Living with Attrition – Ways to Compensate
While the activities discussed in the previous section are important steps towards improving attrition in biopharmaceutical R&D, there is the fact that drug discovery and development will always be fraught with uncertainty. With the exception of Phase II (low – 44%) and Registration (high – 80%) all of the other stages of Discovery and Development show success rates of about 60% (Figure 1, Attrition). Perhaps the vagaries of science mean that a POS of 60% is the best that one can expect.
Certainly the existing therapies for many diseases raise the bar for standard of care that must be met by new entries into established markets (cardiovascular, antiinfectives). Thus, the industry is moving towards areas of unmet medical need, to diseases that are more complex (cancer, CNS disorders, autoimmune diseases, orphan diseases) with unprecedented targets – attrition will be higher. 1 Increased scrutiny by the FDA, which is a good thing, will also impact attrition (Ref 1).
So perhaps high attrition may be inevitable. Another approach to the high attrition in the industry would be to accept it and adapt behaviors accordingly. What then can be changed to improve the situation?
i) Portfolio Optimization.
As noted in a previous section, Kola and Landis showed that some therapy areas have higher attrition than others, Figure 4. They suggest that a company may wish balance its portfolio by factoring in Therapy Area attrition rates. For more information on this subject, the reader may wish to visit the section Portfolio Balancing.
Figure 4, Variations in Overall Success Rates by Therapy Area 2
Kola and Landis also cite a CMR report that found higher overall success rates among biologicals than small molecules. 3 The similarities and differences are further explored in the section Small Molecule, Peptide and Protein-Based Drugs.
It would be logical to build a portfolio pipeline that accounts for attrition at each stage, an Attrition-Based Pipeline. (For more information, please go to the following section – Attrition-Based Pipeline.) Such a pipeline could be considered a Sustainable Pipeline, but as discussed in the section, The Sustainable Pipeline Myth, drug companies rarely, if ever, build a sustainable pipeline.
ii) Planning for Failure.
Accepting high attrition rates means that project leaders should orient their plans with the assumption that they will fail. While there tends to be logical order in the ways things are done in Discovery and Development, there are key variants which arise out of concerns for project failure.
Phase 0. When there is some doubt about the ability to determine doses for Phase 1 clinical trials, especially if the Therapeutic Index may be small, a Phase 0 trial may be warranted. The work that constitutes this phase either precedes or is the early part of Phase 1. Very small, microdoses, of drug are administered to a small number of human subjects – 100 micrograms or 100th of the estimated pharmacological dose, whichever is lesser. 4 The goal in such a study is to obtain basic PK parameters such as clearance, volume of distribution, half-life, etc. The assay for measuring drug substance needs to be quite sensitive, often Positron Emission Tomography or accelerator mass spectrometry measurement of a C-14 labeled version of the drug is required. The value in conducting such studies is to more accurately determine the doses for Phase 1. Phase 0 trials may also assist in refining biomarker evaluation for late stage trials.
Phase 0 is a relatively low cost way to evaluate a drug that might not make it through Phase 1, especially if there are PK issues. The downside to Phase 0 work is that it adds expense and time to the overall clinical evaluation. Phase 0 is thus an attempt to de-risk a drug prior to more expensive trials.
Getting to POC. Accepting high attrition rates means that project leaders should orient their plans with the assumption that they will fail. For projects where proof of concept (POC) is highly questionable, the team may decide to postpone some work that would normally be conducted in Phase I or II to Phase III in order to get to an early decision. Types of deferred work could include defining the best formulation, extended toxicology studies, manufacturing process optimization and pilot studies to identify other indications. Please refer to the section POC at Chorus (Lilly) and Flexion Therapeutics to see how Lilly has organized Development around POC.
iii) Reducing Cost.
Process Improvement. The whole of bio/pharmaceutical R&D represent a staggering number of processes. It would be worthwhile to identify the routine failures in R&D processes and modify them to enhance the potential for project success. Please go to the section Determining Project Risk in Certain Areas & Lean Six Sigma Process Improvement for more on this subject.
Outsourcing, Partnering. Anyone in the bio/pharmaceutical industry is aware of the increase in outsourcing and partnering as strategies to reduce cost and disperse risk. For more on this subject please go to the section In-house vs. Out-source; Vertical Integration vs. Vertical Disintegration.
Conclusion to this discussion on Attrition.
As noted in the previous section, some things can be done to reduce attrition, especially in Phase II and Phase III by preventing projects identified as risky in earlier stages from advancing into these stages. But POS may never be improved above 60%, in which case learning to live with attrition through portfolio optimization, planning for failure and reducing cost may improve prospects overall. It is also fair to say that attrition needs to be evaluated in relation to a number of factors, such as cost, return on investment, and corporate/portfolio strategy.
- “Overcoming Phase II Attrition Problem”, Genetic & Engineering Biotechnology News, (2009) 29, No. 14, GEN_PIIAtt_0809.pdf. ↩
- “Can the pharmaceutical industry reduce attrition rates?” I. Khola and J. Landis, Nature Reviews / Drug Discovery 3, 711, 2004 ↩
- Benjamin, G. A. and Lumley, C. E. Industry Success Rates, 2003, Including Trends in Success Rates, CMR Report Number 03–202 R (CMR International Surrey, UK, 2003). ↩
- R. C. Garner and G. Lappin, “The phase 0 microdosing concept”, Br. J. Clin. Pharmacol. 61, 367–370 (2006). ↩