Phase III
Phase III trials are the pivotal and confirmatory clinical trials required to demonstrate benefit and support approval of a new therapy. While safety continues to be carefully monitored, the primary focus of Phase III trials is efficacy. These studies are conducted in a randomized, blinded fashion and compare the candidate drug either to a placebo or, if it would not be considered ethical to withhold, standard treatment. The scope and design of Phase III trials are often negotiated with regulators prior to trial initiation. The candidate drug must be manufactured and administered in the same manner as would be expected after completion of the clinical trial. In CF, these studies may enroll anywhere from 200 to 600 participants, though these studies may be much larger in more common disease conditions. Phase III trials require multiple institutions to participate, and may include international sites. Two successful “adequate and well-controlled” (21 CFR 314.126) Phase III clinical trials are typically required to obtain FDA approval; these may be conducted in parallel. In some cases, regulatory agencies have negotiated with sponsors to consider drug approval with a single Phase III trial if there is a supporting Phase II study conducted under similar conditions, i.e., randomized, controlled, blinded, etc. Because CF drugs have been chronic therapies, extended safety data is needed, even when clinical benefit is seen after a short interval (e.g., CFTR modulators). This has led to most studies being at least 6 months long. In addition, GCP requires 12 months of drug exposure to assess safety, so many studies have open-label follow up evaluations.