The Controversy of the FDA's Fast-Track Approval Process

The FDA’s fast-track approval process is designed to speed drug development for life-threatening conditions, but has faced increased scrutiny over the years. Now, more evidence suggests that the FDA’s fast-track approval process may not be working as intended.

In this article, I’ll provide an overview of the fast-track drug approval process, highlight a recent analysis of fast-track approved drugs, and discuss the crucial balance between expediting drug approvals and ensuring clinical effectiveness through rigorous trials.

The FDA Fast-Track Approval Process

The FDA created the fast-track program in 1992 to speed drug development to treat life-threatening diseases like HIV and cancer.

While the program speeds up the traditional drug pathway timeline, which may take 15 years to complete, it maintains all the same steps and standards to ensure safety. What differentiates the fast-track process from the traditional drug pathway is researchers can use surrogate endpoints as a means to assess the drug’s clinical efficacy. These endpoints may include non-clinical markers such as tumor response rate, tumor markers, and viral load—measurements that correlate with the primary endpoints like survival and quality of life. However, these surrogate endpoints do not directly measure important clinical outcomes, which we physicians actually care about.

Once the FDA gives a drug fast-track designation, it goes on the market. The FDA does, however, require sponsors of fast-tracked approved drugs to follow up on confirmatory trials. For example, if my HuddleRx drug received fast-track approval on the basis of tumor reduction size, I would need to run a follow up confirmatory trial showing the drug indeed has a significant survival benefit compared to placebo (or standard of care). If the confirmatory trial shows such benefit, the FDA would then convert HuddleRx drug to full approval. If the confirmatory trial doesn’t show such benefit, I’d have to withdraw the drug from market.

The FDA’s power to withdraw unproven drugs from market has been futile. And if my HuddleRx drug is already on market, making millions, am I really incentivized to quickly do a confirmatory trial?

No. And neither are other drugmakers.

In fact, sponsors of one-third of all drugs granted accelerated approval still need to complete their confirmatory trials. Said another way, drugs that may offer no clinical benefit are on the market, being used by patients and paid for by insurers.

I highlighted the entire fast-track approval process below, in case you want some more light reading.

The Deets

A majority of fast-track approved cancer drugs from 2013-2023 did not show clinical benefit after 5-year follow up, according to a recent JAMA publication. More than 80% of all fast-track approved drugs are for cancer.

This cohort study analyzed 129 fast-track approved cancer drugs from 2013 to 2023. 46 of the 129 fast-track approved cancer drugs had at least 5 years of follow-up with the following outcomes:

• 29 (63%): converted to regular approval

• 10 (22%): withdrawn

• 7 (15%): no definitive outcome

The authors used confirmatory trial data of the 29 drugs that were converted to regular approval to assess clinical benefit. Overall, 20 (69%) demonstrated clinical benefit, with the breakdown below:

• 7 (24%): overall survival and quality of life benefit

• 7 (24%): overall survival benefit without evidence of quality of life benefit

• 6 (21%): quality of life benefit without overall survival benefit

• 9 (31%): no evidence of benefit in either overall survival or quality of life

Further, when you look at why the FDA ended up approving the drugs, you find that the FDA continued to use surrogate measures (e.g. response rate) to justify converting the drug from accelerated to regular approval instead of clinical measures such as quality of life benefit. This is the main point of confirmatory trials!

Interestingly enough, time to regular approval conversion isn’t getting faster. Rather, time to regular approval increased from about 1.5 years to 3.5 years and time to withdrawal decreased from around 10 years to 3.5 years over the study’s analysis period.

There have been incredible, life-saving drugs to come out of the fast-track approval process:

• Several HIV medications received fast-track designation in the late 90s, early 2000s, helping thwart the HIV endemic over the past several decades.

• Ibrutinib is now standard treatment for chronic lymphoid leukemia.

• Avastin is used to treat several types of cancer, including colorectal cancer, lung cancer, and glioblastoma.

At the same time, there have been some questionable drugs to come out of the fast-track approval process.

Makena is the first to come to mind….