7.1: Introduction to Biologics

Biologics are revolutionizing the biotechnology and health sector – and the most important biotechnology products of this century. Biologics include vaccines, tissue transplants, gene therapy, & stem cell treatment and may include biological molecules such as proteins, and nucleic acids, living tissues, and cells. The official definition for a biologic – or a therapeutic biological product - is "any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product” (Public Health Services Act, 1944). Some biologics treat a disease or disorder, and some diagnose or prevent them. According to the Public Health Services Act (PHS Act) Section 351 (a) to manufacture and sell a biologic in the US, you must apply and receive a Biologics License (BLA). Since some biologics are considered drugs, they must comply with the FD&C Act Title 21 of the CFR pts 210 and 211 for CGMP and may be overseen by CDER.

History of Biologics Regulation

In 1902, the 57th United States Congress passed the Biologics Control Act in response to the death of children from contaminated vaccines in two separate incidences. This Act set a precedent to "regulate the sale of viruses, serums, toxins, and analogous products in the District of Columbia; to regulate interstate traffic in said articles, and for other purposes, and mandated producers of vaccines be licensed annually for the manufacture and sale of antitoxins, serum, and vaccines" (fda.gov). https://history.nih.gov/exhibits/history/docs/page_03.html

In 1930 the National Institutes of Health was born and in 1937, created the Division of Biologics Control. It was not until 1972 that this division was transferred to the FDA and renamed the Bureau of Biologics, and in 1988, it was moved to the Center for Biologics, Evaluation & Research (CBER). CBER’s regulatory authority is derived from Section 351(a) of the PHS Act of 1944, which required Product License Applications.

As you have probably noticed the definition of drug and biologic overlap and have resulted in confusion about which Center would oversee biologics that act like drugs. The FDA's stated policy is to review each product on a case-by-case basis to determine the Center of oversight, which is usually based on the drug's Primary Mode of Action (PMoA). In 1991, CBER & CDER executed an Intercenter Agreement (ICA) to attempt to clarify the regulation of biologics by outlining which of the Centers should regulate which products. They also clarified combination products in this agreement. Further, in 2003, the FDA transferred some of the therapeutic biological products (well-characterized proteins) from CBER to CDER, hoping to strengthen the product divisions.

In 2009, the Biologics Price Competition and Innovation Act (BPCI Act) created an abbreviated approval pathway for biosimilars. Moreover, in 2014, the FDA released new draft guidance on market exclusivity for biological products approved under 351(a) of the PHS Act.

Depending on the regulatory pathway, a product may have differing premarket submissions channels. It is important for a company to quickly establish the path to take since it affects not only the final approval, but approval on every step of the process, including pre-clinical, and clinical studies. Depending on the assigned Center the product may require a BLA or NDA, and in the case of some combination products, a PMA. More on approvals later in this chapter. The FDA has a review process to help clarify confusion, called the Request for Designation Process (RFD). The RFD helps establish a formal designation of which Center will oversee the regulatory process for combination products or for products where there is no clear jurisdiction. Jurisdictional updates are posted to the FDA website