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[e-drug] Funding bias in clinical trials?

  • From: "E-Drug" <e-drug@healthnet.org>
  • Date: Fri, 14 Apr 2006 12:23:50 +0200

E-DRUG: Funding bias in clinical trials?
[Recent research on outcomes of trials on old and new schizophrenia drugs shows that funding is linked to positive outcomes. Maybe not surprising, but what do we do now with the results of those trials? Copied as fair use with thanks from Druginfo. WB]

Comparison of Schizophrenia Drugs Often Favors Firm Funding Study By Shankar Vedantam Washington Post Staff Writer Wednesday, April 12, 2006; Page A01

Pharmaceutical giant Eli Lilly and Co. recently funded five studies that compared its antipsychotic drug Zyprexa with Risperdal, a competing drug made by Janssen. All five showed Zyprexa was superior in treating schizophrenia.

But when Janssen sponsored its own studies comparing the two drugs, Risperdal came out ahead in three out of four.

In fact, when psychiatrist John Davis analyzed every publicly available trial funded by the pharmaceutical industry pitting five new antipsychotic drugs against one another, nine in 10 showed that the best drug was the one made by the company funding the study.

"On the basis of these contrasting findings in head-to-head trials, it appears that whichever company sponsors the trial produces the better antipsychotic drug," Davis and others wrote in the American Journal of Psychiatry.

Such studies make up the bulk of the evidence that American doctors rely on to prescribe $10 billion worth of antipsychotic medications each year. Davis pointed out the potential biases in design and interpretation that produced such contradictory results. Other experts note that industry studies invariably seek to boost the image of expensive drugs that are still under patent. Moreover, they say, the trials are relatively brief and test drugs on patients with simpler problems than doctors typically encounter in daily practice.

By contrast, when the federal government recently compared a broader range of drugs in typical schizophrenia patients in a lengthy trial, two medications that stood out were cheaper drugs not under patent. The medication that worked best for patients with severe, intractable schizophrenia was clozapine, whose sales lag well behind every other drug in its class. And an earlier leg of the study found that the largely unused drug perphenazine had about the same risks and benefits as far more expensive competitors that are widely assumed to be safer.

Reliance on industry-sponsored studies is not limited to psychiatry, but experts say the problem is exacerbated in areas of medicine where the goal of trials is not to demonstrate cures but to measure symptomatic relief, which allows more latitude in how the results are interpreted and marketed. Now a growing chorus of experts is asking whether the research establishment needs to be reoriented toward publicly funded studies that might better guide clinical decisions and the billions of tax dollars the government itself spends on treatment.

"A perfectly independent agency has to be set up that says, 'Here are the areas where trials must be done,' " said Drummond Rennie, deputy editor of the Journal of the American Medical Association. "There will be two classes of trials -- the believable ones and the non-believable ones."

The problem is not that companies fabricate results, experts say. Researchers, in fact, want drugmakers to sponsor more studies, not fewer. But ostensibly valid industry studies can be misleading in multiple ways, Davis said. Some use too low a dose of a competitor's drug, while others choose statistical techniques that show their drug in the best light. Virtually all test drugs on patients with relatively straightforward problems.

Davis warned that the circular results he found could undermine the confidence of clinicians and patients, and even cast doubt on medications that are genuinely superior. He and Rennie also questioned academic researchers' role in these studies.

Davis, who joked in an interview that he no longer gets to fly first class to Tokyo and Monte Carlo since he stopped accepting money from pharmaceutical companies, guessed that 90 percent of industry-sponsored studies that boast a prominent academic as the lead author are conducted by a company that later enlists a university researcher as the "author."

"We know that happens all the time," Rennie said. "The only reason that the company wants a non-company person as an author is to give credence to an advertisement. . . . The whole entire paper from start to finish is an advertisement. It is a much more subtle and telling ad than anything they can publish as an ad."

Drugmakers defend their studies, and Davis emphasized that the drugs do help patients. But doctors, he said, cannot afford to take the results at face value.

Sara Corya, medical director for neuroscience at Eli Lilly, a company Davis singled out for praise for the quality of its studies, said that conflicting results do not cancel each other out, and that they help clinicians understand the strengths of different drugs. Corya and Davis noted that Lilly has strict rules to prevent author-shopping.

