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.
15 Comments
Dr Rogawski may ultimately prevail in his attempts to get negative clinical data to assess predictiveness of animal models, but he will have less success in getting the animal model data per se. Now that the US Patent and Trade Office has ruled that animal models are to be considered valid intellectual property, any experimental data emenating from these animals is considered confidential proprietary technical information. Thus Dr. Rogawski may be able to obtain an exclusive license to obtain his animal data, but he may well have to pay a high price to obtain it.
http://www.slwip.com/services/ip_papers/transgenic_animals.html
Now let's combine the goal of publishing trial outcomes with the earlier discussions about journals not wanting to print negative trials and concerns about the roles played by medical writers: Who will write up all these trials? Where will the funding for that work come from? How will these materials be made accessible?
It sounds great to talk about the needs of research and advancing medical treatment. But Dr. R is not simply pursuing basic research, he's actively involved in attempting to discover products in direct competition with those he feels have a moral obligation to disclose data that would assist him in his efforts.
This is a little bit like asking academicians to post their best research ideas on the web the moment they have them, on the premise that everyone could then be working on the best ideas whether they were their own or not. Sounds great in principle, but undermines the incentive to generate great ideas.
I am just throwing this out for the purposes of discussion: What about overseas trials? How would this be monitored and should the US taxpayer foot the bill for foreign drug development costs? Should we give all of this info away to everyone including those who might not adhere to these standards?
From my recollection, Eliot Spitzer brough suit against Glaxo in 2004 regarding their failure to publish data regarding depression and suicide in adolescents taking Paxil. Six studies were performed in adolescents in order to extend their patent rights; one favorable was published and 5 were not -the 5 that suggested unfavorable effects.
I think one of the terms of settlement with Glaxo was that they make public all results of clinical trials -positive as well as negative and that such data is not proprietary. I believe that subsequent disclosure led to Steve Nissen's meta analysis and subsequent claim that rosigliazone may have some significant unwanted effects.
@Jim Rick - FWIW, the problem with the suicidality in adolescents in the Paxil studies was really that this was obfuscated by coding and reporting this event as emotional lability. ensuring the trial is reported won't prevent that obfuscation of data (forcing the release of raw datasets would)
My concern is of reports implying that adding adjunctive therapies would be beneficial in stopping SUDEP. Considering SUDEP is sometimes due to cardiac or respiratory events, adding those adjunctives, if they compound over-sedation and contribute to respiratory failure, or if they can cause fluid retention, weight gain, and edema - which could conceivably contribute to cardiac events, the whole story ends up not being told.
Such a report may be read by doctors who may then decide it will keep their patients from sudden death to add these medicines - when there is the possibility of having the reverse effect.
It is irresponsible, imo, to give a slanted view, one way or the other. The potential downside was not reported. Not unless I completely missed it.
Your efforts are much appreciated Ed and Dr. Rogawski.
Dr Rogowski can get all the negative data from JIR.
http://www.jir.com/
Thank you Dr Rogawski for bringing this critically important issue to light. I am appalled by the snarky and insipid comments on this post which indicate the general lack of understanding of this issue and its implications. As a long time (30+ yrs) industry vet, I have come to view this as one of the critical shortcomings in our field. And far too easily overlooked. I have seen trial after trial fail with no results ever revealed. In fact, there is not one single change in our regulations which could do so much so quickly to advance the state of medicine and ultimately the welfare of our companies. Companies are thinking too secularly and not recognizing the communal benefits that will accrue if all their peers adopt this policy. Think of all the redundant trials in untested MOAs across company after company. So much money could be saved by knowing that a target is a dead end and re-investing in a more promising area.
The poster child for this argument in my mind is ONO-2506 which was being co-developed by Ono and its US partner Merck (http://www.clinicaltrials.gov/ct2/results?term=ONO-2506). Both companies trumpeted the potential of this therapy but following completion of phase 3 trials in 2008 there was only a terse statement from Ono that results had not lived up to expectations and further analysis was under way. Merck never breathed a word even as to abandoning the partnership. The CT.gov records have been updated discretely but no data provided. Stroke is clearly a critical health burden and poorly understood in terms of potential disease-altering therapies. To not publish results of a trial like this is criminal in my mind
And as to Lili's comment about peer-review etc. What century are you living in? This is the age of the internet. And every company writes up a detailed trial report for its internal records. Just look at GSK's clinical trials registry which was mentioned in another post. They just post their internal trial reports here - and also on clinicalresults.com - in order to meet requirements. Its not complete (many, many results are missing) so probably not in absolute compliance, but much better than most other companies. So congrats GSK! All it takes is 10 sec for someone to upload the file
@kvan - good points, but there's a chasm between you and the next generation, they don't care, pops.
As bad as the entire process of data collection and sharing of results is now, it is only going to get worse as *globalization* marches on...trade deal with Columbia is being pushed as we speak - expect a global adoption of the loose regulatory requirements of cocaine R&D and manufacturing to be heralded as the new *gold standard*.
Publishing raw data sets of un-monitored data (mega trials) is a good trick for years of yaddayadda analysis and law suits.
Bottom line is clear - big pharma is no longer in the business of medical research.
Kwan, hate to put it tersely but even if you're working with the latest Pentium chip, it doesn't even come close to having the processing power and RAM needed to download and store the massive data dump that is the raw data that you're looking for. Unless you happen to have a server in your basement to run the latest version of SAS off of a UNIX or Windows platform you don't have a chance.
