In addition to these issues, there are pertinent, unanswered, clinical questions regarding approved drugs. There are many clinical deficits (Klein 1993), several particularly salient. Most pharmaceutical trials are short-term, and the optimum maintenance dose is often unaddressed. In the case of antidepressants, this issue has not been subjected to a comparative, randomized trial since approval of the first antidepressant drugs over 30 years ago. This is a formidable obstacle for clinical practice that is not likely to be resolved within the current system of clinical trials. Refractory cases are also rarely studied. Clinicians do not have guidelines for deciding when patients slow to respond to treatments should be switched to other drugs (Quitkin and colleagues). Withdrawal syndromes and their care are similarly neglected.
Basic information necessary to exercise sound clinical judgment is often not available. Clinical trials report results in terms of statistical rather than clinical significance. Without knowing the proportion of patients restored to good social and vocational function, as well as symptomatic decrease, doctors cannot ascertain the clinical utility of the findings.Potential Remedies
This discussion is not an attempt to question FDA standards of safety and efficacy. Stringent guidelines are necessary; however, alternative strategies may remedy the clinical research deficits. It may be possible to institute some of these changes within the current system.
Modification of Phase II drug trials are in order (Klein 1991) to incorporate measures that reflect clinical significance. "Goal attainment scaling"--an individualized list of symptoms developed by doctor and patient--could be used to conduct individualized analyses. Longer Phase II trials addressing maintenance questions should be carried out concurrently with Phase III trials. If the benefits of the drug are not sustained, this would avoid the cost of continuing Phase III trials. Double-blind, randomized, placebo substitution, discontinuation designs in putative responders patients whose improvement cannot be clearly attributed to the medication being tested would be highly effective in evaluating both drug efficacy and withdrawal, prior to parallel group, placebo-controlled trials.
Independent Pharmaceutical Board
An independent board of pharmaceutical experts should be established to review the literature, to monitor foreign regulatory decisions, and to correspond with foreign physicians and regulatory agencies. If a drug warrants review as a probable contribution to the public health, it would be reasonable to extend the pharmaceutical firm's marketing patents seven additional years if FDA approval can be gained. This would not sacrifice current standards, but it would decrease the time to market and utilize any high quality research that has already been conducted. This should be ample economic incentive to promote such research. This could be done on an experimental basis in selected drug areas to determine if it effectively spurs research. If successful, this strategy could be expanded.
Multisite, Collaborative Research Centers
The establishment of multisite, pharmaceutical research centers, as suggested by Ray and colleagues (1993), could foster investigations of foreign drugs and new indications. Collaborative, placebo-controlled studies could be conducted efficiently in such settings. These investigations should include a psychotherapeutic framework to promote compliance and decrease attrition. Psychotherapies could also be investigated as a component of drug trials, affording important comparative information. Collaboration between researchers of different views can address many unexamined questions and decrease experimenter bias.
NIMH can play an important role in piloting and testing the feasibility of such organizations, perhaps allied with the current clinical research center program. These sites for clinical trials could be financed by taxing insurance companies or HMOs, for example. They could also be funded by pharmaceutical companies if sufficient economic incentives are established. By efficiently researching drug treatments, such research centers would decrease patient care costs and would ultimately be highly cost effective.
Psychiatric drug development has seen many successes; yet, the current system has inherent limitations. The importance of these issues for clinical practice should not be underestimated. This discussion is intended to promote active debate and the formulation of additional solutions.