Heavy use of special regulatory mechanisms in the US, highly targeted agents and a focus on orphan indications as the first point of market entry have enabled leading biotechnology companies to produce a surprising number of innovative and profitable cancer therapies, despite the high rates of attrition in the category.
The more than 160 biotechs in Deloitte Recap LLC’s Recap Bioportfolio Index (RB), a database spanning more than 20 years of drug development history, have to date achieved an approval success rate (ASR) of 17.6% (29 out of 164 compounds to have entered Phase I clinical trials), notes a white paper on Innovative Strategies for Oncology Drug Development written by Deloitte Recap senior manager Lisa Natanson.
This is “a significant improvement on published data that report ASRs for cancer therapeutics as low as 5% and 8%”, Natanson writes. It is substantially lower, though, than the reported ASR of 26.1% (expressed as a ‘Phase transition probability’ for Phase I trials to US new drug application (NDA) approval) for investigational oncology compounds developed by the top 20 pharmaceutical companies (based on 2005 sales).
To put these figures into context, cancer therapy development as practised by RBI companies has been characterised by high failure rates at all stages of clinical development, Natanson points out.
Attrition rates for the 164 oncology compounds in Deloitte Recap’s Development Optimizer dataset are 27% for product candidates entering Phase I, 60% for candidates entering Phase II and 33% for those entering Phase III. Moreover, 9% of cancer compounds filed for approval with regulatory authorities in the US and Europe are rejected.
Attrition rates for non-oncology compounds in the Deloitte Recap database are 17% for Phase I, 46% for Phase II and 29% for Phase III – although they are 11% for compounds that reach the approval filing stage.
Regulatory mechanisms designed to speed up clinical development and review times at the US Food and Drug Administration (FDA) have helped biotechnology companies through the process, Natanson says.
All 27 of the US-approved oncology compounds developed by RBI companies employed at least one of four primary FDA mechanisms in this respect, while the majority of products took advantage of two or more mechanisms.
The most frequently used procedures were the Orphan Drug Act of 1983; the FDA’s Accelerated Approval Regulations of 1992 (for therapeutics addressing life-threatening diseases); the fast-track mechanism in the Food and Drug Administration Modernization Act of 1997 (FDAMA); and the priority review provisions in Section 112 of the FDAMA.
In the Deloitte Recap database, cancer drugs took roughly the same overall time to develop as their non-cancer counterparts, despite reports that US clinical development times are generally longer for cancer therapies than for other drugs.
The mean clinical development time – defined as the time between investigational new drug (IND) filing or project start and the submission of a NDA/biologic license application (BLA) – for the 27 RBI cancer drugs approved by the FDA between 1993 and May 2010 was 5.6 years. The mean development time for the 102 RBI non-cancer drugs approved by the FDA between 1982 and May 2010 was 5.8 years.
“Although some published data suggest that FDA mechanisms have negligible impact on reducing drug development times, our data suggest that the use of multiple regulatory mechanisms was prevalent [among oncology compounds] and may have a synergistic effect on speeding the development process,” Natanson comments.
Of the 29 marketed cancer products developed by RBI companies , 41% are large molecules (eight monoclonal antibodies, three recombinant DNA therapies and one dendritic cell therapeutic vaccine) while 59% are small molecules, the white paper points out.
Notable successes have included molecules targeting receptor tyrosine kinases (e.g., Avastin, Erbitux, Herceptin, Tarceva), with a 31% ASR versus 16% for all other targets. Monoclonal antibodies and recombinant DNA oncology compounds in the Deloitte Recap dataset have achieved an ASR of 22% compared with 16% for all other types of technologies (i.e., small molecules, oligonucleotides and naturally derived products).
RBI companies have also tended to focus their initial licensing efforts in oncology on orphan indications as a gateway for market entry. In their first approved indication, 78% of the FDA-approved RBI cancer drugs had orphan status.
An illustration of how rare disease indications for relatively small patient populations can be layered on to build a composite blockbuster is Millennium Pharmaceuticals’ Velcade, whose first US approval in 2003 was for a relapsed and/or refractory subset of patients with multiple myeloma.
“Yet, after multiple label expansions, Velcade has joined the elite club of cancer molecules that generate upwards of US$1 billion annually,” Natanson notes.