Report 2 of the Council on Science and Public Health (A-07)

Generic Substitution of Narrow Therapeutic Index Drugs

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Summary

Objective:  To review the evidence and the arguments surrounding the generic substitution of narrow therapeutic index (NTI) drugs.

Methods:  Previous reports of this Council on generic drugs were reviewed.  Published studies from 2002 through February 2007 were identified through a MEDLINE search of English-language articles, using the MeSH terms, drugs, generic, and therapeutic equivalency.  A total of 103 articles were identified.  Additional articles were identified by a review of references cited in these publications.  In addition, the Web sites of the Food and Drug Administration (FDA) and various medical specialty societies were accessed for articles relevant to NTI drugs.

Results:  Generic drugs are significantly less expensive than brand name innovator drugs and provide an opportunity to reduce spending on pharmaceuticals in the United States.  The FDA considers generic drug products to be “therapeutically equivalent” to brand name innovator products if they are pharmaceutical equivalents and show bioequivalence in healthy volunteers; such products receive an “A-rating.”  The FDA applies the same approval criteria for NTI drugs, which the Agency calls “narrow therapeutic range” drugs.  Some physicians remain concerned about generic substitution of NTI drugs because of small differences between therapeutic and toxic doses and the need for therapeutic drug concentration or pharmacodynamic monitoring.  However, scientific evidence to support these concerns either does not exist or is extremely weak.  In large part, studies reviewed and cited in this report suggest “AB-rated” generic NTI drugs were bioequivalent to their brand name innovator products in patients with diseases for which the drugs are indicated. 

Conclusion:  Consistent with current American Medical Association (AMA) Policy H-125.984(1) (AMA Policy Database), the prescribing physician should ultimately make the decision on whether to allow generic substitution of an NTI drug for an individual patient.  Furthermore, as stated in current AMA Policy H-115.994(4), when a prescription for a generic drug product is refilled (e.g., for a patient with a chronic disease), changing the manufacturer should be discouraged, whenever possible, to avoid confusion for the patient.  For many drugs, especially those with a narrow therapeutic range, therapeutic drug concentration or pharmacodynamic monitoring is necessary  to assure the desired clinical response.  Such monitoring is necessary irrespective of whether the drug is a brand name or generic product.
In addition, patients must receive adequate education to be able to fully understand the nature and proper use of their medications.

RECOMMENDATIONS

The following statements, recommended by the Council on Science and Public Health, were adopted by the AMA House of Delegates at the 2007 AMA Annual Meeting:

1. The AMA reaffrims Policies H-125.984 and H-115.974.(Reaffirm Policy)
2. The AMA will inform the Centers for Medicare and Medicaid Services, America’s Health Insurance Plans, the Pharmaceutical Care Management Association, the National Association of Boards of Pharmacy, the National Association of Chain Drug Stores, the National Community Pharmacists Association, and the American Pharmacists Association about AMA Policies H-125.984 and H-115.974, and urge these payer and pharmacy organizations to support these AMA policies.  (Directive)

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