"The reality is that even in head-to-head comparisons, study results will differ for a variety of reasons, some transparent, some opaque," added Mariann Caprino, a spokeswoman for Pfizer, whose antipsychotic drug Geodon did not perform as well as Zyprexa in two trials funded by Eli Lilly. Pfizer's own studies found that Geodon was superior to Zyprexa in one trial and inferior in another.

"What this all means," Caprino said, "is there is no substitute for the judgment and experience of the clinician in selecting among a fortunately broad palette of medicines."

But several experts say industry-sponsored trials are failing to answer the questions doctors really need answered: Which drug works best for which patient? Are differences in drugs worth the differences in cost? How many patients are likely to recover entirely, rather than just show progress in the right direction? Head-to-head trials of similar medications may show statistical differences in how they perform, but those differences may not mean very much for doctors and patients, said Robert Rosenheck, a Yale psychiatrist.

What a clinician wants to know is whether the patient she is treating will get better on a drug, said Thomas R. Insel, director of the National Institute of Mental Health. "If they are not going to get well, what is the better approach? The public is less interested in statistical significance and more interested in clinical significance."

The difference between the two was highlighted by the recent study of antipsychotic drugs funded by the National Institute of Mental Health. Rather than focus on how some symptom or side effect waxes and wanes, the government trial focused on the big picture: How do typical schizophrenia patients fare on the drugs over the long term?

The results were sobering: Regardless of the drug, three-quarters of all patients stopped taking it, either because it did not make them better or had intolerable side effects. The discontinuation rates remained high when they were switched to a new drug, but patients stayed on clozapine about 11 months, compared with only three months for Seroquel, Risperdal or Zyprexa, which are far more heavily marketed -- and dominate sales.

"Clozapine is better by far than the other antipsychotics," said Carol Tamminga, a psychiatry professor at the University of Texas Southwestern Medical Center at Dallas, who wrote an editorial in the American Journal of Psychiatry about the trial. "The question is: Why do doctors not use it?"

The drug requires more careful monitoring to prevent potentially fatal bone-marrow toxicity, she said, but a national monitoring program ensures it is used properly. Tamminga agreed that marketing may play a role in why the drug is not used more often.

"Clozapine is less marketed," she said. "It is off patent. Even when it was on patent, it has never been as actively marketed as the other drugs."

The government study also provided the big picture missing from company-sponsored trials, said Jeffrey Lieberman, a Columbia University psychiatrist who led the first phase of the study: "The drugs work, but only so well. They are not meeting expectations."

By focusing on the horse race -- which drug is marginally better -- industry studies obscure the reality that better drugs are needed overall, agreed Rennie, who is a professor of medicine at the University of California at San Francisco.

"Finding the 100th similar antipsychotic drug is not where the research should be," he said. "It should be to develop new drugs, not 'me, too' drugs."

Rennie said that government agencies such as the Centers for Medicaid and Medicare Services and the Department of Veterans Affairs that disburse billions of dollars for treatment should rely on publicly funded studies.

"There are lots of questions that drug companies are not going to be primarily interested in," agreed Robert Temple, a senior official at the Food and Drug Administration. He has long been a personal advocate of what he calls a "national problems laboratory."

But Uwe Reinhardt, a political economist at Princeton, said drug companies, device manufacturers and even physicians are reluctant to delve into questions of cost-effectiveness because such inquiries may find that the latest, most expensive treatment is not worth the cost.

"I have come to believe a lot of inefficiency is quite deliberate and supported by Congress," he said. "One person's inefficiency is another person's income."

American Journal of Psychiatry 163:563-565, April 2006
doi: 10.1176/appi.ajp.163.4.563
Practical Treatment Information for Schizophrenia Carol A. Tamminga, M.D.

Schizophrenia, with its pervasive life impairments and the woeful lack of knowledge regarding its molecular pathophysiology, is a distressing mental illness. Its treatments have been empiric and serendipitously discovered, not rationally understood. Moreover, the treatments are partial, in that psychosis is the treatment-responsive symptom domain, whereas cognition and negative symptoms respond minimally. Successful treatments for schizophrenia, inadequate as they are, have been rather recent. Delay et al. first reported the efficacy of chlorpromazine in 1952 (1), and Carlsson and Lindquist identified the mechanism of that action only in 1963 (2). It is this group of dopamine receptor antagonists-direct and indirect, complex and simple, first and second generation-that we have today as our main treatment tools. While we are quick to point out the inadequacies of these medications, it is certainly true that they are far better than pre-1950 approaches (3).

