19 Regulatory Overview: Obtaining Regulatory Approval of a Biological/Cell Product
Michaela H. Purcell, Penny J. White, and H. Davis Adkisson
Abstract
Physicians and corporate sponsors engaged in the clinical development of biological therapies are faced with a regulatory environment that is continually evolving as new, unique products, particularly those derived of living cells, are introduced. This chapter addresses salient milestones in the historical evolution of this regulatory process, U.S. Food and Drug Administration (FDA) classification of biological products, and the process for studying and approving a new biological treatment in the United States. Additionally, the value of and process by which sponsors can obtain guidance through meeting with the FDA is reviewed. Recommendations for assembling effective quality and regulatory teams are discussed.
Keywords: BLA, cellular therapy, clinical research, development of biological therapy, IND, tissue
19.1 Historical Perspective
The process of regulatory oversight of medicinal products is relatively recent in modern culture. Prior to 1906, all drugs and devices could be sold in the United States as freely as any other marketed commodity. There was no requirement that manufacturers disclose product composition, and therefore preparations could be sold containing inactive, harmless mixtures or very toxic chemicals. Since these early days, a barrage of legislation has ensued. Enactments, which have laid the groundwork for product development, and a brief summary of the most relevant to the regulation of biologics are outlined in the following paragraphs.1,2,3,4
In 1902, Congress passed the Biologics Control Act following the death of 22 children from tetanus, 13 of whom received inoculation with contaminated diphtheria antiserum and 9 of whom received contaminated smallpox vaccine. Prior to 1906, there were no central or uniform controls in place to ensure product potency and purity. The Biologics Control Act gave the government control over the processes used to make biological products and the responsibility to ensure their safety for the American public. This authority was assigned to the Hygienic Laboratory of the Public Health and Marine Hospital Service.
In 1906, Congress passed the Pure Food and Drugs Act, which outlawed foods and drugs that were mixed with inferior or impure ingredients (adulterated), or that bore false or misleading claims. However, this law made no reference to biological products. Under another law passed in 1938, the Federal Food, Drug, and Cosmetic Act (FD&C Act) legislated that a biological product was considered to be a drug. Although parts of the 1938 act were applied to biologics, the act did not modify or supersede the provisions of the 1902 Biologics Control Act. After 1938, the appropriate provisions of the 1902 and 1938 acts were used in the regulation of biologics.
In 1930, the Hygienic Laboratory was renamed the National Institute of Health, which became the National Institutes of Health (NIH) in 1948. Biologics control remained part of the NIH until 1972, when it was transferred to the U.S. Food and Drug Administration (FDA), Center for Biologics Evaluation and Research (CBER). Because CBER has unique origins from within the NIH, the regulation of biologics has subtle but impactful differences when compared with the regulation of drugs and devices. This is an important consideration for sponsors who may incorrectly assume that the nuances of drug and device regulation can be extrapolated to biologics, especially in the areas of manufacturing and in the demonstration of clinical safety.
In 1944, Congress passed the Public Health Service Act (PHSA), which covered a broad spectrum of health concerns, including regulation of biological products and control of communicable diseases. Today, the 1938 Food Drug and Cosmetic Act and the Public Health Service Act are the principle laws that govern biologics.
In 1998, the first human embryonic stem (ES) cell was isolated and grown in culture.5 This discovery ignited unprecedented controversy over the right to harvest and manipulate stem cells, which can potentially be engineered into any cell type in the human body, and may also be genetically altered. Exploration of methods by which human stem cells, both embryonic and adult, may be utilized medicinally to replace diseased cells, prevent the progression of disease, or even prevent disease from occurring, has greatly accelerated. In response, the FDA has quickened its efforts to meet scientific discovery in order to assure the safety and clinical benefit of products comprising living cells. The regulation of cells presents exceptional challenges because each cell type is unique, and may not be easily characterized as compared to a traditional pharmaceutical. Although biologics continue to be developed along a similar path as drugs, the FDA is releasing a quickly evolving set of guidances, unique to living cells and even in some cases specific to cell types. In the following sections, the general “roadmap” by which a biological/cell product can be brought to market is discussed.
