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Debates about science, manufacturing, and European regulations will shape the approval process for follow-on biologics in the United States.
Biopharmaceuticals represent a growing proportion of medicines in development and of prescription-drug sales. As economic conditions force patients and benefits providers to reduce their expenses, calls for generic versions of biological therapies are getting louder. But before the US Food and Drug Administration can establish an approval pathway, it must confer with innovator companies and follow-on manufacturers to define how similar follow-on drugs must be to innovator products, improve control of the manufacturing process, manage end-product variability, determine the extent of clinical trials necessary for the approval of a follow-on biologic, and establish patent protection for innovators.
Eukaryotic cells are typical expression systems for therapeutic proteins, including follow-on biologics.
What's in a name?
Industry professionals use various words to refer to generic versions of biologicals, and each word means different things to different people. For a discussion about follow-on biologics to be coherent, the parties must agree on the terms that they will use. FDA defines a generic drug as "a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use" (1). Follow-on biologics that receive European regulatory approval meet all of these criteria and thus, by this definition, could be considered true generics, says Islah Ahmed, medical director in global medical affairs at Hospira (Lake Forest, IL).
Most manufacturers disagree with this interpretation, however. Follow-on biologics cannot be expected to be identical to innovators' molecules because of the products' complex structure and because biopharmaceuticals are sensitive to the manufacturing process, which influences product heterogeneity, says Gillian Cannon, commercial lead at Merck BioVentures (Whitehouse Station, NJ).
HeLa cells, which are used for research purposes, are heterogeneous and difficult to characterize.
Some regulators agree that follow-on biologics cannot be considered generic drugs. "With current methodologies for physicochemical and biological characterization, it is not possible to exclude minute differences that would be undetectable but nevertheless relevant," says Christian Schneider, chairman of the European Medicines Agency's (EMEA) working party on similar biological medicinal products.
Because of living cells' sensitivity and the limitations of manufacturing and characterization technology, the best a follow-on manufacturer can achieve might be a product that is similar to, not identical to, an innovator drug. Hence, the term "biosimilar" was created to distinguish follow-on biologics from generic drugs. The World Health Organization defines a biosimilar as "a biological product used in medicine that would be similar to and would enter the market subsequent to an approved innovator biological through a specific regulatory pathway" (2).
Even before the biopharmaceutical industry was actively pursuing follow-on biologics, manufacturers and regulators needed to be able to compare biologics produced by different manufacturing processes. Before an innovator company could change its manufacturing process (e.g., to scale up production or improve efficiency), FDA required assurance that the modifications would not adversely affect product quality, safety, or efficacy. Without this assurance, a manufacturer would have to undertake a completely new development program that resulted in a second product.
In 1996, the agency published a guidance about the concept of comparability. This guidance required that products' quality attributes after a process change be "highly similar" to the attributes the product had as a result of the original process. The agency also called for process understanding sufficient to predict that differences in quality attributes would not decrease the product's safety or efficacy.
Manufacturers were expected to negotiate which criteria and operating ranges they would measure before and after a process change to establish the comparability of the pre-and postchange products. Comparability could generally be established through analytical testing and biological assays, according to the guidance, but nonclinical and clinical data would be required in some instances (3).
One could argue that any biopharmaceutical for which a manufacturing-process change has been approved using comparability can be the reference for a follow-on biologic because its quality characteristics and process criteria are well defined and testing can demonstrate product similarity. Indeed, the knowledge gained by evaluating comparability and approving process changes has influenced Europe's procedure for approving follow-on biologics considerably, says Schneider.
Although European regulators apply similar principles to innovators' process changes and approving follow-on biologics, one important difference stands out. Throughout the development phase, an innovator accumulates a history of its product, its manufacturing process, and the drug's clinical performance. In contrast, the maker of a follow-on biologic must reverse-engineer the innovator's manufacturing process and establish its own data history. It cannot compare its product with the innovator's at each step of development; it can only compare the two end products.
Many innovator companies and follow-on manufacturers agree that human clinical trials should be a requirement for the regulatory approval of biosimilars. Differences in cell lines and manufacturing processes, and biological drugs' inherent heterogeneity, are grounds for considering a follow-on biologic as a different product from the original drug. Clinical testing must include a robust evaluation of safety, confirm efficacy, and be carried out in the appropriate patient population, says Gail Wasserman, senior vice-president of development at MedImmune (Gaithersburg, MD).
