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.
Centrality of Translational Medicine
Since the mid-2000s, the pharmaceutical industry has been attempting to reduce Phase II attrition by implementing strategies centered on the discipline of translational medicine, which is aimed at obtaining evidence that can help clinical researchers predict outcomes of treatment with experimental agents. This especially involves obtaining proof of concept (POC) that a drug is likely to be safe and efficacious early in development by carrying out clinical trials that are designed to determine POC rapidly and at relatively low cost.
Biomarkers for determining pharmacodynamic, efficacy, and safety parameters are key to these clinical studies; they can also be used to give an indication of likely efficacy much more quickly than clinical endpoints, which are required for registration trials.
In a survey of drug development researchers conducted by Insight Pharma Reports, in conjunction with its recently published report, “Approaches to Reducing Phase II Attrition,” the largest number of respondents’ companies have adopted translational medicine programs aimed at improving the efficiency and effectiveness of early drug development (Figure 1). This is in accord with the widespread reliance on such programs by pharmaceutical and biotechnology companies in recent years.
The report discusses a strategic framework for reducing the risk of Phase II and Phase III attrition due to addressing unprecedented targets. These strategies are designed to identify those targets that have the best chance of success in the discovery phase and employ early-stage POC clinical trials to weed out drugs and targets that do not achieve POC.
The general strategy proposed in the report thus involves both improving the drug discovery and preclinical phases, as well as early development.