Yesterday, FDA published two separate Federal Register Notices (here and here) announcing a Notice of Opportunity for Hearing (NOOH) for the withdrawal from marketing of two firms’ methylphenidate extended-release tablets. The Agency had previously expressed concerns regarding the Therapeutic Equivalence (TE) of these two products based on significantly higher reports of therapeutic failure later in the day than the reference listed drug product (and/or authorized generic). The FDA changed the TE code from AB to BX and requested that the firms either voluntarily withdraw their products from the market or repeat new bioequivalence (BE) studies based on new guidance, which the FDA had issued that changes the metrics for establishing BE to conform with new information that became available to the Agency (see here and here). Neither firm chose to voluntarily withdraw its product from the market at that time. One firm submitted a new BE study that also failed the new BE requirements; the other firm did not submit the results of a new study.
That all occurred almost 2 years ago and now the FDA is initiating the beginning of a final administrative action to permanently remove the products from the marketplace.
Leading up to the decision to request an NOOH to withdraw the applications for the products, the FDA:
- Continued to monitor the adverse event reports relating to therapeutic failure later in the day.
- Reanalyzed data from the original submitted studies in accordance with the new requirements of the revised BE guidance.
- Performed clinical trial simulations, which confirmed their suspicions.
- Reviewed the new BE study submitted by one of the manufacturers.
- Performed its own BE study (single dose, 4 treatments, fully replicated, crossover randomized BE study consistent with the new guidance) on the product from the firm that chose not to submit a new BE study.
- FDA concluded that, based on all of the data in totality, two firms’ products were not bioequivalent to the reference listed drug product, and thus, takes the action outlined in the FR notice to withdraw both sponsor’s products from the market.
FDA has been criticized in the past for not responding to reports of therapeutic inequivalence in a timely manner (i.e., the bupropion extended-release product); however, there is a process (albeit protracted) to do so. FDA takes reports of therapeutic inequivalence very seriously, as they need to get that right before taking any enforcement action. That is also why FDA takes a longer time to approve complex dosage forms of products to be sure it gets the approval right, so as not to undermine the public’s confidence in generic drugs. FDA does a pretty darn good job, as there have only been a handful of actions against products post-approval based on TE concerns, and that is after the approval of over 20,000 ANDAs since the passage of Hatch-Waxman.