Definition of a Guinea Pig: Ask the FDA!

Barely Half of Postmarket Studies Completed After 5 Years

FDA fails to enforce requirements

• by Larry Husten, CardioBrief September 20, 2017 
• 
  

Pharmaceutical and device companies are often taking advantage of a lenient (or, some would say, negligent) FDA to shirk their obligation to perform timely post-approval studies, a new Perspective published in the New England Journal of Medicine shows.

The topic has gained increasing  visibility and importance as the FDA has granted approval to many new drugs and devices without all the evidence that might ideally be required.For safety as well as efficacy, the FDA has allowed much of the burden of proof to shift from pre-approval to the post-approval period.

But in an analysis of 614 post-approval requirements and commitments imposed by the FDA in 2009 and 2010 (the first full years after the FDA gained the power to require these studies), Steven Woloshin at Dartmouth Institute for Health Policy and Clinical Practice and colleagues showed that only 54% of these studies were completed after 5-6 years. They found that 20% of "required" studies had not been started and 25% were delayed or ongoing as of September 2015.

"It's not a secret that we need a better post-market system," said former FDA Commissioner Robert Califf, now at Duke University. "The good news is that technology is no longer the limiting factor -- it's all about culture, organization and priority setting by policy makers, clinicians and patients and their 'carers' (families and loved ones)."

The authors observed that in many cases there didn't appear to be any good reason for the delays. For instance, more than 5 years after approval of buprenorphine/naloxone film (Suboxone), no protocol had been submitted for assessing the risk of QT-interval prolongation, "even though the design of such studies is highly standardized and participants are observed for a limited period."

"The slow, irregular pace of post-approval studies contrasts starkly with the short, rigid deadlines and other shortcuts used to speed marketing approval," the authors wrote.

The FDA should "do more to ensure that sponsors meet post-approval deadlines," the authors urged. Although the FDA has the power to impose fines or other penalties on companies that fail to live up to their obligations, "to our knowledge, it has never imposed such fines." They also recommend that the FDA set shorter deadlines for post-approval studies.

"Woloshin and colleagues offer some useful insights into the FDA's use of post-approval studies to confirm and further evaluate drugs' safety and efficacy at the time of approval," said Joe Ross of Yale University. "While more than half were completed, many were not. This study is only made possible by the efforts at FDA to provide public transparency of the post-approval requirements, but more information could help the public and the profession understand why certain requirements were not fulfilled, whether these studies were intended to provide key clinical information to inform practice (as opposed to safety info that instead came from another clinical study), and even for those studies that were completed, whether the results were published and made available."

Sanjay Kaul of Cedars-Sinai Medical Center said that it is not unreasonable to shift "the regulatory burden from the pre-approval phase to a life cycle-based approach. However, the success of such an approach is predicated on a rigorous and timely post-approval phase. That 1 in 5 post approval studies had not even been started after 5 to 6 years calls into question the degree to which the changes in the FDA's regulatory authority in 2007 have resolved the challenge of reducing the number of unfulfilled post-approval requirements. This can hardly be reassuring given the 21st Century Cures Act which calls for faster marketing of drugs and devices at the cost of stringent evidentiary standards! Even though the FDA has congress-legislated authority to revoke approval of drugs and devices that failed to confirm clinical benefit on post approval studies, it rarely does so! It is difficult to put the genie back into the bottle."

The "bottom line," said Kaul, is that "marketing drugs and devices faster can only be justified if there are much better post-market data to reliably support efficacy and safety."

• https://www.medpagetoday.com/cardiology/cardiobrief/68035

FDA Could Be Sustainable AND PREVENT Harm

The FDA Could Earn Over $60 Million A Day From Enforcing The Law

Stuart Buck

October 14, 2015

Many clinical trials on medicines and devices are subject to a 2007 federal law that requires the results to be publicly disclosed on a federally sponsored website within a year after the clinical trial is over. The reason for this requirement is simple: to give doctors and patients full information so that they can make educated decisions about a given treatment. If disappointing clinical trial results remain hidden, while only the most positive results are published and presented in the media, doctors and patients can be wildly misled.

