CENTER FOR BIOLOGICS EVALUATION AND RESEARCH/CENTER FOR DRUG EVALUATION AND RESEARCH (CBER/CDER)
Since many of the early products of modern biotechnology methods that were developed for the treatment of various diseases of human beings, with the exception of human growth hormone, were biological drugs, not surprisingly there was a quick and steady recognition of the importance of biologics, which were once thought of as mainly vaccine and blood products. Indeed, biologics have almost become synonymous with modern biotechnology methods in the health area.
As biological drugs traditionally have been regulated very differently from other drugs, with the advent of modern biotechnology there were many administrative and legislative initiatives to alter the requirements for biological products to make their regulation more consistent with that of other drugs, particularly with the enactment of the Food and Drug Administration Modernization Act of 1997 (FDAMA). Examples of significant changes in biological drug oversight include the allowance for different types of manufacturing arrangements and the elimination of establishment and product licenses, in lieu of one application, a biologics license application (BLA). Other important procedural changes include a guidance on flexibility pertaining to lot release requirements for licensed biological products. See HHS, FDA, Guidance on Alternatives to Lot Release for Licensed Biological Products, Notice, 58 Fed. Reg. 38771 (1993). Lessened approval requirements were adopted for some “well-characterized” biologics, namely therapeutic DNA plasmids, therapeutic synthetic peptides of 40 or fewer amino acids, monoclonal antibodies for in vivo use, and recombinant DNA-derived products. 21 CFR § 601.4(c)(1).
Along with these key changes and others, FDA issued an abundance of guidance documents or points to consider on a variety of topics pertaining to testing matters, including supplying evidence of the effectiveness for human drug and biological products, making changes to approved applications, demonstrating the comparability of human biological products, and guidances on providing chemistry, manufacturing and controls information. See generally U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Guidance Documents, available at http://www.fda.gov/cder/guidance/.
Perhaps more importantly in terms of its regulation of new kinds of products, FDA developed a number of key policy statements in various areas. Key policies or regulations involve the application of current statutory authorities to human somatic cell therapy and gene therapy products, along with a proposed approach to the regulation of cellular- and tissue-based products. See HHS, FDA, Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products, Notice, 58 Fed. Reg. 53248 (1993) and HHS; FDA, Proposed Approach to Regulation of Cellular and Tissue-Based Products, Availability and Public Notice, 62 Fed. Reg. 9721 (1997). These statements ultimately led in part to the creation of a new 21 CFR Part 1271 entitled Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps), among other initiatives.
The HCT/Ps regulations govern procedures for registration and listing, donor eligibility, current good tissue practices, reporting, and inspection. See 21 CFR Part 1271, Subparts B (procedures for registration and listing), C (donor eligibility), D (current tissue practice), E (additional requirements for establishments), and F (inspection and enforcement).
A key aspect is that HCT/Ps that are minimally manipulated typically are regulated only under section 361 of the Public Health Service Act relating to ensuring that the products do not involve communicable disease concerns, in terms of donor testing and other quality assurance requirements (see Table I). If the products do not meet the criteria for regulation solely under section 361, then they are essentially regulated as biologics, medical devices, and/or drugs, as appropriate, and subject to relevant preclearance or premarket approval requirements. See 21 CFR § 1271.20.
These types of provisions and others have enabled FDA to take the position that somatic cell nuclear transfer (SCNT) methods to clone human beings can involve biological products subject to licensure requirements. For an in-depth discussion of this cloning topic, see Edward L. Korwek, What Are Biologics? A Comparative Legislative, Regulatory and Scientific Analysis, 62 Food and Drug Law Journal 257-304 (2007).
Given the variety of products and technologies involving biotechnology methods and other techniques, the issue of how combination products should be regulated also eventually became subject to legislative and agency initiatives. Procedures for assigning product review responsibilities, based on the primary mode of action of a combination product were eventually adopted. See 21 CFR Part 3. The Medical Device User Fee and Modernization Act of 2002 also established the Office of Combination Products. These products, which are comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, can be subject to a single designated agency responsible for primary jurisdiction. In other words, for example, CBER can regulate medical devices under CDRH authorities. A list of combination product decisions appears at http://www.fda.gov/oc/combination.
With the eventual realization that many biological products were being used as therapeutics similar to other drugs approved by CDER, in October 2003 certain product review responsibilities were redelegated between CDER and CBER. Many biological therapeutic products were therefore transferred to CDER for review, even though they are still regulated as biological drugs. See HHS, FDA, Regulations; Drug and Biological Product Combination, Notice, 68 Fed. Reg. 38067 (2003). The review and approval of biologics such as monoclonal antibodies, cytokines and growth factors now fall within CDER, although vaccines, blood cells, tissues, gene therapy, and related products still are handled by CBER. See, e.g., Transfer of Therapeutic Products to the Center Evaluation and Research, at http://www.fda.gov/CBER/transfer/transfer.htm.
The use of transgenic plants and animals to manufacture pharmaceuticals has been addressed by FDA and other federal agencies in a number of contexts (see below). For example, CBER has developed a guideline pertaining to the use of such animals to produce human biological drugs. See Guidance for the Manufacturing and Testing of Therapeutic Products for Human Use Derived From Transgenic Animals (1995), available at http://www.fda.gov/CBER/ptc/ptc_tga.pxt. See also Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals (Sept. 2002), available at www.fda.gov/cber/gdlns/bioplant.pdf.
