PharmTalk

NIH and the Drug Discovery Pipeline

Brian Cox, ASPET President

A recent article in Newsweek by Sharon Begley and Mary Carmichael (Deperately Seeking Cures, Newsweek, 31 May 2010;  http://www.newsweek.com/id/238078) calls attention to the decline over recent years in the number of new drugs introduced into medical practice. They suggest that NIH funding priorities should be targeted more directly towards the support of the pre-clinical and clinical studies required for the introduction of promising drug candidates into the clinic, arguing that the return on investment in NIH has been ‘approximately as satisfying’ for taxpayers and patients as the return on public investment in the AIG bailout.  This particular argument trivializes complex issues in both cases; here I will not comment on the value of the support of the AIG baillout but would argue that public investment in NIH over many years has indeed provided a very handsome return on investment. NIH-supported research has been fundamental to the development and passage to the clinic of many new drugs that are now reducing deaths from many kinds of cancers, reducing heart attacks and stroke, relieving the symptoms and slowing the progress of arthritis, Alzheimer’s disease and other neurodegenerative diseases, improving the treatment of glaucoma – the list can go on and on.  Without continued funding of fundamental research by NIH at levels comparable to the support provided in recent years there will in the future be no novel drug candidates to be directed into the translational pipeline.

Despite this success, Begley and Carmichael were correct in noting that the number of new drugs making the transition from laboratory into clinical has been fewer in the last few years that in previous decades. The reasons are complex. In the past many of the supposedly new agents introduced each year were designed to mimic the actions of drugs already in use, offering only modest improvements in therapy over existing drugs.  In recent years it has been less cost-effective for drug companies to introduce new forms of old drugs, and it has not been necessary. NIH investment in research on, for example, the human genome and parallel investment in public databases making genomic information available to all, has transformed the identification of novel potential drug targets, and new high throughput screening methods (also developed in part with NIH support) have markedly facilitated the discovery of totally new agents that can attack the newly identified biologic targets. While some of these new agents have indeed made it into the clinic with significant clinical benefit (e.g., Gleevac^R), other novel targets have proved to be associated with unacceptable toxicity as well as potential clinical benefit. Fortunately the toxic effects that result from actions at some novel targets are also being identified earlier in the drug development pathway, resulting in their removal from the drug pipeline earlier and reducing toxicity in initial clinical trials.  Early identification of unacceptable toxicity reduces the fraction of initially tested novel agents that eventually join the ranks of therapeutic drugs of choice, but this is beneficial in reducing the numbers of patients who experience drug-induced side-effects. Increasingly, this type of very basic drug discovery and characterization is being conducted in academic settings and in research institutes supported in part by NIH, rather than in the laboratories of big pharma – another fundamental shift in the drug-discovery process taking place over recent years.

Begley and Carmicheal also argue correctly that the processes required to move a novel agent from laboratory to clinic are not well supported by current funding mechanisms.  ASPET has for many years encouraged the support of training programs for integrative bioscientists who can conduct the pre-clinical studies in animals that are essential to reduce the risk to human volunteers in the initial testing of a totally novel agent in human subjects,. NIH, through NIGMS and working with ASPET, has recently supported the development of training courses in integrated organ systems pharmacology to increase the pool of investigators trained to conduct these studies, but more needs to be done to provide training resources for such individuals, and to develop secure career pathways for them in the future. Another critical shortage is in the training of clinical pharmacologists to conduct the expansion in clinical trial activities that is implicit in the proposals of Begley and Carmichael.  Clinical pharmacology training programs have not been well supported in recent years, yet an increased cadre of trained clinical pharmacologists with experience in designing and implementing efficient clinical trials would not only assist the drug pipeline, but also assist in the better evaluation of existing medications so that only the most effective and safest medications remain in use.

Improved training and support mechanisms in these critical drug evaluation arenas, is becoming critical if we are to exploit effectively the increase in knowledge of genetic and environmental differences between individual patients.  The potential benefits of personalized medicine can only be achieved if novel methods of evaluating drugs effects efficiently in very small numbers of individuals can be achieved. Improved methods for identifying individual differences in responses to drugs are sorely needed.  Such developments will also require a greater flexibility and sophistication by the FDA in its evaluation of requests for drug approvals.