Unfortunately, investigators have found that over half the time, clinical trial sponsors fail to abide by the law, sometimes failing to disclose results even after five years have elapsed. Even more unfortunately, the Food and Drug Administration (FDA) has never once imposed the legally authorized $10,000-per-day fine for failure to disclose a clinical trial’s results.

Compliance With Reporting Requirements

The most recent investigation was published in the New England Journal of Medicine (NEJM) in March 2015. The authors identified 13,327 clinical trials that were registered on ClinicalTrials.gov, that were completed between 2008 and 2012, and that were subject to the 2007 federal law requiring full disclosure. A mere 13.4 percent of the clinical trials actually disclosed their results within the 12 months required by law, and even after up to four years had elapsed, only 50.5 percent had disclosed the results or asked for a delay (see Figure 2 in the NEJM article).

In a twist that ought to embarrass academics, industry-funded trials were more likely to disclose results than the National Institutes of Health (NIH)-funded trials, which were in turn more likely to disclose results than academic medical centers. The authors found 6,599 clinical trials that were overdue on reporting results.

Increasing Fda Enforcement

If the FDA imposed a $10,000 per day fine on each of these 6,599 outstanding trials, clinical trial sponsors would be responsible for $66 million in payments in the first day alone, adding up to over $24 billion per year.

Although the $24 billion figure shows the size and scope of the problem, the collective fines would never reach that amount because as soon as the FDA actually begins enforcing the law, the researchers who conducted these 6,599 trials would finally be incentivized to report the trials’ results.

Why doesn’t the FDA enforce the law? Some have argued that ClinicalTrials.gov is an antiquated and difficult-to-use website. True enough, but given that 38 percent of trials do disclose their results at some point, it is clearly not impossible to do so. This is not a reason to leave the federal law completely unenforced.

The NEJM article states that one reason for lack of enforcement is that a new rule on clinical trial report is still pending. But the 2007 law itself requires basic reporting of results; the only point of a new rule is to expand the requirements to include other items, such as protocols. The mere fact that a rule may be expanded in the future is no reason to leave the current requirements unenforced. Yet another possibility is that the FDA does not want to get bogged down in lawsuits from companies or universities that have a valid reason for delay. But this argument would suggest, at most, that the FDA ought to levy a fine only when truly merited, not that the FDA should never enforce the fine at all.

My proposal: as an experiment, the FDA should give the 30-day notice required by statute, and then set aside a single week in which it will levy the $10,000-per-day fine on all overdue trials. Assuming that there are around 6,600 overdue trials that don’t come into compliance within the 30-day grace period, the FDA would end up imposing over $460 million in fines within a week’s time. In so doing, it would make a strong statement that disobeying the law and hiding clinical trial results is no longer acceptable.

And within a week, compliance with the law would likely shoot up astronomically, and we would have more complete knowledge about how well or how poorly drugs actually work. In turn, we could all make better decisions about how to improve our nation’s health.

http://healthaffairs.org/blog/2015/10/14/the-fda-could-earn-over-60-million-a-day-from-enforcing-the-law/

Questionable Benefit of Implanted Heart Device: Patient Outcomes Tracked by Registry!

 Clots Tied to Heart Pump Open Debate on RisksPatients Face in Trials

By BARRY MEIER

Published: December 9, 2013 The New York Times

                         

A new report showing an increase in blood clots associated with a popular heart device is dividing experts over whether a clinical trial of the implant is potentially too risky for patients.

The debate, which involves a heart pump called the HeartMate II, sheds light on how researchers calculate whether to expose patients to a trial’s risks.

Medical researchers say such decisions are based on objective evidence. But a look at their decisions about HeartMate II trial shows how subjective those choices can be.

The trial, which has already faced delays, is set to start soon, if it receives a final go-ahead. But at least two hospitals that originally agreed to recruit patients for the trial have now withdrawn because of the new findings, while others have decided to stay in.

Some experts contend other factors might also be in play in those decisions, including an investment of years by some researchers to set up the study. In addition, more than $13 million has been earmarked for the trial by the HeartMate II’s maker, Thoratec, and the federal National Heart Lung and Blood Institute.

