At a recent meeting of the Generic Pharmaceutical Association, CDER Director Janet Woodcock said that the FDA is discussing tightening the equivalence limits of generic medicines "so there is less variability.”
In April, the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, voted 11-2 that the agency’s equivalence requirements aren’t’ sufficient for certain medicines. They didn’t offer an alternative, and suggested the FDA list “critical dose drugs or drugs where a small difference in concentration can change patients’ reaction, that may need new standards.
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
Critical dose drugs have a narrow therapeutic index, meaning that "small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions." FDA is consulting the committee on the need to establish separate bioequivalence criteria for these drugs given continuing debate about whether critical-dose drugs require special consideration, the agency explained.
(Currently, the "sameness" of a brand product and a generic version is evaluated based on two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.)
Last month the FDA responded to a request from New Jersey State Senator Joseph Vitale concerning pending New Jersey state legislation that, if enacted, would require pharmacists to dispense epilepsy drugs from the same manufacturer as previously dispensed for certain patients, unless otherwise prescribed.
In its response to Senator Vitale, FDA comments that “[t]o date, we have not seen any scientific evidence that demonstrates a problem with therapeutic equivalence for this group of products or any other class of generic drug products. Those who are questioning the quality of generic epilepsy products have produced only anecdotal evidence.”
And, further:
“[W]e believe that the concerns of some of those raising questions (in particular, physician groups) cannot be dismissed lightly. Because of FDA’s respect for these groups and the concern that patients may lose confidence in their prescribed medications, we have sought to conduct further study. Our decision to further study this issue does not stem from doubt within the agency about data we currently have on approved generic epilepsy products. Rather, it is based on a desire to obtain further independent scientific evidence that might address these concerns.”
Condescending? I suppose it depends how you choose to read it. Does the agency really mean to dismiss the concerns of practicing physicians who see these problems first hand? Maybe PDUFA V funds should be earmarked for FDA staff to attend more neurology conferences to hear about the "scientific evidence” first hand.
More peculiar still is that such statements seem at total counterpoint to the comments of Dr. Woodcock and the unambiguous votes of the advisory committee.
This strikes a very personal note for me. One of my sons has Juvenile Myoclonic Epilepsy. His condition is wonderfully controlled via his meds – and I’d like it to stay that way.
