Learning From the FDA Breakthrough Therapies Pathway

Arrival of the breakthrough therapies era

The expedited USA Food and Drug Administration (FDA) regulatory pathway for 'breakthrough therapies' has already yielded its first two approvals and more than 26 designations, for 30 candidates in 22 indications. Less than a year on, on 1 November 2013, obinutuzumab became the first drug to graduate from the breakthrough therapy programme into the real world. Weeks later, it was joined by ibrutinib. The breakthrough era has arrived, wrote Asher Mullard in an article published online on 29 November in the Nature Reviews Drug Discovery.

Despite the recent approvals, however, speculation remains about the details of the programme. What does it take for an experimental medicine to make the cut, and what benefits will the status confer? As of 8 November, the FDA had awarded 33 designations, of which drug developers had disclosed 26. The public designees consisted of 30 drugs — small molecules, antibodies, antisense agents and enzyme replacement therapies — in 22 indications.

Publicly disclosed anticancer agents with breakthrough designation

In term of anti-cancer agents, a Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for mantle cell lymphoma; in Waldenstrom’s macroglobulinaemia it’s currently in phase II/III clinical testing, and in patients with chronic lymphocytic leukaemia (CLL) and chromosome 17p deletion under new drug approval (NDA) / biologic license application (BLA).

Anaplastic lymphoma kinase (ALK) inhibitor, LDK378, is in a phase III trial in ALK positive non-small cell lung cancer (NSCLC) patients who are resistant to crizotinib.

Palbociclib, CDK4/CDK6 inhibitor, is in a phase II/III clinical testing in post-menopausal patients with ER-positive, HER2-negative, locally-advanced or metastatic breast cancer.

An anti-programmed cell death 1 (PD1) immunotherapeutics, MK-3475, is in a phase III testing in advanced melanoma.

Anti-CD38 monoclonal antibody, daratumumab, is in a phase I/II testing in patients with multiple myeloma after at least three prior lines of therapy.

Anti-CD20 monoclonal antibody, obinutuzumab, has been approved for CLL.

Histone deacetylase (HDAC) inhibitor, entinostat, is in a phase II testing in postmenopausal patients with ER-positive, recurrent or metastatic breast cancer, with exemestane, after progression on non-steroidal aromatase inhibitors.
Anti-CD20 monoclonal antibody, ofatumumab, is under supplemental NDA and BLA for first-line treatment of patients with CLL in whom fludarabine-based therapy is considered inappropriate.

Volasertib, a polo-line kinase 1 (PLK1) inhibitor, is in a phase III testing in patients over the age 65 and acute myeloid leukaemia.

Another ALK inhibitor, alectinib, is in a phase II testing in ALK-positive NSCLC patients who are resistant to crizotinib.

What makes the difference

To put the numbers further in context, the FDA's Center for Drug Evaluation and Research (CDER) had received 106 applications for breakthrough status. The agency declined 48 of these requests, making for a 41% success rate (decisions were still pending for 25 applications). The Center for Biologics Evaluation and Research (CBER), by contrast, had received 13 applications for breakthrough status, of which it had approved none and rejected 10.

The FDA published a much-awaited draft guidance document on expedited drug programmes in June, providing a first official glimpse into the agency's approach to the breakthrough pathway. The FDA laid out the need for “preliminary clinical evidence” showing that a drug offers “substantial improvement” over available therapies on at least one “clinically significant” end point in a “serious or life-threatening disease”.

Drug developers welcomed the draft guidelines as a good start, but noted plenty of outstanding ambiguity. Patient advocacy groups and other organizations seem to agree, based on comments and detailed requests for clarification submitted to the FDA about the guidance. The stakeholders asked among other things, about the evidentiary standards for determining what constitutes adequate “preliminary evidence” or about the difference between “substantial improvement” and “clinical superiority”. The list of questions goes on. The FDA plans to publish a final guidance document next summer that could firm up at least some of these specifics.

Until then, the 26 public designations offer a general overview of the characteristics of a breakthrough drug. Cancer drugs score highly, accounting for 12 (46%) of the designations. The only non-oncologic therapeutic areas with repeat designations are infectious disease (hepatitis C virus) and respiratory disease (cystic fibrosis). The remaining drugs span a wide disease space, and about half of them are for the treatment of inherited conditions.