“You could argue it both ways,” said Dr. Carmelo A. Milano, a cardiologist at Duke University, which has decided not to participate, as has the Cleveland Clinic. “It certainly would be better if we didn’t have this problem.

The HeartMate II is a small pump that continuously pushes blood through the heart. Patients who get the device now are those facing imminent death from heart failure. Even the researchers who put together the new report said they would continue to use the pump in those cases.

The trial, called Revive-It, is intended to determine whether a HeartMate II can also benefit patients who have not quite reached that stage of heart failure. Such patients, who take drugs for their condition, typically struggle to perform physical activities, like walking short distances.

Because heart failure is a progressive condition, the new blood clot study has complicated the question of how to weigh the device’s risks and benefits to less sick patients.

“I would not embark on a clinical study until this problem is understood and mitigated,” said Dr. Robert G. Hauser of the Minneapolis Heart Institute Foundation, who is not involved in the trial.

In the new study, three big hospitals, the Cleveland Clinic, Duke and Washington University in St. Louis, jointly reported that the rate of HeartMate II-related blood clots had increased by nearly fourfold in devices implanted after early 2011.

Some patients died and others underwent emergency operations to get new pumps or transplanted hearts, according to a report in The New England Journal of Medicine.

Experts have yet to find a reason for the increase. But they say it most likely involves factors like changes in the device and changes in how doctors use anti-clotting drugs with such patients.

Long before the new report, however, word of a growing problem with the HeartMate II had been circulating among device experts. And researchers involved with Revive-It had already begun scrambling to understand its potential impact on the trial.

The issue began to take shape in March, when the Cleveland Clinic reported to the Food and Drug Administration and Thoratec that it was seeing a rise in pump-related clots. Physicians at other hospitals were also seeing an increase and were discussing the problem with colleagues at medical meetings or privately.

“There is an incestuous nature to our field,” said Dr. Scott Silvestry, a cardiologist at Washington University

In May, the principal investigators leading the trial — Dr. Keith Aaronson and Dr. Frank D. Pagani of the University of Michigan and Dr. Robert Kormos of the University of Pittsburgh — decided to delay the start of patient recruitment to examine the problem.

At that time, doctors at the Cleveland Clinic were keeping their findings confidential because they hoped to publish them in a medical journal.

But another source of data was available. In recent years, a federally funded registry at the University of Alabama at Birmingham has been tracking the safety of heart pumps like the HeartMate II. Known as Intermacs, the registry was showing that pump-related blood clots associated with the HeartMate II had risen to about 5 percent since early 2011, compared with about 2 percent in previous years.

But the registry also showed a variation in clot rates at differing hospitals, raising the possibility that facilities such as the Cleveland Clinic were outliers.

The trial’s lead investigators, Dr. Aronson, Dr. Pagani and Dr. Kormos, declined to be interviewed. But in a statement, they said the added risk detected by Intermacs was “small” and did not alter the trial’s balance of benefits and risks.

Based on the Intermacs data, officials at the F.D.A. and the National Heart Lung and Blood Institute and a panel of experts appointed by the institute to monitor the study’s safety came to the same conclusion.

“F.D.A. reviewed the Intermacs data and supported the Revive-It team’s decision to move forward,” the three researchers said a statement.

As a result, about 18 major hospitals nationwide again prepared to enroll patients. But now, the recent New England Journal of Medicine study published late last month has raised questions about which blood clot data is more reliable.

In their study, the Cleveland Clinic, Duke and Washington University reported a pump-related clot rate of 8.4 percent, compared with 2.2 percent in earlier years. The increase was significantly higher than the 5 percent rate reported by Intermacs.

Dr. Randall Starling of the Cleveland Clinic said he thought that Intermacs’ data was understating the problem’s scope.

“We believe our data is more accurate,” Dr. Starling said.

However, the import of new report was quickly disputed by the three investigators heading Revive-It. In a statement, they described the hospitals as outliers and said the Intermacs data was more reliable.

Dr. Milano, the cardiologist at Duke, said he thought that the reaction of researchers, who have spent years setting up the Revive-It study, was understandable.

