Phase I trials can be easily overlooked because these studies involve a small number of human subjects. Indeed, most phase I trials may not accurately reflect the safety profile of a new treatment in a general population. Phase I trial results beyond safety profiles are also difficult to interpret. However, a therapy entering phase I trials is reaching a significant milestone in drug development because this marks its graduation from preclinical studies into clinical development.
Finding the dose
Phase I trials are sometimes referred to as “dose finding” or “dose escalation” studies because their primary goal is to assess the maximum tolerated dose (MTD) of a therapeutic. Other parameters in the safety profile of a prospective treatment in phase I trials include the optimal route of administration and the side-effect profile. A dose escalation usually begins with a small group of patients, called a cohort, who receive a starting dose of the therapeutic. Depending on the side-effect profiles experienced by the first cohort, successive cohorts will receive increasing doses of the drug until the clinical investigator determines that the therapy’s side effects have become unacceptable. This dose-limiting toxicity (DLT) marks the highest dose used before the unacceptable side effect appears.
Once the MTD and DLTs have been established, the therapeutic enters phase II trials, which involve larger sample sizes and patients with conditions for which the therapy would be indicated. Dosages used in subsequent trials are usually less than the MTD determined in the phase I trial. Additionally, side-effect profiles observed in phase I studies provide clues to how side effects may be effectively managed in later clinical studies.
Most phase I studies involve human subjects who are healthy volunteers. Some phase I studies involve patients with a pre-existing condition for which no alternative treatments may exist. Phase I studies are prominent in oncology, where novel therapeutics are tested in cancer patients whose conditions are refractory to available treatments. Even then, clinical investigators may view phase I trials as ethically controversial based on the risk-benefit ratio. In a recent issue of the Journal of Clinical Oncology (vol. 24, no. 19), Steven Joffe and Franklin G. Miller analyzed the risks and benefits of phase I trials in cancer patients and concluded that available literature suggested that phase I trials offer neither more nor less therapeutic value to cancer patients than other phases of clinical trials. Additionally, phase I clinical trials have a favorable risk-benefit ratio for cancer patients, who often have advanced cancer and have exhausted available treatment options.
Controversy in the U.K.
This analysis came on the heels of a well-publicized disaster in London, where a contract research organization was conducting phase I trials on behalf of a German biotechnology company. In March of 2006, six healthy volunteers who participated in the dose-escalation study were hospitalized following a severe side effect called angioedema, a swelling condition in which welts form from an allergic reaction. This reaction can sometimes be fatal. The therapy was an immunomodulator intended to treat B-cell chronic lymphocytic leukemia and rheumatoid arthritis. Within less than 10 minutes of receiving the dose, one subject experienced headache, fever and pain. Other subjects experienced vomiting and severe pain. According to the news journal The Scientist, within 12 hours, all six subjects had to be hospitalized due to cytokine release syndrome, in which a massive release of immunomodulating proteins causes a self-destructive immune response. Cytokine release syndromes have been observed in patients with B-cell chronic lymphocytic leukemia taking other antibody-based therapeutics, according to the journal Blood (vol. 94, no. 7).
After investigating, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency concluded that the incident was not caused by errors related to the therapy’s manufacturing, formulation, dilution or administration to the human subjects. However, the agency found that the contract research organization did not adhere to “good clinical practice” guidelines, including 24-hour medical monitoring of human subjects. Although there were no fatalities, this recent phase I scandal may prove detrimental to the public’s perception of the value of phase I clinical trials. This controversy shows the necessity of disciplined monitoring during the clinical trial, both to mitigate the potential damage to human subjects and for the sake of patients who may benefit from the successful development of a promising new therapeutic.