FDA Programs under further scrutiny as new JAMA study criticizes the breakthrough therapy designation, observes GlobalData

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 randomization, proper controls, double-blinding, the use of surrogate endpoints, as well as large enough numbers of enrolled patients.

BTD can be assigned if preliminary clinical evidence suggests an advantage over existing options. Since the program was initiated in 2012, 114 BTD approvals for 77 different drugs have been granted across all therapeutic areas.

However GlobalData, a leading data analytics company, believe that 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.

Fern Barkalow, PhD, GlobalData Healthcare Oncology and Hematology Director commented, “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, would not be a step in the right direction.’’

The FDA’s accelerated approval designation, 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 the successful completion of more robust endpoints in post-market studies.

Barkalow continued, ‘‘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), and it 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 randomized studies, which is not always possible or ethical in the case of advanced cancers and late-stage diseases in other therapeutic areas. One of the criticisms of the FDA’s BTD program 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.

Barkalow concluded, ‘‘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 program highlighted in the recent JAMA article partly as an issue of semantics, and a re-examination of the definition of scientific rigor in this context would be a reasonable next step.’’


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Notes to Editors

  • Quotes provided by Fern Barkalow, PhD, GlobalData Oncology and Hematology Director
  • For further information, 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 favor 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.


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