Factors behind Increases in Attrition
During the past decade, the largest causes of attrition have been lack of efficacy and safety issues (toxicology and clinical safety failures); each of these factors accounted for 30% of attrition.
Pharmaceutical industry executives and researchers often attribute the high rates of attrition seen in development since 2000 to the fact that companies have been addressing more complex diseases with high unmet medical need (e.g., cancer, CNS diseases, autoimmune diseases, HIV/AIDS), and establishing higher standards for success in clinical trials, and for approval due to improved standards of care in many diseases. Ironically, the latter is a result of the success of the pharmaceutical industry in developing improved therapies.
These two factors are usually concerned with efficacy. A third issue often given is increased scrutiny by regulatory agencies, usually about safety.
Targeting complex diseases typically involves discovering drugs that have novel mechanisms of action and/or address unprecedented targets. Drugs that address unprecedented targets are much more likely to fail in Phase II (by a factor of two- to four-fold) than are drugs that address precedented targets. The most common reason for this attrition is failure to demonstrate clinical efficacy.
“On the Phase II attrition issue, I think that what we saw over the past decade was a big change in the drug development game,” Dr. Gombar added. “Part of that change stemmed from the fact that you must have novel drugs. You have to bring new value and real medical value to the marketplace. That naturally drives people to novel targets, which carry higher risk and much more uncertainty. I’m not sure whether Phase II attrition is really an issue or simply a manifestation of how the drug development game has changed.”
Many industry commentators attribute the low numbers of approvals in recent years to increased FDA scrutiny. The high rate of attrition in the drug development process, however, has been severely limiting numbers of NDA and BLA applications submitted to the FDA, especially high-quality applications that can withstand the agency’s scrutiny.
Also, the FDA is asking for more information than in previous years, not only to avoid postmarketing safety problems, but because there has been less scientific and medical literature available for novel drugs submitted in recent years. These drugs have often been designed to address unprecedented targets. FDA reviewers are unfamiliar with these mechanisms and so require more information.
Thus, the high rate of pipeline attrition and the need to address unprecedented targets and mechanisms of action have greatly affected relationships between the industry and regulatory agencies.