A prescription for better drug trials: what ails drug research today? This health law expert cites a lack of openness, the pharmaceutical industry's quest for profits, and disregard for important scientific questions. He offers some proposals for a cure.

When a hugely popular drug like Vioxx is pulled from the market, or a black-box warning is added to the label of an antidepressant, many consumers wonder why these products' side effects were not detected earlier, before thousands of users were exposed to potentially serious harm.

The answer may lie in what many consumer and public health advocates believe is a dangerously ineffective clinical trial system. Too often, they say, a manufacturer's rush to market trumps concerns about patient safety, and limits on public access to trial data leave consumers and even government regulators ill-informed.

To improve the system, critics say, all drug trials should be registered in a comprehensive database at their outset. Unbiased research protocols should be developed. Results should be more available to the public. The benefit: more knowledge and greater safety for consumers.

In this interview, LEONARD GLANTZ, associate dean and professor of health law at Boston University's School of Public Health, discusses these concerns and possible remedies with TRIAL Associate Editor SARA HOFFMAN JURAND.

TRIAL: In your opinion, should there be a comprehensive database of clinical trial information?

GLANTZ: Yes. This idea is part of a larger effort to make data available so that people can interpret it for themselves. There's a proposal at the National Institutes of Health (NIH) that any NIH-funded research, when it's published, should be posted on a free Web site available to the public.

I think another useful idea is to have all the results of all clinical trials available on a free, publicly available Web site. This would be especially important for trials with negative outcomes, which tend not to be published, and for trials that have been discontinued before completion. When clinical trials appear to be heading in the direction of negative results, they may be stopped early and therefore aren't publishable. But they still may provide some useful information.

TRIAL: Should submission of data to the database be voluntary or mandatory?

GLANTZ: Mandatory.

TRIAL: Should the database be open to the general public or just to doctors and researchers?

GLANTZ: It should be open to the general public. Readers would glean information from the database the best they could. It certainly would permit sophisticated users, whether they're doctors, researchers, or public interest advocates, to interpret the data for themselves and their constituencies.

TRIAL: Does open access to information about clinical trials really promote greater safety?

GLANTZ: It can promote greater knowledge, and one can argue that greater knowledge promotes greater safety. Safety isn't just about whether the drug is safe or not safe in a general context, but rather, do people who take it do so appropriately and do they understand the risks and alternatives?

Vioxx is a good example. If the data from clinical trials had been made more readily available to the public, would we have known about the problems with the drug earlier? If all the information known about a new drug must be publicly available, the answer might well be yes. But this requires full and honest disclosure of all clinical data and analysis.

On the other hand, it is certainly true that additional information about drugs becomes available after they are put on the market. So clinical trial registries would be useful, but they would not resolve all the issues with determining safety and effectiveness.

TRIAL: Will the information in these databases be usable or meaningful to consumers?

GLANTZ: It is questionable whether the information currently available is usable by consumers. If you look at drug labels--the information that's now widely available--it's pretty much gobbledygook to most consumers. My guess is that secondary sources or users, such as public interest groups or groups with an interest in a particular disease, will take the information in the database and translate it into language that would be useful to consumers.

TRIAL: What about drug companies' claims that open access to clinical trial data might hurt their competitiveness by helping other manufacturers get inside information on their research?

GLANTZ: It strikes me as a great overstatement. All companies, not just drug companies, generally like secrecy. But clinical trials are conducted very much in public, and the thought that a company's competitors don't know what it's doing is probably not correct.

What open access will do, when the results are published, is let the competitors know whether or not the company is on the right track. This could have an effect on stock markets and some competitive aspects. So a public database may provide a company's competitors with some information on a new drug it's developing, but that company will still be the first to patent and market the drug.

TRIAL: Until this proposed database is established, the International Committee of Medical Journal Editors has announced a new policy that clinical trials have to be registered in a publicly accessible database in order to be considered for publication in the committee's member journals--including the New England Journal of Medicine and the Journal of the American Medical Association. Do you think this will be an adequate incentive for drug companies to register their trials?

GLANTZ: I think it will be an important incentive. Again, it remains to be seen, but I think it's a good start.

One thing that journal peer reviewers often don't know is whether an article includes all the available data about a drug. If an article reports on a trial that lasted 6 months, it's not clear if there's another 12 months' worth of information out there from another unreported trial. All reviewers can do is review what the authors give them from the 6-month trial, and the 12-month (unpublished) information may be quite different.

Having all trials registered and all the information available online would certainly help. And again, the concern really is studies with negative outcomes, which one rarely sees.

TRIAL: Do these proposals--both the medical journal policy and the idea for the comprehensive database--require researchers to divulge drug companies' financial support of research and any other possible biases?

GLANTZ: I don't know if these proposals specifically deal with this area, but I assume so. Since these will be databases of drug companies' research, we will know who is funding it. Databases of NIH-funded research already exist. So potential bias will be pretty clear.

TRIAL: Last summer, an article in the Journal of the American Medical Association reported that racial and ethnic minorities, women, and the elderly were less likely than white men to participate in clinical trials. What does this mean for the reliability of trials, and therefore for drug safety?

GLANTZ: Where there is a lack of diversity, the conclusions that one can reach may apply only to the specific group involved in the trial. It would be problematic for one to draw broad conclusions about safety and efficacy when the research included only a part of the population.

Last fall there was a lot of discussion about a particular drug regimen for heart disease that seems to benefit African-Americans more than it does Caucasians. This is a controversial issue because of the possible political ramifications of identifying race-based biological differences. But on the other hand, this finding demonstrates that different people--different genders, different ages, and different races--may react differently to drugs. When this is the case, it is an important thing to know so that the new drugs can be properly prescribed for patients in these different populations.

