Clinical trials take drugs from the lab to the bedside

Clinical trials are systematic assessments of a drug’s safety, efficacy and optimal use in humans. Perceptions of a drug are formed even before Food and Drug Administration approval, during clinical trials. Sales representatives who understand the role of clinical trials will have insight into physicians’ opinions of how or when a drug should be used.

Phases of drug development

The four phases of clinical trials – phase I, II, III and IV – assess objectives (purpose of the trial) and endpoints (measurable goals of the trial) for a drug in a given indication. The drug is given to increasing numbers of human subjects as it moves along the phases of clinical trials, and the cost of development increases. A phase III trial has more patients than a phase I or II trial, and therefore costs more.

Each of the phases of a drug’s development is designed to answer certain questions.

Preclinical (Is this a drug?): Preclinical studies involve cell or animal models to identify potential drugs.

Phase I (Is the drug safe?): Phase I trials can also be called introductory, pilot, feasibility or prototype studies. Phase I trials test the safety of a drug in a small group of human subjects (less than 100) and identify administration doses and side effects of a drug. Phase I trials can involve healthy human subjects or, in the case of diseases with no known cure, involve patients.

Phase II (Does the drug work?): Phase II trials assess the efficacy of the drug in a given indication. Phase II studies are often expansions of phase I trials (scale-up in more patients). In some cases, drugs have been approved based on results of phase II studies. The robustness of experimental design and timeliness of completion of a phase II trial are important.

Phase III (How does the drug stack up to current treatment?): Phase III trials are sometimes called comparative trials or head-to-head trials. Patients are usually randomized to prevent selection bias, which can skew trial results. Comparisons may be open-label (patient knows which drug is taken), blinded (patient does not know which drug is taken), double-blinded (neither patients nor researchers know which drug is taken) or placebo-controlled (test drug versus placebo) and can involve two or more comparison arms. Phase III trials involve large numbers of patients, sometimes in the thousands and across many countries. It is not surprising that phase III trials are extremely costly and that it can take a long time to complete recruitment, data collection and data analysis for these trials.

Phase IV (How is the drug best utilized?): Phase IV trials are conducted after the drug has been approved. These post-marketing studies add data to support existing drug utility and safety, often as required by the Food and Drug Administration. Pharmaceutical companies are increasing the number of phase IV trials as a strategy to differentiate and expand usage by gathering data that distinguish a drug’s efficacy and safety profiles, and that support use of the drug outside approved indications. In addition, research physicians may propose clinical research ideas for the approved drug to test novel uses or improve endpoints.

Endpoint selection

Endpoints, the goals of clinical trials as measured by certain parameters, are key to a clinical trial’s success or failure. Toxicity, response and survival are examples of clinical trial endpoints. Good endpoints should be measurable, reliable and assessable using standardized procedures or equipment. Biomarkers and surrogate endpoints have received much attention in drug development as a “substitute” for conventional clinical endpoints – for example, looking at changes in a key protein as a surrogate endpoint for a drug’s effectiveness in Parkinson’s disease versus a rating scale. Using surrogate endpoints may reduce cost and development time; however, surrogate endpoints have to correlate with clinical outcome to be valid. Using the previous example, the change in a key protein in Parkinson’s disease must correlate with score changes in the rating scale.

A clinical trial can have many endpoints, but only one primary endpoint. Primary endpoints that are typical of one type of drug action may not be suited for drugs with a novel action in the same disease state. High research costs and the limited patent life of a drug make clinical trial design and clinical trial management critical success factors in maximizing a drug’s life cycle. Therefore, primary endpoint selection can make or break a clinical trial and affect the drug’s time-to-market and time-in-market in a given indication.