Seamless Clinical Trials
On August 10 the US Food & Drug Administration (FDA) issued a 14-page “draft guidance” to assist sponsors in designing and conducting first in human (FIH) clinical trials that accelerate “the clinical development of cancer drugs through multiple expansion cohort study designs,” according to an article by Zachary Brennan in Regulatory Focus, an online publication of the Regulatory Affairs Professionals Society (RAPS). RAPS is a global organization of and for those involved with the regulation of healthcare and related products.
According to the article, the document offers the FDA’s opinions on “the characteristics of drugs and biologics appropriately suited for such an expedited plan, information to include in such investigational new drug (IND) application submissions, when to interact with the FDA and safeguards to protect patients enrolled in FIH expansion cohort studies.” As FDA Commissioner Scott Gottlieb explained, sponsors can condense the usual three phases of clinical trials into one continuous study, called an expansion cohort trial. He added, “A lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials. Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time.”
In Phase I clinical trials, where there are 20 to 80 patients, a given study is supposed to establish the metabolism and pharmacologic actions of an investigational drug, determine the side effects related to increased doses and establish early evidence of efficacy. In FIH multiple expansion cohort trials -- trials with a single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives – development can be expedited by proceeding from determining a potentially effective dose to finding individual cohorts that have trial objectives typical of Phase II trials, such as estimating anti-tumor activity. Objectives of these expansion cohorts may be “assessment of anti-tumor activity in a disease-specific setting, assessment of a reasonably safe dose in specific populations (e.g., pediatric or elderly patients or patients with organ impairment), evaluation of alternative doses or schedules, establishment of dose and schedule for the investigational drug administered with another oncology drug, or evaluation of the predictive value of a potential biomarker,” the draft revealed.
However, the FDA anticipates challenges. The studies pose special challenges and risks, such as exposing patients across multiple cohorts at the same time to possibly substandard or toxic doses of an investigational drug or exposing more patients than needed to attain certain objectives.
According to the draft, “Because of the rapid enrollment and evolving nature of the information obtained in these trials, large numbers of patients are exposed to drugs with unknown efficacy and minimally characterized toxicity profiles. To mitigate such risks and to protect patients, it is imperative that sponsors establish an infrastructure to streamline trial logistics, facilitate data collection, and incorporate plans to rapidly assess emerging data in real time and to disseminate interim results to investigators, institutional review boards (IRBs), and regulators.”