I suppose that you would like there to be some type of government mandated, industry supported network of supercomputers that people such as yourself could access from your laptop whenever you get the itch for some "raw" data, since that is what it would take. As Gordon Gekko, my Wall Street hero used to say, "Sorry, pal, it just ain't gonna happen for you".
I agree results from all studies including failed studies need to be published and reported in clinicaltrials.gov This opinion comes from 24 years of working in the clinical research industry and as a patient. I think there is confusion that raw data is being requested or the report summaries with appropriate and informative data tables. My impression is that "reporting of study results" is much different than just providing raw data. It is not the raw data that is being sought to be provided on clinicaltrials.gov
I just lost a contract monitoring a trial because the data safety monitoring review board (DSMB) said it was futile to continue the study. Safety issues were not identified (they said) but neither the DSMB nor the sponsor would say what actually went askew.
From what I saw from being in the field, it was the result of differences in perception in what the primary objective was amongst the Principal Investigators and the data was not collected consistently. There were design issues in the protocol and the electronic case report forms and problems with the conduct of the study. Additionally, there appeared to be low compliance on the part of the study subjects with adhering to the study treatment regimen.
I also just helped initiate the writing of an abbreviated clinical summary report (CSR) on a study that did not support the hypothesis. The manuscript written by the investigators will most likely never be published even though it contains some very useful clinical information. I am trying to transition into Regulatory Medical Writing and it was my first professional job. Nobody else wanted to write the CSR (was not finished pending additional data from the statistician) because the results did not support the hypothesis. Still, I think it is very important and the FDA, clinicians making medical decisions, and patients all have a right to know why studies are suddenly stopped.
There is much to be learned from the results of clinical research trials that go over the allowed maximum P value of 0.05 or may have safety concerns. The lessons may include: how to improve study designs; how to improve consistent data collection and review; that drug formulations may need to be changed to be more convenient or easier for patients to follow dosing regimens to achieve therapeutic effect; and most importantly the revealing of potential safety issues.
Publications and Clinical Summaries Reports on clinicaltrials.gov of undesirable clinical trial results would save the pharmaceutical industry from wasting money and time resources by making the same mistakes over and over in study conduct or in design. It would help protect patients from future harm by making the clinical information available about potential safety issues. The money saved by sharing the hard learned lessons discovered through very costly and time consuming failed clinical trials would certainly more than cover the costs of paying people like me starting out in Regulatory Medical Writing to wrap-up the clinical trial by writing the CSR that should be submitted to the FDA.
Also, I am constantly amazed how clinical professionals underestimate how much the average patient is able to comprehend in reading publications and reviewing data tables. That is indicated in some of the previous comment posts. The public has a right to know when a study did not succeed and why. I was able to self diagnosis myself with a medical issue that I had been dealing with for over 35 years and was never correctly diagnosed. Doctors placed me on failed drug treatment after failed drug treatment. I helped myself by having enough of doctors throwing drug prescriptions at me, going online, and reading free literature and publications on my symptoms. Laboratory testing that I requested through my doctor proved that even though I was not a trained clinician, I was right about my-self diagnosis and doctors had to concede that I was correct according to the lab results. This enabled a treatment regimen that significantly improved (not cured) my condition. But meanwhile I suffered through drug treatment regimens that either failed or caused other medical problems for over 35 years. Medical professionals are constantly grumbling about how uninformed patients are yet they will not provide adequate information when asked. Even worse they will only write publications when the results support their hypothesis. Often these publications boarder on being marketing pieces for a drug or device product instead of scientific or medical literature.
The public (of which I am included) pay for the clinicaltrials.gov site and we should have full access to the results regardless of whether there were "peer" reviewed publications. This includes access to clinical research results via the CSRs at no cost. Even though I am not a trained clinician, I have been in the clinical research industry for over 24 years. Both professionally and as a patient, I am fed up with doctors and nurses treating me like I am a complete idiot. I know how to review data and read publications; yet, my doctors considered me unable to understand information and would not provide it when I asked for information about the products they were prescribing. I bet there are plenty of people/ patients like me who helped themselves out by finding free publications and information when the trained doctors and clinicians would not take the time to help figure it out.
Bottom line – reporting the results of clinical trials that did not support the objectives or were proven to have safety issues, will save time, money, repeated mistakes, provide clinicians with important information, save people from taking harmful products, and allow people to make more informed choices about their own health, and potentially reduce years of suffering from being misdiagnosed. Rogawski is correct all clinical trial research data should be made available to both clinicians and the public. It will only benefit pharmaceutical corporations if they use it as a learning tool.
It is not the "raw data" that is being requested it is well written honest study summaries with informative data tables. And there are plenty of people like me who would be willing to take on the undesirable task of writing the CSRs on unsuccessful clinical trials. While large documents these summaries could be easily accessed by people from their laptops and would not require a large server systems to review.
I also think it would reduce the trick of meta-analysis because a well written CSR or publication needs to clearly state whether the results supported the primary objective as stated in the study protocol and the methods used to analyze the data.
Dear "Ethical Monitor"
I am currently writing an article on the issue of reporting failed clinical trial results. I would be very interesting in talking to you as you have a unique perspective being both a patient and a professional who has worked in the clinical trial industry. If you would be willing to speak to me, would you email me at mlawton425@gmail.com? Thank you for your time.
-Margot Lawton
so, what about the Chantix clinical trials?? Was their negative data hidden?? Certainly, w/all the negative side effects that accompany that drug...it had to happen early on. Will the mysterious, hidden data show up in the courtroom? What a sham! All of it! We are lied to from all sides. We are totally at the mercy of greedy, selfish, cold hearted companies and people. No one has our back. No one.