Expedited drug approvals: Do the clinical benefits meet expectations?

Pharma News: Accelerated approval is a regulatory pathway available to investigational drugs treating unmet clinical needs. A new study presented at the American Association for Cancer Research (AACR) 2024 showed less than fifty percent (50%) of the cancer medicines approved through the US Food and Drug Administration’s (FDA) expedited approval pathway have demonstrated improved overall survival or quality of life, while being on the US market for at least 5 years.

This holds significance for the Australian market as pharmaceutical companies and healthcare professionals seek alternative pathways within the current Health Technology Assessment (HTA) review to expedite access to innovative therapies and health technologies.

A first-of-its-kind study from the Adelaide Health Technology Assessment (AHTA) found that a significant proportion of regulatory approvals for cancer medicines do not include randomised controlled trials (RCTs).

“There is an increase in the utilisation of surrogate outcomes in oncology research while the association between surrogates and true clinical benefits has been questioned. A lack of direct comparative evidence and the utilisation of surrogate outcome measures results in increased uncertainty about the clinical benefits and risks associated with medicines,” the authors Gao et al noted.

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“The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life,” said Dr Edward Cliff, study author and haematology fellow at the Peter MacCallum Cancer Centre in Melbourne, who presented the findings at the AACR meeting a few days ago.

“In some cancers, these markers work well, but in others they don’t,” explained Dr Cliff.

Within the FDA program, surrogate markers such as progression-free survival, tumour response, and duration of response are utilised for accelerated approvals of cancer therapies. Subsequent to these accelerated approvals, the pharmaceutical companies are obligated to substantiate clinical benefits through confirmatory trials.

To determine whether cancer drugs granted accelerated approval by the FDA ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for MSD’s Keytruda (pembrolizumab) in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for BMS’ Opdivo (nivolumab) for refractory locally advanced or metastatic urothelial carcinoma, both based on tumour response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.

“The reliance on surrogate markers means that these drugs are used for treatment and added to guidelines without solid evidence of real-world clinical benefit,” stated Dr Cliff.

Dr Cliff emphasised that the objective shouldn’t be to abolish the accelerated approval process altogether, as it occasionally provides rapid access to potent treatments for patients. Rather, there’s a need to enhance the system to maintain its speed while ensuring certainty regarding clinical benefits through robust and timely confirmatory trials.

“Clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr Cliff explained. “It’s important for them to have the information.”

In December 2022, the US Congress passed the FDA Omnibus Reform Act. This legislation mandates that companies must have confirmation trials in progress as a prerequisite for accelerated approval and are obligated to provide regular progress reports. Additionally, the Act expedites the withdrawal process for drugs that don’t show a benefit.

The Act faced two recent tests. In February, the FDA used the expedited process to withdraw the multiple myeloma drug Pepaxto (melphalan flufenamide) from the market. Since it had not been available in the US for an extended period, the withdrawal process encountered little contention.

In March, Regeneron revealed that the accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been postponed due to pending enrolment in a confirmatory trial.

Study moderator Dr Shivaani Kummar, medical oncologist/haematologist at Oregon Health & Science University, Portland, said that “the confirmatory trials aren’t happening at the pace which they should.”

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr Kummar noted. For instance, if an agent just shrinks the tumour, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”

Regarding prescribing drugs based on accelerated approvals, she informs her patients that while trials have shown promise, the long-term effects remain uncertain. Together with her patients, they deliberate and make informed decisions.

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