We are at a point where we can ask which, among the multiple antipsychotic treatments, are best for effectiveness, efficacy, and tolerability. The Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, sponsored by NIMH, was carried out to answer these questions. The CATIE investigation is a multicenter, multiphase, multidrug study of most of the actively marketed antipsychotics. A total of 1,493 patients entered phase 1 of the CATIE study, the results of which suggested a superiority of olanzapine in length of time to drug discontinuation (4). The hope that other new antipsychotics with fewer metabolic side effects might offer a similar effect was not fulfilled. Some have pointed out that older drugs like perphenazine, with their lower costs, may now once again become rational first-line therapies. The memory of patients with tardive dyskinesia still haunts many clinicians, however. The debate over less expensive first-generation drugs obscures the sobering results of phase 1.

That first report thus also showed once again the stark reality of antipsychotic drugs-their therapeutic limitations and their problematic side effects, especially the metabolic effects. In this issue of the Journal, the CATIE story is continued. Stroup et al. report on the CATIE phase 2 "tolerability" study, which compared three second-generation antipsychotics (olanzapine, quetiapine, and risperidone) with ziprasidone (new enough to have missed phase 1) in individuals who had stopped their phase 1 medications for tolerability reasons. In addition, McEvoy et al. report on the CATIE phase 2 "efficacy" comparison of clozapine with second-generation antipsychotics in individuals who had stopped their phase 1 medications for poor efficacy. The CATIE studies are a naturalistic design, purportedly closer to what is done in the "real world" of clinical practice than the industry registration trials. They should more directly inform clinical drug use.

The Stroup study began with 43% of the original cohort and sustained a 74% dropout rate between its study start and end (6 months). Although the dropout rates are substantial, they can be understood in light of a challenging methodology, which allowed patients to continue only as long as they and their doctors thought that they could be successfully treated with the drug selected for them. Both olanzapine and risperidone showed superiority in length of time to drug discontinuation, with quetiapine and ziprasidone lagging behind. The relative side effect profiles reflect those seen in the phase 1 study, showing olanzapine with prominent weight gain and metabolic changes (increased cholesterol and triglycerides), risperidone with hyperprolactinemia, and no differences across drugs in ECG (including QT interval) measures. Because many clinicians consider the relative dose levels unbalanced, the effectiveness comparisons are difficult to fully benchmark. But, the side effect outcomes are staggering in their magnitude and extent and demonstrate the significant medication burden for persons with schizophrenia.

The McEvoy study began with only 9% of the original cohort (selected from those whose treatment failed efficacy in phase 1); 69% dropped out of the phase 2 between study start and end. The treatment cohort resembles a "treatment nonresponder" group, in that they were predominantly male, older, and had more previous hospitalizations and higher pretreatment psychopathology scores. In contrast to all previous CATIE reports, this "effectiveness" study shows a clear difference in outcome across study groups. Clozapine showed nearly a three-fold increase in time until drug discontinuation compared with the three new antipsychotics olanzapine, risperidone, and quetiapine (10.5 months for clozapine, compared with an average of 2.9 months for the others). Efficacy outcomes are consistent with the time-to-discontinuation measure. The data help answer the critical clinical question, "What to do if a new antipsychotic fails?" The evidence, clearer than many clinicians might have believed, is that clozapine is the only rational alternative. This answer is only tempered by the significantly greater side effect burden with clozapine, again demonstrated: weight gain, increased metabolic measures, sialorrhea, sedation, and the agranulocytosis that we all know to add in (even though adequate surveillance methodology is now in place). But this is a side effect risk profile that is positively balanced by clozapine's increased efficacy and effectiveness. The suggestion by McEvoy and colleagues that we should "develop models of service delivery that would encourage its [clozapine's] greater use" is an idea that is certainly timely. This study strongly confirms what we have seen before, that clozapine is our most effective drug for schizophrenic psychosis.