“They are more apt to look at the data that suggests there is less of a problem,” Dr. Milano said. Still, at this point, he cannot see asking less-sick patients to get a device. “Knowing what I know, I probably won’t sign up,” he said. The three researchers leading the trial said it was imperative, given the shortage of donor hearts to know whether the device worked in earlier stage patients.

Whatever the case, the National Heart Lung and Blood Institute said in a statement that the study’s safety panel would soon review the new journal report and its implication, if any, for the trial.

In the meantime, specialists are going their separate ways. For example, while Dr. Hauser, the device expert in Minneapolis, says he thinks that the trial should be delayed, cardiologists at the hospital where he works are going forward. And unlike Duke and the Cleveland Clinic, Dr. Silvestry said Washington University hospital was also staying in the trial because it thought that the device’s potential benefits still outweighed its risks.

“We feel our patients will be served by a possibility of enrollment,” Dr. Silvestry said.

FDA responsible for patient safety: not jobs! NEJM article

http://www.nejm.org/doi/full/10.1056/NEJMp1204170#t=article

Perspective

Patient Access to Medical Devices — A Comparison of U.S. and European Review Processes

Saptarshi Basu, M.P.A., and John C. Hassenplug, M.Sc.

N Engl J Med 2012; 367:485-488August 9, 2012

Interview with Dr. Rita Redberg on the approval process for medical devices in the United States and in Europe. (23:44)

            Listen

            Download

 The U.S. process for approving innovative, high-risk medical devices has been criticized for taking longer than the European approval process.1 This contention is often used to support the argument that the Food and Drug Administration (FDA) should lower its standards for approving medical devices, since a slow approval process is delaying Americans' access to innovative and lifesaving technology. But a review of the data, using appropriate end points, suggests instead that it takes the same amount of time or less for patients to gain access to innovative, high-risk medical devices in the United States as it does in the four largest European markets (Germany, France, Italy, and Britain)2 — largely because patient access is generally delayed until reimbursement decisions are made, which often takes substantially longer in Europe than in the United States.

To compare the United States and Europe fairly on this front, three criteria must be considered: the level of device innovation, equivalent start and end points, and patient access as defined by time to reimbursement. First, we focused on innovative, high-risk devices because in the United States such devices require the strongest evidence of clinical benefit and are the subject of most debates about the relative effectiveness of approval processes in different countries. Furthermore, previous studies have shown that lower-risk devices achieve market access in a similar amount of time in the United States and in Europe.

Second, an accurate comparison of time to market access requires measurement of the total time that elapses between application submission and market access. Previous studies have compared the chronologic dates of application submission and market access, but the date an application is submitted varies from country to country.

Third, patient access should be equated with the availability of reimbursement rather than with device approval, because broad patient access to a new device doesn't occur until reimbursement by a national or third-party payer is available. Previous comparisons of the U.S. and European systems have used the approval date to measure process duration, but innovative, high-risk devices don't reach a market where most patients can benefit from them immediately after gaining regulatory approval, though they may be accessible to patients who can afford to pay out of pocket. Rather, there is a second level of review through which public or private insurers decide whether and at what price they will pay for a device. Generally, public systems take longer than private insurers to make reimbursement decisions, and significantly more Europeans than Americans have public insurance. Two thirds of the U.S. population is covered by private health insurance, whereas only a fifth receives publicly funded reimbursement, primarily administered by the Centers for Medicare and Medicaid Services (CMS).

For both private and public systems in the United States, the pathway to patient access to a device starts with the submission of an application to the FDA. The FDA reviews innovative, high-risk devices for safety and effectiveness (clinical benefit) under the premarket approval (PMA) process, and information on the duration of reviews is publicly available. In fiscal year 2011, the FDA approved 40 applications for PMA. The average review time was 13.1 months, with 8.4 months attributed to FDA review time, and 4.7 months to the time the agency waits for the sponsor to address deficiencies in the application (“sponsor time”).3 CMS provides reimbursement for the majority of devices when they earn FDA approval. For a limited number of devices each year, however, CMS conducts a national coverage determination in response to external requests for validation or for devices that have limited or conflicting evidence of clinical benefit. This process averaged 8.6 months over the past 5 fiscal years.4 Although it is difficult to obtain data on how long private insurers take to make coverage decisions, anecdotal information from private insurers suggests that decisions are made within a few weeks to a few months after FDA approval, depending on the amount and quality of evidence of clinical benefit.

