In the 1970s, state health agencies requested federal guidance relating to generic substitution of prescription drug products approved by the FDA.1 This request resulted from the increase in new state statutes that allowed pharmacists to substitute lower-priced equivalent generic drug products for their branded counterparts. Prior to the change in statutes, pharmacists were required to dispense only the exact drug product specified by the prescriber. If the physician prescribed a drug using the generic name, it became difficult for pharmacists to select a drug product that was therapeutically equivalent, because information was not available to determine which drug products were interchangeable. Few pharmacies were capable of stocking the same drug products manufactured by multiple companies. Consequently, a pharmacist would have to choose a specific product to dispense.
In response, the FDA prepared a list with therapeutic equivalence (TE) evaluations for FDA-approved drug products. Proposed in January 1979 and finalized in October 1980, the first edition of the list was to provide to state health agencies accurate, complete, and understandable information regarding approved drug products with recommended equivalent substitutes. Today, this publication lists drugs approved by the FDA as safe and effective for use and summarizes multiplesource drug products that may be substituted, along with TE ratings.2 Titled Approved Drug Products with Therapeutic Equivalence Evaluations, it is less formally referred to as the Orange Book. Legislation that led to the development of the Orange Book is summarized in Table 1.
TE and Reference-listed Drugs
For a generic drug product to be considered therapeutically equivalent in the Orange Book, the generic firm's product must meet certain criteria (Table 2).3 A product is considered therapeutically equivalent if these criteria are met, despite differences in shape, scoring, release mechanisms, packaging, excipients used, expiration date, and storage conditions. A product that is therapeutically equivalent demonstrates the same clinical effect and safety profile as the prescribed innovator's product.
Before a generic drug product is evaluated for TE, a reference-listed drug (RLD) must be identified by the FDA. The RLD is the drug product upon which the generic drug manufacturer submitting the application must compare in vivo or in vitro bioequivalence, depending on the dosage form of the generic drug. By designating one RLD as the standard, significant variations among generic products may be avoided. The FDA provides a list of therapeutic codes designating inequivalence (Table 3). If a manufacturer wishes to market a generic version of an approved innovator's product that is not designated as the RLD, then the generic firm must submit a citizen petition to the FDA. Upon review and approval of the citizen petition, the second brand name drug will be designated as an additional RLD. Subsequently, the firm can submit on application using that RLD.3
TE Evaluation Coding System in the Orange Book
For situations in which more than one RLD is designated for a particular agent, the TE code will be followed by a number (eg, AB1).3
TE codes are comprised of 2 letters. The first letter indicates whether the approved product is therapeutically equivalent to the RLD. If it is, then the drug will be designated with the letter "A."Drug products with a TE code starting with "B" are not considered to be therapeutically equivalent, or there is a problem in bioequivalence. The second letter provides additional information on the basis of the FDA's evaluations (Table 4), such as route of administration or formulation.
The coding system for TE evaluations is constructed to allow users to promptly select a safe and effective alternate drug product that has been evaluated as therapeutically equivalent to another drug product. The coding system may be applied to approved prescription drugs based on bioequivalence studies. In cases when no bioequivalence studies are available, a waiver may be used. With single-source drug products, no bioequivalence data may be needed. Drug products that predate current regulations ("pre-1938"drugs) or drug products not evaluated for efficacy (Drug Efficacy Study Implementation [DESI] review drugs) are not included in the Orange Book.3 After submission of a new drug application or supplement, however, these drugs may be brought to full approval status and then listed in the Orange Book.
Other Useful Information in the Orange Book
The Orange Book provides additional information that may be useful, including listings of discontinued drugs (products not marketed or withdrawn for reasons other than safety and efficacy by the manufacturer), orphan drugs products (including date approved, date granted orphan status, generic name, trade name [if available], indication, and sponsor contact information), and patent and exclusivity data.3
Electronic Orange Book
The 24th edition of the Orange Book was the last annual hard copy published. The electronic Internet version (called the Electronic Orange Book, or EOB) is available through the FDA Web site and is accessible to the public. The EOB can be accessed at http://www.fda.gov/cder/ob/default.htm.4 As of February 2005, generic drug approvals will be listed in the EOB daily. This is due to some states prohibiting pharmacies from using generic products unless they are listed in the Orange Book. The daily updates may also be beneficial to other health care professionals, patients, and caregivers.
The primary concern of the FDA from the regulatory standpoint is to protect American patients from drug products that are not interchangeable due to problems with bioequivalence, pharmaceutical equivalence, or another aspect, which would not allow a drug product to be therapeutically equivalent to another drug product. With the increased use of generic drug products, it appears likely that the Orange Book will continue to serve as a reliable reference for state health agencies and pharmacists in protecting the health and welfare of patients.
At the time of submission, Dr. Nelson was a drug development fellow working in the FDA Center for Drug Evaluation and Research (CDER), Division of Drug Information. Dr. Kremzner is the deputy director of the Division of Drug Information, FDA CDER, and Dr. Kiliany is a team leader, Division of Drug Information, FDA CDER.
For a list of references, send a stamped, self-addressed envelope to: References Department, Attn: A. Stahl, Generic Pharmacy Report, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: email@example.com.
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