Americans are learning a thing or two about clinical trials as they watch the tense, televised push-pull between President Trump promoting a drug combination for Covid-19 based on skimpy, preliminary clinical trial data and Dr. Anthony Fauci promoting caution about the combination. Fortunately, the federal government provides a handy resource for navigating such disputes, ClinicalTrials.gov, where drug makers and other sponsors of clinical trials must report their results.

The Food and Drug Administration bases its decisions largely on the results of such clinical trials, which reveal how effective or safe a drug or device is compared to existing options or placebos. But that decision-making machinery can be thrown off when trial sponsors don’t have to share the results of all of their trials.

We identified a loophole letting trial sponsors do just that and sued the federal government to close it. And we won. But we worry it will prove a hollow victory unless the FDA and National Institutes of Health step up enforcement of an important law, and soon.

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First, some background.

The FDA is good at what it does, but it can make mistakes. Take, for example, Vioxx (rofecoxib), a blockbuster painkiller made by Merck. The FDA approved Vioxx in May 1999. After approval, Merck collected clinical trial results that linked the use of Vioxx to increased risk of heart attack, stroke, and other cardiovascular problems and shared them with the FDA — but not with independent researchers. If researchers had access to all of the data, they could have raised the alarm years before Merck took rofecoxib off the market in 2004.

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Even FDA overseers need oversight, in the form of scientists and researchers who provide second opinions on data from clinical trials.

That’s why Congress passed the Food and Drug Administration Amendments Act (FDAAA) in 2007: to help prevent such tragic mistakes. It’s a transparency law, one that requires companies, universities, and government labs that sponsor important clinical trials to reveal the results to patients, physicians, and independent researchers.

On paper, the FDAAA makes it illegal for trial sponsors to cherry-pick results, meaning publishing favorable results (like data showing safety and effectiveness) while withholding unfavorable ones (like data showing toxicity or lack of effectiveness). If independent researchers have access to all of the data from all trials — favorable and unfavorable — they can double-check the work of the FDA and help keep the public informed.

In practice, the mandate isn’t working nearly as well as Congress envisaged. Results from clinical trials are supposed to be posted on ClinicalTrials.gov but often they aren’t. More than 12 years after the FDAAA went into effect, estimates from numerous independent researchers suggest that roughly one-third of applicable clinical trial results — thousands of them — are missing.

Part of the reason is that in 2016, the FDA’s parent, the Department of Health and Human Services, and the FDA’s sister agency, the NIH, created an improper legal loophole that exempted many clinical trials of FDA-approved products completed between 2007 and 2017 from any obligation to ever file their results with the ClinicalTrials.gov database.

In 2018, we brought suit in federal court to close the loophole. Last month, a federal judge ruled that HHS and NIH had frustrated the “unambiguous” text and intent of FDAAA and ordered the agencies to require reporting and posting of the missing data.

That’s the theory, anyhow. Unfortunately, our court win can’t and won’t enforce itself. When a trial sponsor fails to post results on ClinicalTrials.gov, as required by the FDAAA, the FDA and NIH are authorized to impose penalties, including a fine of up to $10,000 a day and termination of government grant money for noncompliance.

Yet despite widespread noncompliance, these agencies have never imposed a single fine, withheld a single grant, or imposed any other penalty on a noncompliant trial sponsor. One group, the University of Oxford’s Evidence Based Medicine DataLab, estimates that the FDA’s lack of enforcement is so severe (and noncompliance so widespread among trial sponsors) that the FDA has forfeited billions of dollars in uncollected fines.

Why are they ignoring this issue and the revenue it could be generating? The FDA has taken the position that enforcing the FDAAA is entirely optional. In fact, the FDA and NIH have said that even determining whether clinical trials and trial sponsors are in or out of compliance with the FDAAA is a discretionary task — a task that they have chosen not to do.

As a result of the unwillingness of the FDA and NIH to enforce the law, drug companies, device makers, universities, and other trial sponsors have come to expect that they can withhold their results from ClinicalTrials.gov with impunity. Without enforcement, the ClinicalTrials.gov database will remain incomplete and the purpose of the FDAAA will go unfulfilled. Without enforcement, Americans are at greater risk of wasting money on useless medical products and being injured by unsafe ones.

If FDA and NIH prove unequal to the task, Congress will have to step in to force the agencies’ hands.

Christopher Morten is supervising attorney at New York University’s Technology Law and Policy Project. Peter Lurie is president of the Center for Science in the Public Interest. Charles Seife is a journalist and professor at New York University.

  • [For more background details, readers should look at reports by Charles Piller in STAT and Science Magazine.]

    Having worked at the FDA and NIH, I have some insights into why these agencies fail to follow the law: Science has become increasingly politicized. In the case of the FDA, the pharmaceutical industry co-funds the review of clinical trials through PDUFA, but if too much negative data are found in ClinicalTrials.gov, that support may decrease. Then Pharma, investors, and patients will complain and lobby Congress or the President.

    The reality is that about three-fourths of clinical trials don’t change clinical practice for a broad group of patients. In 2005, Dr. John Ioannidis wrote a paper entitled, “Why Most Published Research Findings are False,” followed by many others that reveal multiple biases in research, e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865753/pdf/pbio.2005468.pdf. His work at Stanford needs more visibility because the public doesn’t understand that breakthroughs are rare.

    Due to hype, Congress has pressured the NIH to do more clinical trials, and the NIH is unwilling to reveal their flaws or failure rates, for fear of budget cuts. The agency has both intra- and extramural trials, and uncovering problems would reflect badly on project supervisors. Academic investigators gripe that “data parasites” could preempt publications, but better data curation is often needed. NIH study sections and medical journals have a shortage of good reviewers, and the latter doesn’t want to publish negative results. Readers who point out errors that suggest fraud have been sued for libel, so the culture has silenced critics and dialogue.

