Clinical Research

Recent regulatory changes have rendered Canada attractive for Phase I studies which are now conducted by Merck Frosst in Canada. In the past, these studies were usually carried out in Europe and in the US where the waiting period for regulatory approval of Phase I protocols was shorter.

Phase I trials often start in healthy men, to evaluate the half-life, absorption, distribution, metabolism and excretion of a drug in the human species. Exceptions to the use of men include trials of drugs being developed specifically for women or drugs used in special areas such as HIV/AIDS or oncology. These studies also provide the first glimpse of the drug’s tolerability, and the human safety profile — sometimes markedly different from that seen in animals. For example, MK-679, a predecessor molecule of SINGULAIR® (montelukast sodium), looked good in animals but showed signs of hepatic toxicity in early human studies, ending any further development.

The healthy volunteers involved in Phase I studies are called "subjects" rather than patients and receive an indemnity as compensation for their participation, which often involves clinic visits over several days to provide blood and urine samples. These samples are used to determine how the body absorbs, processes and excretes a medication (pharmacokinetics).

When pharmacokinetics in humans are understood, scientists at Merck Frosst can start to address other questions that may be important before the drug is evaluated in patients with disease, such as maximum tolerated dose, interactions with other drugs or different foods, and the effect on surrogate efficacy parameters. This stage can take a further 1 or 2 years.

Phase II usually marks the first time the new molecule is used in a patient population to treat the target disease. Phase II programs generally take one to two years to complete. These trials are designed to identify the dose and dosage frequency, and collect safety information. Patients are compensated for out of pocket expenses, but otherwise receive no payment for their involvement.

Merck Frosst participates in international Phase III trials that involve study centres around the world and thousands of patients. The successful culmination of a Phase III program is a dossier of research that allows Merck & Co., Inc. to seek approval to market a drug from any regulatory agency in the world.

The design of a Phase III trial will depend on a number of factors. Active (currently marketed) comparators are considered more powerful than placebo comparators, and double-blinding, where neither the patient nor the investigator can tell which drug has been taken, is considered de rigueur. As well, randomization is the norm: by assigning treatments randomly by a computer-generated code the risk of investigator bias is reduced.

Efficacy endpoints are usually clinically significant outcomes, often decided after consultation with the Food and Drug Administration (FDA) in the US. The duration of the study will depend on the indication — it may take up to 3 years to demonstrate a drug effect in osteoporosis, while an effect in coronary thrombosis can be demonstrated in as little as a few days .

The number of patients enrolled is determined by statistical considerations — large differences can be shown with fewer than a hundred patients while demonstrating small differences may require thousands. In a Phase III trial of SINGULAIR®, 895 patients were required to demonstrate similar efficacy in lung function compared to beclomethasone. To study this many patients, 36 study centers from around the world participated⁽¹⁾. This pivotal trial was central to receiving the approval to market SINGULAIR® in over 80 countries.

Phase IV trials, also called post-marketing trials, are conducted to gain experience and monitor safety with a drug in thousands of patients more closely resembling real-life conditions.

Clinical Evaluation Programs (CEPs) examine various aspects of the use of a medication or other treatment within its approved indications in Canada in order to add to the body of knowledge for the product. These trials allow community-based family physicians and specialists to explore the use of these interventions in their practices. CEPs can involve large numbers of physicians and patients across Canada. There are many different types of CEPs. They can be observational studies, exploring the efficacy, tolerability and safety of a medication in a "real world" setting while other CEPs are comparative studies. CEPs can also investigate the appropriate use of therapy and patient compliance in the "real world". CEPs provide physicians with the opportunity to participate in clinical trials. CEPs are designed to provide useful information in areas that may not have been fully investigated previously.