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With an increasing number of drugs in the pipeline, the efficacy and safety of drug trials become even more important. Who are the various entities sponsoring these trials, and what are their goals?
More than 100 medications for mental illness are in clinical testing or awaiting approval from the U.S. Food and Drug Administration, according to the Pharmaceutical Research and Manufacturers of America (PhRMA). Will those new pharmaceuticals be safer and more efficacious and cost-effective than drugs already on the market? How will clinicians, formulary committees, patients and others learn more about these issues, and how reliable will the information be?
Last year, pharmaceutical companies spent an estimated $6 billion to discover and develop medicines for psychiatric disorders and other diseases of the central nervous system. PhRMA estimates that about one-third of company-financed research and development in the United States is devoted to evaluating promising drug compounds in human clinical trials (28.3% in Phase I to III trials and 5.8% in Phase IV trials).
Overall, 70% of the money for clinical drug trials in the United States comes from industry, wrote Thomas Bodenheimer, M.D., in the New England Journal of Medicine (2000). Debates about the quality and fairness of those trials have arisen in the popular press, in the medical literature, and at professional meetings. Among the complaints: Studies are designed to place the comparator drug at a disadvantage; companies use surrogate rather than clinical endpoints; and companies only publish studies that favor their drug and may even stop publication of a negative comparative trial (Bero and Rennie, 1996; Bodenheimer, 2000; Davidson, 1986).
"By and large, the drug companies have been somewhat reluctant to do head-to-head comparisons if they think their drug is not going to come out ahead," E. Fuller Torrey, M.D., executive director of the Stanley Foundation Research Program, told Psychiatric Times.
In contrast, Bill Thies, Ph.D., vice president of medical and scientific affairs at the Alzheimer's Association, believes the checks and balances provided by the FDA and accepted clinical trial protocols help insure reliable results.
"The modern clinical trial methodology is very robust, and I have a high degree of trust in the results," he told PT, although he acknowledged that abuses do occur in rare instances. "A properly designed trial is going to get you an appropriate answer, and it really doesn't depend on whose money is being spent. An improperly designed trial will not get you a good answer, and it won't make any difference who paid for it."
Thies, who has both managed clinical trials and analyzed their results for nonprofit organizations, pointed out that the FDA consults on many drug trials.
"Companies are quite used to consulting with the FDA before they begin these trials, because it certainly doesn't serve their interest to spend $10 million on a trial, and then have the FDA say, 'We really don't like the way it was designed, so we are not going to let you use the results in your labeling and advertising.'"
Any product claims related to safety and effectiveness must be supported by "adequate and well-controlled" studies, according to FDA requirements. In addition, the FDA Modernization Act allows promotion of economic claims based on "competent and reliable scientific evidence," according to PhRMA reports.
Many company-sponsored comparison studies are looking at specific side effects or symptoms, John Newcomer, M.D., associate professor of psychiatry/psychology at Washington University School of Medicine, St. Louis, told PT.
"With the exception of clozapine [Clozaril] for treatment-resistant patients [with schizophrenia], for the other atypical antipsychotics, there are no slam-dunk superior outcomes on efficacy," he said. "You have several drugs, all clearly superior to older antipsychotics from the standpoint of side effects, cognitive benefits, negative symptoms, many measures of quality of life and overall outcomes. But the major distinguishing features of these medications are adverse events The big effects these days are weight gain, glucose the QTc interval and prolactin levels-these are the hot button issues right now."
Some of the other industry-sponsored comparative studies involve pharmacoeconomics. In an Eli Lilly and Company-sponsored study, for example, Karen Rascati, Ph.D., and colleagues from University of Texas at Austin used data from clinical practice in a Texas Medicaid population to examine the schizophrenia-related costs (and total costs) for patients who received olanzapine (Zyprexa) versus risperidone (Risperdal) (Rascati et al., 2001).
The idea that industry predominates in the clinical trial arena is a given, so where do foundations and the federal government fit in?
