Just weeks after the Office of Generic Drugs (OGD ) released a revised bioequivalence (BE) guidance for extended-release generic equivalents of Concerta and took action to revise the therapeutic equivalence code for the two generic approved products to BX (non-substitutable/not therapeutically equivalent), OGD released a new fairly onerous draft BE guidance for Budesonide Extended-Release Tablets (here).
The Guidance calls for a fasting, a fed and an in vitro study to support approval of a generic equivalent. The study designs for the in vivo pharmacokinetic studies should be partial or fully replicate design. Such studies typically take into consideration the subject by formulation effect. In addition, the Guidance suggests that the sponsor may use a referenced-scaled average BE approach, which would take into consideration the variability seen in the reference listed drug (RLD) product in establishing the limits of the confidence interval that must be met. The concept behind the referenced-scaled approach is that the generic should not be held to a stricter standard than the RLD. This approach is useful only for highly variable drug products and the ANDA sponsor must demonstrate the highly variable parameters for the RLD product.
Also interesting is the partial AUC requirements established in the Draft Guidance:
For both fasting and fed studies, the following PK parameters are recommended: Log-transformed AUC8-48, AUC0-t, and Cmax, where AUC8-48 is the area under the plasma concentration vs. time curve from 8 to 48 hours, AUC0-t is the area under the curve from 0 hours to the last measurable time point, and Cmax is the maximum plasma concentration. There should be at least four non-zero measurements of concentrations for the partial AUC8-48.
FDA also explains that ‘[A]s AUC0-t is recommended in place of AUC0-∞, the last sampling time point should be at least at 72 hours.”
The in vitro testing appears to be rather rigorous as well, with OGD asking for a standard 2 hour acid stage to test the enteric coating performance, and dissolution at 6 (count them, 6!) different pH values, and in different buffers. In addition, the Draft Guidance recommends that the dissolution testing be conducted “with 0.5% of and without Macrogol Cetostearyl Ether in the buffer stage at different pH values. In addition, the applicant may also use other appropriate type(s) of surfactant in the multi-pH media at various concentrations and use other appropriate apparatus and rotational speed.”
This is some of the most extensive testing we have seen for an extended release product and is likely a result of the some of the failures of extended-release generic products that have come to light after approval and marketing. Joe Graedon’s web site the People’s Pharmacy in speaking about extended-release generic products states: “The rules and regulations that the FDA relied upon for decades to approve long-acting generic formulations was, in our opinion, flawed. It did not take into account hour-to-hour blood levels but lumped everything together into something called the AUC (area under the curve). This allowed the FDA to approve generic drugs that actually performed quite differently from the brand name product they were supposed to be mimicking.” Well, while I don’t always agree with Joe, in some of these cases, it is clear that FDA learned more about the products performance after approval, but did act to revise the guidance and take necessary action when a problem was found. Is the system perfect? – likely not but there are well over 15,000 generic products that have been approved since the passage of Hatch-Waxman and there have only been a handful of product problems. Granted, if you are a patient that was impacted by this handful of products, then it is a big deal, but it looks like the Agency is fully engaged in trying to assure that criteria for these complex products do take into account what they have learned from other similar long-acting products.
Patients and the FDA have both experienced problems with other extended-release products (most notably bupropion, metoprolol, propranolol and most recently methylphenidate). Mr. Graedon’s concern about the other older extended –release products already on the market may be more real than we had perhaps all thought…let’s hope not.
One piece of good news is that the preliminary report of an FDA-sponsored study conducted at the University of Cincinnati Neuroscience Institute to determine if slight differences in the bioavailability of two antiepileptic drugs that had been shown to be bioequivalent had a negative impact on therapeutic performance when the products were substituted. The study finds no difference in performance or breakthrough seizures or difference in adverse event profiles. The article regarding the study can be found here.