A generic attention deficit hyperactive disorder (ADHD) drug manufactured by Mallinckrodt has been found by the US Food and Drug Administration (FDA) to not be sufficiently equivalent to its reference drug, Concerta.
Generic drugs are approved through FDA's abbreviated new drug application (ANDA) process. During that process, FDA is primarily concerned with data showing the generic drug is bioequivalent to the reference listed drug (RLD), sometimes referred to in common parlance as the "brand name" drug.
Bioequivalence refers to the "absence of a significant difference" between the bioavailability—specifically the extent and rate of absorption of two (supposed) pharmaceutical drug equivalents over the course of a period of time, at the same dose and under the same conditions. "The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug," FDA explains on its website.
Read more about bioequivalency and bioavailability studies here.
Drugs that are deemed to be bioequivalent are, for regulatory purposes, essentially the same.
To assist this process, FDA also published draft guidance on hundreds of different generic drugs establishing the recommended approach by which companies can demonstrate equivalence. For methylphenidate hydrochloride (Concerta) extended-release (ER) oral tablets, FDA recommends two studies: One under fasting conditions and the other under fed conditions.
Companies may also "waive" certain in vivo testing on lower-dose versions of the drug (18 mg, 27 mg and 36 mg) so long as their drug generates acceptable data in its 54 mg dose.
But even when these guidance documents are followed, sometimes equivalency problems are uncovered after a generic drug is approved.
Consider the case of the antidepressant bupropion. In September 2012, FDA announced that it had asked Israel-based manufacturer Teva Pharmaceuticals to stop distributing Budeprion XL (bupropion) 300 mg after it conducted testing and found that significant differences existed between Budeprion and Welbutrin XL 300 mg, its Reference-Listed Drug (RLD) in the Orange Book. Teva marketed Budeprion on behalf of Impax, which owned its application and manufactured the drug.
Though a similar review in 2007 had found the drugs existed within acceptable tolerances of one another, a 2012 review by FDA found the opposite. "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg," FDA wrote in its findings.
One of the most basic problems may have come from how the drug underwent bioequivalence testing. FDA said the product was approved at the 300 mg dose based on studies conducted using the 150 mg dose. "This methodology was based on FDA's guidance at the time the products were approved," explained FDA. The agency also noted the lower dose was used as the basis of approval due to concerns that the higher dosage could cause seizures in otherwise healthy adults, and this concern caused FDA to grant Teva/Impax a waiver for the studies-a process it refers to as "waiving up."
FDA would ultimately reissue bioequivalency standards for the drug at the 100, 200, 300, 450 and 522 mg dose levels.
Teva's drug was formally withdrawn by FDA in March 2013, and withdrawals of other manufacturers' drugs soon followed.
Other Drug, Similar Concerns
FDA's concerns about extended-release generic drugs haven't just been limited to antidepressants, however.
Last year FDA issued an update to its Adverse Event Reporting System (FAERS) indicating that it was aware of the potential for "Certain methylphenidate Hydrochloride ER tablets" to lack the intended therapeutic effect. Though the agency did not recommend any course of action at the time, it said it was in the process of evaluating the issue "to determine the need for any regulatory action."
Now the agency is taking action based on the validation of those concerns.
In a press statement issued by the Irish pharmaceutical company Mallinckrodt, the company confirmed that its generic Concerta tablets were suspected by FDA to "not be therapeutically equivalent to the category reference drug Concerta."
"As a result, the agency indicated that it has reclassified Mallinckrodt’s ANDA 202608 for methylphenidate ER dosage strengths of 27mg, 36 mg and 54 mg from AB (freely substitutable at the pharmacy level) to BX (presumed to be therapeutically inequivalent)," Mallinckrodt said, referring to the classification of generic drugs within FDA's Orange Book.
The change follows FDA's issuance of brand new bioequivalency guidance for methylphenidate ER in November 2014. FDA's Federal Register announcement of the guidance contained no mention of any potential problems with current testing measures for the drug, however.
"Although the Draft Guidance has an open comment period through January 5, 2015, the agency nevertheless confirmed that this change would be reflected on November 13, 2014 in the on-line Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations," Mallinckrodt observed.
The company said it stood behind its products and believed they were safe and effective for their stated indications. "We believe that the FDA’s actions are not supported by sound scientific evidence and not consistent with the best interests of patients," Mallinckrodt's CEO, Mark Trudeau, said in a statement. The company said that while it has been made aware of problems with some patients switching from Concerta to its approved generic, those cases represent a small number of patients relative to how many have taken the drug. “We believe this very low reporting rate is in line with response rates recorded for patients switching between different formulations of existing products,” Trudeau said.
While the drug has not been withdrawn from the market, based on FDA's actions with non-equivalent versions of bupropion, the agency could press Mallinckrodt to voluntarily withdraw its product.