Clinical trials are the foundation of evidence-based medicine and generate the data that underpin the benefit–risk assessment that informs regulatory body decisions regarding approval. The relative benefit/risk of a new treatment is also influenced by the extent of the unmet need and available treatment options.
Clinical trial programmes investigate the efficacy and safety of a new drug for a particular disease in humans. A clinical development plan includes studies that test relevant hypotheses to support the anticipated drug label. This involves hundreds, sometimes thousands, of patients and takes, in the best case, around 7 years to complete.
Phase I trials are the first to test a drug in humans and usually involve a few healthy volunteers. Toxicity, maximum dose tolerated and pharmacokinetics are part of this first evaluation.
In phase II, the drug is received by a small number of patients with the disease to begin efficacy testing and identify an optimal dosage regimen (maximum effect/minimum adverse events [AEs]), based on a dose-response curve. Although trial phases proceed sequentially, phase I and II may run in parallel to reduce overall development time e.g. drug interaction, bioavailability and dose range studies may occur at the same time. A control group limits bias by masking study participants (single-blind) or both participants and investigators (double-blind) to which treatment a subject receives. Randomising the treatment allocation helps to control for other variables that may affect study outcomes.
Around a third of drugs entering clinical development progress to phase III trials, which enrol a large number of more diverse patients, to establish efficacy and research safety in particular populations, by testing the doses identified in phase II. Trials including the drug, an active comparator and placebo are usually recommended, however, appropriate design is judged on a case by case basis. Considerations include the risk to a patient of taking a drug with inferior efficacy and the relative safety of the experimental drug versus comparators. Primary endpoint analysis usually encompasses the full analysis set, and exploratory analyses may be conducted in defined trial population subsets, but this increases the probability of false-positive results. Evidence is considered more robust if consistent treatment effects are found across all trials and subgroups of a trial within an application. Results from these pivotal trials (phase III) are critical for seeking marketing authorisation in a defined indication.
Some aspects of trial design will be considered, using the development of biologic DMARDs for rheumatoid arthritis (RA) treatment as an example. EULAR and ACR guidelines highlight the recent progress in the diagnosis, assessment and treatment of RA, which has impacted the development of new therapies, particularly biological agents. RA trials are powered for efficacy and also allow detection of prevalent AEs but numerous factors may affect trial duration. Recently, ethical issues have restricted placebo use to 12 weeks, and while this may be sufficient to demonstrate a significant effect of the drug on RA signs and symptoms, X-ray-assessed structural damage and functional outcomes require much more time. Recently, the detection of a significant structural effect versus placebo or active control has become more difficult. Alternative imaging techniques that are more sensitive to change, and requiring a smaller sample size are both under discussion with regulatory agencies. Furthermore, limiting trial duration or sample size forgoes analysis of long term safety and efficacy outcomes, which may be particularly relevant in chronic diseases. Guidelines advocate careful observation for mode of action-related AEs e.g. severe infections, particularly opportunistic infections, but also malignancies or cardiovascular events. Many trials therefore include long–term extensions, although these may be limited by selection bias, limited power to detect AEs and ethical considerations surrounding withdrawal of an effective drug. Authorities request an extensive risk management plan to detect rare AEs through long term surveillance in the real world.
Cooperation between pharmaceutical companies and regulatory authorities will continue to refine procedures and best practices in clinical trials to test the safety and efficacy of new drugs to the highest standards.
Disclosure of Interest M. Le Bars Employee of: Bristol-Myers Squibb