When an innovator seeks approval for a process change, it is not necessarily required to perform clinical trials if analytical testing can establish the similarity of the pre-and postchange versions of its drug. Yet innovators argue that the standards should be different for a follow-on biologic because it is produced with different raw materials through a different process. A follow-on manufacturer does not have the innovator's historical and clinical data, they argue, and must develop its own.
Although sophisticated analytical techniques have emerged, they cannot fully characterize protein drugs' complex structure. The industry does not yet have the understanding to relate the analytical testing alone to clinical performance, says Wasserman. A minor change in a biological drug's structure could have significant clinical consequences, thus clinical testing should be required.
In addition, analytical testing cannot easily predict immunogenicity, says Jeffrey R. Mazzeo, biopharmaceutical business director at Waters (Milford, MA). For example, characterization methods can measure protein aggregation, but scientists cannot be sure whether aggregates will cause an immune response in the body. Nor can they predict whether aggregation will occur after an injection is administered. Although analytical testing can detect contaminants, it cannot readily identify and quantitate individual host-cell proteins, which could potentially be immunogenic, says Mazzeo.
For these reasons, the most definitive way to establish a biosimilar's safety, efficacy, and comparability to a reference drug is through clinical testing in humans. "Given where we are with testing today, there's no way around it," says Mazzeo. "They're going to have to do a head-to-head trial against the innovator product and demonstrate that the safety profile and the efficacy are the same."
The Biotechnology Industry Organization (BIO) asserts that Johnson & Johnson's (New Brunswick, NJ) experience with its Eprex drug demonstrates the need for clinical testing during the approval process for follow-on biologics. In 1998, the European health authorities asked the company to stop using human serum albumin (HSA) as a stabilizer for Eprex, which had been marketed for 10 years with no reports of immunogenicity problems. The company replaced HSA with polysorbate 80, which caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers into the drug. The plasticizers stimulated an immune response that resulted in pure red-cell aplasia, a severe form of anemia (4).
"The Eprex case shows that one protein can be different from another in ways that cannot be detected in the laboratory but are seen only by the body's exquisitely sensitive immune system," says a statement on BIO's website. "If one change to a well-established complex manufacturing process, made by the manufacturer who has intimate knowledge of the process, can cause a problem with immunogenicity, surely the risk is even greater with an entirely new manufacturer and process—as will be the case with follow-on biologics" (5).
Although innovators and makers of follow-on biologics generally agree about the need for clinical testing, they disagree about the extent of testing that should be required. Follow-on manufacturers argue for a limited amount of clinical studies, but many innovators assert that full clinical-trial programs should be mandated because the drugs' inherent variability means that follow-ons must be considered new products, according to Mazzeo.
Yet some industry professionals are not convinced that clinical trials should be required for the approval of follow-on biologics. They argue that manufacturers of these drugs should not be held to higher standards than are innovator companies. Given that complicated biological drugs such as the influenza vaccine are approved every year in the US under the Public Health Service Act without clinical trials, they argue that requiring clinical trials for follow-on biologics would be unnecessarily burdensome to follow-on makers (6).
At most, some argue, the requirements for approving follow-on biologics should be the same as those for approving new biologics. The comparability standard that innovators meet to obtain approval for manufacturing-process changes could be applied to follow-on biologics. The standard has already been used to approve processes as different as a follow-on manufacturer's would likely be.
One example involves Biogen Idec's Avonex multiple-sclerosis treatment. A joint venture between Rentschler Technology (Laupheim, Germany) and Biogen Idec developed BG9015, a beta-interferon product, and tested it in clinical trials. After the joint venture failed, Biogen Idec developed the cell line for Avonex, also a beta interferon, and created a manufacturing process for the biological at a new facility in a different country. Biogen Idec submitted Avonex for FDA approval, relying on the clinical studies of BG9015. FDA approved the product after determining that Avonex was comparable with BG9015 on the basis of biological, biochemical, and biophysical analyses and pharmacokinetic studies in humans (7).
Because BG9015 was produced by a joint venture, Biogen Idec had access to manufacturing information and important intermediates required to make the product. The maker of a follow-on biologic, however, would seek to compete with the innovator and would not have this advantage (8).
