FDA Stresses The Importance Of Engaging With The Agency Early and Formally

FDA Stresses The Importance Of Engaging With The Agency Early and Formally

April 3rd, 2022 // 8:47 pm @

In February 2022, FDA organized a public oncologic drugs advisory committee or ODAC meeting to review a sintilimab application that was based on the ORIENT-11 clinical trial done in China only. Instead of following the regular method of reviewing the risks and benefits of one drug, the FDA committee only voted on one question.

It was whether more clinical studies should be done to show applicability to the American population and American medical practice before a final FDA decision.

The ODAC voted 14-1 for needing more clinical studies. This could delay the approval of sintilimab’s approval in the US for several years. Still, at least 25 drug applications in China are awaiting FDA approval. But a more important question is whether the committee’s decision matters outside of the sintilimab issue.

This is a complex question, but many regulatory professionals note that drug sponsors must engage with the FDA often and as early as possible if they want FDA approval.

ORIENT-11 is a phase III trial that is randomized, double blind and controlled by placebo to assess if sintilimab is safe and effective when used with platinum chemotherapy and pemetrexed as an initial or first line treatment for those with advanced non-small cell lung cancer.

Trials are only done in China, so sintilimab’s approval hinges on the agency’s regulatory flexibility as stated in 21 CFR 314.106. This regulation states that a drug application based only on overseas clinical data that meets US criteria for FDA approval can be approved if the data is related to the population in the US and medical practices in the country.

After listening to presentations from the sponsor and the agency, most ODAC panelists said the clinical study wasn’t applicable to the American population because the patients in ORIENT-11 are not as diverse as the US population.

Also, the clinical study endpoint and comparator arm are not the approved care standard for United States medical practice. Further, the consent forms needed to be updated as soon as pembrolizumab was FDA approved by the regulatory drug agency in China.

Last, the FDA inspections were too limited in scope to review data integrity and trial conduct.

However, FDA didn’t say that clinical trials done in one foreign country cannot be approved by FDA for use in the US. Rather, FDA says it will apply 314.106 in a flexible way, depending on the kind of drug and the data available.

Here are some critical tips based on the sintilimab review for sponsors that want FDA approval for foreign-based clinical strategy:

First, sponsors should, whatever their clinical strategy, meet and communicate with FDA formally and as early as possible if they want FDA approval in the US market. If you only engage in informal communication, this could be an expensive error.

For example, Eli Lilly and Innovent were about to start sintilimab in the US when FDA’s Richard Pazdur, the director of Oncology Center of Excellence, said Chinese sponsors were allowed to start PD-1/PD-L1 inhibitors to the American market during a 2019 FDA meeting.

But in February 2022, only a week before the above committee meeting, Dr. Pazdur, noted that drug applications wanting approval from data from one foreign country must be representative of the American population for FDA regulators to be more flexible.

Pazdur defended his change by saying he can change his mind. He noted during the committee meeting that comments at an informal meeting are not FDA policy.

The sintilimab’s ODAC meeting should tell drug companies and sponsors that informal FDA communication shouldn’t be relied on to make regulatory or business decisions. Also, if the drug wants to come to the American market, you should work with FDA formally during the earliest drug development phases.

If you engage with FDA early, the agency can give official regulatory advice about clinical trial conduction and clinical study design. This can be vital when doing clinical trials on foreign countries with different care standards or regulatory policies that differ from the US.

On the ORIENT-11 issues, FDA has said it would have told the sponsors to do a non-inferiority clinical trial that compared sinitlimab with an anti-PD-L1 chemotherapy program featuring an overall survival endpoint, and not a placebo arm featuring a progression-free survival endpoint.

Subscribe Now

Featured Partner