SHORTNESS OF BREATH – Is the FDA Suffocating Drug Innovation?

Researched-based biopharmaceutical company AstraZeneca announced encouraging overall survival (OS) results for their drug Imfinzi (durvalumab), which is used to treat first-line extensive-stage small cell lung cancer (SCLC). Imfinzi combined with standard-of-care medicine, etoposide, and platinum-based chemotherapy showed significant improvement in OS compared with chemotherapy alone, and demonstrated the versatility of combining immunotherapy for treatment in small cell lung cancer treatment. But with API manufacturing moving increasingly overseas—instigated, in part, by new FDA regulation stipulations—could concerns over the quality of drugs similar to the PD-L1 inhibitor stall other breakthrough treatments?

API production has traditionally been done in the home country of pharmaceutical companies, but due to interest in cutting costs and increasing profits, many corporations have moved manufacturing overseas – causing more rigorous guidelines and inspections to be put into place. However, where a portion of the final phases of production was normally done back in the company’s home country, intense screenings of the imported product have moved interest to the entirety of the process being outsourced. 

The quality of APIs can vary, and the efficacy of any drug is reliant on the integrity of its production. Poorly manufactured APIs can cause serious illness and even death. In response, the FDA has stepped in and tightened standards, with violations resulting in fines and recalls. One critically important phase of production is the removal of reaction by-products, including color bodies and metals. Ecosorb® multi-functional adsorbents are a family of highly efficient adsorbents combining the rapid kinetics of fine particles with excellent filtration characteristics. Ecosorb powders can be used in a stirred reactor, or as a precoat or deep bed operating mode, where the adsorbent is added directly to the filter, eliminating contamination of the reaction vessel.

While likely unintended, the FDA is potentially compromising vital phases of API production such as proper filtration by driving manufacturing of investigational finished drug products overseas. Currently, a batch of investigational API cannot be imported without an Investigational New Drug application (IND), which can only be obtained with analyses and stability data on the product. This is encouraging manufacturing outside the U.S. to the potential detriment of patients. There is also impact on other points in the drug development cycle, such as preclinical testing. Some preclinical testing must be completed prior to filing for an IND, but initial U.S. clinical trials can only occur after an IND is opened and in effect. 

This means that pharmaceutical firms must implement at least two separate imports prior to initiation of clinical trials. And according to FDAlawblog.net, imported API for clinical drug product can only enter the U.S. from the day the IND becomes effective, and no sooner than 30 days after its submission. Because of this, clinical trials for it cannot be available for use on day 30, when subjects are able to be enrolled. Therefore, the clinical trial can only begin when that API is manufactured into drug product and sufficiently testing for release: ”In essence, FDA’s current interpretation of its regulations may delay the importation of API at critical times during the development cycle and thus result in an overall delay to drug development. ”

Fortunately, Imfinzi is presently approved for unresectable, stage III NSCLC in the United States. The company is also evaluating the drug in late-stage studies for treating stage IV NSCLC. Manufacturer AstraZeneca is headquartered in Cambridge, UK, with R&D facilities in Gaithersburg, Maryland.