The use of food plants and animals to produce pharma products and industrial chemicals has been especially controversial because of the fear that such organisms can end up in the food supply (see CFSAN and BRS discussions in this Part III).
Another very controversial area particular to biologics is the ability of FDA from either a procedural or scientific standpoint to approve so-called “generics” or other versions of previously approved biologics. This subject has become relevant because many blockbuster biologics are now coming off patent. Primary among the difficulties is that the applicable law, section 351 of the Public Health Service Act, does not contain provisions that explicitly allow generics as the FFDCA does for most other drugs. Recent attempts to remedy this situation legislatively have not been successful for a variety of reasons.
Moreover, many scientific issues have been raised about whether biologics, which typically are complex proteins, can be produced in a duplicate manner similar to conventional so-called small molecule drugs subject to the FFDCA. Questions of substitutability and, moreover, of performance compared to the innovator have been the subject of extreme debate. The recent approval by FDA of a section 505(b)(2) application for a follow-on version of human growth hormone has fueled speculation about the ability of FDA to approve so-called “generic” biologics. For a discussion of some of the issues see Public Workshop: Scientific Considerations Related to Developing Follow-On Protein Products, Sept. 14-15, 2004 at http://www.fda.gov/cder/meeting/followOn/followOnPresentations.htm. See also Edward L. Korwek, Towards Understanding the “Generic” Debate about Biologics, J. Biolaw & Bus., Vol. 7, No. 4, 2004.
Another very hot topic area relating to biologics involves the development of new medicines tailored to a person’s genetic make-up, sometimes called personalized medicine (PM) or pharmacogenomics. Key to the development of PM, which has the ability to target medicines to those who presumably would benefit the most, is the development of biomarkers in the context of diagnostics. FDA has developed a table dedicated to biomarkers entitled Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels, available at www.fda.gov/cder/genomics/genomic_biomarkers_table.htm. In addition to publishing a relevant guidance, including one on pharmacogenomics data submissions, the agency has also developed a website dedicated to genomics. See Genomics at FDA, available at http://www.fda.gov/cder/genomics/default.htm. The importance of PM has also been recognized as part of the agency’s Critical Path to New Medical Products, available at www.fda.gov/oc/initiatives/criticalpath/ and Challenge and Opportunity in the Critical Path to New Medical Products (Mar. 2004) available at www.fda.gov/oc/initiatives/criticalpath/whitepaper.html.
A historically difficult area originally involving growth hormone or insulin products and biological drugs, all of which can have complex protein structures, relates to the market exclusivity provision of the Orphan Drug Act, which pertains to drugs for rare diseases or conditions. The exclusivity provision specifies that the same drug cannot be approved for the same orphan use until the expiration of seven years from the date of approval of the first drug. The question of what constitutes the “same” drug for purposes of the orphan exclusivity provision was unclear for quite a while until the topic was clarified by regulations in late 1992. See 21 CFR Part 316.
For a discussion of the early confusion regarding the standards for orphan exclusivity, see Edward L. Korwek, Orphan Drug Trials and Tribulations: Profitability, Patient Ceiling, Market Exclusivity, AIDS, and Biotechnology, 3 Reg. Affairs 133 (1991). For an early case on orphan drug exclusivity, see Genentech v. Bowen, 6786 F. Supp. 01 (D.D.C. 1987). Other orphan drug exclusivity cases include Berlex Lab, Inc. v. Food and Drug Administration, 42 F. Supp. 19 (D.D.C. 1996).
Suffice it to say, the scope of the orphan drug market exclusivity provision as it applies to complex biological products such as monoclonal antibodies and vaccines is still complex and challenging. See, e.g., HHS, FDA, Draft Guidance for Industry: Interpreting Sameness in Monoclonal Antibody Products Under the Orphan Drug Regulations, Availability; Notice, 64 Fed. Reg. 40381 (1999).
The current orphan exclusivity standards for “sameness” of macromolecules involve a mix of chemical and clinical-based tests that can differ in terms of application depending upon whether the drugs are proteins, polysaccharides, polynucleotides, or are complex, partly definable. See 21 CFR § 316.3(b)(13). Similar standards exist for “orphan” veterinary drugs that are for minor uses or minor species. See 21 CFR § 516.3(b).
Generally, in vitro diagnostic tests for AIDS or any other disease or condition are medical devices. AIDS kits for screening or confirming HIV infection associated with blood banking operations, however, are licensed under the PHS Act as biological devices. Intercenter Agreement Between the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health pt. IV (1991). Other tests intended for use in the detection of HIV and not associated with blood banking practices are regulated by CBER as biological devices. Consequently, such products are subject to medical device requirements but are reviewed and approved by CBER.
One of the significant roles that CBER continues to play in the AIDS testing area pertains to the approval of tests that are not intended to ensure the safety of the blood supply. These include tests intended to assess the genotype and/or phenotype of HIV viruses isolated from patients to determine potential drug resistance aid in directing appropriate therapy. CBER also regulates home test kits designed to detect the presence of HIV infection and home specimen collection kits. Both of these can involve nonblood samples, such as urine and saliva.
