I wanted to start a new thread to discuss the actions MSB will be taking in the coming weeks. Many people seem to be suggesting the CRL is a means to an end. Actually, it is a means to approval. In the announcement it states:
"As there are currently no approved treatments for this life-threatening condition in children under 12, Mesoblast will urgently request a Type A meeting with the FDA, expected within 30 days, to discuss a potential accelerated approval with a post-approval condition for an additional study."
This means MSB will be disputing the finding from the FDA and will now move to get them to overturn their decision. This will take 2-3 months, also exactly enough time to see the results from the COVID-19 study. This is not a rejection, it is a means for the FDA to buy additional time and for MSB and the FDA to find a way forward.
Type A meetings are created to dispute the findings and to find a way forward. Ultimately approval will come down to the negotiations between MSB and the FDA in the Type A meeting.
Please only add to this discussion if you have anything meaningful to add.
Here is a very good link that explains CRLs and the various ways the FDA uses them:
https://www.lexology.com/library/detail.aspx?g=d2eb3a37-b341-4087-ac70-5e5e905b3256
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.
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. Applicants receiving a CRL have 12 months to respond to the FDA in one of three ways under § 314.110(b)(1)-(3):
- 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.
- 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.
- 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.
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.
(20min delay)