Generic drugs naturally become encouraged and supported by the drug administration agency of each country as they regard medical cost control as a key part in the medical policy. To develop generic drugs, the imitation object—RLD (Reference Listed Drug) shall be determined. The U.S. pharmaceutical product regulations have developed for a long time and become a system. U.S. FDA administers chemical drugs, biological products and also veterinary drugs. How does FDA determine the RLDs for products of different categories?
The U.S. new drug application is generally divided into three types, namely, New Drug Application (NDA), Abbreviated New Drug Application (ANDA), and OTC (over-the-counter) application. The new drug application also includes two steps: Investigational New Drug (IND) application and New Drug Application (NDA).
The ANDA, Abbreviated New Drug Application, is called "abbreviated" mainly because of the Hatch-Waxman Act passed in 1984. Such applications are not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must provide materials to demonstrate product bioequivalence (for example, it has no differences with the original drug). Once such pharmaceutical product is approved, the applicant can produce and market the safe, effective and cheap alternative.
A generic drug producer needs to demonstrate that its generic drug has the same active ingredient, production quality standard, dosage form, specification, route of administration, use and dosage, etc. with the RLD in the application data, with the label and package insert basically the same with the RLD except for the necessary adjustments, and demonstrate that the generic drug is bioequivalent with the RLD. And what needs to be emphasized is that the pharmaceutical products referenced by the generic drugs must be the RLDs on the Orange Book.
Generally speaking, there are four key review points for ANDAs, namely bioequivalence review, pharmaceutical product package insert review, chemical/microbiological review, and plant site inspection, wherein, the bioequivalence review is the key, therefore, in the materials submitted, the material to prove the bioequivalence is the key part for a product to be approved by FDA. Bioequivalence is generally evaluated by comparing the bioavailability of the generic drug and the RLD specified in the Orange Book in healthy volunteers, with the research possibly including the pharmaceutical product’s bioavailability before and after feed.
The followings are an introduction of the Orange Book, Green Book and Purple Book used in generic drug applications.
Orange Book
I believe that we are all familiar with the Orange Book of which the formal name is Approved Drug Products with Therapeutic Equivalence Evaluations. It includes all the drugs approved, including new drugs and generic drugs, by FDA according to the safety and effectiveness principle, and it has detailed drug approval information, and all patent and market exclusivity period information, etc. involved by new drugs. This publication has a new edition every year and is updated and supplemented every month.
The Orange Book is composed of four parts: (1) approved prescription drug products with therapeutic equivalence evaluations; (2) approved OTC drug products for those drugs that may not be marketed without NDAs or ANDAs because they are not covered under existing OTC monographs; (3) drug products with approval under Section 505 of the Act administered by the Center for Biologics Evaluation and Research; and (4) a cumulative list of approved pharmaceutical products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing.
In addition, the Orange Book also includes indices of prescription and OTC drug products by trade or established name (if no trade name exists) and by applicant name (holder of the approved application).
Green Book
Green Book, i.e.,...
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