Multinational Monitor

JUL/AUG 2004
VOL 25 No. 7


Monopoly Medicine: The Built-In Inefficiencies of a Patent-Based Pharmaceutical R&D System
by James Love

It’s in the Genes: Patent Barriers to Genetic Research
by Lee Drutman

Buy the Numbers: Publishers Seeks Special Database Monopoly Protections
by Robin Gross

The Great Global R&D Divide
by Gunnar Westholm, Bertrand Tchatchoua and Peter Tindemans


The Rise of the Free Software Movement: Freedom from Proprietary Control
an interview with Richard Stallman

A Conspiracy of Silence: The Suppressed Evidence About Anti-Depressants
an interview with Charles Medawar


Behind the Lines

A Healthcare R&D Treaty

The Front
Rigging the System - Lay Does Perp Walk - Remembering Paul Klebnikov - "The Shame of Humanity" - Grief for the Reefs

The Lawrence Summers Memorial Award


Names In the News


A Conspiracy of Silence: The Suppressed Evidence About Anti-Depressants

an interview with Charles Medawar

Charles Medawar is the executive director of the London-based Social Audit, a British public interest group. Medawar is a specialist on medicines policy and corporate accountability. Social Audit's work on anti-depressants helped bring to widespread public attention the risks and side effects of anti-depressants, and drug regulators' failure to ferret out these hazards. Medawar is the co-author with Anita Hardon of Medicines Out of Control: Antidepressants and the Conspiracy of Goodwill.

Multinational Monitor: How effective are the blockbuster anti-depressants?

Charles Medawar: If you look at the performance of these drugs in large populations, you get a very consistent pattern. These drugs are generally shown to be more effective than a placebo, a dummy drug, but the data for large populations disguises the reality as most individuals would experience it.

I suspect what happens with these drugs is that a relatively small proportion of people -- perhaps 10 to 15 percent -- will find the drugs to be extremely effective. Another small proportion of a comparable size will find the drugs quite unacceptable and intolerable, and a small proportion of those would find them potentially dangerous. For the vast majority of users -- perhaps as high as 80 percent -- it would make very little difference whether they took one of the drugs or a placebo.

The other thing one can say about the measured performance of these drugs is that in spite of the different mechanisms of action -- some drugs for example work on the serotonin system, and others do not -- there are no measurable differences in effectiveness. Considering the claims made for the different kinds of anti-depressants, that seems astonishing.

I also have to add a caveat to the first point I made. The evidence that shows these drugs to be more effective than placebo comes from published trials. What has become clear as a result of the investigations surrounding the anti-depressant crisis is that a good deal of evidence is not published. In other words, the drug manufacturers are publishing the trials that demonstrate positive results and often not publishing the results of trials which do not show positive results.

There is an outstanding example of this in relation to the FDA's efficacy requirement -- that the sponsor of the drug (the manufacturer) should produce evidence from two trials demonstrating greater effectiveness than placebo. Because of the relatively weak effect of the anti-depressants, it seems that the manufacturers normally conduct eight studies of drug against placebo in order to come up with two positive results. I'm sure the four or five or six trials that demonstrate no difference between drug and placebo are submitted to the regulators, but they are identified as something else, for example, safety studies. The trials which do not demonstrate effectiveness are not submitted to satisfy that particular requirement of the FDA, and the FDA apparently has no objection to this. What should happen is a meta-analysis of all trials conducted to the same protocol -- to take account of the results of all the studies done, and not simply the ones most favorable to the manufacturer.

MM: What are the risks and dangers of using these drugs?

Medawar: The risks are very unpredictable -- you really don't know who is going to experience what in advance. The risks are compounded by the fact that the manufacturers, essentially for marketing reasons, tend to recommend a single uniform dosage for everyone. A one-size-fits-all basis is extremely convenient for marketing, but seems quite inappropriate, considering what we know about the subtleties and variations of individual response. And in extreme cases, the consequences may be very serious.