    Almost a decade after the Ioannidis article, Drs. Collins and Tabak acknowledged problems with rigor and reproducibility in a 2014 Nature paper. More recently, the 21st Century Cures Act mandated the NIH develop plans to address the issues, but some requirements (e.g. sex and gender inclusiveness) will add effort, but may not improve experimental variation. New NIH grant managers are naïve about these matters, and have too little time to assess the quality of work, so they cannot replace more experienced scientists. An alternate approach might be to fund more data curation or work to confirm key findings in a field.

    The unchecked accumulation of bad data in basic science and clinical trials hampers scientific progress. Learning about biases and confounders in research helps researchers to avoid mistakes in the future and can save time, money, and lives. Without such exposure, many scientists will not be well-trained, and if academia, publishers, industry, and government don’t fully support open data access, society will be the loser.

  • To Authors, I do not understands why are you bashing FDA at the time when it is crucial to support its role? Where were you in last ten years, you should be writing one article every week or every month to bash it, but no, only when it is needed the most, you want to jeopardize an institution image. Support our institutions at the time of crises. If you are not part of solution, do not be part of the problem.

  • This piece has a point of view and exaggerates it. I don’t disagree with transparency, when it comes to industry sponsored studies – there are ample sad examples prior to 2007 – and of the need for FDAAA, but in my time in an academic institution, doing regulatory work, I didn’t encounter any issues with sponsors indifferent with complying. Actually, the exact opposite. And as for academic researchers, their careers “thrive or die” based on their publications and medical journals have required registration to clinicaltrials.gov for article submission for publication review, for over a decade.

    Re:”…requires companies, universities, and government labs that sponsor important clinical trials to reveal the results”. There are many trials in the university and government-sponsored space, that while useful are, in themselves, not important to any reassessment of stds of care.

  • Thank you for the great work. What you have done is the start of desperately needed changes. Not only do we see the lack of disclosure but, as a result, organizations such AMA, Association Orthopedic Surgeons will reject valid results due to a lack of disclosure of the sponsors or if any conflict of interest could exist.

  • Why does the FDA wantpeople to die? ignoring China vitamin C trials.. I have gone 20 years avoiding respiratory illness with mega doses of vitamin C 3000- 12000 a day. and can knock any virus out of my body in a couple days, the himalayan salt therapy works too.all by itself. They don’t want people to get well. There are thousands of studies fda won’t ackowledge. The people will see it as the truth of your lies will revealed soon.
    ..avoid completely if I apply prevention. FDA did a study on what. 200 mg as a “large dose” what a joke!
    We know they’re pushing drugs for $..and It will catch up with them and media who suppress the truth.
    Read the science, stop killing people with your drugs. my friend lost her eyesight.. your wonderful drugs. I am better with Q10 ..as the med made my heart beat faster, Here a simple deficiency of magnesium and Q10 causes heart attacks, and strokes. Why would you want anyone to know they could be healthy from such a simple scientifically proven, needed inexpensive supplement without side effects..aw no money for you. I also reversed me poor vision.. borderlibe bifocals..to not needing glasses. What a racket..So here I am..One person who hasn’t needed to go Dr. for bs.. glasses, colds, flu..what’s a flu, Don’t get ut anymore and never a shit.. chronic bronchitis..I cured last time..2O years ago.. Vit C n garlic..5 days gone naturally.. Thankfullly found because the prescription caused severe pain!
    The FDA makes me sick..Why would it be illegal to Say vitamin cures something. ? Do you know how stupod it sounds that a “cure” can only be lab created? manmade? Keep playing God, they will regret it when in hell. I bet you, thet all wear glasses.. but Here I am.. not a doctor.. just a person with an open mind who understands logical science behind natural Cures. 1st of they get to the root cause.. which us often deficiency..and have one where in medical books so much is idiopathic.. word for idiots who believe this crap.
    So
    Vitamib C cured scurvy.. because it’s caused by a deficiency.. and so are most chronic illnesses.and guess what I have been curing more chronic issues with natural foods..praying..knowing God will take care of this. The RDA is outdated..Our soils are depleted..and not getting what we used to from healthy food. Add tgat to the rediculous diabetes causing food pyramid and ask yourself if you realky believe the fda is looking out for us.. that it’s ok to approve drugs for dry eye and arthritis that causes cancer or glaucoma. ?
    Too bad there aren’t many real journalists with integrity.
    CD

    • Scurvy is a deficiency made by lack of vitamin C, so its treatment is actually big doses of ascorbic acid. All the supplements are more or less good to supply your health, but to argue against the actual proof of drugs means that you dont have a clue about how they work. I think the problem with USA is that politicians are involved, corruptable and the laws are not sufficient(or not applied). I am a pharmacist and in a lot of european countries the laws of drugs and supplements are much more severe and regulated periodicaly. You have to understand that each drug has its bad actions(for example the anti arrhythmic treatment use drugs that cause arrhythmia, because the balance of the heart is so fragile and its hard to make it work without affecting other tissues). For a lot of health problems its hard remake the balance and when u have it u have to treat it… Its hard to recover from a chronic disease, and more than 70% of the illnesses are caused by imbalance, not by a deficiency which have its natural occured treat(so u cannot find a cure in nature for all the diseases, otherwise the chemists are struggle to modify and create complicated structures in vain.) To make such statements like yours u have to evaluate a lot of things. I agree that some of the laws and autorities have interests in promoting companies or drugs.

    • I agree that the FDA does a huge disservice to the American pe people. They are corrupt.

  • Could you provide any statistics showing compliance to reporting? I saw something recently indicating pharma sponsors are in the 90%+ range but academic sponsors have much poorer compliance. Do you have different figures?

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