Medical Journals Demand Greater Clinical Research Trial Disclosure

SUSAN DENTZER:

Sara Bostock's daughter was a recent college graduate who committed suicide after taking an antidepressant.

SARA BOSTOCK (FDA Hearing, February, 2004):

My daughter Cecily had only been taking Paxil for two weeks before she died. She stabbed herself twice in the chest with a large chef's knife.

SUSAN DENTZER:

Stories like hers have fueled a controversy over whether some antidepressants trigger suicidal thinking and behavior in children and adolescents. In turn, that controversy has sparked another one: Should drug makers publicly disclose results of all tests they conduct on their drugs, even those that show that the drugs don't always work, or that they cause dangerous side effects?

That issue came to a head in 2003, as regulators in Britain studied whether there was a link between antidepressants and suicidality. Lawrence Diller, a California pediatrician and expert in children's behavioral health issues, describes what the British officials found.

DR. LAWRENCE DILLER:

What came to light was eight unpublished studies performed by the drug companies so they could get their patent extended under something called the pediatric rule, but under no obligation did they have to publicize or publish those findings.

SUSAN DENTZER:

Some of those unpublished studies showed that many antidepressants, like GlaxoSmithkline's Paxil were ineffective at treating depression in children. The studies also showed that some kids treated with the drugs did exhibit suicidal thinking and behavior. The drug manufacturers had given those studies to the U.S. Food and Drug Administration when they sought the patent extensions. But the companies have traditionally contended the studies were proprietary information, and FDA officials have said they believed they lacked the authority to make the studies public.

Now a drive is under way to force drug makers to disclose their study data, especially when it's negative, or shows that drugs do not work. In June, New York Attorney General Eliot Spitzer sued GlaxoSmithkline, arguing that it committed fraud by withholding the negative data on Paxil. In August, the company settled the suit without admitting fraud. But it agreed to publish data from all its drug trials on a publicly available database.

Now some members of Congress, medical journal editors, and groups like the American Medical Association are calling for a public database listing all companies' drug trials and the study results. The subject was a focus of a congressional hearing today.

HENRY WAXMAN:

What we're seeing in effect is that the pharmaceutical industry has systematically misled physicians and patients by suppressing important data on their drugs.

SUSAN DENTZER:

This week the pharmaceutical companies' trade group, PHRMA, announced it would create its own database, in which companies could voluntarily disclose the results of trials testing drugs' effectiveness.

JOSEPH CAMARDO, Senior VP, Wyeth:

We would like to support, we do support the PHRMA proposal and favor having a centralized, which I believe to be somewhat more easily searchable for a physician.

SUSAN DENTZER:

But some lawmakers said the industry's move is unlikely to settle the debate over who should maintain the database, and just how much information companies should have to disclose.

RAY SUAREZ:

A group of prestigious medical journals added new fuel to this debate yesterday when they announced they would not publish the results of clinical trials unless a trial is registered from its very start in a public database. That group of journals includes the New England Journal of Medicine and the Journal of the American Medical Association.

Two differing views now on research and the level of disclosure: Alan Goldhammer is with the Pharmaceutical Research and Manufacturer's Association of America, a trade group representing leading pharmaceutical companies. And Kay Dickersin is director of the U.S. Cochrane Center, part of an international project reviewing drug trials. She is also a professor of community health at Brown Medical School.

Professor Dickersin, let me start with you. If you're just someone who gets a drug prescribed and starts taking it the way it says on the label, occasionally reads a story in the paper about the FDA approving one drug or another for use, what is at stake for you? Why is this issue an important one?

KAY DICKERSIN:

I think the public believes that when they receive a drug treatment for — a recommendation for a drug treatment that that is based on solid research evidence. The public thinks about the way evidence is used in practice as that doctors know the full scope of evidence that's out there.

As a matter of fact, if you use the example of baseball, for example, we think that — we know that there's a book that has all baseball statistics in it. We know how often Cal Ripken has hit homeruns off a given pitcher, and we have the full scope of all of baseball, Minor League, Major League, but we don't have a book like this for all of medicine.

In fact, in medicine, we don't have a very good organizational system of all the research that's been done. But I don't think the public is fully aware of this.

RAY SUAREZ:

It is important to have a database like that?

KAY DICKERSIN:

A database would be wonderful.

ALAN GOLDHAMMER:

Yeah, PHRMA believes that a database of clinical study results in an easy, accessible form, so that both physicians and patients can access this information, is important. The announcement that we made last Tuesday was actually the culmination of a three-year effort to examine how pharmaceutical companies communicate political study results and how we can do a better job of doing that.

RAY SUAREZ:

But in your new plan to create a database, aren't submitting these clinical trials, isn't it voluntary among your members and voluntary and self-regulated by PHRMA?

ALAN GOLDHAMMER:

It will be a voluntary database. And it's important to remember that even though it is going to be voluntary, the commitment from the heads of America's pharmaceutical companies have committed to this database. The board of directors has endorsed it, which consists of many of the CEO's of our industry, and we think that this is too important an issue to wait until Congress or somebody else can act. We need to get the database up and running now.

RAY SUAREZ:

Well, Professor, is a voluntary and self-regulated database at least a good start to get more of this information out where you want to be able to find it?

KAY DICKERSIN:

I don't think it's likely to work. We have a mandatory registry of clinical trials that is from legislation for serious and life-threatening diseases. We now have two studies that have shown that industry has not complied with the law. In fact, they have only registered about 50 percent of the studies that they're doing.