In Europe, by contrast, most of the 27 member countries of the European Union (EU) have publicly financed health care systems; such systems cover approximately four fifths of the populations of the four largest device markets. All EU countries require devices to first obtain a Conformité Européenne (CE) marking, which refers to a symbol shown on products that indicates market approval throughout the EU. The CE marking process is conducted by for-profit, third-party “notified bodies” that have been accredited by a member country to assess device safety and performance but do not evaluate effectiveness (which requires more clinical data). Although publicly available data are limited, anecdotal information from notified bodies suggests that the process takes 1 to 3 months, excluding sponsor time.

Most European patients do not have access to innovative, high-risk devices as soon as the devices receive a CE marking. Each country must first make a decision about reimbursement, a process that varies substantially among countries.5 Though a CE marking can be granted on the basis of fewer clinical data than are required for FDA approval, European standards for reimbursement are often similar to or higher than those that the FDA imposes for device approval. European countries may require additional data on the device's safety and effectiveness, as well as on cost-effectiveness.

In France, a centralized body makes reimbursement decisions after assessing the safety and effectiveness of individual devices. Reimbursement decisions in Italy are devolved to the various regions, and Britain and Germany conduct broader assessments of device types or procedures, rather than of individual devices. Typically, innovative devices not covered under an existing diagnosis-related group (DRG) require review under the lengthier Health Technology Assessment process, which assesses safety, clinical benefit, and cost-effectiveness. Government-provided information on time to reimbursement varies by country. Estimated time frames are an average of 71.3 months in Germany, a range of 36.0 to 48.0 months in France, a range of 16.4 to 26.3 months in Italy, and an estimated 18 months in Britain.

Using this information, we determined that the time it takes to bring innovative, high-risk devices to patients in the United States is similar to or shorter than that in the top four European markets (see figure

Missing graphic:  Comparison of Time to Market in Premarket Approval and Reimbursement Processes.

 The public (CMS) process in the United States takes approximately as long as those in Italy and Britain, approximately half as long as that in France, and less than a third as long as that in Germany. The difference in time to market access is even greater when it comes to private insurers (covering the majority of the U.S. population), which often make reimbursement decisions within a few months after FDA approval.

To further illustrate this point, we compared the time to approval for five innovative, high-risk medical devices available in France, Italy, and the United States (see table

Missing graphic: Comparison of Time to Market Access for Five Innovative Devices in France, Italy, and the United States.

These case studies indicate that the average time to market access for these devices was 26.3 months in France, 30.8 months in Italy, and 15.3 months in the United States.

These numbers may not fully capture the reasons why a device reaches the market more quickly in one country than in another and do not reflect experiences with all innovative, high-risk devices. However, unless one uses equivalent standards in terms of the level of risk, the start and end points of the process, and the key end point of market access, accurate comparisons cannot be made.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on August 1, 2012, at NEJM.org.

SOURCE INFORMATION

From the Office of Planning, Office of the Commissioner, Food and Drug Administration, White Oak, MD.

FDA Approval Is Faster!

LINK

FORBES   BUSINESS | 6/19/2012 @ 10:15AM

More Proof FDA Is Faster Than Other Drug Regulators

This guest post was written by Joseph Ross, an assistant professor of medicine at the Yale University School of Medicine and Nicholas Downing, a third year medical student, also of Yale University School of Medicine. Ross has done extensive study of how new drugs are approved. In this article, they provide more evidence that the FDA’s review process is not longer than that in other countries.  (FiDA blog bold added.)

Last month, we published with our colleagues a study in the New England Journal of Medicine examining the time required by three prominent pharmaceutical regulators to review applications for new drugs that have never before had medical uses.

Our main finding: the FDA was nearly two months faster than the European Medicines Agency and Health Canada, the primary regulators for the European Union and Canada. This is true both for the time it takes for the FDA to do the first regulatory review and for total regulatory review time of these applications.

