But Careful Ethics Review Still Important
Institution Bulletin vol 5, issue 3
Phase I trials often raise troubling issues for ethics committees, who must decide when it is appropriate to expose healthy research participants to the risk of an investigational drug when there is no prospect of direct benefit. This assessment is complicated by widely reported tragedies from Phase I trials. To place the risks of Phase I trials into context, a research team led by Dr. Ezekiel Emanuel recently undertook a meta-analysis of data from 394 Phase I trials conducted by Pfizer Pharmaceuticals over a span of seven years. The findings, published earlier this summer, are revealing: in the 394 trials very few severe adverse events occurred, and the vast majority of adverse events could be characterized as mild. These results are reassuring, but ethics committees and researchers must continue to be vigilant in ensuring that Phase I studies in healthy participants are designed and executed with care.
“Phase I” trials are the very first studies conducted in humans when a new drug is being developed. Some Phase I studies (such as oncology trials) are conducted in patients, while many are conducted using healthy participants. Some Phase I studies are “first-in-human” and involve the first administration of a new investigational drug in a human being. Phase I studies are largely non-therapeutic; as described by the FDA, they should be designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.
Some authorities maintain that nontherapeutic trials should be conducted in humans only if the subjects are exposed to no more than minimal risk. And, over the years a number of highly publicized incidents have highlighted the possibly significant risks of Phase I research. In 1999, Jesse Gelsinger, an 18-year-old with liver disease caused by a genetic defect, died in a Phase I study in a gene therapy experiment. In 2001, Ellen Roche, a 24-year old healthy volunteer, died from inhaling hexamethonium, a chemical that induces asthma.
And then, in 2006, TGN1412, a monoclonal antibody being developed by TeGenero Immuno Therapeutics, was administered to six humans for the first time. After the initial infusions of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multi-organ failure. One participant lost fingers and toes to amputation.
These highly publicized tragedies often overshadow the review of Phase I trials. Emanuel and his team tackled a meta-analysis of data from Phase I studies conducted by Pfizer Pharmaceuticals at its three Phase I units from 2004 through 2011 to assess the overall safety of Phase I trials. The Pfizer data set included only non-oncology studies and studies involving healthy study subjects. The team aggregated reports of adverse events logged by investigators into categories of “mild”, “moderate”, and “severe”; they also reviewed the reports of “serious adverse events” that had been submitted to the FDA.
The meta-analysis showed that in the 394 studies, over one third of participants who received study drug (36%) experienced no adverse events at all. Of the 63% who did experience adverse events, the majority (85%) of those adverse events were mild. The most common adverse events reported were headache, drowsiness, and diarrhea.
In the seven years’ worth of data reviewed, only one percent of the adverse events were characterized as severe. Moreover, only 0.31% of the adverse events among the participants who received the study agent were reported to the FDA as serious adverse events. No deaths were reported.
The study team counsels against generalizing these meta-analysis results to all Phase I studies. The data may not generalize, for example, to the Phase I trials of other companies, research contract organizations, or publicly funded Phase I units. They may not generalize to the type and range of nononcology drugs being studied by other pharmaceutical or biotechnology companies or research institutions. Before 2011, Pfizer was developing few biological agents, and thus this sample included few studies of biological agents such as TGN1412.
How should the members of an ethics committee greet the results of this meta-analysis? Certainly there is some comfort in knowing that in at least some Phase I trials, the foreseeable risks to study participants rightly can be assessed as minimal.
This data also is a reminder to view the TeGenero incident in context. Commentators have argued that the adverse events suffered by the TeGenero study participants were avoidable and the severity of the incident was exacerbated by the novelty of the study agent, inappropriate study design, incomplete assessment of available data, a failure to reconcile inconsistencies in the nonclinical safety data, and a failure to take appropriate clinical precautions in the conduct of the study. One common criticism, for example, is that the dosing of the study subjects occurred too rapidly given the novelty of the study product.
Increased vigilance since the TeGenero incident about the design and execution of Phase I trials almost certainly has improved the safety of such studies, and ethics committees should continue to exercise vigilance. Some key questions for ethics committees to ask of Phase I trials are listed below. Many of these issues are not unique to Phase I trials and should be considered in all interventional trials of investigational new drugs. Nevertheless, they are of particular importance for Phase I trials:
- Does the investigator and study team have experience with Phase I trials and the attendant safety monitoring and dose escalation decisions?
- Does the site have the resources to stabilize and resuscitate individuals in acute emergency situations?
- What is the site’s proximity to a hospital or emergency facility?
- If the study is first-in-human, does the preclinical data support the proposed first dose?
- If the study is first-in-human, will the first dose be administered so that a single subject (the “sentinel subject”) receives a single dose of the active investigational drug, with a period of observation before the next subject receives a dose?
- Do the study’s inclusion/exclusion criteria specify that subjects should not have received any investigational drugs for at least 30 days?
- If women are included as subjects, what measures will be taken to screen for pregnancy? For male subjects, has the need for protection of partners from seminal exposure been considered?
- Does the protocol clearly identify a set of stopping rules at both the cohort level and subject level?
- Does the site have a robust consent process?
- Is the compensation appropriately tailored to the amount of time subjects will be participating in the trial?
Phase I trials are essential to our drug development process. The newly published meta-analysis finding that most of the adverse events experienced in Pfizer’s Phase I trials were mild helps place the risks of Phase I trials into context. Ethics committees must continue to scrutinize proposed Phase I trials, but an ethics committee now can be more confident that the risks of properly designed Phase I trials are not inherently higher than the risks of other interventional trials.
 21 CFR §312.21(a)
 Nelson, D.& Weiss, R,. The Washington Post (Jan. 31, 2000)
 Although the hexamethonium study was not officially classified as a Phase I trial, it nevertheless had the same characteristics as other studies that involve the first introduction of a treatment in humans.
 H Attarwala, “TGN1412: From Discovery to Disaster,” J. Young Pharm. 2(3): 332–336. (Jul/Sep 2010)
 EJ Emanuel, supra n.1
 “Serious adverse events” are defined by the Food and Drug Administration as events that result in death, a life threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. 21 CFR part 321, subpart B, section 32(a)
 See, e.g., C. Horvath & M. Milton, “The TeGenero Incident and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event?” Toxicologic Pathology vol. 37, no. 3, pp. 372-383 (April 2009)
 H Attarwala, supra n.7
 For further discussion, see ABPI, “First in Human Studies: Points to Consider in Study Placement, Design and Conduct” (January 2011)