Clinical Success of Complex Biological Therapies: Be Careful What You Wish For...
Authors: Malcolm K Brenner
Journal: Molecular Therapy (2010)

Would-be gene and cell therapists have longed for the day when they could escape the sneer that their field was 5 years from success—and has been that way for 20 years. Fortunately, our wish has been granted, for an increasing number of reports of clinical success in genetic diseases and cancer are appearing in high-profile journals and are being widely acknowledged. But now that this first stage has passed, we are left with what is in many ways a more intractable problem. How do we ensure that safe and effective complex biological therapies (CBTs) become licensed products that are sufficiently viable from a commercial standpoint to be widely distributed as the standard of clinical practice? In a series of articles over the coming year, Molecular Therapy will examine these issues in more detail, but I will begin by outlining the problem here. Some gene and cell therapy approaches—for example, the use of plasmid or virus injection or unmodified banked cells—may be relatively simple to develop, implement, and disseminate; most, however, will not be. Instead, they are true complex biologics that are almost impossible to fit into the standard model of drug development on which modern medicine has come to largely rely. Unlike small-molecule or even protein therapeutics, CBTs are often individualized, may need multiple iterative early-phase clinical studies to optimize each component, have extensive embedded intellectual property, and are expensive to manufacture and distribute. Moreover, CBTs are intended to be curative rather than ameliorative, and so a single treatment may substitute for the conventional chronic administration required for small molecules and proteins. Of course, many of these same problems apply to preexisting complex biologics such as organ transplants, and in particular to allogeneic hemopoietic stem cell transplantation (HSCT), that have long been established as standards of clinical practice. Unfortunately, introduction of their modern equivalents has become much more difficult and complex, owing to profound changes in the regulatory and medical-economic climate. If HSCT protocols were being introduced now, they would be shut down on toxicity concerns long before their benefits could become apparent. Although the above concerns have discouraged commercial interest in developing CBTs, several factors are beginning to change this appraisal. With the rise in the power of genomic/proteomic/metabolomic analyses of diseased tissues and host responses, it is becoming feasible to design and develop more personalized therapeutics targeted to the specific disease state of an individual. As a consequence, pharmaceutical companies are coming to appreciate that their standard model of drug development and marketing will no long apply even to new “standard” drugs, giving them a strong incentive to develop creative approaches to individualized drug development. Implementing these new approaches will require dialogue with drug regulatory agencies to establish new criteria for registration that increase access to effective agents while minimizing any increase in risk. Once agreed on, these criteria could almost certainly be extended to CBTs. Second, the development in the United States and Europe of an increasingly centralized payer system will favor introduction of therapies that have the optimal pharmacoeconomic profile—with fewest side effects, highest quality of life, and greatest persistence of benefit. Comparative effectiveness/health-services analyses of CBTs will almost certainly favor many of them over conventional agents and should lead to diversion of centralized funding to their support. In the United States, this shift will probably be aided by the National Institutes of Health, which is already supporting or considering supporting registration trials for CBTs, albeit on a more limited scale than could be achieved either by industry or by the US Department of Health and Human Services as a whole. Finally, success breeds optimism, and the recent approval of the Provenge vaccine for prostate cancer has undoubtedly provided a fillip to industrial interest, although successful commercialization of this approved CBT may be a challenge. In Europe, CBTs are called “advanced therapy medicinal products,” or ATM-Ps. Unfortunately, this is a misleading acronym because, unlike the more familiar type of ATM, an ATM-P can currently only consume rather than dispense money. Our desire for the next 5 years is that we will reverse this tendency, and in subsequent issues of Molecular Therapy we will discuss how this wish may be fulfilled.