Donald F. Klein, MD

While pharmaceutical research in the United States provides for unparalleled high quality of treatment, many drugs already proven effective in other countries may never become available here due to a combination of obstacles. 

Among them are the economic and legal requirements inherent in the FDA drug-approval protocol that often deter pharmaceutical firms from taking the initiative, both in conducting clinical trials for new drugs, and in studying alternative uses for existing medications.

The Food and Drug Administration (FDA) has a standard procedure by which pharmaceutical companies present drugs for study. If Phase I trials show a drug to be safe for humans, this is followed by lengthy and expensive Phase II and Phase III trials. The cost exceeds $250 million per agent and the time from patent to market is, on average, 12 years. For pharmaceutical manufacturers, the economic incentive for undertaking this substantial economic risk is a period of marketing exclusivity for approved drugs.

Constraints against importing foreign drugs makes even their informed usage by U.S. patients difficult, therefore U.S. pharmaceutical companies do not pursue the marketing of foreign drugs. Drug companies may decide that it will not be profitable to undergo the stringent procedures associated with FDA approval. Foreign studies and regulatory decisions are often considered unacceptable support, and the drug manufacturer must follow protocols required for FDA review. Companies may also be wary of the potential for raising safety questions that are not easily resolved. Such controversies could dampen the foreign drug market. Some foreign drugs will eventually be introduced, but after long delays. Clozapine (Clozaril) and clomipramine (Anafranil) are examples of foreign drugs that were substantially delayed by company hesitation. Examples of psychiatric drugs available in Europe that may never be marketed in the United States include moclobemide, mianserin, sulpiride and flupenthixol. Moclobemide is an MAO inhibitor without dietary restrictions or hypertensive crises and has a favorable side effect profile. Mianserin is a noncardiotoxic, nonanticholinergic, effective antidepressant. Sulpiride is an antidepressant that is often quickly effective in treating refractory cases and has antipsychotic properties at higher doses. Flupenthixol is an antipsychotic with limited side effects.

A number of difficulties emerge when U.S. doctors prescribe foreign drugs for their patients. Because the FDA does not have a clear policy or relationship to customs officials regarding the importation of foreign drugs for personal use, enforcement of restrictions has been erratic. The drugs may not be consistently available if intercepted at the border. If confiscated drugs are forwarded for FDA review, there are recommendations to local officials, but none of these are binding.

If doctors prescribe these drugs for their patients, other problems come to light. The prescribing clinician must inform the patient that the drug is experimental and obtain informed consent. This disclosure may decrease treatment credibility and deter compliance. 

Doctors themselves have reason for concern. Even if a foreign product is the drug of choice for a disorder, it is unclear whether prescribing physicians in the United States are covered by their malpractice insurance. This uncertainty entails significant personal risk. These issues must be addressed for drugs not marketed in the United States.

Another often-neglected area of development involves new indications for FDA approved drugs. Even if there are studies supporting a drug's use for other disorders, the FDA prohibits the pharmaceutical companies from advertising additional indications without formal approval. The associated costs often cannot be recouped, and companies may not pursue approval. 

This is not a minor concern since many first-line treatments for psychiatric conditions involve alternative indications. Tricyclics were the standard antipanic drugs for many years, but none were ever presented to the FDA and awarded this indication. Clinicians can legally prescribe a drug for alternative indications, but restricted publicity may preclude awareness of its use. Also, insurance companies may not cover the cost of a drug prescribed for unapproved indications.

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.

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.

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.

	Klein DF. Clinical psychopharmacologic practice: the need for developing a research base. Arch Gen Psychiatry. 1993;50(6):491-494.
 

	Klein DF. Improvement of phase III psychotropic drug trials by intensive phase II work. Neuropsychopharmacology. 1991;4(4):251-258.
 

	Quitkin FM, McGrath PJ, Stewart JW, et al. Chronological milestones to guide drug change: when should clinicians switch antidepressants? Arch Gen Psychiatry. 1996;53(9):785-792.
 

  Ray WA, Griffin MR, Avorn J. Evaluating drugs after their approval for clinical use. N Engl J Med. 1993;329(27):2029-2032. [Comments.]

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While pharmaceutical research in the United States provides for unparalleled high quality of treatment, many drugs already proven effective in other countries may never become available here due to a combination of obstacles.

Donald F. Klein, MD

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