Making a New Medicine Part 4: What Happens After Approval?

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.

Postmarketing studies are frequently planned before a drug has received regulatory approval, and some may be requested by application reviewers as a condition of approval. Even though Phase 3 trials are much larger than earlier phases, they are still small (100-3000 participants) and may not be fully representative of the full patient population. However, considerable design and execution effort goes into minimizing this effect. Postmarketing (or Phase 4) studies are performed to increase the range of safety and efficacy data to a broader patient group, look for weak safety signals (present in 1 in 10,000 or fewer patients), or address areas of concern for the application review panel. Other studies are often conducted to study the effect of the new drug in related diseases (referred to as new indications) or in combination with other medicines to improve efficacy or patient quality of life (improving treatment outcome or reducing the number of medications taken). Any studies for a new or expanded indication are performed under a new IND.

The results of postmarketing studies may eventually lead to approval of the drug for over-the-counter use. The proton-pump inhibitor omeprazole is a good example because it was first approved for prescription use in the treatment of gastrointestinal reflux disease and then later approved for over-the-counter use to control heartburn caused by excess stomach acid). The application for the new indication is filed as a supplemental NDA for FDA pre-market approval. Other postmarketing activities include monitoring and investigating adverse events related to the use of the new drug and reporting them to regulators, supporting routine regulatory inspections of the manufacturing facilities for the drug, and making quality-driven changes to the manufacturing site, process, or components based on the better understanding of the new drug over time. Updates to the NDA are required for these changes, and some will require review by the regulatory agency before they can be implemented.

As I noted in part 3, an approved NDA for a drug product is a living document within its approval region and is the license under which the drug product may be manufactured and distributed in the area. As such, it has a life cycle that allows for adaptation over time. Each year, during the period of commercial production, the license holder is required to file an annual report with the approval agency giving details of the production, distribution, and stability of all drug product batches on the market in the region. Deviations from the approved manufacturing process may occur, and each must be investigated for root cause(s) and corrective/preventive actions taken. New safety signals may be discovered through adverse event reporting systems, and these may lead to labeling updates. Other changes may be needed to expand or change the sites of manufacturing, replace equipment, and update any aspect of the drug’s production based on an improved understanding of it over time. Routine inspections by regulators check the performance of each facility to ensure they meet the Good Manufacturing Practice (GMP) regulations. The inspectors also confirm the processes used for the drug product meet the specifications of the current license. The findings from these inspections may require additional changes to the NDA.

Any critical changes (for example, in equipment, manufacturing facilities, or test methods) must be proposed, approved, and managed using a change control system. All changes are also reported to the approval agency using a regulatory pathway. At the FDA, these four pathways are:

1. Major changes, or those most likely to affect the safety or efficacy of the drug product, must be reported using a Prior Approval Supplement (PAS). As implied, the PAS requires regulatory approval before any batches made with the change in place can be distributed.
2. Moderate changes, which may affect the safety and efficacy, are usually reported as a Supplement – Changes Being Effected in 30 Days. This type of submission is abbreviated as CBE30, and the FDA has 30 days from receipt to review and inform the license holder whether the change requires a PAS or additional information in the CBE30 before drug product made using the change can be distributed.
3. Some types of moderate changes can be reported using a Supplement – Changes Being Effected or CBE. In these cases, the drug product made using the change can be distributed immediately, but the FDA may order distribution to cease if it disapproves of the change after review.
4. Minor changes, with no impact on the safety or efficacy of the drug product, are made as needed and reported in the annual report described above.

Due to these additional reports and supplements, the NDA grows in size and complexity over a drug’s lifetime, which may span many decades. It requires careful oversight, maintenance, and updates to meet current regulations. This is the job of the license holder’s regulatory group, with help from the license holder’s quality systems and any manufacturing, packaging, or distribution subcontractors (CMOs) approved by the license.'

Learn More

Umscheid, Margolis, and Grossman’s 2011 review of clinical trials covers postmarketing studies in more detail. [2] Common postmarketing activities for FDA-approved drugs are listed on their Step 5 website. [3] The guidance on postapproval changes [1] and quality systems [4] are good sources of additional information on maintaining the product license.

This is the end of my four-part series on new medicine development. I’m happy to partner with you to make sure your event is a success. Book me to speak on the drug development process here .

References

[1] U.S. FDA, “Guidance for Industry: Changes to an Approved NDA or ANDA,” 2004. Accessed April 30, 2024. https://www.fda.gov/media/71846/download

[2] 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

[3] U.S. FDA, Step 5: FDA Post-Market Drug Safety Monitoring website. Accessed April 30, 2024. https://www.fda.gov/patients/drug-development-process/step-5-fda-post-market-drug-safety-monitoring

[4] U.S. FDA, “Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations,” 2006. Accessed April 30, 2024. https://www.fda.gov/media/71023/download