Albeit 15 years too late, the authorities have also now acknowledged that there are major risks of dependence -- when you want to stop taking the drug, you can't because of sometimes severe withdrawal effects. The other notable risk is with drug-induced feelings of suicidality. It is now accepted that there is such a risk in young people, adolescents and young adults, but I suspect that the risk actually applies to all age groups. On top of those major risks, there are a number of other side effects, sometimes extremely nasty: weight gain, loss of libido and mood swings are three of the most commonly mentioned side effects.

The drug monitoring systems that we use once drugs are actually on the market are extremely inadequate in picking up the extent of such side effects. There is still no really effective monitoring of clinical experience, and it certainly doesn't help that user reporting about these drug reactions tends to be ignored.

MM: When did the evidence emerge of the risks as they now are understood?

Medawar: I am now pretty much convinced that the risks of dependence arising from severe withdrawal reactions were available from the studies that were carried out before these drugs were even brought to market, between 10 and 16 years ago. The risk of suicidality was certainly first mentioned as a suspicion well over a decade ago; but it was barely investigated at the time. There has been a rumbling concern, but the issue was never properly addressed until 2003.

The regulators would defend themselves, saying that they need scientific validation of harm before they can issue warnings. But what about their democratic responsibilities? Of course they need to follow good science, but even in the face of uncertainty, users need to know of the existence of risk.

There's another, more general point worth making here. Once the regulators license a drug, if they later discover problems with that drug, they are not only investigating problems with the drug -- they are also in effect looking into the possibility that they have overlooked something, or made some bad mistake. So they have a vested interest in not admitting their own failings. That's one reason why I would argue that the pre-licensing scrutiny of a drug and the post-licensing surveillance should be conducted as separate functions, preferably by separate agencies.

MM: How did you come to recognize the problems with anti-depressants?

Medawar: In the late 1980s, I worked as an advisor in a (government) legally aided action brought by people who were alleging problems arising from dependence on tranquilizers. So I knew something about the problems of dependence, and the kind of anguish that that can cause users.

In 1994, I was invited by the journal Nature to review a book called Listening to Prozac.

Reading that book suggested very strongly to me that the anti-depressants posed exactly the same kind of risk of dependence because of severe withdrawal symptoms. The withdrawal symptoms were not at that time acknowledged; they were being described as "relapses" into depression. In other words, when people stopped taking a drug, and then felt wretched and got depressed, the manufacturers and the regulators all said, "Well, that shows that the drug has been working because when you stop it, you get ill again. Therefore you need to keep taking the drug."

That was exactly what had happened with the benzodiazepine tranquilizers (which include, for example, Valium). So, in that book review, I quite strongly floated the concern that we were now embarking on yet another round of prescribing a class of dependence-inducing drugs, just as we had previously with the benzodiazepines -- and before them the barbiturates, and the bromides and even the major opiates, all now well recognized as drugs of abuse.

So I thought there was a problem looming. In 1997, I published a 20,000-word monograph explaining the reasons I thought that dependence would emerge as a problem and suggesting that the regulators do something about it.

For the next five or six years, the British regulators actively resisted anything that I proposed and generally rubbished the idea.

Finally, in 2003, they set up a committee of inquiry, which has yet to pronounce on the subject but which I am confident will conclude there is indeed a problem with severe withdrawal leading to dependence. If they are honest, they will also admit that that problem was in fact evident from the very earliest work ever done on these drugs.

MM: What was the role of patients in focusing attention on these issues?

Medawar: The advent of the Internet means that, for the first time, users actually have some forum and opportunity across borders to compare notes. This really amounts to a sea-change in the history of medicine.

Largely because of the mass media, the time it has taken to recognize the problem of dependence has become increasingly shorter over the years. With barbiturates, it took about 60 years. With tranquilizers, it took about 30 years, from about 1960 to 1990. With the anti-depressants, we're now down to about the 15-year level.

I think the Internet is going to change things permanently. I really don't think any regulators can credibly dismiss reports from patients any longer. Certainly the British regulators have now accepted that patient reports need to be taken into account, although I have precious little confidence in their ability to actually organize effective patient reporting. The FDA does accept patient reports, but when it does drug evaluations I suspect it very much sidelines them as "not medically validated."

