Fun of the colors of China and U.S. RLDs

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., Approved Animal Drug Products, is applicable to animal drug products. This publication was first published in January 1989, has a new edition every year, and is updated and supplemented every month. The publication came out because of the Generic Animal Drug and Patent Term Restoration Act (GADPTRA) signed by the President in 1988, which requires Abbreviated New Animal Drug Applications (ANADAs) to provide safety and effectiveness materials as required by the Federal Food, Drug, and Cosmetic Act (FD&C Act), and also requires each sponsor of an approved animal drug product to submit to the FDA certain information regarding patents held for the animal drug or its method of use. Such information as well as a list of all animal drug products approved for safety and effectiveness constitutes the Green Book published.

There are 8 sections in the Green Book. The first section lists approved drug products, sorted by trade name and then by NADA number; the second section lists active ingredients and each approved product containing that active ingredient (the first and second sections will not contain products voluntarily withdrawn by their sponsor); the third section lists patent information as provided by the sponsors of approved animal drug products, and products voluntarily withdrawn will appear in this section if they have unexpired patents; the fourth section lists exclusivity periods granted for new uses or claims approved subsequent to enactment of GADPTRA; the fifth section lists any approved products that are currently the subject of a Notice of Hearing and thus may not be used as a basis of an ANADA; the sixth section lists animal drug products whose approval has been voluntarily withdrawn by their sponsors since GADPTRA was enacted; the seventh section lists the actions on ANADA suitability petitions that have been received by the FDA since the enactment of GADPTRA; the eighth section is reserved for monthly updates.

Purple Book

To develop the biosimilars of biological drugs, reference products are also required. FDA also provides selection of reference products for R&D of biosimilars, namely, the Purple Book. The Purple Book lists biological products, including any biosimilar and interchangeable biological products, licensed by FDA under the Public Health Service Act (PHS Act). The Purple Book includes the date a biological product was licensed under 351(a) of the PHS Act and also includes whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product).

Orange Book of China

Compared with the stringent generic drug system of the U.S., China’s generic drugs do not have high quality though it is a big country of generic drugs. Numerous Chinese pharmaceutical enterprises have been developing rapidly in recent years, however, the low-level repetition of pharmaceutical products is serious due to weak industrial base, and Chinese generic drugs have the same chemical ingredients with the original drugs, but still have a gap with them in efficacy and even safety.

On the other hand, the starting point and threshold for Chinese generic drugs are low: FDA specifies that generic drugs can only imitate original drugs in the U.S., while generic drugs in China are allowed to imitate other marketed Chinese-produced generic drugs and will be deemed conforming if the difference is less than 30%. As such, the bioavailability becomes lower and lower and the pharmaceutical product effect becomes poorer and poorer as the imitation goes on.

To eliminate such unhealthy development of generic drugs, China started to implement the quality and efficacy consistency evaluation of generic drugs from March 2016, and has achieved preliminary results so far. In addition, the Center for Drug Evaluation (CDE) drafted the Catalogue of Marketed Drugs in China (Draft for Comment) as directed by CFDA, which can be called the Orange Book of China and currently does not include much content and many varieties, however, will be gradually increased and expanded the corresponding content with the inclusion of new varieties. Pharmaceutical products to enter the Catalogue must meet any of the following conditions according to provisions: 1. Innovative drugs, improved new drugs and imported original pharmaceutical products approved based on complete and normalized safety and effectiveness research data; 2. Generic drugs approved according to the new chemical drug registration classification; 3. Pharmaceutical products that pass the quality and efficacy consistency evaluation; 4. Other pharmaceutical products determined by the CFDA.

The setting up of the Catalogue of Marketed Drugs in China has significance in two aspects: it will define the objective standard for the development of generic drugs in China, on the one hand; it will provide great guidance for promoting the generic drug development, on the other hand.

Seen from the current situation, the work on RLDs has just begun in China, and has a significant gap with the level of developed countries, however, we believe that one day, the pharmaceutical industry of other countries will start to concentrate on studying the Orange Book of China as China’s regulatory system continues to be reformed and improved.

By Zhulikou431