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This blog is the second part in our “Strategizing for NDA\BLA” series. The first part can be found HERE – “Mind the Gap(s): Early Identification of Issues is Key for a Successful NDA or BLA” Webinar

Pharmaceutical marketing applications, whether a new drug application (NDA) or biologic licensing application (BLA), are massive undertakings. They can contain tens to hundreds of thousands of pages of documents. Therefore it behooves a sponsor to plan such an application well in advance. Often planning for the application is postponed until the pivotal Phase 3 clinical trials are nearing completion or are finished. From the experiences we have had at CATO SMS, it is a better approach to start significant planning efforts as the Phase 3 portion of the development of a drug is beginning rather than ending (if not even sooner).

The Importance of a Thorough Gap Analysis

One of the first things that should be done when thinking about submitting a NDA or BLA is a thorough analysis of anything that might be missing from the development program, also known as a gap analysis. Gap analyses at CATO SMS include reviews by experts in regulatory affairs; chemistry, manufacturing, and control (CMC); nonclinical development; and clinical development. Findings in each of these domains are then presented in relation to how they affect the potential fileability of the marketing application. Performing this gap analysis at the end of Phase 2 (EOP2), rather than at the very end of development can help identify missing documents or studies that may be required to support the application.

From the regulatory perspective a number of key items should be addressed in the gap analysis. A review of all prior commitments the sponsor has made to the reviewing division including CMC, nonclinical, clinical, and statistical commitments is critical. Any outstanding commitments need to be rectified before an application is filed.

Once all commitments are identified, a clear plan of communication with FDA is critical. Meetings with FDA should occur as early in the process as possible. A great source of information regarding gaps in a development program is the agency itself. They will have expectations and will communicate them during these meetings. It is critical when the division provides recommendation that the sponsor ensures that their interpretation of the recommendation is in line with what FDA is suggesting. The danger in misinterpreting a recommendation is that unmet commitments might be missed, resulting in delayed submission, a refusal-to-file, or a complete response letter that won’t be received until months after the submission takes place.

Having All of Your Documents in Order

Another key to a successful marketing application is to generate a complete and detailed list of documents to be included in the application. It is helpful to organize this list into a detailed table of contents (TOC) for the NDA/BLA. Organizing the TOC by module helps identify any outstanding information need and plan for the authoring of any necessary documents. This TOC can be used as a document management tool in preparing the application. While modules 2 and 3 are somewhat proscribed, module 1 requires identifying all of the needed forms and country-specific information, and modules 4 and 5 require the mapping of studies to the correct location within the submission. A number of CMC recommendations can streamline the approval process. A solid rationale and quality data plan should be in place allowing the identification of critical quality attributes and/or critical process parameters for the manufacture process.

During the development process inevitable changes are made as the manufacturing process and analytical methods for a drug or biologic mature. Data should be available to show the comparability of the final product with the investigational products used in the clinical trials. Changes in manufacturing may affect the stability of the product and new analytical methods may reveal previously unknown stability issues, therefore older stability data may not be useable in the marketing application.

Planning for FDA Inspections

Planning should also begin for potential FDA inspections. These inspections include inspection of selected clinical sites from the pivotal studies and pre approval inspections (PAIs) of CMC sites involved in manufacturing. A PAI-readiness plan is highly recommended to ensure all manufacturing sites are ready for inspection. Critical findings in these inspections are likely to cause significant delays in approvals. Along with the PAI-readiness plan, an analytical control strategy should be in place. Mock inspections are an excellent way to identify potential findings in the actual FDA audit.

A gap analysis of the nonclinical program also has specific recommendations. The program should be examined for any potential missing studies that are likely to be required by FDA. Are the toxicology and safety studies sufficient to support the dose and duration of use of a product? Are all reports complete, final, and signed by the study director, including a histopathology report signed by the lead pathologist? Do these reports include standardized data requirements for toxicology studies (CDISC) and are data provided in the Standard Exchange of Nonclinical Data (SEND) format? Currently, SEND is required for most toxicology, carcinogenicity, and safety pharmacology studies. If not, it may be necessary to go back to the contract research organization (CRO) that carried out the studies and finalize them. It is good to do this survey early as the process of finalizing reports can take a surprisingly long time.

Plan to submit all reports to the NDA or BLA, regardless of whether they have previously been submitted to an IND. During our review process, we also identify the appropriate location in the submission based study type for each nonclinical report in module 4.

Late-Phase Nonclinical Studies

It is recommended to run late-phase nonclinical studies in parallel with the Phase 3 clinical program. Late-phase studies include pre- and post‑natal reproductive toxicity studies and 2-year carcinogenicity studies. Agreement should be reached with FDA regarding which nonclinical studies are needed before submission of the marketing application and which studies can be nonclinical postmarketing commitments. It may be possible to perform the longer term studies, like the 2-year carcinogenicity study, after approval, in selected indications.

Finalizing the Submission

Finally, the clinical portion of development should be thoroughly reviewed, including all biopharmaceutic, pharmacokinetic, pharmacodynamics, and safety and efficacy study reports. During the review process, we carefully assess whether the data is suitable to support an NDA or BLA. Also during this process, we identify which reports go where in the application’s module 5. Like nonclinical reports in module 4, each type of clinical study is located in pre-specified locations in module 5 of a submission,

Data for all studies will need to be submitted in an agreed upon data format. The format could be a legacy or CDISC (STDM/ADaM) format as determined through discussion with FDA. Both datasets and SAS programs for each study should be submitted. Some reports will also need site level summary data (Bioresearch Monitoring or BIMO datasets). These datasets are used by the agency in determining a plan for site level inspections and include tabular listings of site information (Part I) and subject data listings by site (Part II). A data submission plan developed well ahead of submission makes this process run more smoothly.

Completion of the clinical portion of the submission is often rate limited by writing of the integrated summary of efficacy (ISE) and integrated summary of safety (ISS). Because these documents often deal with studies with disparate dosing schemes, endpoints, and randomization, integrating the data across studies can be time consuming. It is critical to have a well-defined, written statistical analysis plan (SAP) for each integrated summary. The ISE and ISS should break subjects into different subgroups or tiers. Analyses should examine whether subgroup respond differently (ISE) or exhibit different safety profiles (ISS). Planning for the integrated summaries should involve early engagement by biostatisticians to best determine how data can be effectively and informatively integrated. The ISS and ISE are really the crux of a marketing application and should be planned accordingly. Plan to finalize the SAP after the pre-NDA or pre-BLA meeting and generate all of the tables, figures, and listings outlined in the SAP. The final versions of these summaries drive your proposed labeling and have critical impacts on how your product will be marketed.

Final Thoughts

By performing a gap analysis on all regulatory, CMC, nonclinical, and clinical data at hand you should end up with a complete TOC and written report for your application submission. The TOC will allow you to identify what information you have to support the application and what information still needs to be collected. The TOC is also an incredibly powerful tool when building the submission. Documents can be tracked as they are placed into the eCTD build and quality control reviews can be documented. A final benefit of this detailed TOC is that it allows for much easier understanding of scope and cost of a marketing application. All of these benefits make a gap analysis a vital part of any marketing application preparation. Performing the analysis earlier rather than later allows you time and flexibility in gather any missing data and reduces the likelihood of a refusal-to-file or complete response letter.

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