So there is a lot more work to be done before patients have the voice that they need in order to ensure that the drugs they take are reasonably safe and effective. But I think the anti-depressant crisis marks something of a watershed. Patient accounts on the Internet made the problem obvious years before the regulators actually recognized what was going on. That was also true with the benzodiazepines, but the forum in that case was provided by legal actions and the media, not by the Internet.

MM: How do your efforts to generate patient accounts contrast with the post-marketing surveillance in the United States and in the UK?

Medawar: I wouldn't make any claims to have produced credible scientific data. What I think I have been able to do, mainly by monitoring websites and by analyzing the many thousands of reports that have come into our website, is to produce a volume of data that cannot possibly be dismissed as fantasy or irrelevant. At the very least, these data make a compelling case for further investigation, which for years did not happen. I believe that, years ago, evidence from users provided overwhelming evidence of a problem and of the need to warn. What the regulators in fact did was to fail to investigate properly, and then decline to warn against possible risks, because they hadn't established the actual levels of harm.

Especially in America, the regulators use a system of post-marketing surveillance, which very much plays second fiddle to the data from clinical trials that are conducted before the drug came to market. If you look at the label of drugs produced in the United States, you will often see detailed data, down to the last decimal point, defining how these drugs performed in clinical trials that were conducted over a decade ago. The extent to which post-marketing data -- based on actual, widespread use -- modifies the profile of the drug originally established in clinical trials verges on pathetic. There is a tendency to dismiss post-marketing reports as anecdotal, not scientific and not systematic.

British regulators, with some justification, claim to have the best post-marketing system in the world. Yet it is also a system that is patently inadequate. The level of reporting of adverse drug reactions from all doctors probably amounts to only about 1 percent of all reportable reactions. One reason of course is that doctors tend to be very shy about breaking new ground: for example, if they've been told endlessly that withdrawal symptoms are in fact a manifestation of relapse, they are likely to believe that for many years until the evidence comes through to put them right.

MM: How does the industry structure clinical trials to shade the results?

Medawar: The companies that sponsor these drugs are multi-billion dollar organizations whose fortunes depend on the success of probably no more than half a dozen drugs, their blockbusters above all. Naturally they love those drugs like mothers love their babies. It is quite natural for them to find every possible way of advancing the reputation of those drugs, and demonstrating the triumph of benefit over risk.

Companies routinely use all kinds of ploys to demonstrate drug benefit and lack of risk. They manipulate the results, for example, through selection of investigators, selection of trial subjects, the design of the protocol, the interpretation of data, and where and whether the data is published at all. All of these things can make a substantial difference to the perceived benefits and risks of the drug.

And companies increasingly have the regulators on their side. Certainly the posture of the British regulators is to trust companies to play fair. Among other things, this means that regulators routinely rely on the sponsor companies' evaluation of their own data -- their clinical summaries -- rather than looking critically at the data itself.

The investigation of just the two major suspected side effects of anti-depressants, suicidality and drug withdrawal reactions, has so far taken the best part of 18 months. And yet most regulatory agencies will approve a new drug in something on the order of 30 to 40 working days. There are two ways of interpreting this difference. One is that the regulators are dragging their feet in the current review of anti-depressants. The second is that they are putting into this review the kind of effort that they ought to be putting into the evaluation of new drugs. If the regulators were to scrutinize new drug applications with the fervor that certainly the British authorities demonstrated in reviewing the risks of anti-depressants, they would be far more likely to establish some more realistic equation of benefit and risk.

MM: What does it mean to make choices about who is eligible for participation in the trial? How can that effect the outcome of a test?

Medawar: Well, for example, you can exclude people who you would consider at high risk for safety problems. A series of studies by a team led by a man called Zimmerman in 2002 profiled people who had been prescribed anti-depressants in general clinical practice and found that only 13 percent of the people who actually received anti-depressants would have been eligible for inclusion in clinical trials.

In the same way, anti-depressant drug trials will routinely exclude pregnant women and children. Yet you know that these drugs will be used by pregnant women or women liable to become pregnant or children. But you reduce the risk if you select trial subjects with a view to demonstrating the benefits of drugs rather than exposing their risks.

