ESOT 2013 Report – Academic, industrial and regulatory barriers to progress in transplant immunosuppression

Randall Morris, San Francisco, USA – Failure to make therapeutic progress is a real challenge in the transplantation field. On the face of it, the goals set up by clinicians for themselves and their patients – to develop safer and more effective means to increase the number of transplantations and recipient survival, at less effort and cost – should be achievable in the modern era. However, there are a number of barriers stopping this ambition from being fulfilled. Professor Emeritus Randall Morris from Stanford University carried out a series of informal and anonymous interviews with professional stakeholders in academia, the pharmaceutical industry and within the US Food & Drug Administration (FDA) and discovered that contrary to what one might expect, lack of time and money is not the main issue – instead, our increasingly risk-averse society and culture seems to be the predominant barrier against developing better and safer immunosuppressive therapies.

 

Transplantation registry data in the US shows that long-term (beyond one year) survival in patients undergoing kidney transplantation remains the same today as it was in the 1980s [1]. The five-year mortality following a kidney transplantation is, in fact, higher than for a number of cancers, including melanoma, kidney and colon cancer [2, 3]. Add to this that there are currently around 200 new chemical entities (NCEs) undergoing Phase III trials in these cancers, versus not a single new immunosuppressive agent, and it is easy to see the urgent need for progress in this field.

 

One important barrier uncovered by Professor Morris is the reluctance of government funding bodies to support what is perceived as ‘high risk’ proposals, such as in the field of immune tolerance. Instead, a shift towards supporting safe proposals together with decreased overall funding is seen to provide incremental advantages.

 

Basic academic research is burdened by being isolated from clinical and regulatory requirements and inadequate protection of intellectual property, whereas clinicians increasingly find themselves caught between the need to spend more time with patients whilst at the same time being expected to produce publications to secure appointments. Clinical scientists also perceive that there may be professional disadvantages to working on projects involving high-risk patients.

 

The pharmaceutical industry has suffered from a general loss in productivity in the last couple of decades. Since 2000, the number of approved NCEs per year has dropped by a third and sales have halved despite a doubling in R&D spending [4]. The impact of generic competition on innovation was mentioned as a key reason, together with a focus on short-term performance metrics and risk- and loss-aversion similar to that experienced by clinicians.

 

However, the biggest barrier to emerge from Professor Morris’ survey is the FDA and the decision-making process surrounding new drug applications (NDAs). The role of the FDA is to protect the health of the general public (risk averse behaviour) whilst at the same time give patients access to clinically beneficial therapies (risk-seeking behaviour) – at the moment, each FDA NDA decision process is open to interpretation between these two modalities which creates uncertainty, and there is a need for applying more stringent clinical judgement when interpreting data on serious adverse events and deaths in transplantation trials.

 

Having outlined the major barriers, Professor Morris concluded his talk by stressing that the field of transplantation still offers favourable opportunities for research and development, thanks not only to the great unmet therapeutic need but also to the multitude of molecular targets and availability of excellent experimental models, but that these barriers must be overcome before any real progress can be achieved.

 

References

1.Lamb, K.E., S. Lodhi, and H.U. Meier-Kriesche, Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant, 2011. 11(3): p. 450-62.

2.USRDS, Annual Report. 2011.

3.NCI, Surveillance Epidemiology & End Results. 2012.

4.Garnier, J.P., Rebuilding the R&D engine in big pharma. Harv Bus Rev, 2008. 86(5): p. 68-70, 72-6, 128.