The field copy which is used by FDA inspectors during pre-approval manufacturing inspections is a copy of the Quality section (Module 3) plus form FDA 356h and the NDA summary. The field copy is only requested for the NDA and ANDA (not for BLAs). This separately bound copy should be sent directly to the appropriate field office.X19
The “Guidance for Industry-submitting MAs according to the ICH CTD format”X19X describes the US typical documents and their content. The content of the CTD sections is not in the scope of this guidance document.
Besides the usual CTD sections, which are requested for all ICH regions the additional documents, are requested for an NDA or BLA in USAX19X which are listed in appendix 4 (“XAPPENDIX 4X: Table of contents for an NDA in USA “).
Additional to the pre-approval inspection o manufacturing sites other types of inspections might be carried out and can influence the NDA/BLA review process. These inspections are conducted by the CDER’s Biosearch Monitoring Program and can include: drug sponsors, clinical investigators, institutional review boards (IRBs) and contract research organizations (CROs).X18
UReview at CDER
When the NDA is submitted, it is forwarded to one of CDER’s drug review divisions, which is responsible for the therapeutic class responsible for this kind of application.
During the first review phase an evaluation of the relevant parts of the application is performed by the responsible review functions which are medical, biopharmaceutical, pharmacology, statistical, chemistry and microbiology reviewers.
Each reviewer makes an assessment of the submission in his/her area of expertise. After the review a written evaluation with conclusions and recommendations is issued by each
reviewer. The written evaluation of each reviewer is forwarded to the division director or to the office director. He/She checks the conclusions and recommendations of each reviewer and decides on the actions to be taken on the submission. The outcome is that one of the action letters, i.e. approval letter, approvable letter or not approvable letter, is issued. The FDA has the possibility to use Advisory Committees throughout the review process. X18
The following steps are identical for CBER and CDER and are described under the headline
"Review at CDER or CBER".X18
UReview at CBER
For an application submitted to CBER, FDA is requested to tight review timelines and performance goals based on PDUFA. These timelines are only applicable for biological products for which user fees have to be paid, but CBER tries to review also “non-user-fee”
applications within the same timelines. They have also some additional goals like meet the set timelines for responding to industry requests for meetings, providing meeting minutes of health authority meetings to industry or communication of results of review if sponsor responses to clinical hold. X18
The following steps are identical for CBER and CDER and are described under the headline
"Review at CDER or CBER".X18
UReview at CDER or CBER
Due to the US regulations the FDA is asked to inform the applicant as fast as possible of:
• Deficiencies - which are easy to correct - particularly those contained in the CMC and the control sections
• Insufficient data in any of the sections
• Technical changes requested to facilitate review.
This is done by an information request letter. In case of major scientific issues, this has to be addressed in a formal action letter.
This procedure was established in order to allow the applicants to submit supplements as early as possible during the review process and before the review period is finalized.
The next step in the review process is the so-called “Ninety-Day Conference”. FDA will invite applicants to a review meeting approximately 90 days after receipt of the submission in order to discuss the status of review, to mention the deficiencies and to discuss other issues of mutual interest. In case a personal meeting cannot be arranged this meeting can be replaced by a telephone conference if both parties agree.
As prerequisite for approval of an application, the FDA will check whether the medicinal product meets the relevant legal standards. Depending on the type of application the legal standards are:X18
• In the case of full applications, these standards include requirements for safety, efficacy, manufacturing controls, and labeling.
• In the case of abbreviated applications, these standards include requirements for manufacturing controls, labeling, and bioequivalence (if applicable).
It is advisable that applicants look at FDA guidelines, recommendations and policy statements to assist in submitting NDAs and BLAs.
The FDA notifies the applicant via an action letter if the product has been approved (approval letter) or unapproved (complete response letter) at the end of the review period.
There are in principle three types of letters, which FDA can issue: approval letter, approvable letter, and not approvable letter.
The FDA will issue a not approvable letter if they believe that the NDA cannot be approved.
Within the not approvable letter any deficiencies in the NDA are described. The applicant will respond to a not approvable letter within 10 days of the date of the letter for full applications in one of the following forms: X18
• Resubmit (i.e. a formal response to the action letter) or acknowledge the intent to file a resubmission to the NDA or BLA
• Request for a reasonable extension of the review period to be able to provide the appropriate response
• Request for a hearing
Before the FDA finalizes the review cycle and issues an approval letter they may request more data or ask for a clarification about existing data or some other element in the NDA/BLA. In such a case FDA will issue an approvable letter. With issuing an approvable letter FDA believes that the NDA or BLA can be approved once the applicant will provide the additional requested information or agrees on specific conditions (like changes in labeling).
The approvable letter will describe the additional information requested by FDA or the conditions to which the applicant have to agree in order to obtain the approval.
The approvable letter will be answered by the applicant within 10 days of the date of the letter or number of days specified in the letter in one of the following forms:X18
• Resubmit (i.e. a formal response to the action letter) or acknowledge the intent to make a resubmission to the NDA or BLA
• Request for a hearing
• Withdrawal of the application
• Request for a reasonable extension of the review period in order to be able to provide the appropriate response to the approvable letter. When an extension is granted, the
applicant must respond within the agreed time period. If not done, FDA will consider the application as withdrawn.