The age groups that you consider, the sex and race will also make a difference with anti-depressants. Another factor is the extent to which genetic variations between different subjects will make a difference to the way in which the drug is metabolized. No systematic attempt was made in anti-depressant drug trials to distinguish those people who would metabolize the drugs more slowly than others. From a mass marketing perspective, I'm afraid patients are just considered as a homogenous whole, with uniform needs. So all of this is compounded by the philosophy of one size fits all.

With a drug like Prozac, you could say with absolute certainty, based on the manufacturers' own trials, that at least half of all people who receive that drug would do just as well in terms of efficacy if prescribed one quarter of the recommended dose -- and of course there would be the added benefit of a reduced risk from exposure to the drug. You could say that for certain because you know with anti-depressant drugs that 30 to 40 percent of people are going to respond as well to a placebo as to the active drug.

But the way in which the regulators operate seems to assume that, if one or two people out of every 10 benefit -- i.e. if there is a statistically significant benefit demonstrable across a whole population -- then everyone should be exposed to the risks even if they will not enjoy anything like the same benefits.

MM: In what way is commercialization of drug testing a shift from what happened before, and what are the implications?

Medawar: Drug testing is a big business. Over the last generation, that business has shifted appreciably from an academic setting, usually in teaching hospitals, to commercial organizations. I am sure this has made a considerable difference in the way in which drug results are obtained, interpreted and reported.

Another difference is the tendency to do multi-center trials, which basically means that in a number of different centers a small number of patients are recruited, all tested to the same protocol -- and then it is the company that writes up and interprets the results. And all kinds of things can slip between the cracks, or get lost: the tendency to put best foot forward and to overlook the possibility of risk or harm is pretty deeply ingrained.

I think when you look back at a lot of the early anti-depressant trials, you see that suicidality was quite often reported. But the investigators very rarely attributed that to taking the drug. It was just too easy to say, "Well, suicide or suicidality is associated with depressive illness, and that must therefore be what caused it." The tendency is to make very optimistic assumptions -- and because so much is done in secret, these are pretty much unchallengeable assumptions.

MM: What is the importance of the lawsuits filed by the New York attorney general charging that drug companies suppressed data on the harmful side effects of anti-depressants?

Medawar: I imagine it will interpret what is happening with anti-depressants in a way which causes us to re-think and substantially re-adjust the way we evaluate and approve drugs.

One of the immediate consequences of that action was to exert a considerable amount of pressure for disclosure of data, data which has hitherto been regarded as commercially confidential.

If you look at the reasons for this commercial confidentiality, you find that it has not to do with the protection of in-house know-how or technologies that that are being developed by companies. The confidentiality arises because of commercial sensitivity. Sensitivity is a very different thing from, say, a trade secret.

In the UK, for example, commercially sensitive information is information that could affect the share price of the company. Once you get into that particular ballpark, you are in effect saying that any information about benefit may be made public, but all information about risk is commercially sensitive. So you automatically stack the benefit-risk equation hugely in favor of benefit.

MM: How effective would disclosure of all tests, positive and negative, be as a remedy for the various problems you have identified?

Medawar: If disclosure were the rule rather than the exception, I think it would make a very decisive difference. First of all, the volumes of data that regulators deal with are far too great. If the data were made public, the regulators could rely on others -- including competing manufacturers -- to take on some the evaluation work that is needed.

At the moment, competition among drug makers is based on who can keep the best secrets. If you want competition on the basis of drug efficacy and safety, it seems reasonable that one drug manufacturer might criticize the results of another manufacturer if the results were questionable.

Clearly no drug manufacturer wants a major disaster on their hands and no major drug manufacturer is going to feel at all comfortable about mass marketing a drug which they know poses significant dangers. But so long as the regulatory system is so weak as to fail to disclose those dangers, companies will always face the temptation to go too far.

The State of New York v. Glaxosmithkline

In June, New York Attorney General Eliot Spitzer filed a lawsuit against pharmaceutical giant GlaxoSmithKline (GSK), charging the company had illegally suppressed clinical study information showing that an antidepressant failed to perform better than a placebo in children, while raising the risk of suicide in children receiving the drug.