"A reasonable clinical trial is going to [cost] between $4 [million] and $30 million, and that is an expense unlikely to be undertaken by a nonprofit organization," Thies explained. "Our budget on a yearly basis is running $18 [million] to $19 million for grant funding, and a good-size clinical trial could take all of that. So clearly, if we are to move the field forward toward an answer for this disease, we are not doing the best job we can if we put all of our dollars into a trial."
The bulk of the Alzheimer's Disease Foundation grant monies are spread across small, investigator-initiated awards that run between $50,000 and $200,000 per year.
"We have a fairly broad mandate, so we support basic science studies, a small amount of clinical studies and caregiver research," Thies said.
The National Alliance for Research on Schizophrenia and Depression (NARSAD) is one of the largest donor-supported organizations in the world and is devoted exclusively to supporting scientific research on brain and behavior disorders. This year it expects to award $13.6 million in grants (some over a two-year period), in addition to funds it expended to cover second-year grants from 2000. Since 1987, it has awarded $112 million for 2,543 grants to 1,344 scientists at 172 different institutions in 18 different countries.
"We have funded comparative studies in the past and will undoubtedly fund more in the future," Audra Moran, director of NARSAD's Research Grants Program, told PT.
One young investigator, Nathan Shapira, M.D., received a $60,000 NARSAD grant to evaluate the efficacy and safety of tramadol hydrochloride (Ultram) versus risperidone in the treatment of outpatients with Tourette's syndrome (TS).
Without a grant from NARSAD, this type of research is unlikely to be done, Shapira explained to PT. Even though both risperidone and tramadol have been found to be helpful in the treatment of tics (Bruggeman et al., 2001; Shapira et al., 1997), Shapira said these are off-label uses. It is unlikely the pharmaceutical companies would file applications with the FDA for this indication, given that tramadol is almost off-patent.
The lifetime prevalence of TS and other tic disorders is estimated at 0.5% to 1.6% in the United States, and they are frequently comorbid with obsessive-compulsive disorder, said Shapira. He added that pain, particularly in the shoulders, arms and eyes, is associated with tics, either from the tics themselves or efforts to suppress them. Tourette's syndrome can be attenuated by modulation of the opioid system and tramadol, approved as an analgesic, binds to opioid receptors and inhibits the reuptake of norepinephrine and serotonin as well.
The Stanley Foundation Research Program expended $21.3 million last year for research on schizophrenia and bipolar disorder, including an estimated $5 million for clinical trials. Fuller-Torrey said that over the next two years total Stanley Foundation funding will rise to $35 million to $40 million, with $15 million to $20 million for drug trials (Table).
"We will be emphasizing novel agents and things that drug companies are not going to do, not only in terms of head-to-head trials, but also medications that have been put aside because they weren't viewed as profitable, or medications that are off-label or medications that are already generic and are thought to have mood-stabilizing or antipsychotic properties."
Another type of study that drug companies are unlikely to undertake includes one that examines longer-term problems of their drugs once they have been approved by the FDA. As an example, Fuller-Torrey cited typical antipsychotics, which suppress prolactin and turn out to be pretty good contraceptives, so the pregnancy rate among women with schizophrenia is low. But clozapine and olanzapine do not suppress prolactin, so there is a predictable increase in the number of pregnancies among women with schizophrenia who are switched from haloperidol (Haldol) to olanzapine or clozapine.
Most of the comparative studies that the Stanley Foundation is funding are based on efficacy and side effects, but they are not really long trials, Mark B. Knable, D.O., medical director of the Stanley Foundation, told PT.
One of the larger trials is being conducted in cooperation with the National Institute of Mental Health and the Stanley Foundation Bipolar Network. It is the first systematic assessment in bipolar depression of the comparative efficacy of bupropion (Wellbutrin), sertraline (Zoloft) and venlafaxine (Effexor), three newer antidepressants that have different mechanisms of action.
