 2014 to 2018, Hermanowicz didn’t report any payments from pharmaceutical companies on his annual “outside professional activity” forms, which ProPublica obtained through a public records request.

[…]

Approved in 2016, the drug, better known by its trade name, Nuplazid, has been associated with more than 2,000 patient deaths and 10,000 other adverse events, according to FDA data — figures that one expert has called an “important warning signal.” But for Hermanowicz, those concerns were overblown.

Nuplazid “got some attention in CNN recently with maybe an increasing risk of death, which I don’t think is valid,” he told the crowd. “They didn’t really do a careful analysis. They just said people took this medication and then they died.”

When Hermanowicz first connected with Acadia, as early as 2012, it was a relatively unknown firm, with no drugs on the market. But biotech insiders had high hopes for the company, which for over a decade had been developing Nuplazid to treat severe psychosis associated with Parkinson’s.

Hermanowicz became one of the drug’s primary advocates. Besides serving as an investigator in the trials, he also published several studies on its safety and efficacy.

In August 2015, he co-wrote an Acadia-funded study in the American Journal of Managed Care on how to manage the symptoms of Parkinson’s disease, emphasizing the need for effective treatment options. The next year, a study that he co-wrote called the drug “an important advancement” and a “first choice for treatment of Parkinson’s disease psychosis,” and he said it had a “better safety profile than current treatments.” In both studies, Hermanowicz disclosed his ties to Acadia.

The FDA’s clinical review reached a different conclusion. Conducted in 2016 by Dr. Paul Andreason, it found an increased risk of harm and death. Nuplazid failed two clinical trials, and patients experienced double the rate of adverse events of those on a placebo. Based on reviews of similar drugs, Andreason determined that Nuplazid’s safety profile was “not adequately safe” for treating Parkinson’s-related psychosis.

“We needed more controlled trial data to identify what the risk was,” said Andreason, who has since left the FDA.

When Nuplazid came before the FDA’s approval committee, Hermanowicz testified at the meeting, expressing the hope that the drug “will be available to me to provide to my patients.” In the company’s press release celebrating the approval, Hermanowicz said he was “delighted.” He was the only nonemployee quoted.

After Nuplazid hit the market, reports of deaths associated with the drug surged. “It’s a very high number” of deaths, said Diana Zuckerman, president of the National Center for Health Research. While it’s difficult to determine why there are so many fatalities, she said, the drug’s benefit isn’t worth the risk. In hundreds of cases, patients’ hallucinations, which are supposed to subside with the drug, were instead aggravated.

“This is not a particularly effective drug,” she said. “So what is the risk you are going to take?”

Last year, an FDA analysis found no “new or unexpected” safety risks related to Nuplazid. Acadia has maintained that the drug is safe for patients, and that the multitude of adverse events reflects its patient population, which is mostly elderly and in an advanced stage of Parkinson’s disease. “Our top priority is patient safety and we stand by the established efficacy and safety of Nuplazid,” said Maurissa Messier, a senior director for corporate communications at Acadia, in an emailed statement. Acadia is now seeking approval for Nuplazid to treat the millions of people who suffer from dementia-related psychosis, such as Alzheimer’s disease.

Hermanowicz has continued to publish studies supporting Nuplazid, lead medical education courses sponsored by Acadia and receive large consulting payments from the drugmaker without disclosing them to the university.

Some faculty members do take pains to comply with the university’s policy on outside income. Dr. Anjay Rastogi, a professor and clinical chief of nephrology at UCLA medical school, meticulously tracks all payments he receives from industry in a centralized spreadsheet — and remits the required portion, which he said funds academic enrichment, teaching or research.

“We need to disclose everything, I disclose more rather than less,” he said. “In my opinion, it’s fair that we help the university, and they help us as well.”

Read original story here.