Spitzer's suit says that Glaxo concealed three key pediatric studies concerning the efficacy and safety for children of paroxetine, sold under the brand name Paxil.

Although paroxetine is not approved by the U.S. Food and Drug Administration (FDA) for prescription to children, doctors routinely write "off-label" prescriptions for the product for children, a practice permitted under FDA rules. More than two million prescriptions for Paxil were written for children and adolescents in the United States in 2002. Nearly 900,000 of these prescriptions were for youngsters whose primary diagnosis was a mood disorder, the most common of which is depression.

"By concealing critically important scientific studies on Paxil, GSK impaired doctors' ability to make the appropriate prescribing decision for their patients and may have jeopardized their health and safety," said Spitzer in announcing the suit.

GSK responded in a statement that it "has acted responsibly in conducting clinical studies in pediatric patients and disseminating data from those studies. All pediatric studies have been made available to the FDA and regulatory agencies worldwide. We have publicly communicated data from all pediatric studies."

Spitzer's complaint cites a 1998 GSK memo which states that the company must "manage the dissemination of these data in order to minimise any potential negative commercial impact." In its statement, GSK claimed that, "As for the 1998 memo, it is inconsistent with the facts and does not reflect the company position."

Later in June, GSK announced a new policy, whereby it would post on the Internet summaries of the results of clinical trials it conducts. Spitzer welcomed the announcement, but indicated the lawsuit would proceed.

Excerpts from the complaint -- the initial presentation of the case against GSK -- follow:

GSK's Studies Concerning the Safety and Efficacy of Paroxetine in Treating Children and Adolescents with MDD [Major Depressive Disorder]

GSK conducted three randomized, placebo-controlled, double-blind clinical studies to assess the safety and efficacy of paroxetine in treating children and adolescents diagnosed with MDD. These studies are referred to by GSK as studies 329, 377 and 701.

GSK management approved the final clinical reports for studies 329 and 377 in 1998 and for study 701 on July 31, 2001.

GSK has represented that studies 329, 377 and 701 were "well designed and appropriate to investigate whether paroxetine was efficacious in children and adolescents with MDD." The FDA has also referred to them as "well-controlled trials."

GSK conducted two additional studies that were extensions of studies 329 and 701. The extension of study 329 (final clinical report approved by GSK on October 31, 2001), which included only youngsters with MDD, was not randomized. It was designed to evaluate relapse rate and longer-term safety, not efficacy. Study 716 (final clinical report approved by GSK on September 16, 2002), was not randomized, placebo-controlled or blind (all participants received paroxetine during the extension) and included participants from completed studies of pediatric patients with MDD (study 701) or OCD [Obsessive Compulsive Disorder]. It examined the longer-term safety of paroxetine.

GSK's studies did not demonstrate that paroxetine is efficacious in treating children and adolescents with MDD.

Two of the three GSK placebo-controlled studies (377 and 701) failed to show that paroxetine was more effective than placebo or that there was any evidence of efficacy for treating MDD in children and adolescents. Ö

Another placebo-controlled trial, study 329, presented a mixed picture of paroxetine's efficacy in treating MDD in a pediatric population. Ö

GSK's studies showed the possibility of a link between paroxetine and an increased risk of suicidal thoughts and acts in adolescents. Combined, studies 329, 377 and 701 showed that certain possibly suicide-related behaviors were approximately two times more likely in the paroxetine group than the placebo group. The extension phase of study 329 and study 716 provided support for the presence of such a risk in youngsters taking paroxetine. ...

GSK's Presentation of Positive Information and Misrepresentation and Suppression of Negative Information

Because its studies failed to demonstrate efficacy for paroxetine in treating MDD in children and adolescents and suggested a possible increased risk of suicidal thinking and acts for these youth, GSK sought to limit physicians' access to only the most favorable aspects of the data from these studies. To accomplish this, GSK embarked on a campaign both to suppress and conceal negative information concerning the drug and to misrepresent the data it did reveal concerning the drug's efficacy and safety.

