Blog | Thursday, April 18, 2013

Are generic drugs bioequivalent and interchangeable?

Use of generic drugs has the potential to reduce annual consumer spending on prescriptions by billions. A study published in the New England Journal of Medicine and discussed in the New York Times Economix blog in 2012 looked at Medicare Part D expenditures and correlated them with drug prescribing patterns. The regions of the United States with the highest Medicare expenditures were those where more name brand drugs were prescribed. But, are generic drugs as safe and effective as name brand drugs?

Generic medications become available after brand name drugs go off patent (usually 10 to 14 years after coming to market). The pharmaceutical industry maintains that the high cost of brand name drugs relates to the research and development required to innovate and bring new products to market. Advertising and promotion are also, no doubt, a major factor.

A generic drug is a drug that has been determined to be the bioequivalent of a brand name drug in terms of its active ingredient. Standards for proving bioequivalence are defined by the FDA and are similar to standards used in Canada, Japan and Europe. Here's what the FDA website says about bioequivalence: "One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug."

The following graph illustrates the bioavailability of two drugs, Drug A and Drug B. The statistics may be difficult to understand, but to be determined bioequivalent the 90% confidence interval of the ratios of the mean bioavailability, or "area under the curve" (AUC), of the two drugs and their peak concentrations (Cmax) must be in the ranges of 80% to 125%. In more concrete terms, analyses of numerous studies of bioequivalence have shown that differences in blood concentrations of the active ingredients of branded versus generic drugs are generally less than 4%.

Once a generic drug is deemed to be bioequivalent by these statistical standards it is not required to go through the same extensive clinical safety and efficacy trials, as a newly innovated brand name drug applying for its initial patent.

What are some pitfalls of using generics? The inactive ingredients in generics compared with branded drugs are not required to be the same. Therefore allergies to these fillers and inactive compounds can be an issue. Also, special consideration should be taken when changing from a branded drug to a generic drug, or when changing between generics, if the drug has a narrow therapeutic index. Some drugs with narrow therapeutic indices include thyroid medications, anti-epileptics and warfarin.

Here are some examples of issues that come up with generics.

The adhesive contained in a fentanyl transdermal patch differs depending on whether the patch is generic or brand name. Some of my patients have developed allergies to the adhesive in the brand name patch (as opposed to the generic,) others complain that the generics don't stick as well.

Along the lines of narrow therapeutic index, I can recall two separate instances in which a patient was changed to a new warfarin generic drug product. In each case the patient's PT and INR (coagulation test) had been stable for months, but after the change their levels of anti-coagulation became too high. This took some detailed history-taking to figure out. One review of the literature suggested that generic warfarin and Coumadin products are equally effective and safe and uphold the FDA's criteria for bioequivalence, yet the authors still suggested that patients limit switches amongst warfarin products and brand and monitor anti-coagulation after making changes.

If a product is deemed bioequivalent then it is also deemed "interchangeable" and pharmacists are not required to inform physicians when they change a patient from brand to generic, or when they change from one generic to another.

Another patient, who reports a high level of drug sensitivity, noticed that a particular generic of nortriptyline used for chronic insomnia was more effective for him than others.

Thyroid medication is known to vary amongst the generics and Synthroid brand in terms of clinical effects. While the FDA has deemed these various products to be bioequivalent and interchangeable many endocrinologists disagree. In attempt to address this issue in 2004 a Joint Statement was issued by the major endocrinology professional societies making recommendations on the topic.

The most recent controversy regarding generics has to do with biological drugs, or "biologics." Because of the inherent complexity of these innovator drugs, which are derived from living cells, the concept of "biosimilar" has replaced bioequivalent for the generic products being developed. As reported last week in the New York Times, the pharmaceutical industry is currently engaged intense lobbying to prevent biosimilar generic biologics from coming to market as competition to the numerous, ultra-expensive biologics whose patents will be expiring in the near future.

The science behind the FDA approval process for generic drugs is rigorous. My advice, it can be smart to try a generic. There is no evidence that these products are of lower quality, or less effective than name brand products—though they are not required to go through clinical efficacy trials. However, be wary of minor fluctuations in the clinical effects of your medications when switching between name brand and generic, and amongst different generics, and be aware that your pharmacist may change your generic from one manufacturer to another without your knowledge (the pill should look different).

What is your experience with generic medications versus name brand products?

Juliet K. Mavromatis, MD, FACP, is a primary care physician in Atlanta, Ga. Previous to her primary care practice, she served on the general internal medicine faculty of Emory University, where she practiced clinical medicine and taught internal medicine residents for 12 years, and led initiatives to improve the quality of care for patients with diabetes. This work fostered an interest in innovative models of primary care delivery. Her blog, DrDialogue, acts as a conversation about health topics for patients and health professionals. This post originally appeared there.