September 2004

Show Us the Data: What Will a Mandatory Clinical Trials Registry Mean for Drug Development... And Do We Need One?

John E. Calfee
AEI

Today we are dealing with two different, albeit related trends: the first is the relatively recent public debate over the effects of the selective serotonin reuptake inhibitor (SSRI) category antidepressants used for children eighteen and under; the second concerns the formation of a public registry of pharmaceutical trials, and perhaps biomedical devices.

David Fassler, M.D.
Clinical Associate Professor of Psychiatry
University of Vermont College of Medicine

Dr. Fassler offered his opinion as a practicing child and adolescent psychiatrist, a trustee of the American Psychiatric Association (APA), and a delegate representing the American Academy of Child and Adolescent Psychiatry (AACAP) at the American Medical Association (AMA) House of Delegates.

Dr. Fassler's personal involvement in the development of a national registry of clinical trials truly began last summer with the publication of "Registering Clinical Trials" in the Journal of the American Medical Association by Doctors Dickersin and Rennie. While the idea of creating a national registry has been around for over thirty years, this piece served as a "call to arms," once again stimulating both public and professional dialogue. The article raised concerns over the unnecessary duplication of data and a general sentiment of institutionalized inertia in the drug development process. These research concerns were coupled with clinical issues expressed at the AACAP assembly meeting.  Practicing physicians were distrustful of the accuracy and validity of the data available to them and identified a lack of comprehensive information regarding the safety and efficacy of treatment interventions.

Dr. Fassler introduced a resolution to the AMA House of Delegates on behalf of the APA and the AACAP that urged the association to evaluate the accuracy, validity, and reliability of outcome data from clinical trials, and to explore the association between outcomes and sources of funding. The objective was to make as much scientifically accurate data as possible available to practicing clinicians, patients, and researchers.

The debate over a national registry collided with the SSRI controversy at the FDA hearings in February 2004. At these hearings, previously unpublished studies were made available to participants, once more illuminating the fact that not all collected data reaches practicing physicians or the general public. This lack of access to data has been called "one of the greatest roadblocks in our effort to understand the safety and efficacy of medications such as SSRI antidepressants." In June 2004, the AMA issued a report in response to Dr. Fassler's resolution. The report documented the pervasive problem of publication bias.  It concluded that studies with positive findings were more likely to be published than those with negative or no significant findings, and that this pattern of selective publication distorts the medical literature. The AMA suggested that the U.S. Department of Health and Human Services establish and maintain a complete registry of all clinical trials that is available to the public. It also recommended that institutional review boards consider registry at the trial's inception as a prerequisite for funding approval. 

The AMA report, coupled with the FDA hearings and Elliot Spitzer's recent lawsuit against GlaxoSmithKline, has brought this issue to the forefront of the medical dialogue.  As a result, the International Committee of Medical Journal Editors recently announced that registration of clinical trials at inception will become a requirement for publication.

Dr. Fassler offered the following proposal for establishing a national clinical trials registry:

1. Information regarding all clinical trials conducted in the United States which involve human subjects would be entered into a national registry.
2. Each clinical trial would be required to offer the same information (for more information, see slides accessed through the main event page).
3. The registry would not contain raw data, as too much information could prove detrimental.
4. Each trial would be assigned a unique alphanumeric identifier given by the database administrator.
5. The registry would include all clinical trials which involved human subjects and thus is not limited to pharmaceuticals, but includes surgical interventions, medical devices, etc.
6. The registry would include at a minimum all Phase 2, 3, and 4 trials, as well as all other trials and studies involving the use of a therapeutic intervention to test a specific hypothesis.
7. Registration of trials would be a requirement of Institutional Review Board (IRB) approval.
8. Only data from registered clinical trials could be submitted in support of applications for FDA approval.
9. The registry would be accessible to the general public.
10. The registry would contain appropriate qualifications and disclaimers necessary to explain the nature of the information presented (the general public would be better able to understand what the independent peer-review process is and how to weigh the data).
11. Registration would be required for all trials conducted in the United States.

Dr. Fassler acknowledged that the proposal overlooks a number of issues with respect to the logistics of operating such a registry, including where it should be housed and how it should be funded.  Nonetheless, he expressed the view that a registry of this kind would enhance the ability of physicians to care for patients, improve the validity and reliability of medical research, and ultimately save lives.

