The FDA’s Breakthrough Therapy designation (BTD) recently came under fire in a study published in JAMA in July by three researchers at Yale. The authors maintain that contrary to the beliefs of stakeholders, including physicians and the general public, some of the pivotal trials used to support the BTD were missing elements of a rigorous study design such as randomisation, proper controls, double-blinding, the use of surrogate endpoints, as well as large enough numbers of enrolled patients.

However, given the types of advanced indications with high unmet need, in which developers tend to seek BTD, it is not surprising that so-called less-rigorous studies are the standard. FDA officials, including Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, reinforce the view that the nature of the disease for these patients does not allow for drug development conducted in the same time frame as those studies of higher degrees of scientific rigour.

Since the programme was initiated in 2012, 113 BTD approvals for 76 different drugs have been granted across all therapeutic areas. BTD can be assigned if preliminary clinical evidence suggests an advantage over existing options. On the other hand, through the FDA’s accelerated approval designation, which was first introduced in 1992, 27 drugs received this status for 34 different indications since 2012.

The accelerated approval programme allows for submissions based on the use of surrogate endpoints, with the intent that the initial approval would be followed up by a regular approval based on successful completion of more robust endpoints in post-market studies. As an example, for most cancer indications, progression-free survival (PFS) is used as a surrogate endpoint for initial approvals, especially because it is quicker to measure than a clinical endpoint such as overall survival (OS).

PFS has since been validated as a fairly good surrogate endpoint for many cancer types in a variety of studies. FDA guidance issued in 2007 titled, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’ recommended that PFS be used only in the context of randomised studies, which is not always possible or ethical in the case of advanced cancers and late-stage diseases in other therapeutic areas.

Specific guidance for lung cancer

While the guidance has not been updated since 2007, in 2015, the FDA issued guidance specific for lung cancer, titled ‘Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics,’ which stated that at an Oncologic Drugs Advisory Committee (ODAC) meeting on lung cancer in 2003, a positive vote of 11 to 8 was recorded in favour of the use of PFS as an endpoint to evaluate drug effect in metastatic non‐small cell lung cancer for consideration of regular approval, and not just accelerated approval.

One of the criticisms of the FDA’s BTD programme mentioned in the JAMA article refers to the use of surrogate endpoints, yet the evidence is mounting that not only is PFS a valid surrogate endpoint, but it is now acceptable for regular approval in at least one oncology indication.

Given the nature of certain advanced forms of disease and the few available options and time left for patients with these diseases, it may be more productive to view the criticisms of the FDA’s BTD programme highlighted in the recent JAMA article partly as an issue of semantics, and a re-examination of the definition of scientific rigour in this context would be a reasonable next step.

Certainly, requiring parameters for approval that are not very feasible to achieve within the population of patients with advanced diseases, those that are without other reasonable treatment options, is not a step in the right direction.