RAY SUAREZ:

Well, under the FDA Modernization Act of 1997, I know not a law that everybody thinks about every day, but wasn't one of the provisions of that law that clinical trials be registered and be made public and have their results findable?

KAY DICKERSIN:

Absolutely. That law from 1997 was that all trials of serious and life-threatening diseases, whether they're funded by industry or others, would be registered. The results were… that was the optional part, but they had to register the trial itself. It hasn't happened. And this wasn't even optional. So the law has not been enforceable, and there also hasn't been enough funding that was allocated to the law itself. So it's been very hard to get compliance.

RAY SUAREZ:

Well, Alan Goldhammer, if one of your members passes through the regulatory hurdles necessary for approval for a drug, why would subsequent clinical trials be done? Give us an example of why continued testing goes on with these.

ALAN GOLDHAMMER:

A good example of this would be to add a new indication to a drug. For instance, I develop an antibiotic for strep throat. I want to study it for pneumonia. That's one example. Second good example would be a new patient population. I may have studied the drug in adults, and there may be some very good utility and importance to study it in children.

RAY SUAREZ:

So if Acme Drug Company takes its strep compound to check it for pneumonia and finds it doesn't work for pneumonia, it's up to Acme whether it tells anybody about that?

ALAN GOLDHAMMER:

The expectation is that Acme would post a summary of that study to the database we've developed so if a physician was looking up Acme drug company and looks up their antibiotics, and not only would they get the FDA-approved prescribing information, a bibliography of references of studies that were published in the peer reviewed medical literature, but they would also get a summary of this study that clearly stated that for pneumonia, Acme drug doesn't work.

RAY SUAREZ:

Is that what happens in practice, Professor?

KAY DICKERSIN:

Well, right now there is no register that has results although they are voluntarily possible through the register that exists. I think there are a couple problems here. Number one, the register, the database that's being proposed by PHRMA would only be for the new drugs that they're using, at least the way I read their proposal. They've said that they will post meaningful trial results. It's not clear what meaningful trial results are.

And furthermore, they're going to be useful to the practicing physicians. Well, there are many more people who could use these results than the practicing physicians. So I'd say this doesn't go far enough. I'm glad that the drug companies are responding to the criticism, but we really need something that everyone participates in, where we have a register in a single place and you don't need to go multiple places to try find the information that you need.

RAY SUAREZ:

Professor, if the FDA approves a compound for use for one particular malady, why is it so important that information be made public that it doesn't work for other ones?

KAY DICKERSIN:

Well, for one thing, drugs are used for many more conditions than they are labeled for. And so it would be important to see all the data for the multiple uses in which drugs are used, employed.

RAY SUAREZ:

Well, Mr. Goldhammer, Congress started holding hearings. There have been proposals on a regulatory regime to do what you want to do voluntarily. Why does your organization want to avoid a law?

ALAN GOLDHAMMER:

We think it's far too important to wait for Congress to deliberate. I would use the example of the clinical trials database that Professor Dickersin commented on. That law was passed in 1997. The database was not available for industry posting until 2002 — five years. PHRMA believed it was far too important to wait any longer to get a database in a central location that would provide the clinical study results to physicians, the information they need to make prescribing decisions.

RAY SUAREZ:

Well, Professor, is PHRMA's proposal a good start until or in absence of regulatory regimes put in place? Congress may not act, the bill may not pass. Is this at least a step in the right direction?

KAY DICKERSIN:

Well, I think they might as well put it together if they want to do that. I think we can move more quickly than we have in the past. This database was available before 2002, I believe. I think the guidance for drug companies was not available until some time after the law was passed.

However, I think we could move more quickly than was moved in the past if some funding was allocated for the drug registry. I also want to point out that PHRMA's proposal is for a database. And they have explicitly said it's not for a trial register, which is what clinicaltrials.gov, which is what he's referring to from the law is. And PHRMA does differentiate between a registry and a database.

RAY SUAREZ:

Is there a threat to the brand value of many of the patented compounds that your members sell if it becomes known that it failed a test, that it didn't do so well in a clinical trial? Is there an incentive not to produce results when you find out that something doesn't work the way someone theorized before the test started?

ALAN GOLDHAMMER:

No I think to the contrary, Ray. I think the interest of the industry has always been to maximize the benefits of their medicines, both for the physicians who prescribe the medicine and for the patients that take those medicines; if a drug has been shown not to work for a certain patient population, that's important and relevant information that should be readily and easily accessible to the physician.

RAY SUAREZ:

And the moves of the journals, professor, does the fact that JAMA, the Journal of the American Medical Association, that the New England Journal has made its move and said it won't publish clinical trials… it won't… it wants the bad trials along with the good, shortly said, is that a step in the right direction, in your view?

KAY DICKERSIN:

Absolutely. It's wonderful what they're doing. I think the journal editors' main purpose is to ensure that we all have access to knowledge, which is where I'm coming from and others like me, are as well. It's patients who participate in these randomized trials and when they do that, they sign a consent form saying that they're agreeing to participate on the condition that they are contributing to human knowledge about science.

And, in fact, when you go back and ask patients, why did you participate in a trial, it's largely a matter of altruism and trying to help science and medicine in the future. If these results are never published, then they're not helping science, and, in fact, that covenant between investigator and patient is broken. Some of the challenges that we have here, the tension, is between commercial interests and ethical issues, and serving the public, who has, in fact, contributed to knowledge.

RAY SUAREZ:

Professor, Mr. Goldhammer, thanks a lot.

ALAN GOLDHAMMER:

Thank you.

KAY DICKERSIN:

Thank you.