Thursday, September 09, 2004
Medical Journals to Require Registration of Drug Trials
The recent controversy about the safety of antidepressant medication
has brought another issue to the forefront. (Use the search function
in the Corpus Callosum sidebar and search for "antidepressant" to see other posts on
this subject.) For many years, there has been concern in the medical
profession abut the selective publication of drug trials. What this
means is that an experiment that shows that a drug works is more likely
to be published than an experiment that shows no effect. Thus, it is
possible for medical professionals to develop a false impression about
the effectiveness of a particular treatment.
That such selective publication could occur is surprising to many people. However, it order to understand it, it is important to understand the circumstances in which many of these experiments are done.
Studies of medical treatments always are expensive. Funds available in the public sector are highly limited. Therefore, much of the funding comes from the companies that are developing the new treatments. Companies traditionally have been secretive about their research and development. This is not unique to the pharmaceutical industry.
To illustrate: I happen to live a couple of miles from the Chrysler Proving Grounds. The area is surrounded by a high fence, and inside the fence are high earthen berms. This makes it impossible for anyone who is not authorized to see the new models being tested.
Since the development of a new drug usually costs hundreds of millions of dollars, it is understandable that the companies would be a secretive as possible. The government of the United States of America traditionally has allowed a high degree of secrecy. This is what allowed the situation to arise in the first place. Unfortunately, there have been unintended consequences: people probably have been subjected to ineffective treatments because of this.
Congress, and the FDA, are currently holding hearings and committee meetings to address this. As is customary in the United States of America, the political process is moving slowly. In the meantime, the medical profession has taken action to correct the situation:
From the Journal of the American Medical Association (JAMA):
This is a wonderful idea. It will not cost very much, and it will be effective. There will be loopholes, to be sure: a drug company easily could conduct a study and not register it. They still could use the results of the study to obtain FDA approval of a medication. However, the action of the ICMJE will be a powerful incentive for researchers to operate in an open manner. It also will give Congress and the FDA a model to build upon, once they finally get around to doing something.
Naturally, the open publication of all drug trials will have unintended consequences. Not all of the consequences will be good. Stock market speculators will watch the registry for early clues about the prospects for pharmaceutical companies. Pharmaceutical companies will risk tipping off the competition with the registration of their studies. Consumers will search the registry, and may draw erroneous conclusions from what they find there. for that matter, stock market speculators also will draw erroneous conclusions, but then, it's their money to loose.
Another unintended consequence will be that it will be necessary for consumers and stockbrokers to get a better education in science. If they are going to read the registry and make any sense of it, they will have to have a basic understanding of research design, statistics, and the ability to critically analyze complex information. This, in fact, will create a small industry of people who do nothing but read the registry every day, and prepare reports about the implications of what is published there.
That such selective publication could occur is surprising to many people. However, it order to understand it, it is important to understand the circumstances in which many of these experiments are done.
Studies of medical treatments always are expensive. Funds available in the public sector are highly limited. Therefore, much of the funding comes from the companies that are developing the new treatments. Companies traditionally have been secretive about their research and development. This is not unique to the pharmaceutical industry.
To illustrate: I happen to live a couple of miles from the Chrysler Proving Grounds. The area is surrounded by a high fence, and inside the fence are high earthen berms. This makes it impossible for anyone who is not authorized to see the new models being tested.
Since the development of a new drug usually costs hundreds of millions of dollars, it is understandable that the companies would be a secretive as possible. The government of the United States of America traditionally has allowed a high degree of secrecy. This is what allowed the situation to arise in the first place. Unfortunately, there have been unintended consequences: people probably have been subjected to ineffective treatments because of this.
Congress, and the FDA, are currently holding hearings and committee meetings to address this. As is customary in the United States of America, the political process is moving slowly. In the meantime, the medical profession has taken action to correct the situation:
From the Journal of the American Medical Association (JAMA):
Clinical
Trial Registration
A Statement From the International Committee of Medical Journal Editors
Early Release Article, posted September 8, 2004
JAMA. 2004;292:(DOI 10.1001/jama.292.11.1363).
Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor's product.
Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of 2 approaches to treatment (noninferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial's existence and its important characteristics. [...]
The ICMJE [International Committee of Medical Journal Editors] member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (eg, phase 1 trials), would be exempt.
The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organization. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. [...]
A Statement From the International Committee of Medical Journal Editors
Early Release Article, posted September 8, 2004
JAMA. 2004;292:(DOI 10.1001/jama.292.11.1363).
Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor's product.
Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of 2 approaches to treatment (noninferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial's existence and its important characteristics. [...]
The ICMJE [International Committee of Medical Journal Editors] member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (eg, phase 1 trials), would be exempt.
The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organization. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. [...]
This is a wonderful idea. It will not cost very much, and it will be effective. There will be loopholes, to be sure: a drug company easily could conduct a study and not register it. They still could use the results of the study to obtain FDA approval of a medication. However, the action of the ICMJE will be a powerful incentive for researchers to operate in an open manner. It also will give Congress and the FDA a model to build upon, once they finally get around to doing something.
Naturally, the open publication of all drug trials will have unintended consequences. Not all of the consequences will be good. Stock market speculators will watch the registry for early clues about the prospects for pharmaceutical companies. Pharmaceutical companies will risk tipping off the competition with the registration of their studies. Consumers will search the registry, and may draw erroneous conclusions from what they find there. for that matter, stock market speculators also will draw erroneous conclusions, but then, it's their money to loose.
Another unintended consequence will be that it will be necessary for consumers and stockbrokers to get a better education in science. If they are going to read the registry and make any sense of it, they will have to have a basic understanding of research design, statistics, and the ability to critically analyze complex information. This, in fact, will create a small industry of people who do nothing but read the registry every day, and prepare reports about the implications of what is published there.
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