Several aspects of these two studies may create controversy and challenge us to think creatively about solutions. The possibility of a dose disparity across the administered study drugs, often cited (even in these two articles themselves) as possibly accounting for outcome differences, highlights the crudeness of our dosing measures. To develop equivalent dose ranges across drugs, one needs an objective measure of drug action (other than merely clinical effect); such a goal is currently feasible using human molecular imaging techniques and should be undertaken. Because we know some sites of the molecular site of action (i.e., the dopamine and serotonin receptors), objective dose-equivalence estimates could be derived with additional research. Remington et al.'s report in the March issue of the Journal, which used PET imaging to establish a dose range for long-acting risperidone, is an example of such research (5). Also, to aid translation to practice, the CATIE study utilized a new operational definition of effectiveness: treatment discontinuation for any reason. Sky-high drug discontinuation rates were seen, suggesting rampant drug dissatisfaction and inefficacy. However, in the context of this multiphase study, such a high switching rate may reflect the real behavior of conscientious clinicians working with inadequate medications in a setting where drug-switching options are invited. Treatment discontinuation for any reason might be more a measure of physician hopefulness for a next medication than an estimate of failure of the current treatment.

There has not been a previous set of treatment studies that has so clearly shown the tradeoffs for persons who need antipsychotic medication. There is no clear "winner" among the second generation of antipsychotics, weighing effectiveness and efficacy against side effects, nor a clear "loser." It is only clozapine that is superior, although its side effects are clearly challenging. These data make it abundantly clear that the risks and benefits of any single medication need to be weighed individually with each patient, and that side effect risk needs to be weighed repeatedly during treatment. Side effects need to be continuously monitored and medication adjusted to maintain optimal medical and psychiatric health in the individual person. The CATIE results are packed full of timely, pertinent, interesting, and provocative data pointing up issues about how we should treat, monitor, and advise our patients with schizophrenia in order to help them maximize their health and recovery.

The metabolic and other somatic effects of olanzapine and clozapine also have implications for psychiatric practice. As long as psychotropic medications were considered relatively free of side effects, psychiatrists could practice in settings appropriate to other mental health counselors. However, medication treatments with high side effect burden demand clinical settings that are capable of detecting and managing serious side effects. This knowledge means that the clinician's office needs to be equipped to efficiently monitor antipsychotic drug side effects. Blood pressure cuffs, scales, body tape measures, a process for plasma chemistry monitoring and electrocardiograms, and qualified consultants for medical questions become important components of practice. Dynamic information of drug side effects needs to take a prominent place in a patient's psychiatric chart. Medical consequences of psychiatric drugs are real, preventable, and require focused monitoring. Clinicians will need to have systems for the effective monitoring of drug side effects to maintain and promote physical health among patients as well as psychiatric health.

That these studies were NIMH-funded increases our confidence that they are as free from marketing or other bias or "spin" as possible. However, we do notice that the results of the CATIE studies, although broader and denser than our previous knowledge, are confirmatory of the efficacy and side effect data that we already know-data derived from pharmaceutical studies. This observation should increase our confidence in the results of drug registration studies, limited as they are to the comparative efficacy of one (possibly two) compounds.

Of course, these studies point up the great medical need of schizophrenia. Only knowledge of the molecular basis of this psychotic illness will facilitate rational treatment development. Much remains to be learned. We will have to respond actively to the critical need for new schizophrenia treatments and a real understanding of disease mechanisms with creative research, bold leaps of creativity, and astute clinical observation. The time is right for innovative collaborations between clinicians, basic and translational neuroscientists, and industry to identify research strategies and successful molecular understanding, thereby promoting rational treatments. Moreover, the field must create and sustain teams of people to test innovative treatments, represented most recently by the CATIE consortium.


Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NC5.914, Dallas, TX 75390-9070; Carol.Tamminga@UTSouthwestern.edu (e-mail).

Dr. Tamminga reports an ad hoc consulting relationship with Jansen Pharmaceuticals. Dr. Freedman has reviewed this editorial and found no evidence of influence from this relationship.

1. Delay J, Deniker P, Harl J-M: Traitement des états d'excitation et d'agitation par une méthode médicamenteuse derivee de l'hibernothérapie. Ann Med Psychol 1952; 110:267-273 2. Carlsson A, Lindquist M: Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963; 20:140-144 3. Tamminga CA: Development in somatic treatments. Am J Psychiatry 1994; 151(June suppl):216-219 4. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209-1223 5. Remington G, Mamo D, Labelle A, Reiss J, Shammi C, Mannaert E, Mann S, Kapur S: A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry 2006; 163:396-401