Robert Steinbrook
New England Journal of Medicine

Dr. Steinbrook is currently a national correspondent for the New England Journal of Medicine (NEJM) and served as a deputy editor there from 1993 to 2001. As both a regular journal contributor and an editor, he was able to offer a unique perspective on the thinking behind the September 16, 2004, statement of the International Committee of Medical Journal Editors (ICMJE) published in NEJM ("Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors").

Medical journal editors are responsible, first and foremost, for producing good medical journals. They must work to provide the best available information to clinicians, researchers, and patients, and to uphold the high standards and integrity of the journals and medical literature they publish. In the constantly changing field of medicine, not all conclusions will go unchallenged, and they will often evolve with further research. "Selective reporting" of clinical trials hinders scientific dialogue. Selective reporting of clinical trials does occur; researchers and medical journals are generally more excited to present positive or non-inferiority trials than negative ones. However, this reporting practice can distort the body of evidence used by clinical decision-makers. To address this problem and promote publication of the full range of clinical evidence, the ICMJE "proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all eleven ICMJE member journals will adopt a clinical trials-registration policy to promote this goal."

The ICMJE has not advocated a particular registry, but it has endorsed certain criteria: that a registry be accessible to the public at no charge, that it be open to all prospective registrants, and that it be managed by a not-for-profit organization.  The journals will require as a condition of consideration for publication that a study register in a public trials database. The registry's main purpose would not be to report data. That would continue to be the responsibility of medical journals and the existing peer-review process. Rather, it would contribute to the public record all trials that prospectively assign "human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome."

There are three different but related areas where a trials registry would advance medical knowledge:

First, it would help practicing physicians and their patients. It would provide physicians with the most up-to-date information about drug/device development and facilitate the trial recruitment process. Without information about trials, one cannot make the connection between a sick patient and a trial that could help them. The FDA Modernization Act of 1997 and the establishment of their registry www.clinicaltrials.gov attempted to facilitate this connection for studies of serious and life-threatening diseases, but there is still room for improvement. 

Second, those in medical practice use drugs and devices that are approved by the FDA. Drugs and devices may be used "off-label" at a physician's discretion. As has been discussed with the current antidepressant debate and the anti-arrhythmic controversy of ten or fifteen years ago, it is essential that doctors get the best data on off-label drug and device use to treat their patients.

Third, for medical research, which often involves investigational drugs, there is an ethical obligation to safeguard human subjects.  A national registry could function as a clearinghouse of information about possible side effects and toxicities of the drugs, interventions, or devices being studied. That information is vital for researchers as well as individuals considering volunteering for a trial.

A journal editor serves as a guardian of the integrity of the medical literature. A registry would increase transparency of the clinical trials process, provide a better evidence pool from which to draw conclusions, and hopefully help to improve medical practice.

Alan Goldhammer
PhRMA

As the associate vice president for regulatory affairs at PhRMA, Dr. Goldhammer discussed his organization's efforts to shape how the industry conducts trials and communicates the results.

In June of 2002, the PhRMA board of directors approved a standard set of principles for its members when conducting trials and disseminating those results. This set of guidelines highlighted PhRMA's commitment to communicate results of trials, regardless of outcome. Section 4A reads, "We commit to the timely communication of meaningful results of controlled clinical studies, of marketed products or investigational products that are approved for marketing, regardless of outcome."  This commitment to share findings that are positive, indeterminate, or negative is an important element in maintaining the integrity and transparency of the clinical trials process.

In the spring of this year, PhRMA's board once again reaffirmed its support of these principles and released an updated version of them. This new document made a crucial further commitment to improve the transparency of the clinical trials process. In it, PhRMA determined that communicating trial results in a medical society meeting or other specialized forum is insufficient. The results must be communicated in a way that meets the needs of the general public. To meet those needs, PhRMA has developed a database of clinical study results for its members. (Please see the slides available with the livestream video for a visual demonstration of how this database will operate.)

From the outset, PhRMA made a conscious decision to create a results database, not a national registry. Unlike a registry, which is used to notify the public of ongoing and completed trials and could be too cumbersome for practicing physicians to use, this database serves as a clearinghouse of results from completed clinical trials. The idea was to create a user-friendly central place where researchers, practitioners, and patients, can go for information about drug trial results. (Note: the database is mandatory for but not limited to PhRMA's member organizations, and goes live on October 1, 2004: www.clinicalstudyresults.org).

The database is formatted for use by the general public, and thus is searchable by multiple indicators, including company name, drug name, and keywords. While PhRMA will be monitoring this database when it is first launched, the organization hopes to turn maintenance over to an independent company, to greater ensure accuracy, efficacy, and integrity. It is necessary to remember that this database is for informational purposes only and reinforces that prescribing decisions should be made using the approved package inserts (pharmaceutical labels). PhRMA is legally required only to supply facts about on-label use for FDA-approved drugs and devices. Therefore, this database will not contain information about off-label usage, nor will there be any promotional information for additional uses.

