ARE BRAND AND GENERIC DRUGS REALLY EQUIVALENT?


Many health care professionals are concerned about how generic drugs compare to their brand name counterparts. The FDA believes that generic drugs can be substituted with the full expectation that they will have the same clinical effect and safety profile as the innovator (brand) drug. However, there is still debate over whether generic products are truly equivalent, particularly narrow therapeutic index (NTI) medications such as antiepileptics, immunosuppressants, anticoagulants, and levothyroxine. 


The FDA has a stringent process 
for generic drug approval and requires that generic drugs be both pharmaceutically and therapeutically equivalent to the brand name medication. Pharmaceutical equivalence means the generic drug must have the same active ingredient in an identical strength, dosage formulation, and route of administration. Therapeutic equivalence refers to the bioavailability of a drug product and is measured by the rate and extent of absorption. A generic drug product must be bioequivalent to the innovator product, meaning that a comparable amount of active ingredient is available at the site of action. 


A big area of controversy is how bioequivalence is defined and statistically calculated. Bioequivalence is usually measured in small crossover studies of volunteers who take both the generic and brand name product. Serial serum drug concentrations are obtained and compared. To be considered equivalent, the FDA requires (with 90% confidence) that both the maximum concentration (Cmax) and area under the time versus concentration curve (AUC) of the generic product be within 80% to 125% of log-transformed data of the brand. 


This statistical method leads to a widespread misconception that doses (or drug levels) of generic products differ by up to 25% compared to the brand. In fact, most generic drug products differ from the brand by less than 4%.1 Generic drug concentrations that vary by more than 10% are unlikely to pass bioequivalence testing because the range of possible values within the 90% confidence interval becomes too broad.1


PAs should understand that most generic drugs are tested for equivalence against the brand name product only. Therefore, it is possible that two generic formulations are not equivalent to each other. Although this is likely insignificant for most medications, it may pose a problem for narrow therapeutic index drugs. Patients who regularly receive generic medications from different pharmacies or manufacturers may experience adverse effects or treatment failure. This can manifest as an unstable anticoagulant effect, breakthrough seizures, or erratic thyroid function. After checking compliance and refill history, the clinician may find it worthwhile to consider if the patient is receiving the medication from different sources. The problem is not usually the generic product, but rather switching from different brand or generic manufacturers once stabilized.


Each state has its own generic substitution laws; however, pharmacists may not substitute a generic medication when prescribers specifically indicate that it is not permitted. The required language varies from state to state (for example "brand medically necessary" or "dispense as written"), but the wording should be clearly written on the face of the prescription. Another option is to request that a specific generic manufacturer be used for each refill.


Finally, providers should be aware of permissible differences allowed by the FDA between brand and generic products. These include shape, scoring, packaging, expiration time, excipients, and release mechanism (for example, microencapsulation versus matrix). Release mechanisms that change a product from an immediate-release to an extended-release formulation are not considered equivalent, as these are different dosage forms. Excipients, or inactive ingredients, can also pose a problem. Some patients may be allergic to a preservative, dye, or flavoring added to a particular formulation. In most cases, however, generic substitution is preferable, safe, and effective and results in a significant cost savings for both the patient and health care system. JAAPA


Larissa DeDea, PharmD, BCPS, PA-C, is a clinical pharmacist with Northern Arizona Healthcare, Flagstaff, Arizona. In addition to being board certified in pharmacotherapy, she is a graduate of the Yale University PA program.

REFERENCE


1. Generic drug variability. Pharmacist's Letter/Prescriber's Letter. 2008;24(7):240704.