Generic Drugs: Why the Controversy?

If generic drugs are just as effective and just as safe as their brand counterparts, but don’t cost as much, why is there any concern amongst some practitioners and patients?

By one estimate, almost 70% of prescriptions filled in the United States today are for generic drugs. According to the Food & Drug Administration (FDA), that percentage was only 14% in 1984. Much of the increased usage has resulted from the escalating cost of brand medications and the increasing attempts by managed care plans to control these costs by preferential coverage of generic rather than brand medication. This of course is predicated on the assumption that generic medications are both equally efficacious and equally safe as their brand counterparts. The FDA supports this view but many practitioners and patients think otherwise.

A meta-analysis cited by the FDA itself (Kesselheim et al. 2008) illustrates the paradox. In this review, 47 articles were identified covering nine subclasses of cardiovascular medications, of which 81% were randomized controlled trials. There was clinical equivalence (i.e. equal efficacy) in from 71% to 100% of the subclasses. The analysis demonstrated that there was no evidence for brand superiority over generic. However, among the 43 editorials that were also reviewed, 53% of actual practitioners expressed a negative view of generic drug substitution!

To understand the different interpretation of the same data, a brief review of the approval process for generic medications is in order.

In 1984 the Hatch-Waxman Act was passed in Congress, allowing approval of generic copies of any medication originally approved after 1962, without requirement of pre-clinical and clinical testing. What this meant was that the Abbreviated New Drug Application (ANDA) Process for generic drugs would be streamlined. Generics would be reviewed in the same manner as new drug (original brand) applications as far as labeling, toxicity, chemistry, manufacturing, controls, microbiology, inspection, and testing. But unlike brand medications, generic drugs would not be required to have expensive, time-consuming preclinical (animal) and clinical (human) data to establish safety or efficacy. Instead, the generic company would have to show bioequivalence of the product to be between 80-120% of the brand (innovator) product. Demonstration of bioequivalence requires measuring the amount of time it takes for the product to reach the bloodstream in 24 to 36 healthy volunteers, instead of hundreds or thousands of unhealthy patients. The reasoning was that an equal amount of the active ingredient in the blood stream from a generic medication should give the same effects as that of the same active ingredient in the brand medication.

The assumption was that equal pharmacokinetics (what the body does to the drug) would result in equal pharmacodynamics (what the drug does to the body). This may sound reasonable until it is realized that requirements for the active ingredients in the generic medication do not extend to inactive ingredients. Inactive ingredients in a medication can -- and do -- affect safety and efficacy. For example, patients can be allergic to different fragrances, dye colors or gluten content from the different inactive ingredients. Under the present regulations, generic companies are not required to use the same inactive ingredients in their products nor the same “release” mechanism for the active ingredient. As a result, the generic medication can cause different side effects and may not be as effective. There is no requirement to directly compare the safety and efficacy of the generic with the brand name drug before giving the generic marketing approval.. It is only when the practitioner receives complaints from the patient that “the generic isn’t working as well” or “I never had these side effects before” that the FDA is made aware of a deficiency, real or imagined. Those patients whose first use of a particular medication is a generic version, would have no available comparison with previous success and therefore an unsatisfactory “first time” experience can result in stopping the medication altogether.

The FDA is aware of such reports, but responds that “if problems with interchangeability of drug formulations occur, they occur only for a small subset of people.” (http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicine) The Agency does not have the authority or resources to perform the necessary clinical studies to actually compare generic and brand efficacy and safety, so they encourage the generic pharmaceutical companies to do so. This is an expensive undertaking, and the generic companies have no incentive or requirement to do so, and thus have not.

Here is The reason for the controversy: a practitioner is responsible for patients who may be in that “subset” of total number of patients needing the brand name medication, but there is no way of knowing beforehand which patients may be in that “small” subset. It may be small theoretically, but for a given patient in that group it will be a “100%” experience.

One approach to solving this concern is for practitioners to start prescribing with the brand medication, whose safety and efficacy has been tested on large numbers of patients for a given illness. Then if the patient is satisfied with its pharmacodynamics (i.e. efficacy and safety), a switch to a cost-saving generic alternative should be attempted. However, if efficacy or safety issues arise, a return to the proven brand would be reasonable.

In addition, patients and practitioners should be informed by the pharmacist of the company name for the generic they are dispensing. The patient must be his/her own advocate and remember that generic products may use different inactive ingredients. Therefore, the patient has to be aware that if one generic which is “working” is switched to a different generic when the prescription is refilled, the resulting clinical experience may differ.

The traditional philosophy followed by most practitioners is: “if something is working well, don’t change it” and thus their reluctance to switch from a “working” brand to an untested generic. Only by such reasonable compromises as outlined above can important economic issues defer to more important efficacy and safety concerns. And allow practitioners to follow their primary rule: “Do no harm.”

References

Kesselheim, A.S, Misono, A.S., Lee, J.L., Stedman, M.R., Brookhart, M.A., Choudhry, N.K., (2008) Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease JAMA 2008;300 (21):2514-2526)

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