PhRMA is committed to a dialogue with all stakeholders on the issues of clinical trials results-including pharmaceutical companies, practitioners, researchers, and patients--in the hopes of arriving at the best possible common ground.

Sally Satel, M.D.
AEI

Dr. Satel addressed the subject of a mandatory clinical trials registry through the current controversy over whether selective serotonin reuptake inhibitor drugs (SSRIs) provoke suicidal thinking and behavior in patients under eighteen. How might that controversy have evolved differently if such a registry were in place?

Last June, New York State attorney general Eliot Spitzer sued the maker of an antidepressant for withholding unfavorable information about the safety and effectiveness of a drug. The suit, filed in the New York Supreme Court and settled this summer, claimed that GlaxoSmithKline conducted at least five studies on the use of Paxil in children and adolescents but only published the one study showing a positive effect. This intensified calls for a government-sponsored registry of trials so that doctors would have wider access to clinical trial results.

First, consider the clinical realities that no registry could have affected.  One is the known risk of antidepressants in all patients, not just children. As early as the 1960s, doctors knew that these medications could precipitate suicidal activity. The neurotransmitter changes they induce can cause the patient's energy to return before his hopelessness fades. Patients no longer immobilized by their misery can now have enough energy to end it. Another small fraction of patients could flip into mania or a manic psychosis, or develop a severe form of agitation (akathisia) that might also trigger a suicide attempt. This is why standard teaching for beginning psychiatry residents emphasizes that they watch patients very closely when starting an antidepressant. In the mid-eighties the SSRI drugs came on the scene. Eventually they too were observed to spark suicidal activity and akathisia in a small percentage of patients.
 
This brings us to the second clinical reality that would be untouched by a registry. That is the high likelihood--up to 80 percent according to the American Academy of Child and Adolescent Psychiatry--that the medications are prescribed by primary care doctors and pediatricians, not child psychiatrists. Unfortunately, these well-meaning doctors may be too ready to hand out drugs for minor conditions, fail to monitor the patients closely enough, or both.

Still, there are some things that might have changed had a registry been in place.

But first, recall the recent history of the SSRI debate. In May of 2003, the FDA examined data on "emotional lability"(an adverse effect) in subjects presented by GlaxoSmithKline in connection with clinical trials in pediatric patients. Because some adverse effects seemed as if they might have been suicidal in nature, the FDA asked GSK--and ultimately the eight other drug companies who submitted pediatric data--to review their SSRI drug trials and re-submit the information on adverse effects under the umbrella category "possibly suicide-related events."  What the FDA received from the companies showed that such events were highly uneven. In fact, many of the trials found no increase in "apparently suicide-related behavior." For example, in three trials for major depressive disorder treated with Paxil, one showed a six-fold increase, and the other two showed no difference between placebo and drug. (For Prozac: one trial with no difference between placebo and drug; Zoloft: four-fold increase drug over placebo in one trial, no difference in the other). If these data were available to doctors and the public, not just the FDA, they might have suppressed some of the anxiety generated about safety.

Nonetheless, there were some trials showing self-harm, as noted above. How could transparency have helped?

First, it might have served as a stimulus for changing trial design. If the data on self-harm were available to all, it might have resulted in calls--from other researchers, physician groups, the FDA, or watchdog groups--to revise the design of these trials so that suicidal thinking and activity were built into the methodology and systematically examined as outcome measures.

Second, questions about self-harm might have alerted journal editors to questions to be asked. Editors at major publications like the New England Journal of Medicine can be very active. When a paper is submitted, there are often multiple exchanges with the researchers who wrote it if the paper appears publishable. During those many exchanges, the editors often ask the authors to include more data in the paper. Sometimes they even ask the researchers to go back to their raw data and do more statistical analyses.

In these regards, transparency might well have been an asset. On the other hand, the FDA--which did have all the safety data--felt that the  "possibly suicide-related event" designation was too crude. It contained incidents ranging in seriousness from a hanging attempt, to lightly scratching one's arm, to a girl who slapped herself in the face. It was impossible to know what those events meant and to distinguish between a true effort to end one's life and a non-lethal bid for attention.  Indeed, the only objective, irrefutable fact was that no child had actually killed himself during the trials--something people are often surprised to hear, given the media attention.  So the FDA asked suicide experts assembled by Columbia University to determine whether instances of self-harm that occurred during clinical trials were truly suicide attempts. Just looking at posted data on adverse effects would not have been all that informative.

