With many blockbuster brand drugs at or near the edge of the so called “patent cliff”, and with significant technical hurdles in biosimilar development, some generic companies are shifting their attention to additional dosage forms or niche products to create product portfolio diversity. One of the market segments that offers multiple sub-billion-dollar product opportunities is the non-sterile semi- solid and liquid topical drug segment. To gain a good grasp on the Chemistry, Manufacturing, and Controls (CMC) and Bioequivalence (BE) requirement, generic companies need to constantly scan the regulatory landscape and build a network of service providers with expertise in generic development. This article provides a list of must-see resources, which are publicly available, to guide the selection and development for an Abbreviated New Drug Application (ANDA). While some of the information in this article applies to most ANDA products, much of the focus is placed on topical generic products.
Brand Drug/Reference Listed Drug (RLD)
A Brand Drug or Brand Name Drug is the drug marketed under a proprietary, trademark-protected name. The Reference Listed Drug (RLD) is the approved drug product to which new generic versions are compared to show that they are bioequivalent. Occasionally, when a Brand Drug is discontinued or not available on the market, the FDA will designate a single source drug product– a generic on the market at the time of designation–as RLD. Except for a few revived brands, the Brand Drug is typically the RLD.
In 2017, FDA also introduced Reference Standard (RS) in addition to RLD. A company seeking approval to market a generic equivalent must refer to the RS in the ANDA. RLD is not always the RS, e.g. Lidex (Brand Drug of fluocinonide topical solution) was discontinued on the market, then re-introduced. During the discontinuation, FDA designated a generic product (Taro) as new RLD. After Lidex re-introduction, FDA restored the RLD status for Lidex, and assigned Taro product as RS.
Drugs@FDA is an online database provided by FDA for brand drug/RLD’s and their therapeutic equivalents. A simple search by Drug Name, Active Ingredient or Application Number or advanced search with additional information such as FDA action dates can be performed. The search returns detailed information about a drug product, such as Application Number, Active Ingredient(s), Chemical Type (for NDAs), Review Classification, and Original Approval Date, as well as links to Therapeutic Equivalents, Label Information, and Approval History and Related Documents, etc.
- Therapeutic Equivalents: RLD and all of its Therapeutic Equivalents (i.e. generic products) are listed in this page, along with TE Code and other product information.
- Label Information: Label is also known as the Prescription Information or Package Insert. The FDA approved label is the official description of a drug product which includes indication; who should take it; adverse events; instructions for uses by pregnant women, children, and other populations; and safety information for the patient. Labels are often found inside drug product packaging, hence the name “Package Insert”. On the consumer website sponsored by the brand company, Label Information can be found under Prescription Information.
- Approval History and Related Documents: A list of Action Dates in chronological order with links to PDF files of Approval Letters, Approval Type, Reviews, Labels, and Patient Package Insert may be provided, with exception of some older RLD’s and most of generic products. The review documents can provide useful information to assist with generic product development, even with some FDA redaction of these documents for confidentiality purposes.
The Orange Book, or Approved Drug Products with Therapeutic Equivalence Evaluations, identifies drug products approved on the basis of safety and effectiveness by FDA. Since February 2005, FDA has been providing daily updates on the Electronic Orange Book. A mobile app was also made available for download in 2015. A search on Orange Book can be executed using key words such as Active Ingredient, Proprietary Name, Applicant Holder, Application Number and Patent.
A wealth of information regarding the RLD and existing generic products can be found in the Orange Book Database. For example, a particular TE Code may be indicated for a RLD or generic product. The TE Code is the coding system constructed to allow users to quickly determine whether FDA has evaluated a particular approved product as therapeutically equivalent to other pharmaceutically equivalent products (first letter) and to provide additional information on the basis of FDA’s evaluations (second letter). For example, AT indicates a topical product that FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products. Whereas AB indicates that a drug product that is considered to be therapeutically equivalent to other pharmaceutically equivalent products with adequate in vivo and/or in vitro evidence supporting bioequivalence.
The other critical information one may find in the Orange Book is the patent and exclusivity of the RLD. If applicable, Orange Book will list Patent No, Expiration Date, Drug Substance or Drug Product Claim, and Patent Use Code. The resource for conducting a simple patent search is presented in the following section of this white paper. Exclusivity and its expiration provide additional protection to the brand drug. Together with patent expiration date, exclusivity can have great impact on the timeline and strategies of generic drug development.
Aside from FDA databases, a number of user-friendly websites aimed at physicians, health care professionals, and consumers provide label/package insert and related information that can assist in the selection and development of a potential ANDA product.
- DailyMed: Official provider of FDA label information by National Institutes of Health (NIH). The drug labeling information on DailyMed is the most recent submitted to FDA and is currently in use. The search on DailyMed is intuitive with usage of key words such as proprietary drug name, generic drug name or manufacturer name etc. The search can be also conducted using National Drug Code (NDC code).
- Physicians’ Desk Reference®: Physicians’ Desk Reference (PDR) is considered the authoritative source on prescription drugs. The first edition began in 1946. It is widely used by doctors, pharmacists and healthcare professionals in virtually every physician’s office, pharmacy, clinic, and library. PDR contains full, FDA-approved drug label information, including warnings and precautions, drug interactions, and hundreds of full-color product images. The cost of hardcopy of PDR is less than $100.
- Epocrates®: Epocrates is PDR’s direct online competitor, and offers a variety of features, including free Drug Information, Pill ID, etc. The paid version includes more advanced features aimed at physician use. However, the free Drug Information section is helpful for generic development purposes. A handy and useful feature is the drug retail price, which is surprisingly difficult to find online due to heavily advertised commercial websites and search engines.
In this article, I present several convenient and valuable sources of information to research brand/RLD and generic products. They are primary sources of information for topical product development.