GSK's Release of Study 329 and Concealment of the Unfavorable Studies

An internal GSK document from 1998 concluded that, in light of the mixed efficacy outcomes from study 329 and the entirely negative results of study 377, GSK's "target" was "[t]o effectively manage the dissemination of these data in order to minimise any potential negative commercial impact."

As part of its campaign to "manage the dissemination of these data," the document recommended that GSK prepare and cause the publication of a full article on the only study with some favorable conclusions, study 329.

Thereafter, and in accordance with the recommended plan, an article that described and analyzed the results of study 329 was published in a professional journal. The authors of this article included two GSK employees who authored GSK's final clinical report for study.

Although it allowed the data from study 329 to be published, GSK concealed and suppressed studies 377 and 701, which failed to show that paroxetine was more effective than placebo in treating MDD in children and adolescents.

While information from study 377 was presented at a medical convention in 1999, neither study 377 nor study 701 has ever been published, and they remain unavailable to physicians, as are the results of the extension phase of study 329 and study 716. (Interim results from study 716 were presented at a medical conference in 2002.) Ö

GSK's Provision of Misinformation to its Sales Force. Which Is the Company's Liaison to Physicians

GSK has repeatedly misrepresented the safety and efficacy outcomes from its studies of paroxetine as a treatment for MDD in a pediatric population to its employees who promote paroxetine to physicians. These sales representatives are the GSK personnel who routinely have personal contact with the physicians who decide whether to write prescriptions for paroxetine.

On a cover memo that transmitted the published article concerning study 329 to "All Sales Representatives Selling Paxil," Zachary Hawkins, GSK Paxil Product Management, stated, "Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression." (Type face as in original.)

Study 329 did not demonstrate remarkable efficacy and safety in treating adolescent depression. Although the memo contained the boiler-plate language, "FYI Article will be stamped: This article is for pharmaceutical consultants' Information only. Do not use it with, or distribute it to physicians," it is clear that this was the intent. GSK would have had no reason to provide this information to sales representatives other than to use it to falsely characterize study 329 in their communications with physicians. Indeed, it appears that these sales representatives had paroxetine "targets" for psychiatrists who treat only children and adolescents, because GSK informed its sales force that these targets would be eliminated in 2003. Ö

GSK's Misrepresentations in its Medical Information Letters: November 2001 through January 2003

GSK provides information concerning off-label uses of its drugs to physicians through its Medical Information Letters, but only when the physician makes an unsolicited request for the information.

As of November 2001, GSK had completed and approved the final clinical reports on studies 329, 377 and 701, and the extension phase of study 329. GSK issued Medical Information Letters in November 2001 and January 2003, both of which misrepresented the information concerning the safety and efficacy of paroxetine for treating MDD in children and adolescents as GSK knew it at the time. Ö

GSK's Disclosure of the Studies to Regulatory Agencies and its Admissions Concerning Efficacy and Safety

In 2002, as part of its application for FDA approval of paroxetine to treat OCD in children and adolescents, GSK submitted the final clinical reports for studies 329, 377 and 701, which assessed the safety and efficacy of paroxetine in the treatment of MDD in pediatric patients. GSK subsequently provided these materials to the drug-regulatory agencies of other countries.

The studies raised issues for all the drug-regulatory agencies regarding the efficacy and safety of pediatric use of paroxetine for treating MDD.

In documents submitted in response to safety and risk-benefit issues raised by various drug-regulatory agencies, including the FDA, the UK's Medicines and Healthcare products Regulatory Agency and the European Agency for the Evaluation of Medicinal Products, GSK admitted that studies 329, 377 and 701 "all failed to separate paroxetine from placebo overall and so do not provide strong evidence of efficacy in this indication." Ö

GSK misled and deceived physicians and consequently the patients who relied on their professional judgment. GSK deprived physicians of the information needed to evaluate the risks and benefits of prescribing paroxetine for children and adolescents with MDD. By doing so, GSK deceived these physicians, irrespective of whether or not they would have prescribed paroxetine if GSK had disclosed the material facts that were known at the time. ...


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