19.2 Regulation of Human Cells, Tissues, and Cellular and Tissue-based Products
All therapeutic products are regulated in the United States by the FDA based upon their derivation and mode of action. Human cells and tissue products are regulated under The Code ofFederal Regulations, 21CFR 1271.3 (d),6 which defines human cells, tissues, and cellular and tissue-based products (HCT/Ps) as those articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer to a human recipient. The FDA has constructed regulations to prevent the transmission, introduction, and spread of communicable disease through HCT/Ps.
•Minimally manipulated7;
•Intended for homologous use;
•Manufacture does not involve combination with other articles except for water, crystalloids, or a sterilizing, preserving, or storage agent that does not introduce additional safetyconcerns; and
•Either;
a) Does not have a systemic effect and is not dependent on metabolic activity of living cells for its primary function, or;
b) Has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function and is for
•autologous use,
•allogeneic use in a first- or second-degree blood relative, or
•reproductive use.
19.3 Regulation of Biological Products
All products not meeting the definition of an HCT/P will be regulated as a biologic, drug, and/or device and will require premarket approval from the FDA. Biological products (including cell therapies) are derived from living sources (human, animal, or microorganism) and act through a metabolic mode of action. Such products cannot be fully characterized and are regulated within the particular expertise of CBER. CBER regulates cellular therapy products, human gene therapy products, and certain devices related to cell and gene therapy. The directive of CBER is to assure safe collection, manufacture, storage, and usage of biological products.
In contrast, drug products, which can be structurally characterized and interact chemically with the body, are regulated within the Center for Drug Evaluation and Research (CDER). Devices, which function via their physical structure in vivo, fall within the jurisdiction of the Center for Devices and Radiological Health (CDRH).
Though great efforts in providing consistency among these divisions are ongoing, it is wise to understand their inevitable bureaucratic differences. This becomes even more nuanced in situations where one is developing a “combination product.” In such cases, more than one agency division will have responsibility for oversight, and it will be internally decided among divisions which entity will take on a lead role as they partner in their evaluation of the product.
19.4 The Investigational New Drug Application Process
Current federal law requires that a drug/biological product be approved for marketing before it can be shipped across state lines. The exemption to this law, by which an investigational drug or biologic can be studied in humans, and shipped across state lines is through the Investigational New Drug Application (IND) process. It is through this process that the FDA evaluates whether the chemistry and manufacturing controls (CMC), laboratory, and animal studies have demonstrated sufficient safety to allow study in humans.
INDs are submitted by sponsors. Sponsors can be individual investigators, commercial enterprises, or even government agencies. Throughout the clinical investigation of the biologic, the sponsor holds full responsibility for complying with all applicable laws and regulations relative to the product’s development. The sponsor may delegate duties to various collaborators, but in the end is the accountable party.
The required content of the IND can be found in the FDA Code of Federal Regulations 312.23.8,9 An abbreviated summary is provided in ▶ Table 19.1. It should be noted that throughout the investigational life of the product, annual reports are submitted by the sponsor to the FDA to update the contents of the IND and inform the agency of all pertinent information regarding the development history of the investigational product.
Table 19.1 Content of the Investigational New Drug Application (IND)
Section | Content |
Cover sheet (Form FDA-1571) | Name of the biologic, all contact information of the sponsor, and if a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, full identification of all contractors, and a listing of the obligations transferred; identification of the phase or phases of the clinical investigation to be conducted; and commitment not to begin clinical investigations until an IND is in effect; Institutional Review Board (IRB) oversight and compliance with all other applicable regulatory requirements. |
Introductory statements | A statement of all components, route of administration, broad objectives, and planned duration of the proposed clinical investigation (s), previous human experience, with reference to other INDs if pertinent, investigational or marketing experience in other countries that may be relevant to the safety of the proposed clinical investigation(s); rationale for research study, the indication(s) to be studied; estimated number of patients to be administered product and a summary of risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the investigational product. |
Investigator’s brochure |