Improving the throughput of the drug pipeline from laboratory to clinical by enhancements along the lines of those proposed here may require the development of new business models for drug development.  It is not clear that big pharma is set up appropriately to take on these tasks, although large drug companies have proved very adaptable to circumstances in the past and may be able to reinvent themselves again in an era of personalized medicine and required comparative effectiveness evaluation.  As noted above, there has already been a trend to move drug discovery to research units in academic settings, such as the Vanderbilt Program in Drug Discovery lead by Jeff Conn (http://www.connlab.com/jobs.html), the Drug Discovery Institute at the University of Pittsburgh lead by John Lazo  (http://www.upddi.pitt.edu/). Such entities may be better placed than freestanding small biotech companies to withstand the uncertainties inherent in drug discovery and the volatility in the availability of essential venture capital. We can also expect that new entities will emerge to conduct pre-clinical testing and clinical trials in the near future.  The optimum model for the bench-to-bedside pipeline remains to be determined; several variants may emerge. 

NIH has served the nation very well for more than 60 years; its record in supporting basic discoveries in biomedical science that have been critical for the identification of novel drug targets has been unrivaled anywhere in the world.  The drug discovery process now faces many new challenges. These will best be met if support for NIH remains strong and consistent. Basic science, largely funded by NIH, is the foundation on which all future developments must rest.  

Pharmacology is a key integrative medical science discipline.  In the following article, Myron Toews discusses educational opportunities offered through ASPET and NIGMS in integrated organ systems approaches to drug development.  All graduate students and others interested in careers relating to drug development should consider these opportunities.

"Making Molecules Into Medicines—The Critical Role of Integrative and Organ Systems Pharmacology Training"

Myron Toews, University of Nebraska Medical Center IOSP Summer Short Course Director

Making molecules into medicines is a major goal of the discipline of pharmacology. However, making molecules into medicines cannot occur until those molecules have been studied in the "integrative" environment of multiple cell types working together as isolated organ systems and of multiple organ systems working together in the intact animal. Providing a strong introduction to the principles and the laboratory methods for studying drug action in isolated organs and intact animal systems is the goal of the four NIH-funded Integrative and Organ Systems Pharmacology (IOSP) Short Courses being offered again this summer.  The leadership of ASPET strongly encourages all pharmacology students, postdocs, and faculty to consider these short courses, in particular their importance for enhancing career opportunities and advancement.

The major advances in molecular biology, cellular biology, and genetics over the last 30 years have greatly advanced the potential as well as the popularity of "cellular and molecular pharmacology", changing the focus for many training programs from "medicines" to "molecules". An unfortunate consequence of the exciting advances at the molecular end of the pharmacology spectrum is that the more traditional components of pharmacology that can only be studied in intact animals, isolated organs, or multi-cellular tissue preparations have received short shrift in many pharmacology graduate and post-doctoral training programs. As a result, the pharmaceutical industry now finds it very hard to identify and recruit pharmacologists who have the expertise needed to move their molecules into medicines. Industry leaders have commented that "gene jocks and screeners are a dime a dozen" but that "integrative pharmacologists are hard to find and are paid premium salaries" as a result. Even for those who are not "skilled" in any particular aspect of IOSP, having sufficient exposure to the general concepts to be able to effectively communicate with their more integrative counterparts in industry is viewed as a major strength, helping to translate molecular knowledge into the appropriate organ system or intact animal studies to test efficacy, potency, and safety prior to moving drugs toward human studies.

It was because of a strong push from ASPET and a strong push from the pharmaceutical industry that the National Institutes of General Medical Sciences began funding a set of IOSP Short Courses to help pharmacologists begin their move into more integrative and translational directions.   Four IOSP Short Courses are available this summer at Michigan State University, University of Nebraska, University of North Carolina, and Vanderbilt University.  Details on each can be found at:   http://www.aspet.org/Page.aspx?id=312

 All four courses include a similar introduction to the basics of using animals and tissues in pharmacology research, but each course offers unique aspects in terms of emphasis on specific organ systems or disease entities , variations in the specific animal and tissue model systems used, and other differences in terms of industry involvement, individually tailored components, and campus environments. All of the courses have received strongly positive feedback from previous students, so potential students can pick the course that is best for them based on content, location, or whether the course is early, middle, or late summer.  The IOSP summer short courses draw faculty from many different institutions to provide the needed expertise, which also provides students a broad exposure to IOSP research and policies in both industry and academia.

 The ASPET web site also has information about the  ASPET-Integrative and Organ Systems Sciences (ASPET-IOSS)  fellowships that are available for those who want to take advantage of more advanced training opportunities to pursue this type of research training directly in an industry setting:  http://www.aspet.org/uploadedFiles/Advocacy/Support_for_Integrative_and_Organ_Systems_Sciences/ASPET-IOSS%20FUND%20Guidelines.pdf?n=5996).

DO NOT take the risk of leaving your molecules "in the bottle or on the bench". Register for one of the IOSP Short Courses this summer and start working on "making your molecules into medicines!!"