ABSTRACT
The phrase combination clinical trial pertains to a clinical trial whose treatment or intervention groups include one that represents a combination of pharmaceutical products: two or more drugs, biologics, or medical devices. To date, most combination clinical trials involve two drugs, each at fixed doses. One example is Arthrotec1, a fixed combination of the Diclofenac1 and
Misoprostol (Cytotec1). Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) similar to ibuprofen (e.g., Motrin1 or Advil1) used to treat osteoarthritis symptoms. Misoprostol (see Chapter 13) is used to prevent gastric ulceration from developing due to chronic dosing with NSAIDs. Another example is Dyazide1, a fixed combination of Hydrochlorothia-
zide and Triamterene, used to treat hypertension. Hydrochlorothiazide and Triamterene are diuretics that reduce blood pressure by ridding the body of excess water. Triamterene also has potassium-sparing properties. Yet another example is Actifed1, a fixed combination of Triprolodine and
Pseudoephedrine, used to treat seasonal allergic rhinitis (SAR) as well as other respiratory ailments. Triprolodine is an antihistamine that is used to treat hay fever-like symptoms. Pseudoephedrine is a sympathomimetic and is used to alleviate nasal congestion. Hay fever-like symptoms and nasal congestion are the hallmark symptoms of SAR. The U.S. Food and Drug Administration’s (FDA’s) policy under the Fed-
eral Food, Drug, and Cosmetic Act regarding fixed-combination dosage form prescription drugs for humans is as follows [1]: ‘‘Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects (of the combination) and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.’’ Let A denote a drug at a fixed dose, and B denote a different drug at a fixed
dose. Let AB denote the (fixed-dose) combination drug product of A and B. Some interpret the FDA policy requirement necessary for approval of the
combination as the demonstration that it is better than each of its components; i.e., that AB>A and AB>B, and therefore that the design for clinical trials to establish the effectiveness of the combination only needs to contain three treatment groups-AB, A, and B. A case may be made for this interpretation providing the effectiveness of
both A and B has been established. However, if neither A nor B is known to be effective in treating the disease being studied, then a Placebo group is also needed [2]. The inclusion of a Placebo group enables not only the effectiveness of the combination to be established but also permits an assessment of the extent to which each component contributes to the effectiveness of the combination. This chapter reviews the design of combination clinical trials, discusses the
effectiveness of a combination, and illustrates the basis for estimating the contribution that each component makes to the combination. Three examples are also provided.
