Cytokine Storm Umbrella
by Deirdre Sokol
April 2007
Following the serious adverse events experienced by volunteers participating in the TGN1412 study, clinical researchers and regulatory authorities have engaged in extensive dialogue about how to maximize the safety of healthy volunteers.
In response to the 2006 TGN1412 incident, in which six healthy volunteers dosed with the novel monoclonal antibody developed cytokine release syndrome with multi-organ failure, the U.K. Secretary of State for Health established an Expert Scientific Group (ESG) to investigate the event. The group was charged with providing recommendations for future trials of biological molecules with novel mechanisms of action, new agents with a highly species-specific action and new drugs directed toward immune system targets.
The final report of the ESG, written by Sir Gordon Duff, professor of molecular medicine at The University of Sheffield, in Sheffield, U.K., and chairman of the Commission on Human Medicines, an advisory body to the Medicines and Healthcare products Regulatory Agency (MHRA) in London, U.K., concluded that the pre-clinical testing of TGN1412 “did not predict a safe dose for use in humans,” even though the existing regulatory requirements were met. Additionally, the Duff Report contains 22 recommendations intended to improve safety of future first-in-human Phase I clinical trials.
By the Numbers
Of particular interest to the biotech community are two recommendations encouraging the availability of expert advice in the process and preparation of clinical trial applications involving drugs considered high-risk. Recommendation six states: “For appraisal of applications for trials of higher risk agents … the regulator should have access to additional opinion from independent, specialist experts with research knowledge of their fields.”
Recommendation seven states that “an Expert Advisory Group (EAG) of the Commission on Human Medicines, or a similar body, might undertake this [advisory] role with a core membership of appropriate experts and the ability to co-opt additional expertise as the need dictates.” The Commission advises the MHRA—as well as its European counterpart, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA)—on the quality, efficacy and safety of medicines.
Recommendations six and seven stimulated discussion in the biotech research community about whether voluntary or mandatory application is necessary to avoid future situations like the TGN1412 incident. In a December 2006 press release, MHRA chief executive Kent Woods stated, “the MHRA has already implemented nationally the recommendations outlined in the report that affect the Agency’s procedures for authorizing trials. Some recommendations will need to be taken forward at EU level and the Agency has already started discussions with other European regulators to take these forward as a priority.”
Other agencies involved in the TGN1412 study, such as the Paul-Ehrlich-Institut (PEI), are considering the recommendations. PEI, which reports to the German Ministry of Health, approved a protocol for a German trial of TGN1412 based on an application submitted by Parexel, the contract research organization charged with conducting the trial. “In the past, [the agency] occasionally asked external experts for their opinion, in particular when high-risk products were evaluated,” says Ulrich Kalinke, Ph.D., head of the department of immunology at PEI, in Langen, Germany.
Kalinke welcomes the Duff Report’s recommendations, but he also expresses some reservations. Clinical trial applications typically are completed in two months, including time for external expert counsel. If external expert opinion becomes mandatory for all first-in-human trials, recruitment of experts would become more difficult, and the timeline would have to be extended by at least one month, Kalinke says. Moreover, budgetary restrictions compounded by the price of external expert opinion and the amount of work associated with certain products make seeking additional advice prohibitive. “Therefore, we think that the advisory activities could be more attractive if they became an important part of scientific curricula and added scientific merit as publications do,” Kalinke says.
Identifying Risk
Although recommendation six of the Duff Report calls for access to additional opinions for the appraisal of trial protocols involving high-risk agents, it does not call for government oversight. Recommendation seven, however, specifically suggests an EAG of the Commission on Human Medicines—or a comparable body—serve as the provider of the additional opinions. What remains to be seen is whether regulators in the U.K. and throughout Europe will begin requiring additional expertise before approving protocols of trials with high-risk agents, a prospect that Kalinke says is neither reasonable nor plausible.
“We do not understand recommendations six and seven in a way that CHMP should oversee and be responsible for approving protocols for first-in-human trials,” he says. Rather, having individual member states approve clinical trial applications “is an appropriate solution because studies are carried out locally, and local ethics committees play an integral part in the approval procedure.”
Collaborative Effort
This method advocates intensive communication between sponsors, regulators and physicians involved in the study, Kalinke says. “Already now the Scientific Advice Working Party at the EMEA in London develops and improves protocols for clinical trials … with specific emphasis on first-in-human studies,” he says.
Additionally, Kalinke and two PEI colleagues wrote a letter that was published in Nature Biotechnology in May 2006. The letter included recommendations to improve safety in trials of monoclonal antibodies. Their suggestions were centered on better identifying high-risk monoclonal antibodies that “warrant more stringent regulatory oversight.”
First-in-human drug trials typically proceed without incident and rarely produce unexpected results. When an unfortunate event does occur, it creates an opportunity to advance the science and safety of this critical step in the drug development process. The recommendations set forth by the Duff Report, as well as those from Kalinke and colleagues, add to the dialogue between regulators, researchers and industry on ensuring the safety of volunteers in Phase I trials.
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