With generic drugs now making up nearly 70 percent of all medications prescribed in the US it is no surprise that the issues of bioequivalency and interchangeability of branded drugs and generics remained front and center this morning at the second day of the AAPS meeting.
The FDA has come in for a fair amount of criticism from companies and consumers alike. We wrote yesterday about the concerns about bupropion/Wellbutrin and Ambien but these are only two of the cases in which it has been questioned whether drugs certified by the FDA as bioequivalent are indeed therapeutically equivalent.
For a fairly comprehensive treatment of the alleged problems of non-bioequivalent generics , check out Glenn Lammi’s legal brief.
This morning, we had a chance to hear from the FDA and an explanation of when the agency believes there may be grounds to modify the current procedure for approving generics as bioequivalent.
Dr. Robert Temple, Director of the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research and Acting Director of the Office of Drug Evaluation I, argued that for the large majority of drugs bioequivalency is relatively straight forward but also walked through where differences between two drugs might or might not be indications of the potential for therapeutic efficacy differences.
He opined that for two drugs that meet FDA bioequivalency standards, interchangeability depends on two factors: the sensitivity of the drug effects to differences in concentration and where one is on the dose response curve.
On the first point, it matters a lot whether a drug takes effect slowly or quickly, both in terms of the intended effect and the potential for side effects. When the drug is specially created to take effect quickly or to have high concentrations at certain times, testing the concentration at more time points is an important part of demonstrating that the two drugs really can be substituted for one another without big changes in the effects. Ambien is an example. Another is ADHD drugs which are designed to have high concentrations at some times and lower concentrations at others.
But Dr. Temple indicated that in the case of drugs that may take hours, days, or weeks to work completely, for instance antidepressants, beta-blockers, and coumadin, he felt it is highly unlikely that small deviations in concentration and release would have much of an impact on therapeutic effect. The shape of the curve, arguably, is not as critical.
That speaks against the complaints about Wellbutrin (bupropion) that we heard about, and wrote about, yesterday since the drug’s effects develop over weeks. Indeed, Dr. Temple attributed the complaints about the generic bupropion at least partially to patients blaming reoccurrence of symptoms to the drug change even though they would have returned whichever drug the patient was on. He made a similar argument about patients on anti-seizure medications who say that their seizures came back after they moved to a generic.
On the second consideration in determining whether existing bioequivalence standards are adequate, placement on the curve, Dr. Temple identified cases where the closeness of the pharmacokinetic profiles are important, generally where one is on the steep part of the curve. However, few drugs fall in this area, usually oncology drugs. He suggested that when one is on the plateau, differences in release rate are not very important, offering the example of drugs such as fluoxetine where the drug is equally effective at 20, 40, and 80mg doses and can be taken once a week with little difference in effect from taking it once a day.
