Bioequivalence and Interchangeability of Generic Drugs

Manufacturers must conduct studies to determine whether their version is bioequivalent to the original drug—that is, that the generic version releases its active ingredient (the drug) into the bloodstream at virtually the same speed and in virtually the same amounts as the original drug. Because the active ingredient in the generic drug has already been shown in testing of the brand-name drug to be safe and effective, bioequivalence studies only have to show that the generic version produces virtually the same levels of drug in the blood over time and thus require only a relatively small number (24 to 36) of healthy volunteers.

Although people generally think of oral dosage forms, such as tablets, capsules, and liquids, when they think about generic prescription drugs, generic versions of other drug dosage forms, such as injections, patches, inhalers, and others, must also meet a bioequivalence standard. The U.S. Food and Drug Administration (FDA) sets bioequivalence standards for different drug dosage forms.

The manufacturer of the brand-name drug also must prove bioequivalence before a new form of an approved drug can be sold. New forms include new dosage forms or strengths of an existing brand-name drug product and any other modified form that is developed, as well as new generic drugs. Sometimes the form that was originally tested is modified for commercial reasons. For example, tablets may need to be made sturdier, flavoring or coloring may be added or changed, or inactive ingredients may be changed to increase consumer acceptance.

The U.S. Food and Drug Administration (FDA) evaluates every generic version of a drug. The FDA approves a generic drug if studies indicate that the original brand-name drug and the generic version are essentially bioequivalent. The FDA also makes sure that a new generic drug contains the appropriate amount of the active (drug) ingredient, that it is manufactured according to federal standards (Good Manufacturing Practices), and that the generic version differs from its brand-name counterpart in size, color, and shape—a legal requirement.

Theoretically, any generic drug that is bioequivalent to its brand-name counterpart may be interchanged with it. For drugs that are off patent, the generic drug may be the only form available. To limit costs, many doctors write prescriptions for generic drugs whenever possible. Even if the doctor has prescribed a brand-name drug, the pharmacist may dispense a generic drug unless the doctor wrote on the prescription that no substitution can be made. Also, insurance plans and managed care organizations may require that generic drugs be prescribed and dispensed whenever possible to save money. Some insurance plans may allow a consumer to select a more expensive brand-name product prescribed by the doctor as long as the consumer pays the difference in cost. However, in some state-run programs, the consumer may not have a choice. If the doctor prescribes a generic drug, the pharmacist must dispense a generic drug. In most states, the consumer may insist on a brand-name drug even if the doctor and pharmacist recommend a generic drug.

A book published by the FDA each year and updated periodically also provides guidance about which drugs are interchangeable. This book, Approved Drug Products With Therapeutic Equivalence Evaluations (also known as "the orange book" because it has a bright orange cover), is available both in print and online to anyone but is intended for use by doctors and pharmacists. (See Approved Drug Products With Therapeutic Equivalence Evaluations.)

The substitution of a generic drug can sometimes cause other problems for the consumer (see table When Generic Substitution May Not Be Appropriate). A doctor may write a prescription for a brand-name product and discuss the brand-name product with the consumer. If a pharmacist dispenses an equivalent generic product and the label does not also list the reference (brand-name product), the consumer may not know how the generic product relates to the drug the doctor prescribed. To prevent this confusion, most pharmacies now include the reference brand name on the label when a generic product is substituted.

Other drugs for which generic substitution may not be appropriate include drugs that are said to have a narrow margin of safety because the toxic dose is too close to the effective dose for the drug to be used safely.