Brand vs generic
Under FDA regulations, companies seeking approval for generic formulations of approved drugs must demonstrate that their products are the same as the brand-name drug in terms of:
- active ingredients
- strength
- dosage form
- route of administration
- packaging label.
In addition, the pharmaceutical company must demonstrate that the generic form is absorbed and distributed to the part of the body at which it has its effect at acceptably similar levels to the brand-name drug. All medications—new or generic, in clinical trials or approved, prescription or over-the-counter—must be manufactured under controlled conditions that assure product quality.
However, some studies have disputed this equivalency. In 1 study, patients with schizophrenia receiving generic olanzapine had lower serum concentration than patients with schizophrenia taking equivalent dosages of brand-name olanzapine.4 Similarly, studies comparing generic and brand-name venlafaxine showed significant differences in peak plasma concentration (Cmax)between generic and brand-name compounds.5
The FDA has considered upgrading the manufacturers’ warnings about the risk of generic medications, but has delayed the decision to 2017.6
FDA’s approval process for generic drugs
To receive approval of a generic formulation in the United States, the FDA requires that the generic drug should be compared with the corresponding brand-name drug in small crossover trials involving at least 24 to 36 healthy volunteers.
Bioequivalence is then established based on assessments of the rate of absorption (Cmax and area under the plasma concentration-time curve [AUC]). The FDA’s criteria are designed to achieve 90% confidence that the ratios of the test-to-reference log-transformed mean values for AUC and Cmax are within the interval of 80% to 125%. The FDA accepts −20% to 25% variation in Cmax and AUC in products that are considered bioequivalent. This is much less stringent than its −5% to 5% standard used for brand-name products. The FDA publishes a list of generic drugs that have been certified as bioequivalent, known as the “Orange Book.”5
Considerations when substituting generic medication
Because of the growing number of generic formulations of the same medication, generic–generic switches are becoming more commonplace. Theoretically, any 2 generic versions of the same medication can have a variation of up to 40% in AUC and Cmax. Generic medications are tested in healthy human controls through single-dose studies, which raises concerns about their applicability to the entire patient population.
Bioequivalence. It is a matter of debate whether bioequivalence translates to therapeutic equivalency. For medications with a narrow therapeutic index, the FDA has accepted that these 2 phenomena are not necessarily linked. With the exception of a few medications, including lithium and some anticonvulsants such as divalproex sodium and carbamazepine, serum level of the medications usually does not predict clinical response.
Inert ingredients. Generic medications can include inert ingredients (excipients) that are different from those in their branded counterparts. Some of these inactive ingredients can cause adverse effects. A study comparing paroxetine mesylate and paroxetine hydrochloride showed differences in bioequivalence and clinical efficacy.7
In some cases, brand-to-generic substitution can thwart clinical progress in a stable patient. This small change in the medication could destabilize the patient’s condition, which, in turn, may lead to unnecessary and significant social and financial burdens on the patient’s family, school, community, and the health care system.
Recommendations
In the event of a change in clinical response, clinicians first should evaluate adherence and explore other factors, such as biological, psychological, medical, and social issues. Adherence can be adversely affected by a change in the physical characteristics of the pill. Prescribers should remain cognizant of brand–generic and generic–generic switches. It may be reasonable to adjust the dosage of the new generic medication to address changes in clinical effectiveness.
If these strategies are ineffective, consider switching to a brand-name medication. Write “Dispense As Written” on the prescription to ensure delivery of the branded medication or a specific generic version of the medication.
An insurance company might require prior authorization to approve payment for the brand medication. To save time, use electronic forms or fax for communicating with the insurance company. Adding references to FDA statements and research papers, along with the patient’s history and presentations, would be prudent to demonstrate doubts about efficacy of the generic medication.