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.
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