Making a New Medicine Part 3: Safety, Efficacy, Production, and the New Drug Application (NDA)

The discovery and development of a new medicine is a complex and lengthy process. Many founders begin their search for a new therapy without understanding these details. In my experience, most of the public views drug development as “the news reports that scientists show it works in a mouse, so my doctor will be able to write a prescription next week.” In an educational effort for summer break, I offer this four-part series describing the different stages of drug development, which are applicable in all regulatory jurisdictions.

Assuming the Phase 2 results meet the efficacy criteria of the protocol and the business criteria of the company, Phase 3 trials will commence. These studies are performed on a larger number of subjects (usually 100-3000) with a diagnosis of the target disease to evaluate the safety and efficacy of the lead compound in a more widely representative group. Phase 3 trials are distributed across multiple sites, are always blinded (double blinding is most common), and collect data similar to that of Phase 2 trials. The data and results of previous trials are used to refine the design and execution of the Phase 3 studies. Success rates for compounds reaching Phase 3 are better than at other stages, but the overall likelihood of a lead compound progressing from Phase 1 to regulatory approval is only about 10%. This value is from an excellent analysis of published data on clinical trial success rates by Hay and colleagues ([2], pg. 41).

Starting in preclinical development and increasing during clinical investigation, considerable effort is put into the development and validation of the processes for manufacturing the lead compound and its final dose form, known as the drug product. This work is necessary to produce clinical trial supplies (and placebo, if used in the trials), batches to demonstrate the shelf life of the product, and process qualification batches to show the new drug product can be reproducibly manufactured at commercial scale. Product labeling and final packaging, as well as marketing elements, are also developed. Regulatory personnel are gathering and reviewing data and results from all development phases and assembling the initial regulatory filing, known as the New Drug Application (NDA). Project teams at this point include members from every group that participated in any development stage to ensure the data in the application correctly represents the design and performance of the proposed new drug.

The New Drug Application (NDA) for the lead compound will, when approved, become a living document, frequently referred to as the license or filing for the drug product. Most regulatory agencies follow the global standard for the structure and content of an NDA. This is specified in the International Council for Harmonization (ICH) Common Technical Document, or CTD [3] The ICH is a nonprofit association of global regulatory agencies and pharmaceutical industry representatives with the mission to promote discussions between the two to harmonize existing requirements for drug registration and recommend new or updated standards. The CTD was one of the first work products of the ICH. It provides a structure for preparing an NDA that facilitates regulatory filing in multiple jurisdictions. A completed CTD contains 5 modules (see the image above). Module 1 contains the region-specific information for filing. Module 2 is a summary of the remaining modules, which cover Quality (Module 3), nonclinical studies (Module 4), and clinical studies (Module 5). It can take several months to sort, comprehend, and assemble the relevant data into a coherent final document. Once complete, the final version is submitted (generally in an electronic format) to the regulatory agency or agencies in the regions where the drug product will be marketed.

The submitted CTD is assigned to a review team composed of experts familiar with the therapeutic area and technical disciplines of the drug product. The reviewers examine the filing to determine if it is complete. Once complete, the review team members evaluate their assigned sections of the document and submit their findings to the review project manager for inclusion in the final “action package.” Personnel from the regulatory inspection branch visit the nonclinical, clinical, and manufacturing sites stated in the file to confirm studies were appropriately performed and the reported results are accurate. Additional experts may be consulted on questions of special expertise. The reviewers frequently engage the sponsor’s filing team in a structured dialogue to clarify details and identify missing information. At the end of the review process, which generally takes several months, the review team decides whether to approve the drug. If approvable, the reviewers work with the sponsor on the final labeling and prescribing information. If not approved, the review team will provide feedback on needed information, and the sponsor may resubmit the updated application. Only 50-60% of NDAs are approved during the first submission, and the approval status is clear for most new drug products after 3 rounds of submission (Hay et al., pg. 45-46 [2]; these values include Biologics License Applications [BLAs] along with NDAs).

Learn More

For more details on Phase 3 trials, I’ll refer you once again to the review of clinical trial concepts published by Umscheid, Margolis, and Grossman in 2011. [1] I also recommend the article on trial Phase success rates by Hay and colleagues for an evaluation of the rates of success and potential failure modes for different drug and disease categories. [2] Read more about the activities involved in process validation in an FDA guidance. [4] Dive into labeling (a regulatory specialty of its own) at this FDA website [5]. The ICH webpage is an excellent place to learn more about the CTD. [3] This FDA website is a useful starting point on the application review process. [6]

Part 4 of this series reviews the post-NDA approval activities for the new medicine. You can catch up on Part 1 of this series, Discovery and Preclinical Development, here ; and Part 2, Introducing Clinical Trials, here .

References

[1] Umscheid, C. A., Margolis, D. J., & Grossman, C. E. (2011). Key concepts of clinical trials: a narrative review. Postgraduate medicine, 123(5), 194–204. https://doi.org/10.3810/pgm.2011.09.2475

[2] Hay, M., Thomas, D. W., Craighead, J. L., Economides, C., & Rosenthal, J. (2014). Clinical development success rates for investigational drugs. Nature Biotechnology, 32(1), 40-51. doi:10.1038/nbt.2786

[3] ICH.org , The Common Technical Document (CTD). Accessed April 30, 2024. https://www.ich.org/page/ctd

[4] U.S. FDA, Guidance for Industry: Process Validation: General Principles and Practices, 2011. Accessed April 30, 2024. https://www.fda.gov/files/drugs/published/Process-Validation–General-Principles-and-Practices.pdf

[5] U.S. FDA, FDA’s Labeling Resources for Human Prescription Drugs website. Accessed April 30, 2024. https://www.fda.gov/drugs/laws-acts-and-rules/fdas-labeling-resources-human-prescription-drugs

[6] U.S. FDA, Step 4: FDA Drug Review website. Accessed April 30, 2024. https://www.fda.gov/patients/drug-development-process/step-4-fda-drug-review