The European approach
Many American makers of biologic drugs view the European approach to approving follow-on drugs favorably. To date, EMEA has approved 13 follow-on biologics, or about 67% of all applications (9). The European path is reasoned, scientifically balanced, and would be a good basis for an American approval process, says Jim Green, senior vice-president of preclinical and clinical development sciences at Biogen Idec (Cambridge, MA). Indeed, FDA and EMEA have included follow-on biologics on the agenda for upcoming joint discussions.
EMEA developed guidelines about quality, nonclinical considerations, and clinical considerations for biologicals. The agency also published guidances for particular classes and products. Product-specific guidances describe specific proteins such as insulin, growth hormone, and erythropoietin. These proteins are relatively small and easy to characterize.
Makers of follow-on biologics must demonstrate to EMEA that their products have comparable biophysical and chemical characteristics to the reference products, says Ahmed. To do this, an applicant must compile a data set (i.e., a full quality dossier) by characterizing its product (e.g., performing biochemical analysis and bioactivity analysis) at each stage of production and comparing it with the innovator product.
EMEA usually evaluates bioequivalence with a case-by-case approach, rather than according to a standard. This method provides regulatory flexibility because the drugs' inherent variability and the lack of alternative therapies sometimes persuade regulators to accept wide margins of equivalence, says Schneider. But margins should be justified adequately during discussions between applicants and regulators, he adds.
Acceptable differences between drugs depend on the inherent risk that the bio-similar poses. "Biosimilars that simulate an endogenous protein, such as erythropoietins, are usually perceived as higher-risk biosimilars, thus reducing the regulatory tolerance to differences in side effects or immunogenicity," Schneider says.
In addition to analytical testing, nonclinical and clinical data are usually required, says Schneider. The guidance documents list the standards for clinical-trial requirements for various classes and products. These requirements vary, however, according to the product and the availability of acute and reproducible characterization methods. Other factors that affect clinical-trial requirements include the drug's molecular complexity, therapeutic window, safety profile, and indications. Overall, European clinical requirements for follow-on biologicals are usually much less onerous than for new biologicals, says Schneider.
EMEA also requires postapproval monitoring for follow-on biologicals that are administered for long periods. This requirement is intended to provide additional confirmation that the follow-on's safety and immunogenicity profiles are similar to those of the reference product. "I think that's important to maintain within the context of a US approval system," says Green.
The American way
The Public Health Service Act provides a framework for the approval of innovative biological drugs, but no US law explicitly enables FDA to approve follow-on biopharmaceuticals. The Hatch–Waxman Act of 1984 established an abbreviated pathway for the approval of small-molecule generic drugs, and regulators have used it to approve follow-on versions of small protein drugs that are well understood (e.g., human growth hormone and insulin). Larger proteins such as antibodies are more complex and seem to require an entirely new approach. In March 2009, legislators introduced two bills to Congress that would provide a method for FDA to evaluate and approve follow-on biologics.
The Waxman bill. Rep. Henry Waxman (D-CA) introduced the first of the two bills, "Promoting Innovation and Access to Life-Saving Medicine Act." This bill is similar to the Hatch–Waxman Act in many ways. The Waxman bill would not require new clinical trials for follow-on biologics. Instead, an applicant could use the innovator's safety and efficacy data as long as these data showed that the follow-on product and the reference product had highly similar molecular structures; that the follow-on would not exhibit clinically meaningful differences in safety, purity, and potency with the reference product; that the follow-on and the reference product had the same mechanism of action; and that the follow-on and the reference biologic product had the same use, method of administration, dosage, and strength.
The Waxman bill would also allow FDA to determine that an approved follow-on biologic was interchangeable with its reference drug. This designation would let pharmacists substitute a follow-on for a branded biological as long as the prescription did not forbid it.
Finally, the Waxman bill also grants patent protection for innovators' biologic drugs. New biopharmaceutical products would receive five years of exclusivity, and products with new indications would receive three years of protection. If a manufacturer undertook pediatric studies of its drug, the bill would grant the company six additional months of exclusivity (10).
The Eshoo bill. Less than a week after the Waxman bill was introduced, Rep. Anna Eshoo (D-CA) introduced the "Pathway for Biosimilars Act." The Eshoo bill would require the maker of a follow-on biologic to submit data from clinical trials that compared the product's immunogenicity with that of the innovator's product. FDA could only waive the requirement for clinical trials after it published a guidance that described what data would justify a determination about the immunogenicity of a follow-on product in a particular class (11).
