Recent trends in the U.S. Food and Drug Administration’s (“FDA’s”) utilization of Complete Response Letters (“CRLs”) would indicate there may be a disconnect between the intended use of CRLs and the reality of how they are actually being used by the FDA. Pharmaceutical companies seeking to acquire FDA regulatory approval for their New Drug Applications (“NDAs”) or Abbreviated New Drug Applications (“ANDAs”) will often receive a CRL from the FDA instead of an approval.

CRLs were created in 2008 under 21 C.F.R. § 314.110 as a way to inform the applicant that the FDA had found that, while the application could not be denied and was not denied, it could not be approved in its submitted state because it was deficient in showing that the drug in question was, compared to its risk factors, safe, effective, and manufactured in a way that ensures its purity, stability and uniformity. However, the FDA’s current use of the CRL does not always live up to that purpose.

The Complete Response Letter

CRLs under § 314.110 were designed to “describe all of the specific deficiencies that the agency has identified,” in an NDA as submitted, and the CRL will offer suggestions to address any such deficiencies. These deficiencies may include issues with the drug’s manufacture, safety, efficacy, bioequivalence (for ANDAs), stability or quality of the final product, statistical errors in the application or issues with the proposed drug label. 21 C.F.R. § 314.110(a)(1)-(4). Applicants receiving a CRL have 12 months to respond to the FDA in one of three ways under § 314.110(b)(1)-(3):

  1. Responding to the CRL by resubmitting–The applicant can resubmit the application in its entirety, addressing each of the deficiencies described by the FDA in the CRL, using the suggested methods offered by the FDA in the CRL, or by applying the applicant’s own solutions. The significance of the changes to the application will grant the FDA from two to six months of additional application review time.
  2. Withdrawal–The applicant can withdraw the NDA or ANDA in its entirety. Note that such a withdrawal is without prejudice and allows the applicant to refile an application.
  3. Request an Opportunity for a Hearing–The applicant can request the opportunity to meet with the FDA to discuss whether there are grounds for denying the application under § 505(d) and (j). However, applicants should be warned that these hearings are open and public hearings, and granting the hearing does not bind the FDA to actually reconsider the application.

These responses allow an applicant to respond to a CRL for the purpose of addressing the issues the FDA raised and could, if left unaddressed, be the basis for a rejection of the application.

Though this is how CRLs are supposed to function, there are indicators suggesting the FDA has been using them for additional or alternative purposes. Under 21 C.F.R. § 314.100, the FDA has only 180 days in which to respond to a drug application with either an approval, rejection (very rare) or CRL. Given the complexity of NDAs and ANDAs, and the volume submitted annually to the FDA, 180 days may be insufficient for an application examiner to adequately and accurately respond.

As a result, CRLs are regularly used by the FDA in order to “buy time” to review the application. This is evident in the CRLs many companies receive containing bases for holding the application deficient citing issues or guidance documents entirely irrelevant to the application in question. Because even minor changes to the application under the resubmission option in § 314.110(b)(1) will award the FDA at least an additional two months to process the application, plus the 12 months an applicant is allowed to respond to the CRL, such letters are a valuable tool in acquiring additional time to examine the NDA or ANDA and for the FDA to process other applications.

Knowing the FDA uses CRLs for such purposes can help applicants in responding to them. For example, should an applicant receive a CRL containing references to irrelevant guidance documents or other references, it might be a signal the application reviewer requires additional time. As such, turning around a quick resubmission of the entire application under § 314.110, as opposed to taking a greater portion of the 12 months allotted to an applicant,  may not actually help the application’s chances of being approved. It is imperative that a drug applicant take time to draft a considered response to a CRL and communicate with the FDA employee examining the application including a clear explanation why guidance-based solutions and other resolutions offered by the FDA are inapplicable.

The Context of CRL Responses Matter

The receipt of, and a company’s response to, a CRL can have an impact on a company’s business, including the company’s ability to raise funds and manage shareholder reactions depending on how CRLs are viewed. Despite what is apparent misuse of this administrative tool by the FDA, CRLs are and should be viewed by the recipient as an opportunity to strengthen its application and therefore the chance of approval.

Responding, however, is a complicated and detailed process. Failure to respond to an issue or application discrepancy could decrease the chances for a subsequent approval. However, receiving and responding to a CRL leaves unanswered questions, such as “how does a response affect a small business waiver of filing fees?” Can preclinical data already received and accepted as part of an IND approved be the basis for deficiencies cited in the CRL? If such preclinical data has already been received and accepted by the FDA as part of a company’s IND, but guidance has changed, can the company be expected to redo data that was acceptable at the time and has no effect on the safety profile and be required to constantly redo the data in order to satisfactorily respond to a CRL?