One thing to keep in mind about drug-company research is that its main purpose is not scientific. Its purpose is commercial: The goal of the pharmaceutical industry is to create products that can be sold. Often, underlying scientific questions--for example, Which populations does this drug work in?--are not explored. The issue for a particular company is, Can we get this drug approved? Once a drug is approved for any population or any condition, doctors can lawfully prescribe the drug for anything, for use by anyone.

It is useful and important to increase diversity in drug-company trials, so that the data can be accumulated and interpreted as it relates to different populations. The NIH has its own rules that require including different races and both genders in the research it funds.

TRIAL: What can researchers do to increase the diversity in clinical trials?

GLANTZ: The FDA should consider requiring that medications be tested in a number of different populations.

The protocols for pharmaceutical-industry research are not created by the researchers who conduct the trials, but by the pharmaceutical companies. Those companies pay close attention to FDA requirements.

Again, the goal of the drug company is to create products it can sell. Drug companies are not scientific institutions, and they should not be thought of that way. This is not a criticism of them. This is merely a description of them. They were not established for the purpose of advancing science; they were established to sell products.

TRIAL: Many researchers see ethical problems with using children in clinical trials. What are the alternatives to ensure drugs are safe for children?

GLANTZ: Research without consent is a very questionable undertaking. It's not always unethical. The difficult question is, Under what circumstances can we do research without the subject's consent? This is a question not just for young children. It's a question for anyone who might be made a nonconsenting subject, including people with certain kinds of mental illnesses and people with intellectual disabilities.

I think it is fair to say that the prevailing view among medical ethicists is that one can conduct research without the subject's consent if there is a good reason to believe that the research procedure itself will benefit the subject as well as provide information. When one is doing research that does not directly benefit the subjects and places them at some risk, conducting research without consent raises some very serious ethical problems.

For the most part, research on children is done under circumstances where, if the researcher's hypothesis is correct, the individual subject will benefit. For example, a child with otherwise untreatable cancer may be given chemotherapy in a research context because there is reason to believe, based on other research, that this new agent will improve the child's health.

So the general rule is that you don't start using a new drug on children. You use it first on adults and those who can consent. When it appears to work, you then move it into the child population, once you begin to understand the risks and benefits of that drug.

TRIAL: What else needs to be done to improve the clinical trials process?

GLANTZ: It has to be more open from beginning to end.

The review process needs to be open--and by "the review process" I mean the local review process, including institutional review boards that review this research. Institutional review boards are federally mandated review committees within research institutions. In order to use humans in research and to be able to submit the findings to the FDA, the company must submit the research protocols to institutional review committees for approval.

A review board must include at least one person from outside the institution. I don't think requiring only one institutionally nonaffiliated person is enough. It seems to me that the more the public knows, the better off we will be.

I think that we should try to remove as much bias as possible. There is really no question anymore that there is a relationship between who funds a study and chooses the investigators, and the study's outcome. When you compare the results of research paid for by private industry to research paid for by the NIH, you see very different results. This is troubling. I don't attribute this to corruption. I think the companies find researchers who are favorably inclined to their products and are willing to use the companies' protocols, which are designed in ways that will tend to yield positive results.

Let me give you an example: Many years ago, a drug company was working on an antibiotic for the treatment of otitis media, an ear infection in children. In trials, if the researchers used certain outcomes, such as hearing loss determined by one hearing test, it would appear that a particular antibiotic was better than another course of treatment. If the researchers used a different hearing test, it didn't appear that way.

So the question of who should select the outcomes to be used in a particular clinical trial becomes very important. Needless to say, it is in the interest of the drug company to choose the outcome that is most likely to show positive results. We need to find a way to design trials so they are not influenced by the profit goal.

Dr. Marcia Angell, in her recent book called The Truth About the Drug Companies, which is pretty controversial, said there should be a national institute that evaluates drugs. It is not clear to me why the public should pay for research if the result is a drug-company monopoly on products that would be approvable due to this institute's research.

While drug companies should continue to pay for the research on their drugs, there's no reason why they should design the trials or pick the researchers. It would be best to have a system where the drug companies say, We think this is a good drug, and we're willing to spend $500 million finding out if it is a good drug.

The companies would then provide that money to an independent agency that would choose the researchers and create the research design. I don't think that's realistic in the current political climate, but it's the kind of thing that needs to be done. I think tinkering is not enough at this point.

TRIAL: How will improving clinical trials and making the data more widely available increase drug safety?

GLANTZ: All drugs carry risks. Aspirin carries risks. You want people to be well-informed users. And you don't want people to overestimate drugs' effectiveness. At this point, direct-to-consumer drug advertising, the information drug companies now provide to consumers, is designed not to inform but to sell. A requirement that the raw data also be available to the public is one way to try to counterbalance drug companies' positive spin.

My guess is that if you asked people if Vioxx and Celebrex are better than ibuprofen at treating the pain of arthritis, I think most people would say yes. Do you agree?

TRIAL: I think most people would say yes.

GLANTZ: But they would be wrong. The manufacturers don't make that claim, though you wouldn't know that by watching their ads, full of smiling, apparently pain-free people. The advantage of Vioxx and Celebrex and that class of drugs was supposed to be lower rates of side effects, in particular stomach bleeding.

There needs to be much better regulation of the tone of drug company ads, which certainly would seem to overstate the effectiveness of those drugs and understate the risks.

Consumers need better information. They need a better understanding of the limits of drugs and a better understanding of the risks.