Unlike the Waxman bill, the Eshoo bill would only allow FDA to determine that a follow-on product was interchangeable with an innovative biological after the agency published a final guidance that described what data would justify a determination of interchangeability.
The Eshoo bill would grant more patent protection for innovators' products than would the Waxman bill. New biopharmaceuticals would receive 12 years of market exclusivity under the Eshoo bill. If a new indication were approved for an existing biological within eight years of the product's approval, the product would receive 14 years of exclusivity. Like the Waxman bill, the Eshoo bill would grant six additional months of exclusivity to innovators that undertook pediatric studies of a biopharmaceutical (11).
Reactions to the bills
The Waxman bill enjoys the support of the Generic Pharmaceutical Association. It would enable FDA to take a case-by-case approach to approving these therapies. "We're interested in flexibility for good science rather than in a rigid, predetermined structure," says Marc Goshko, executive director of legal affairs at Teva Pharmaceuticals (North Wales, PA).
BIO supports the Eshoo bill. Merck recognizes the need for an abbreviated approval pathway for follow-on biologics. "There still remains a need for clinical studies to demonstrate safety, efficacy, and lack of deleterious immunogenicity for bio-similar products," says Cannon.
As science and manufacturing technologies improve, biopharmaceuticals will become easier to produce. An approval process for follow-on biologics in the US would help improve patients' health and make needed medicines more affordable. In the absence of international standards for follow-on biologics approval, Congress must create a regulatory pathway through legislation. At a minimum, an approval mechanism must ensure that follow-on products react in the human body the same way as their respective reference products, says Bill Haddad, CEO of Biogenerics (Brewster, NY). A pathway should also provide patent protection for innovators' products and allow patents to be challenged.
Despite ongoing debate, some believe that an approval pathway could be established soon. "It took us 35 years to reach Hatch–Waxman from the early efforts of Senator Estes Kefauver," says Haddad. "It won't take us that long to get a fair and equitable biotech law. When the dust settles, as it did following Hatch–Waxman, we will look back and wonder, 'What in the hell was all the fuss about?'"
1. FDA, "Generic Drugs: Questions and Answers," www.fda.gov/cder/consumerinfo/generics_q&a.htm, accessed Apr. 27, 2009.
2. World Health Organization, "WHO Informal Consultation on International Nonproprietary Names (INN): Policy for Biosimilar Products," www.who.int/entity/medicines/services/inn/BiosimilarsINN_Report.pdf, accessed Apr. 27, 2009
3. FDA, Guidance for Industry: Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (Rockville, MD, June 2005) www.fda.gov/CbER/gdlns/ichcompbio.htm, accessed Apr. 30, 2009
4. D. McCormick, "Small Changes, Big Effects in Biological Manufacturing," Pharm. Technol. 28 (11), 16 (2004).
5. Biotechnology Industry Organization, "Why is Patient Safety a Concern in the Biosimilars Debate?" www.bio.org/healthcare/followonbkg/PatientSafety.asp, accessed May 4, 2009
6. Code of Federal Regulations, Title 42, The Public Health and Welfare (General Services Administration, Washington, DC, 2003), sec. 262, www.fda.gov/opacom/laws/phsvcact/sec262.htm, accessed May 4, 2009.
7. Berlex v. FDA et al., US District Court for the District of Columbia, Oct. 7, 1996, www.fda.gov/ohrms/dockets/dailys/04/mar04/031904/80n-0208-ref0001-19-Tab-11-vol126.pdf, accessed May 15, 2009.
8. C. Webster et al., "Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products?" Biopharm. Int. 16 (7), 28–37 (2003).
9. G. Perry, "Biosimilar Medicines: Towards Global Development and Monoclonal Antibodies," presented at the 7th EGA Annual Symposium on Biosimilar Medicines, London, Apr. 2009.
10. H.R.1427, "Promoting Innovation and Access to Life-Saving Medicine Act," US House, 111th Congress, 1st Session (Washington, DC), Mar. 11, 2009, http://thomas.loc.gov/cgi-bin/query/F?c111:1:./temp/~c111RCfWrl:e0:, accessed May 5, 2009.
11. H.R.1548, "Pathway for Biosimilars Act," US House, 111th Congress, 1st Session (Washington, DC), Mar. 17, 2009, http://thomas.loc.gov/cgi-bin/query/F?c111:1:./temp/~c111S3Mkrr:e0:, accessed May 5, 2009.