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David Baxter PhD

Late Founder
Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy
by Mark Moran
Psychiatric News June 1, 2007
Volume 42, Number 11, page 17

Patients can contact their pharmacy and ask whether they have changed manufacturers and request the original formulation. Typically, pharmacies can accommodate such requests.

The call came out of the blue. "It was a patient I had seen years ago for depression," APA President-elect Nada Stotland, M.D., told Psychiatric News. "She had been completely stabilized on a medication and had in fact decided to let her primary care physician prescribe it. That was her decision, and she did well for several years. But when she called, she said she was extremely depressed and asked to come and see me."

Predictably, Stotland said, there were events in the patient's life that might have touched off a relapse, in particular the anniversary of a painful loss. But the patient had lived through the same anniversary for a few years without a relapse?why would she have relapsed now?

Reviewing past events, Stotland and her patient realized something else: she had recently switched from the name-brand medication to a generic formulation. "I wrote her a prescription for the name brand," Stotland said. "And in a couple of weeks she was back to baseline."

Stotland is not alone in reporting anomalous cases of patients' having sometimes dramatically varying responses to medication that in retrospect appear to be related to a switch from name-brand to generic or from one manufacturer's generic formulation to another.

"It is not unheard of," said Philip Janicak, M.D., a psychopharmacologist at Rush University Medical Center. "I think it is much more the exception than the rule, and overall it's not a serious problem. But when it occurs in an individual, it can be serious."

Janicak explained that Food and Drug Administration (FDA) requirements around bioequivalence of generic products are fairly strict: a generic must have between 80 percent and 125 percent bioequivalency to its name-brand product?a window of 20 percent less or 25 percent greater potency.

"Generally, that kind of variation is not going to make a difference in terms of efficacy or toxicity," Janicak said. "But imagine a large pharmacy that negotiates with different generic manufacturers and buys a generic formulation from one manufacturer that has 80 percent bioequivalency to the name brand. Then imagine the pharmacy switches manufacturers to one that markets a generic that has 125 percent bioequivalency.

"That's a 45 percent difference in bioequivalency that theoretically can make a significant difference for the patient," he explained. "If it's a downward shift, it could affect efficacy; if it's an upward shift, it could affect toxicity."

Janicak said it is also not impossible for particularly sensitive individuals to have variable reactions to the inert materials in a compound. "Individuals can sometimes be allergic and react differently to whatever substance goes into making up the capsule or the tablet."

In an e-mail response to a request for information about the topic, the Office of Generic Drugs (OGD) at the FDA said the agency is attentive to reports of potential nonequivalence of formulations.

"We believe that the standards for bioequivalence in the Office of Generic Drugs are adequate to assure safety and effectiveness of the approved products," the OGD stated. "Approval of a generic product depends on meeting standards for purity and potency of the drug substance and drug product as well as bioequivalence. All products approved by the Office of Generic Drugs (OGD) have met the usual chemistry and manufacturing standards and were found to be bioequivalent to the associated brand products. We believe that these products can be safely substituted for the reference product without any further patient monitoring.

"While the FDA generally relies on the Adverse Event Reporting System, Med-Watch, and postmarketing safety reporting as the sources for surveillance monitoring, OGD further monitors and assesses reports of nonequivalence and problems when patients are switched from brand to generic and generic to brand products," the spokesperson said. "These reports are not always submitted within the framework of the monitoring system relied upon for new drug products. Thus, the FDA is attentive to reports of potential nonequivalence."

The OGD also asserted that the actual difference in bioequivalence is typically far less than the 80 percent to 125 percent allowable difference.

According to the OGD, bioequivalency studies submitted to the FDA over a several-year period indicate that the average difference is less than 4 percent. Those studies are described in the preface to the FDA "Orange Book" under "statistical criteria for bioequivalence."

The preface to the "Orange Book" also describes the somewhat complex method by which bioequivalency tests are performed. According to the OGD, these are the essential features of that process:

  • A typical bioequivalency study uses 24 to 36 normal subjects who take one dose of the test product (generic) and the reference product (brand) with a suitable washout period.
  • The plasma drug concentration at several sampling times from each patient is recorded, and at the end of the study the concentrations from each sampling time are totaled and averaged for two measures?total drug absorbed and peak drug absorption value.
  • Another calculation is made for the "confidence interval," which measures the variability of both of those values from individual to individual. If the values are very consistent between subjects, the confidence interval is very small.
  • If the values are not consistent and show significant variability between patients, the confidence interval is very wide. And if the confidence interval for either of the two measures?total drug absorbed and peak absorption value?fall outside the 80-125 percent bioequivalency window, the generic is not approved for sale.
As Janicak explained, the FDA's method for using confidence intervals would seem to ensure that any drug approved would have a bioequivalency that would?for most patients?be closely equivalent in terms of efficacy and toxicity to the name brand.

Still, he cautioned, "most patients" is not the same as "all patients," and whether the 24 to 36 normal subjects used in the agency's bioequivalency tests represents the full range of individual variation in the way drugs are absorbed across the pharmaceutical using population is uncertain.

"There will always be outliers," Janicak said. "Those are the people who may be getting into trouble."

Janicak described a patient who had been stable on Zoloft (sertraline) for years, but had a dramatic relapse when switched to the generic formulation.

Jeffrey Lieberman, M.D., chair of APA's Council on Research, agreed. "Many clinicians have patients who have experienced variation in response when switching from a name brand to a generic," he told Psychiatric News. "In some cases these have been related to side effects; in other cases, it has been a difference in efficacy. We have some impressions, but we need systematically collected data."

Stotland said physicians in other specialties have reported similar cases. She said she is expecting the AMA House of Delegates to address the issue during its annual policy meeting this month in Chicago. (Stotland is a member of the AMA Section Council on Psychiatry.)

So how should clinicians advise their patients who experience dramatic changes in medication response? They should tell their patients to contact their pharmacy and ask whether the pharmacy has changed manufacturers; if so, the patients should request the original formulation, Janicak said. "Typically, pharmacies can accommodate patients on a request like that."

The "Orange Book," formally titled "Approved Drug Products With Therapeutic Equivalence Evaluations," is posted at :acrobat:.
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