LINCOLN TSANG, PhD, FRSC, FIBiol, FRPharmS, and NATHAN CORTEZ
Contents
1.1 Introduction 3 1.2 United States 4 1.2.1 How the United States Defines Biologics and Biopharmaceuticals 4 1.2.2 Legal Foundations for Regulating US Biopharmaceuticals 5 1.2.3 Legal Requirements for US Biopharmaceuticals 7 1.3 European Union 11 1.3.1 How EU Law Defines a Biological Medicinal Product 11 1.3.2 Legal Foundation for Regulation of Biological Medicinal Product 12 1.4 Japan 16 1.5 Conclusion 18 References 18
1.1 INTRODUCTION
Compared with other types of pharmaceutical products, products derived from a biological source or a biotechnological process are structurally complex and involve manufacturing processes that require tight control to ensure their safety, quality, and efficacy. Biological products, because of their sheer size, are orders of magnitude more complicated than small-molecule drugs. This can be seen by a comparison of molecular weight, which can be used as a measure of the size of a given product. Moreover the product arising from the manufacturing process is often not a pure, homogeneous mixture. Rather, various forms of these molecules are usually present in the final product.
In scientific terms, conventional biological products such as blood-derived clotting products, vaccines, and those derived from high technology such as those employing a recombinant DNA technology are characterized as biological products. Because of these differences in respect of the product characteristics and manufacturing process, the regulatory oversight of biological products is distinguishable from conventional pharmaceutical products based on small molecules. This chapter addresses legal framework governing biological products principally in the United States and in the European Union. The regulatory landscape in Japan is briefly described particularly in relation to the recent changes to Japan's Pharmaceutical Affairs Law.
1.2 UNITED STATES
The United States has one of the most active and sophisticated systems in the world for ensuring the safety and effectiveness of biopharmaceuticals. To understand this system, it is important to understand (1) how the United States defines biopharmaceuticals and biologics, (2) the legal foundations for regulating these products, and (3) the rules that apply during various stages, including research, development, approval, and marketing. This section also highlights how the United States regulates biologics in relation to drugs.
1.2.1 How the United States Defines Biologics and Biopharmaceuticals
US law does not have a single, simple definition for biologics or biopharmaceuticals. The Food and Drug Administration (FDA) recognizes that most biologic products "are complex mixtures that are not easily identified or characterized". Traditionally biologics are substances that are derived from living organisms, such as humans, animals, plants, and microorganisms. Today biologics include these substances as well as those produced by biotechnology. A federal statute defines biological product as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound) that is "applicable to the prevention, treatment, or cure of a disease or condition of human beings". The corresponding federal regulation uses similar language, but clarifies several key terms:
1. A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes filterable viruses, bacteria, rickettsia, fungi, and protozoa, among other things.
2. A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.
3. A toxin is a product containing a soluble substance poisonous to laboratory animals or to human in doses of one milliliter or less (or equivalent in weight) of the product, and having the property, following the injection of nonfatal doses into an animal, of causing to be produced therein another soluble substance that specifically neutralizes the poisonous substance and that is demonstrable in the serum of the animal thus immunized.
4. An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal that specifically neutralizes the toxin against which the animal is immune.
The regulation also clarifies how additional products may be biologics if they are "analogous" to certain categories of products listed in the definition. A product is a biologic if it is analogous to the following:
1. A virus, if prepared from or with a virus or agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the specific strain used.
2. A therapeutic serum, if composed of whole blood or plasma or containing some organic constituent or product other than a hormone or an amino acid, derived from whole blood, plasma, or a serum.
3. A toxin or antitoxin, if intended, regardless of its source of origin, to be applicable to the prevention, treatment, or cure of diseases or injuries of human through a specific immune process.
Although these definitions seem to be relatively concrete, biological products come in many forms, including drugs, devices, and "combination" products. The FDA regulates biopharmaceuticals as both drugs and biologics because they meet both definitions. US law, as described above, defines biological products by referring to several categories of tangible products. In contrast, the law defines drugs by their functions. The term drug means "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man" and "articles (other than food) intended to affect the structure or any function of the body of man". Thus the definitions of drugs and biologics are not mutually exclusive, which allows the FDA to regulate some products as both.
1.2.2 Legal Foundations for Regulating US Biopharmaceuticals
To understand how biopharmaceuticals are regulated in the United States, it is helpful to understand the underlying legal bases for regulation, how these laws have evolved, and how regulatory responsibility for biologics has shifted. Currently the Public Health Service Act authorizes the FDA to ensure the safety, purity, and potency of biologics. The FDA approves biologics for marketing under section 351 of the Act. The FDA also regulates biopharmaceuticals as drugs under the Federal Food, Drug, and Cosmetic Act. Thus the FDA now delegates responsibility for regulating biopharmaceuticals to two centers within the agency: the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Regulation under the Public Health Service Act precludes the manufacture of generic, or "follow-on" biologicals and "biosimilars."
The foundations for this regulatory system were set in 1902 with the Biologics Control Act, the first legislation to regulate a specific class of drugs. The Biologics Control Act was a response to tragedies in St. Louis, Missouri, and Camden, New Jersey, in which several people died after taking diphtheria and small pox vaccines. The purpose of the Act was to authorize the regulation of certain biologics, require manufacturers to obtain licensing, and authorize the government to inspect manufacturing facilities. The Act prohibited companies from selling or transporting biologics that were either not manufactured at facilities licensed and inspected by the government or not labeled with the manufacturer's name and an expiration date.
