Will FDA Withdraw an Approved Application Over Product Quality Problems?

January 6, 2020

There have been some recent headlines where the acting FDA Commissioner and other senior agency officials have stated that the FDA will consider the use of its full authorities to take action, if appropriate, in the wake of data accuracy issues with a recently approved gene therapy product (see the statements here).

Sooner or later the question that is likely to come up is whether FDA would withdraw approval of an application for a drug because there are product quality and CGMP problems with the manufacturer.

Two rules provide the FDA with the authority to withdraw an approval of an application.  Section 505(e) of the federal Food, Drug and Cosmetic Act (FDCA) (or 21 USC § 355(e)) gives FDA the authority to withdraw approval of a drug, after providing adequate notice and an opportunity for a hearing, if the FDA finds that the manufacturer has failed to correct known CGMP violations in a timely manner (see the statute here).  But in some limited cases using the discretion granted to the FDA in the regulations found at 21 CFR § 314.200(g) the FDA can move to withdraw an approval of an application without a hearing (see the regulation here).

There are two examples from the past that provide some insight into the situations that can compel FDA to withdraw an approval when the manufacturer has product quality and CGMP compliance problems.  In a Federal Register notice published on August 12, 2012, the FDA withdrew approval of 27 abbreviated new drug applications (ANDA) held by Ranbaxy Laboratories, Ltd. (see the notice here).  In a February, 2009 letter to the manufacturer, FDA determined that there was a “pattern and practice of submitting untrue statements of material fact and other wrongful conduct, which raise significant questions regarding the reliability of the data and information contained in applications…” (see the letter here).  The withdrawal of the applications was a condition of a consent decree that the manufacturer entered into with the U.S. government in January 2012.  The decree stemmed from investigations beginning in 2008 and later Warning Letters and import alerts that revealed many CGMP problems with Ranbaxy’s drug manufacturing and testing at facilities in both India and the US, and data integrity problems at its India operations.

The second example comes from the Copanos & Sons court case decided in 1988.  The manufacturer produced sterile injectable human and animal drugs for applications approved by the FDA.  Over a three-year period, the FDA inspected the manufacturer’s facilities on multiple occasions.  The agency found numerous CGMP violations during each of these inspections.  The FDA issued a Form FDA-483 after each inspection, detailing the nature of the violations.  Despite repeated promises to come into compliance with the CGMP regulations, the manufacturer did not implement corrective actions.  It also violated voluntary agreements to stop distribution of its products until it was in full compliance with the CGMP regulations and kept false records in an attempt to conceal its violations. 

The FDA eventually published a Notice of Opportunity for a Hearing (NOOH) in the Federal Register, in which the agency proposed to withdraw the manufacturer’s application approvals for the sterile injectable products.  In response to the notice, the manufacturer requested a hearing and moved for summary judgment.  Its hearing request included declarations and other exhibits designed to show that the company was in compliance with CGMP regulations.  The FDA denied the manufacturer’s request and withdrew its approval of the company’s applications. (John D. Copanos and Sons, Inc. And Kanasco, Ltd. v. Food and Drug Administration and Frank E. Young, M.D., Ph.D., Commissioner of Food and Drugs, 854 F.2d 510 (D.C. Cir. 1988)). You can see a copy of the decision here.

But the court also had some cautionary words for the FDA.  The NOOH consisted largely of a highly detailed chronological regulatory history and conclusory allegations that the facts stated in it satisfied the relevant legal standard for withdrawal of an approval.  The NOOH failed, however, to organize the relevant facts in any way that would show how FDA met this standard.  This came perilously close to obscuring the basis for the agency's action, and thus denying the applicant a meaningful opportunity to respond.   

In the future, the agency would be well advised to adopt a format for its notice that would clearly reveal (1) each CGMP violation that forms a basis for the withdrawal action, the specific regulation governing this violation, and the date or dates on which it was observed; (2) the date or dates on which the applicant received proper written notice of the violation; and (3) the date on which the violation was corrected or later observed to be still uncorrected. (Copanos,854 F.2d 510 at 526).

By looking at these two examples, we can learn three important points when considering whether a manufacturer is likely facing a situation where FDA could withdraw an approved application because there are CGMP and product quality problems.

  1. The Ranbaxy situation involved a manufacturer which persisted in a pattern and practice of submitting untrue statements of material fact in several abbreviated applications for generic drugs. The agency’s actions in response to a manufacturer that has more limited data integrity issues affecting a single or a smaller number of new drug or abbreviated applications or underlying CGMP data may not meet the same standard and those situations could be distinguished from the actions the agency took against Ranbaxy.

  2. In the Capanos & Sons case, the FDA resorted to acting under the regulations to withdraw approval of the applications only after its patience had finally been exhausted after years of inspections, re-inspections and negotiations with the manufacturer had proved fruitless to encourage the manufacturer to achieve voluntary compliance.  There were also aggravating factors in the case where the manufacturer was not acting in good faith and concealing material information from the FDA.  It was another example of recidivist behavior by a manufacturer.

  3.  FDA has an obligation to provide a manufacturer with adequate notice of how it has failed to meet the legal standard for withdrawal based on CGMP violations and not only rely on a set of disorganized facts and conclusory statements.

Because these examples illustrate that a combination of persistent and recidivist wrongful behavior  were common elements presaging the agency’s resort to withdrawing approval of an application does not mean manufacturers should become complacent. 

The public health risk calculus can change dramatically with different facts or novel therapies that would enable the government to distinguish these cases and act differently.   And always keep in mind that FDA has an array of advisory, administrative and enforcement tools at its disposal that it can use while it builds an administrative record to meet the legal standard for withdrawing an approval.  These alone or in combination can have dire consequences on a firm well before facing any decision by FDA to withdraw an approval.

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