"It is a large study, and the goal of that study is not only to find out which antidepressant is best, but also what is the risk of an antidepressant producing a relapse of mania," Knable said.
The major source for federal funding for psychiatric disorders comes from the NIMH. At a symposium at the recent American Psychiatric Association's annual meeting in New Orleans, NIMH's mental health effectiveness trials, as well as some smaller efficacy trials, were discussed.
"NIMH effectiveness research clearly is the result of several forces that emerged in the early- to mid-1990s," said Michael Thase, M.D., of University of Pittsburgh, who co-chaired the symposium with Gary Sachs, M.D. "First, in the area of psychiatric therapeutics, it became abundantly clear that there was a large disconnect between what we knew from randomized clinical trials and what was done by practitioners on an everyday basis. Most frightening was the notion that 85% to 90% of the people with disorders would be excluded from clinical trials. Secondly, it became clear that we were entirely dependent, in terms of our knowledge of new treatments and their relative merits, on the information funded by the very companies that would serve to benefit from the information about the new treatments."
Congress' goal of doubling the National Institutes of Health budget also has given NIMH more monies to conduct these clinical trials.
Some of the recent grant and cooperative agreement-funded studies include a comparative study of mood stabilizers in children and adolescents with bipolar Type 1 and a comparison of olanzapine, risperidone and molindone (Moban) in the treatment of early-onset schizophrenia, according to Benedetto Vitiello, M.D., chief of NIMH's child and adolescent treatment and prevention intervention and research branch.
In 1999, NIMH awarded a $42.1 million federal contract for the Clinical Antipsychotic Treatment Intervention Effectiveness (CATIE) research program. It comprises two multicenter, longitudinal (five-year) clinical trials designed to evaluate the effectiveness of atypical antipsychotic medications in schizophrenia and Alzheimer's disease.
Scott Stroup, M.D., assistant professor of psychiatry at University of North Carolina and one of the co-investigators on the schizophrenia study, noted that atypical antipsychotics can cost about 10 times that of typical antipsychotics. The studies will look at the effectiveness of these drugs in real-world settings.
"We are conducting the trial at 50 geographically diverse sites, including community mental health centers, Veterans Affairs hospitals, academic medical centers and private practices places where people with schizophrenia really get treated in the United States," he said.
The inclusion criteria for the 1,500 patients is broad. Patients can be 18 to 65 years old, they can have comorbid medical illnesses or substance abuse, and they can be receiving concomitant medications.
While NIMH is spending millions of dollars for the effectiveness trials, Vitiello added that it still supports a lot of efficacy and safety trials.
"So it doesn't mean that there is a change in the interest of the Institute in receiving applications that are targeted to answer questions of traditional, very well-controlled experimental trials," he said. "These trials must address an important question and not be likely to be duplicated or supported by other sources."
Bero LA, Rennie D (1996), Influences on the quality of published drug studies. Int J Technol Assess Health Care 12(2):209-237.
Bodenheimer T (2000), Uneasy alliance: clinical investigators and the pharmaceutical industry. N Engl J Med 342(20):1539-1544 [see comment].
Bruggeman R, van der Linden C, Buitelaar JK et al. (2001), Risperidone versus pimozide in Tourette's disorder: a comparative double-blind parallel-group study. J Clin Psychiatry 62(1):50-56.
Davidson RA (1986), Source of funding and outcome of clinical trials. J Gen Intern Med 1(3):155-158.
Rascati K, Barber BL, Lage MJ (2001), Olanzapine versus risperidone treatment of schizophrenia: a comparison study. NR296. Presented at the 154th Annual Meeting of the American Psychiatric Association. New Orleans; May 8.
Shapira NA, McConville BJ, Pagnucco ML et al. (1997), Novel use of tramadol hydrochloride in the treatment of Tourette's syndrome. J Clin Psychiatry 58(4):174-175 [letter].