Finally, the current controversy stems from uncertainty over whether risks associated with the medications are offset by their benefits. The benefits issue is really the key to the debate.  What would a registry potentially have told us about this?

From a research perspective, those benefits do not appear overwhelming. (Prozac, however, seems to fare somewhat better than other SSRIs.) In pediatric trials of depression, the drugs are only slightly more effective than placebos. Doctors relying on published data would not know this since there was selective publication of the most promising data.

Nor would they know, however, that in many of the drug-company sponsored trials, the sickest--and most medication-responsive--children are often excluded from participating. This leaves too many subjects enrolled in clinical trials with relatively mild to moderate depressions that would get better anyway, without medication.
 
In the end, a registry might well have helped in terms of modifying trial design to look more closely at the suicide question, which might have given doctors a more realistic picture of drugs' effectiveness in moderately depressed kids.

The greatest contribution of a registry would have been to dispel the secrecy and temper the perception that drug companies were hiding something awful.

There is important research still to do, namely studies designed to assess aggravation of suicidal thoughts and behavior in kids who are already suicidal--which we do not yet have--and studies with very ill children who have been symptomatic for a while. We also need studies that look at the long-term effects of treatment on the risk of suicide.

My strong intuition is that these studies will show that the suicidal behavior and suicides prevented by using these medications far outweigh the risks associated with the medications.

A national registry could have dispelled the aura of secrecy surrounding drug trials and corrected the perception that large pharmaceutical manufacturers were hiding dramatic evidence of harm. 

Bert Rein
Wiley Rein & Fielding

Mr. Rein is a partner in the law firm of Wiley Rein & Fielding specializing in litigation and government regulation of business.  He underscored concerns about the possible adverse consequences of a mandatory registry.

An important consideration in developing a registry is whether it will be limited to on-label, off-label prescribing, or include both. Restricting use of a medication to those indications for which the FDA has approved it relies on comprehensive data that has been exhaustively reviewed by the FDA. Off-label prescribing--using the drug for non-approved medical purposes--relies primarily on physician-to-physician word of mouth and the medical literature.  Thus, a clinical registry of raw, unevaluated results may be of marginal benefit to approved uses and arguably have only a "promotional" effect on unapproved uses.  Still, if physicians are going to make choices about the use of approved drugs and devices, should a national registry include information about off-label uses? If not, should there be some mechanism through which information about such uses is regulated and tested for validity?

Theoretically, everyone should have complete information that is easily shared, but the current model by which advances in medical care occur is a competitive one.  It depends on economic incentive, and intellectual property is important. Drug companies, obviously, do not want to help their competitors.  Thus, tension exists between a system in which we continually share information about results and trials and everybody advances more quickly, and one in which research and development is driven by economic incentive. If the latter is preferable, we must accept the implicit secrecy that goes along with this type of system. 

There are some fundamental questions that need to be answered as this debate continues. What is the role of a registry regarding on-label use?  How will the presented data be interpreted and used, and does the existence of a registry suggest that people should not trust the FDA reviewing process?  Why do we need to see the data for ourselves?  And what do we do with regard to controlling the information about off-label uses?

Additionally, who is really going to use this registry?  Can individuals evaluate this data capably?  What is the purpose of flooding both patients and physicians with this information, and where can they turn for analysis and distillation? It is highly unlikely that patients will be benefited by increased access to raw data, and physicians likely do not have time, thus creating an opening for a new industry of middlemen who analyze and distill.  Does this, then, defeat the purpose of a registry?  In all likelihood, those motivated by economic interest will use the registry. Trial lawyers will look with great care to find loopholes in accountability for liability purposes, especially if there is a delay between the trials themselves and the published findings.  When does the duty to warn a trial participant of possible dangers arise?   Will competitors use the registry against one another? How will it affect manufacturers of products like dietary supplements who are not regulated by the FDA?

Lastly, if all is revealed, at what point do drug companies gain a voice?  Can they speak out about off-label uses, something there is currently no public forum for?  And can they respond directly to critics who use the information provided by the registry to attack the drug companies?

It is quite evident that a national registry will not be cost-free.  There is a high likelihood that a mandatory registry will confuse the public. And that it will pose a threat--or at the very least a perception of threat--to the pharmaceutical industry if a registry distorts the competitive environment. 

AEI research assistant Nell Manning prepared this summary.