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Over the past few years, there has been controversy over clinical trial results that remain unreported. This has stoked concern, for instance, when data may provide information about side effects. At the same time, other researchers may be precluded from learning clues needed to proceed on related drug development. However, these issues pertain to studies on drugs that are not commercialized as well. In a recent paper in Science Translational Medicine, a pair of academics argue that “translational medicine cannot approach its full potential if negative drug developments are unpublished” (here is the abstract). And they cite an ethical duty for insisting on disclosure. We spoke with Michael Rogawski, one of the co-authors and chair of the Department of Neurology at the UC Davis School of Medicine, about the need to disclose trial data. This is an excerpt…
Pharmalot: So why raise this issue and why now?
Rogawski: When I participated in a translational working group of the International League Against Epilepsy on how to encourage the development of more effective epilepsy therapies, I realized that negative clinical data was critically important in assessing the predictiveness of animal models. Then, sometime later when I was writing a review article I asked a company for the clinical trial results on a product they had abandoned. I let them know that I hoped they would publish their trial results as even negative studies provide important scientific information and the patients who participated in the trials expect that the information derived from their participation will benefit mankind. The terse answer was that the company “does not intend to publish the results of the epilepsy trial.
So, this is a problem that has concerned me for some time, but we’re now at a critical moment where the NIH has the opportunity to require sponsors to post the results of clinical trials on the ClinicalTrials.gov web site. A new law that many people may not be aware of requires the results for most drug and device trials to be posted on ClinicalTrials.gov. However, there is a loophole that exempts trials of products that are still in development and if they are never approved, the results don’t need to be posted. A provision in FDAAA (the Food and Drug Administration Amendments Act of 2007) Section 801 allows HHS to require results reporting for clinical trials for drugs and devices not approved by the FDA. In the law, Congress gave the NIH the ability to formulate regulations that require sponsors to do this, to post results on this web site, even for drugs and devices not approved by the FDA. They’re going to publish draft regulations by the end of the year and then there will be a public comment period.
As I dug into this, I began to realize that there were quite a lot of changes going on in this area. The FDAMA (the FDA Modernization Act of 1997) required anyone doing a clinical trial to post an announcement posting on ClinicalTrials.gov. The original intent was to help patients find relevant clinical trials. Then, when concerns were raised about selective reporting, ClinicalTrials.gov was seen as a way to keep track of all the trials that have been done. More recently, they have made a requirement to post basic results. I don’t think a lot of people realize that. But if you go to the web site, there are few clinical trials with results actually there, as this is all so new. Even drug companies seem to be confused about the requirements.
Going into the future, the results from all clinical trials for approved products will have to be up there. But that raises the question about publication. I guess some people thought this would be sufficient. But it’s not. Our position is it’s still necessary to publish results of clinical trials in the peer-reviewed literature.
Pharmalot: Why is that?
Rogawski: The results data in ClinicalTrials.gov is simply presented in tables. There’s no presentation of detailed analysis or an interpretation as in a journal publication. And there’s minimal review. ClinicalTrials.gov could become the primary repository for the results of clinical trials of drugs and devices. And some people may feel that publication in a peer-reviewed article is no longer needed.
We’re arguing that you still need to write up the results.
Pharmalot: So you’re saying some results are located on ClinicalTrials.gov, but not all?
Rogawski: There’s a whole separate tab on every entry for results. If no study results are available, it will indicate that. For terminated products, you may never see the results published. There’s a loophole in the law that allows them (sponsors) to be exempt from posting the basic results when the product hasn’t been approved.
Pharmalot: What are these exemptions?
Rogawski: There are a couple of ways a study can be exempt. One way is to study the drug for another indication. Delayed submission is permitted when sponsor is seeking a new use. The other way is if a drug or device is never approved. In principle, although it’s not stated this way, if the sponsor never submits the particular product for FDA approval, then they don’t have to post the basic results. The current law only applies to agents approved by the FDA. Let’s say the sponsor submits an NDA and the agency gives a complete response letter saying they have to do X, Y and Z, and the sponsor never does that. They decide it would be too expensive to do further clinical trials and they decide to abandon the product. Then they also don’t have to put data on ClinicalTrials.gov.
What we maintain is that it’s unethical to do that. It’s a basic principle of clinical research – it’s espoused in the fundamental ethics of clinical trials, such as in the Declaration of Helsinki, which states that “authors have duty to make publicly available results of research on humans and are accountable for the completeness and accuracy of their reports….Negative and inconclusive, as well as positive results should be published or otherwise made publicly available.”
Pharmalot: And so you’re hoping the HHS will close this loophole, as you call it.
Rogawski: We’re hoping HHSs will use its authority under FDAAA 801 to require sponsors to report results with any trial registered with ClinicalTrials.gov, even for any product that is abandoned… There’s potentially useful information in any clinical trial and if it’s not available, it diminishes public knowledge. It may even place patients in later trials at risk. There could be some data showing this particular product causes green spots. It would be important to know this the next some time somebody considers developing a drug that acts by a similar molecular mechanism.
Pharmalot: But a drug maker may argue that intellectual property is at stake, whether or not they choose to continue development, because disclosure may somehow give a rival an edge, right?
Rogawski: HHS may decide to balance with the interests of pharmaceutical companies with the public interest. They may decide it’s commercially damaging to require companies to publish the results of trials with abandoned products. We think it’s a fallacious argument. We understand that many sponsors consider data proprietary… They put all this money into it and may want to continue work on the product later on or try for a different indication, and they may perceive that negative trial data would impair that. And they may consider it a waste of time and money to write stuff up when it isn’t going to go anywhere…We think it’s incorrect, but I guess companies may think that way.
Pharmalot: You mentioned you also believe all trial results should be published as well? How does this tie in?
Rogawski: I’ve noticed that it’s often the case that sponsors do not publish results when they’re abandoning the product. In my own area, which is the development of anti-epileptic drugs, we have a problem. We use animal screening models to identify drugs, but we don’t know how valid the models are because we don’t know much about the cases where a drug was effective in the models, but not in clinical trials because very little information about failed drugs is available publicly.
That’s what stimulated my concern. We make the assumption that these animal models are highly predictive, but it could be a flawed assumption because we don’t have the full set of data. There could be situations where drugs don’t work in the clinical trials. I do know of situations like that, being in this field for as long as I have, but we don’t know why there was a failure – lack of efficacy, the sponsor ran out of money, or perhaps there were idiosyncratic reactions?
So I also believe the companies should voluntarily publish negative results in the peer-reviewed literature. I believe they have an ethical responsibility to do that, but ethics is not the same as the law. In my view, many companies are not acting ethically by not reporting trial results.