Since the 1902 Act, the laws and regulations for biologics have steadily evolved, and responsibility for regulating biological products has shifted several times. In 1903, the federal government issued the first biologics regulations, administered by the Hygienic Laboratory in the Public Health and Marine Hospital Service. The regulations required manufacturers to annually renew their licenses and make their facilities available for unannounced inspections. In 1919, the regulations were amended to require manufacturers to report changes in manufacturing methods, equipment, and personnel. The regulations also required manufacturers to maintain manufacturing records and submit certain product samples for government inspection and approval.
These initial laws and regulations laid the foundation for the current biologics regulatory scheme. From the beginning the United States regulated biologics and drugs differently. The government did not regulate nonbiologic drugs until it passed the Pure Food and Drugs Act in 1906, which did not address biologics or the 1902 Biologics Control Act. In fact Congress did not formally recognize the difference between drugs and biologics until after it passed the 1938 Federal Food, Drug, and Cosmetic Act (FDCA). In 1944, Congress reenacted the 1902 Biologics Control Act and recodified the Public Health Service Act. A major issue was the definitional overlap between drugs and biologics.
Between 1902 and 1972, regulatory responsibility for biologics transferred several times, ultimately settling with FDA, as shown by this brief timeline of the relevant transfers:
1930 The Hygienic Laboratory within the Public Health and Marine Hospital Service is redesignated as the National Institutes of Health (NIH).
1937 The NIH is reorganized, and responsibility for biologics is transferred to the Division of Biologics Control. In 1944 it is renamed the Laboratory of Biologics Control.
1948 The Laboratory of Biologics Control is integrated into the NIH's National Microbiological Institute, which later becomes the Institute of Allergy and Infectious Diseases.
1955 Responsibility for biologics is transferred to the new Division of Biologics Standards, a new independent entity within the NIH.
1972 The Division of Biologics Standards is transferred from the NIH to the FDA, becoming the Bureau of Biologics.
1982 The Bureau of Biologics is merged with the Bureau of Drugs to form the National Center for Drugs and Biologics (NCDB).
1983 The biologics component of the NCDB is renamed the Office of Biologics Research and Review, within the Center for Drugs and Biologics (CDB).
1988 CDB split into two centers, the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER).
2003 Transfer of therapeutic biological products from CBER to CDER.
The steady stream of reorganizations in many ways reflects the difficulty of both categorizing and regulating biologics. The FDA continues to struggle with these responsibilities. For instance, since the FDA created CBER in 1988, the agency has both overhauled the way it approves biologics, and once again shifted responsibility for certain biologics. First, the FDA established a single approval application, the Biological License Application (BLA) through the Food and Drug Modernization Act of 1997 (FDAMA), the most comprehensive rewrite of food and drug laws since 1938. Second, in 2003, the FDA shifted responsibility for therapeutic biologics from CBER to CDER, given CDER's role in regulating therapeutic drugs. CDER's new responsibilities include a wide array of biological products, including monoclonal antibodies for in vivo use, therapeutic proteins, and immunomodulators. CBER retained authority over traditional biologic products such as vaccines, allergenic extracts, antitoxins, blood, and blood products, as well as products composed of human, bacterial, or animal cells.
1.2.3 Legal Requirements for US Biopharmaceuticals
The regulation of biologics continues to evolve. The transcendent growth of biotechnology research, spurred by the Human Genome Project, almost ensures that biologic regulations will require further tinkering to accommodate new products. The following is a brief synopsis of relevant US laws and regulations at various stages, including research, development, approval, and marketing. Where relevant, we highlight where the rules for biologics differ from drugs.
Research and Development The United States heavily regulates the research and development of biologics. At the preclinical stage, FDA requires companies to comply with regulations on good laboratory practices (GLPs) at 21 CFR part 58. The GLP regulations seek to ensure the quality and integrity of preclinical safety data submitted to the FDA. GLPs apply to nonclinical (preclinical) laboratory studies intended to support research or marketing applications, and address a broad range of topics, including personnel, facilities, and equipment. Ideally preclinical studies to support safety are subject to GLPs and should be supported by a statement that the study was conducted in compliance with the good laboratory practice regulations in 21 CFR part 58, or if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance (21 CFR 312.23 (8) (iii)).
At the clinical stage, FDA sets minimum standards for clinical trials through several regulations and guidance documents, collectively known as good clinical practices (GCPs). GCPs are designed to ensure the quality and integrity of data submitted to FDA and protect the rights of human subjects. GCPs govern key personnel involved in clinical trials-particularly sponsors, and investigators-and address several important areas, including informed consent, institutional review boards (IRBs), and investigational new drug (IND) requirements.
Informed consent is governed by both federal and state law. These laws generally require that before participating in clinical trials, human research subjects state in writing that they understand the risks of the trial and are participating voluntarily. Each informed consent document must contain several elements required by FDA regulations.
IRBs are also governed by federal and state law. FDA regulations require IRBs to provide initial and continuing review of clinical trials. IRBs must ensure that investigators and sponsors protect the study subjects, obtain adequate informed consent, and adhere to other safeguards and reporting requirements. Moreover FDA regulations require IRBs members to meet specific membership criteria.
Investigational biologics are subject to the FDA's investigational new drug (IND) requirements. The IND application is the first formal submission to FDA, and the application must be submitted before initiating any clinical studies. It is not a request for commercial marketing approval; rather, it is a request to be exempt from the federal statute that prohibits shipping "unapproved" drugs across state lines. Thus an IND permit allows the product to be shipped during investigational studies. The purpose of the IND requirement is to assure the FDA that the safety and rights of subjects will be protected in all phases of the investigation, and that the quality of the studies are adequate to permit the FDA to evaluate the product's safety and effectiveness.
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