Differing Approaches to Experimental Therapeutics: Are We a World Apart?

In this issue of Molecular Therapy, Hemminki et al.¹ report their human clinical experience in Finland with an oncolytic adenovirus, Ad3-hTERT-E1A, via their Advanced Therapy Access Program (ATAP). Like other commonly used oncolytic adenovirus vectors, the critical viral E1A gene was placed under transcriptional control of a cancer-selective promoter to direct E1A gene expression and thus virus replication and cytolysis to cells with active expression of the human telomerase reverse transcriptase (hTERT) gene. This particular vector is novel, however, because it is based on adenovirus serotype 3 rather than the more commonly used type 5, and it may have several advantages for cancer therapy as described in the article. In this report, 25 patients with incurable cancer were treated with the virus and followed for side effects and efficacy. The authors conclude that toxicities were similar to those of Ad5 vectors and indicate that they observed evidence of signs of efficacy in most patients.

The ATAP was designed to allow patients with incurable cancer to receive novel, experimental therapeutics and to enable physician–scientists to more rapidly evaluate their clinical use. These are laudable goals, and as a physician–scientist who studies novel therapeutics in the laboratory and cares for patients with often incurable cancer, I am in favor of moving the field forward—even if only incrementally. Nevertheless, there has been much discussion at international meetings and behind closed doors about the program's scientific merit and its ethical grounding. Simply put, such a program would not be allowed in the United States. The ATAP is regulated by the Finnish Medicines Agency, and this new report provides us the opportunity to stimulate discussion about its value.

From a purely scientific perspective, some have argued that the program is difficult to justify. Drug development studies classically begin with phase I studies to learn more about the biology of the treatment, including pharmacokinetics and pharmacodynamics studies, as well as safety of doses with carefully designed dose escalation in small numbers of patients. Only after a safe dose and/or regimen has been defined are phase II, and then randomized, controlled phase III, studies conducted, which are designed to test efficacy. This paradigm has been time-tested and, with some exceptions, is thought to minimize risk and be the most expedient method of confidently determining the safety and utility of new therapies.

In the ATAP there do not appear to be many exclusion criteria nor any attempts to study a uniform series of patients or to limit treatment to the test article. Those enrolled in the program had diverse characteristics, representing 12 cancer types and ranging in age from 3 to 73 years. Some were given virus by the intratumoral route and some by the intravenous route, each having received a variety of prior therapies, including other viruses only weeks apart, and most were given at least one concomitant treatment such as oral cyclophosphamide (intended as an antiangiogenic strategy). Biological correlative studies such as biodistribution may be informative to the field, even if obtained from only a few patients. The marked variability among subjects is such that each case essentially represents a separate, single-patient experiment, so it is unclear to what extent the knowledge gained is generalizable. In general, it is difficult to draw conclusions from experiments with n = 1. That said, the vast majority of medical advances in history were built on initial case reports.

For some, the program also raises ethical considerations, in terms of both safety and efficacy. The title itself could be construed as misleading, as the word “therapy” implies clinical benefit—something as yet unknown for oncolytic viruses in general and for Ad3-hTERT-E1A in particular. Typically for early-phase clinical trials that are designed mainly to test safety, institutional review boards in the United States discourage the use of statements in consent forms that imply therapeutic benefit. Furthermore, early-stage trials seek to avoid exposing patients to undue risks in the face of uncertain benefit. Thus, exclusion criteria for early-phase clinical research studies are carefully and thoroughly vetted by local and national regulatory reviews to exclude subjects most likely to be at significant risk of experiencing complications. Arguably, adults who provide informed consent should be allowed to determine what risk they are willing to undertake. The concern is that patients with incurable cancer are desperate and willing to try almost anything, and physician–scientists believe in their research and may be desperate to help their patients. Thus, potential benefits may be oversold and risks downplayed. Moreover, current ethical principles dictate a higher standard regarding vulnerable populations such as children, so in general new agents are tested in children only after some minimal amount of safety data has been obtained in adults. As a pediatric oncologist, I'm somewhat conflicted about this last point; it has been said that children die from cancer just as efficiently as adults, so they certainly deserve early access to novel therapeutics.

Finally, there is the potential for clinical benefit. Cancer phase I research trials often show antitumor activity in at least a subset of subjects, be it actual tumor responses or merely temporary stabilization of disease.² The knowledge from such studies can provide important clues of efficacy that may guide subject inclusion for subsequent phase II or III studies. But given the various concomitant therapies in this study, can we be confident about their conclusions of benefit?

The potential scientific and clinical gains combined with the controlled nature of highly regulated clinical studies to minimize risk justifies the conduct of phase I trials. Outside of the confines of a carefully regulated clinical trial, in which each individual patient is an uncontrolled experiment, is the likelihood of benefit sufficient to warrant relatively unrestricted access to the experimental agent, including by vulnerable populations? Are the scientific findings robust enough to justify the resources? Could the scientific gains be realized by limiting accrual to only a few subjects, thus exposing fewer patients to the risks? It appears that the US and European authorities answer these questions differently.