As mentioned above FDA has also the possibility to issue a complete response letter. Such a letter is issued if FDA will not approve the NDA, ANDA or BLA in its present form for one or more reasons. This procedure is laid down in revised 21 CFR Part 314.110 effective August 11, 2008F22F. Within the complete response letter all deficits, which FDA has identified during the review cycle within the application for not approving the product, are mentioned. If possible FDA will also recommend further actions for the application in order to put the application in place for conditions for approval.X18
In case FDA asks for Phase IV studies all agreements regarding the schedule and nature of the Phase IV study will be mentioned in the approval letter.
If FDA approves a medicinal product the product can be put on the market. As soon as the product is approved for marketing FDA is obliged to make some research information from applicant available to public, which were evaluated through the experts of CDER or CBER.
These documents are referred to as Drug Approval packages (formerly known as Summary Basis for approval). The drug approval package contains the rational for approving the medicinal product. In addition, it contains the approval letter, professional labeling, PIL and the reviews from the CBER or CDER reviewers (e.g., medical, chemistry, pharmacology,
22 Code of Federal Regulations, Title 21 – 21 CFR Part 314.110 effective August 11, 2008 http://edocket.access.gpo.gov/2008/pdf/E8-15610.pdf and
http://law.justia.com/us/cfr/title21/21-clinical, statistical, etc) as well as administrative Information and correspondence. This information can be made available through the Freedom of Information (FOI) Act per 21 CFR Part 20F23F. These drug approval packages contain normally between 50 – 1500 pages. To make the handling of these approval packages more comfortable FDA prepares a ToC and identifies the pivotal studies of the medicinal product. The pivotal studies are the essential studies for the application on which basis the efficacy and safety of the medicinal product can be proven. Abstracts of the pivotal studies are also included in the ToC.18
UOther registration procedures
FDA has established three formal procedures to accelerate the development and review process. These procedures are applicable for drugs and biologics that address unmet medical need or for serious life-threatening diseases or conditions.F24F
These three procedures are fast track product development, priority review and accelerated approval.
UAccelerated Approval
FDA regulations, published in 1992, allow “accelerated approval” for drugs or biologics products which provide meaningful therapeutic benefit…over existing treatments. This type of procedure is applicable for the treatment of a serious or life-threatening disease.
The procedure allows the approval based on clinical trials using “a surrogate endpoint that is reasonable likely… to predict clinical benefit.” instead of using standard outcome measures like survival or disease progression.
Another possibility for the use of this procedure are drugs for which the use could be considered safe and effective only under set restrictions which could include limited prescribing or dispensing. For these types of drugs FDA normally requires postmarketing studies after the approval.X24X
UFast-Track Mechanism
The Food and Drug Administration Modernization Act of 1997 (FDAMA, P.L. 105-115)F25F directed the secretary to create a mechanism whereby FDA could designate as “Fast Track”.
The “Fast track” is designed for certain products that met two criteria:
• The product must concern a serious or life-threatening condition
• It has to have the potential to address an unmet medical need
23 Freedom of Information (FOI) Act per 21 CFR Part 20 (cf. XXX)
http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm138408.htm - dated 01.09.2009
24Susan Thaul, FDA Fast Track and Priority Review Programs, CRS Report of Congress - Order Code RS22814, February 21, 2008 http://www.nationalaglawcenter.org/assets/crs/RS22814.pdf - dated 01.09.2009
25Food and Drug Administration Modernization Act of 1997 (FDAMA, P.L. 105-115) http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmend mentstotheFDCAct/FDAMA/FullTextofFDAMAlaw/default.htm - dated 22.10.2009
The two main goals of the fast track are on the one hand making approval more likely and on the other hand the shortening of the approval time.
After FDA has granted a fast track designation the manufacturer is encouraged to meet with the FDA in order to discuss development plans and strategies before the official submission of the NDA/BLA. The advantage of the early interaction with FDA is that issues like elements of clinical study designs and presentations whose absence at NDA/BLA can lead to a delay in approval decision of NDA/BLA can be clarified earlier. 24X
On the other hand, FDA offers similar interactions to any sponsor who asks for FDA consultation throughout the development phases of a medicinal product. A unique option within Fast Track is the opportunity of a rolling submission, i.e. to submit sections of an NDA/BLA to FDA as they are ready, rather than the standard requirement to submit a complete application at one time. X24X
UPriority Review
In comparison to the fast track or accelerated approval, the priority review process starts only when a manufacturer officially submits an NDA/BLA.
Therefore the priority review does not have any influence on the timing or content of steps taken during the drug development or the testing of safety and efficacy.
The priority review can be used for medicinal products, which are intended to address unmet medical need. In such a case the duration of review (NDA/BLA) can be shortened from 10 months (full review time for a normal NDA/BLA) to 6 months (priority review of NDA/BLA).
The priority review is not explicitly required by law, but FDA has established it in practice, and various statutes, such as the PDUFA, refer to and sometimes require it.
In appendix 5 an overview table with the comparison of mechanisms to hasten product availability is attached (“XAPPENDIX 5X: Table of Comparison of Mechanisms to Hasten Product Availability“).X24
The accelerated approval, fast track mechanism and priority review are not described here in more details.