Pink Sheet is part of the Business Intelligence Division of Informa PLC

This site is operated by a business or businesses owned by Informa PLC and all copyright resides with them. Informa PLC’s registered office is 5 Howick Place, London SW1P 1WG. Registered in England and Wales. Number 8860726.

This copy is for your personal, non-commercial use. For high-quality copies or electronic reprints for distribution to colleagues or customers, please call +44 (0) 20 3377 3183

Printed By

UsernamePublicRestriction
UsernamePublicRestriction

FDA SHOULD "STREAMLINE" DRUG TOXICITY/INEFFECTIVENESS REPORTING

Executive Summary

FDA SHOULD "STREAMLINE" DRUG TOXICITY/INEFFECTIVENESS REPORTING process, the American Academy of Family Physicians (AAFP) recommended in an Aug. 7 "white paper" on generic drugs. Calling the current procedures "burdensome and often without positive results," AAFP maintained that they "do not encourage the reporting of problems related to brand name or generic substitutes." The recommendation is one of five formulated from a two-year literature review conducted by the academy's committee on drugs and devices and approved by the academy board last week. The academy's congress will vote on the recommendations at the AAFP annual meeting on Sept. 16-18 in Los Angeles. The white paper also "supports the position that there should be no blanket approval of generic substitution." Furthermore, the AAFP recommended that there should never be mandatory substitution in certain "critical" cases involving: patients 75 years and older; diseases for which it has been shown concurrent therapy is destabilizing, including depression, asthma, congestive heart failure, diabetes mellitus, cardiac problems, and psychoses. AAFP also advised that antipsychotics and loop diuretics should not be substituted for because of the "wide range allowed for [generic] 'equivalency.'" The academy also criticized FDA's basic assumption in the approval of generic products -- that bioequivalent products are therapeutically equivalent. "The bioavailability of a drug in serum or urine measurements cannot be assumed to mean that the drug is therapeutically equivalent," AAFP maintained. Therefore, the white paper asserts, "the FDA methodology of testing a generic product . . . is lacking in credibility" in that it fails to consider "first pass metabolism, active metabolites of the chemical, age, sex, dissolution, absorption, gastric pH, influence of other diseases and drugs, and effects of ingestion with food alcohol or in tobacco user." FDA standards for bioequivalency in the the literature range from +/-10% for warfarin; +/- 25% for anti-arrhythmic drugs; and +/- 30% for antipsychotic drugs, the academy noted. "It is clear from our review that some drugs have an extremely narrow therapeutic window," such that" even a 10% over-or-under dosage may be dangerous in our patients." FDA previously addressed this issue in a February 1988 Bioavailability Task Force report. The task force found that the FDA standard of +/-20% to be adequate to assure bioequivalence of generic products. Although the task force indicated that there may be some merit in a +/-10% approval criteria, it pointed out that only about 1% of generic drugs would fail to pass the criterion since the mean bioavailability difference for generic drugs is 3.5%. Asserting that "the testing required by FDA does not document that bioequivalency equals therapeutic equivalency," the academy urged the agency to require "scientifically reliable methodology to insure therapeutic equivalency, rather than bioequivalency." The academy claims that "drugs approved by the FDA as generically equivalent (i.e., listed as class 'A' in the FDA 'Orange Book') have frequently not been found as effective as their brand name counterparts." In 1987, FDA appointed a Therapeutic Inequivalence Action Coordinating Committee (TIACC) to investigate reports of therapeutic inequivalence. To date, the committee has completed investigations of approximately 11 products and has concluded that the reported therapeutic failures had stemmed more often from manufacturing problems and not from drug inequivalency. However, this year the agency tightened requirements for therapeutic failure reporting in its July 10 proposal for Title 1 (ANDA review and approval) requirements under the 1984 ANDA/patent act. Both NDA and ANDA holders are required to notify FDA of any increase in reports of therapeutic failures within 15 days ("The Pink Sheet" July 17, p. 17). Earlier this year, FDA Office of Drug Standards Director Peter Rheinstein, MD, warned generic manufacturers at the National Association of Pharmaceutical Manufacturers meeting in Puerto Rico that issues about anticonvulsant bioequivalency may affect other generic drugs. Rheinstein predicted that if generic drug manufacturers "can't maintain the concept of therapeutic equivalence and interchangeability in the anticonvulsant area, it is going to be rough all over the place" ("The Pink Sheet" Feb. 6, p. 10). In 1988, two anticonvulsants were recalled -- Pharmaceutical Basics' carbamazepine and Sidmak's phenytoin -- because of seizure reports.
Advertisement
Advertisement
UsernamePublicRestriction

Register

PS016073

Ask The Analyst

Please Note: You can also Click below Link for Ask the Analyst
Ask The Analyst

Your question has been successfully sent to the email address below and we will get back as soon as possible. my@email.address.

All fields are required.

Please make sure all fields are completed.

Please make sure you have filled out all fields

Please make sure you have filled out all fields

Please enter a valid e-mail address

Please enter a valid Phone Number

Ask your question to our analysts

Cancel