Attrition – Reasons for Failure

Despite the importance of Attrition, there is surprisingly little in the public domain on reasons for failure (or perhaps not surprising). We will do our best to present what is out there. A group from AstraZeneca recently published an amazingly candid view on the subject, which will feature in this section

Discovery.  The reasons for attrition in Discovery have yet to be tabulated across the industry. Analyses of attrition in Discovery likely occur within individual bio/pharmaceutical companies and in private consortia. It is unfortunate that industry-wide data on attrition in Discovery is not available. Attrition cannot be reduced unless it is tracked – see the Section on Tracking Attrition.

Development. There have been studies on attrition in Development however, but these data tend to be contained within private consortiums whose members share data to see how they compare to each other but whose data is often kept within the consortium – see the section Benchmarking through a Consortium. Kola and Landis use such data (Datamonitor, Pharmaceutical Benchmarking Forum) in their 2004 report which states that in 1991 40 % of attrition in Development came from poor pharmacokinetics, Figure 1, but by 2000 poor PK had dropped to less than 10%. 1 Between those two periods, however attrition due to safety issues rose from about 20% in 1991 to over 30% in 2000. Factors that should be controlled in Preclinical Evaluation (PK, toxicology, and formulation) which accounted for about 60% of the failures in 1991 were still 46% of failures in 2000. Interestingly, lack of efficacy had not changed between 1991 and 2000, hovering around 30% of failures.

 

Figure 1, Reasons for Project Failure in the Clinic (Ref 1) (It should be noted that the authors show attrition for each criterion as a percentage.  The percentages for each criterion in 1991 sum to 100%, while the percentages for each criterion in 2000 sum to about 105%, which is why we show the data as a pie chart.)

We are left to speculate on what some of the categories mean in detail, e.g. Commercial.  Also we are now 10 years beyond the last period when reasons for project failure in the clinic was reported.  Presumably the pie chart has changed a lot since then.  Unfortunately, this oft-cited report on reasons for project failure in the clinic is also the only one in the public domain.

The only other tid-bit we have found in the public domain comes from Bjornsson in his slide set 2 which provides some attrition categories that have been used by the CMR consortium, Table 2.  In this set Commercial is a grab bag for anything that has to do with cost, and surprisingly lacks things like competition or pricing pressures from Third Party Payors.  Also Bioavailability is seen as a Scientific reason for attrition but Formulation Issues are seen as a Technical reason (as if science is not involved).

Table 2. Attrition Categories, CMR quoted by Bjornsson (Ref 2)

Unfortunately, he was presumably constrained from showing percentages in a manner similar to Kola and Landis.

On this barren landscape of important data came the report in June of 2014 from a group at AstraZeneca, detailing attrition in the corporate portfolio, reasons for project failure and how the company chose to reduce attrition. 3  Unlike previous discussions of terminations this paper provides reasons for project closure at each stage, Figure 2.

AstraZeneca Reasons for Failure

#click to enlarge

Figure 2. Causes of Project Failure in the AstraZeneca Portfolio (Ref 3).

Understandably 82% of project closures in in Preclinical Evaluation were due to Safety. That is where one would expect Safety issues to arise and lead to project closure if necessary. But as seen in the figure, projects closure due to Safety continued in Phase 1, IIa and IIb, albeit by a decreasing percentage. The authors of the study hold management responsible for failing to make the hard decision to terminate a project on Safety. Also understandable is that project failure in Phase IIa and IIb were largely due to efficacy. This is where human efficacy is determined. But the authors found that 40% of the projects that got into the clinic and closed, had a lack of data that demonstrated a clear linkage of the target to the disease, or lacked validated animal disease models.

We suggest you continue the read in the next section, An Unprecedented View of Attrition in a Corporate Portfolio where these issues are dealt with further. This section also segues onto the section Ways to Improve Attrition in Phase II and III

  1. “Can the pharmaceutical industry reduce attrition rates?” I. Khola and J. Landis, Nature Reviews / Drug Discovery 3, 711, 2004
  2.  “Does Pharmaceutical Predictivity Translate to Productivity in Drug Development? If So, How?”, Thorir Bjornsson, May 2010, presentation to NGP Summit in Los Angeles in 2009, and at FDA in Silver Spring, Maryland, and Critical Path Institute in Tucson, Arizona, in 2010, http://dl.dropbox.com/u/6886618/Pharmaceutical%20Predictivity%20May-2010.ppt.pdf
  3. “Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework” D. Cook, D. Brown, R. Alexander, R. March, P. Morgan, G. Satterthwaite, M. Pangalos, Nat. Rev. Drug Disc. 2014, 13, pp. 419-429