But our original measure of regulatory review time only included the time an application actually spends being reviewed by the FDA and its peers. For some drugs, the total time can be longer, as a company may need to conduct additional research before resubmitting a drug to regulators. Investors and industry are focused on the total time it takes to go from submission to approval.

So we re-crunched the numbers. Our analysis is limited because it included only applications that were eventually approved, since only this information is made publicly available by all three regulators.

But we found more proof that the FDA is faster than its peers. 

As can be seen in the accompanying figure(on website), the FDA was the fastest of the three agencies, even when we look at the total time from submission to approval, including time when both the agency and the industry applicant were “on the clock”. The median time to approval was 322 days at the FDA, compared to 366 days at the EMA and 409 days at Health Canada.

Our comparison is complicated by the fact that all three regulators do not behave in the same way, but we would expect that to make the FDA look slower – and it doesn’t. Among these applications that were eventually approved, the EMA approved almost every one in a single review cycle, 96%, whereas 3% required two cycles and 1% required three cycles. In contrast, 62% and 69% of applications were approved by the FDA and Health Canada in a single review cycle, respectively. More than 30% of applications required multiple reviews before approval. For the FDA, 36% required two cycles and 1% required three cycles; for Health Canada, 24% required two cycles, 4% required three cycles and 3% required four or more cycles.

You might think that extra requests for statistical analysis, data collection, or even new clinical trials would make the FDA process more time-consuming than that in other countries, but it doesn’t.

Nevertheless, there are more nuances to this story. You can see in the Figure that there was much more variation in time to approval among applications to the FDA. More than half of approvals were complete within one year, but there were many examples of the FDA requiring 800, 1000, even 1200 total days before approval. For instance, the well-known anti-cancer drugs Sanofi‘s Eloxatin and Novartis‘ Gleevec were both approved in less than 80 days, however it took more than 10 years from initial submission to approval for Sabril, and anti-seizure medication, and Asclera, a sclerosing agent to treat varicose veins.

A lot of the variation in FDA time to approval can be attributed to whether one or more cycles of review were required. Among the 62% of applications the FDA approved after a single review, the median time to approval was 278 days. In contrast, the median time to approval was 765 days among the 38% of applications that required multiple cycles of review.

Interestingly, applications within the hematology, oncology, and immune-modulating and anti-infective therapeutic classes were most likely to receive FDA approval after a single review. Applications within the musculoskeletal and pain and psychiatry and central nervous system therapeutic classes were most likely to require multiple cycles of review.

It is important to point out that there is no right review speed or right number of cycles of review. The FDA may have been acting appropriately in these slower reviews that required additional cycles. These applications could have raised important safety concerns or included poorly designed trials that could not support approval. Perhaps the FDA was right to request more statistical analysis, additional data collection, or even new trials, from the applicants.

One can argue that FDA has been cautious in ways that benefit the public. There are certainly cases where the FDA did not approve a drug, and other countries did only to have to withdraw it for safety reasons. Examples would include Acomplia for obesity and Thelin for pulmonary arterial hypertension. On the other hand, some medicines, like AstraZeneca‘s Iressa for lung cancer or perfenidone for idiopathic pulmonary fibrosis, are being used in other countries but are restricted or not approved by the FDA. But either way, a tortoise-like pace is not one of the FDA’s problems.

Comment:  Joleen Chambers

Thank you for your research!  After a family member experienced a serious adverse event from a failed implanted medical device designed by the Mayo surgeon and approved by FDA without clinical testing, I began advocating for safer implanted medical devices.  Legislation to renew MDUFA must be complete by September 2012, yet the medical device industry is balking at contributing financially to oversight that would protect patients from harm.  The 'talking points' are focused on speeding 'innovations' to a (unconfirmed & DTC marketed) demanding and growing pool of desperate patients and the need to maintain jobs-at-all-cost for workers in the profitable medical device industry.  Bill Walton has been hired to lobby Congress. The industry threatens that if it is not placated they will go to other countries.  Let them go so there are fewer American victims in medical and legal purgatory!