42 BioExecutive International MAY 2006

T hroughout the world, the pharmaceutical regulatory review and approval processes in the United States are

well known and venerated. But is the country lagging in its development of a mechanism for approving generic biological products? Or, is the United States appropriately moving with caution out of deference to the compli-cated legal and scientific issues raised by follow-on biologics?

The European commission, acting on a recommendation by the European Medicines Agency (EMEA) Advisory Committee on Medicinal Products for Human Use (CHMP) recently granted its first marketing authorization for a follow-on biologic. Sandoz’s generic human growth hormone Omnitrope was approved in mid-April and repre-sents the first biosimilar product to be marketed in the European Unin (EU). Omnitrope is a follow-on version of Pfizer’s Genotropin (somatropin recombinant). The CHMP has also recommended that regulators approve generic forms of two recombinant growth hormones, paving the way for the first European approvals of biosimilar biological products. The two products—Sandoz’s generic human growth hormone Omnitrope, a version of Pfizer’s Genotropin (somatropin recombinant), and BioPartner’s generic growth hormone Valtropin, which is BioPartner’s follow-on version of Lilly’s Humatrope (somatropin [rDNA origin] for injection)—represent the first application of the European

Union’s new approval process for “biosimilar” products. In addition, other countries have already approved generic biological products and those products have entered their local mar-kets. Sandoz’s Omnitrope in Australia was authorized by the Therapeutic Goods Administration in September of 2004 for treatment of growth dis-orders in children, and launched in November 2005. PLIVA’s erythropoietin (EPO) biogeneric was approved by the Croatian Agency for Medicinal Products and Medical Devices in June 2005. PLIVA’s product is a generic version of Janssen-Cilag’s Eprex (epoetin-alfa), primarily indicated for the stimulation of red blood cell pro-duction in patients undergoing dialysis therapy for chronic renal failure and patients undergoing chemotherapy treatment. In anticipation of further marketing authorizations, PLIVA has entered business deals with Barr Laboratories and Mayne Pharma of Australia to facilitate pursuit of EU and U.S. approval.

Meanwhile, in the United States, the potential for any such follow-on biologic approval is at a standstill. The products contemplated by Sandoz, BioPartner, and PLIVA face a novel situation for a therapeutic product in the United States: no viable approval pathway accepted by the U.S. Food and Drug Administration (FDA). The FDA names two fundamental barriers to an approval pathway in the United States. First, does the FDA currently have the statutory authority to approve follow-on biological products? Second,

PUBLIC SCIENCE POLICY

Follow-On Biologics: The Evolving Regulatory Landscapeby Gary C. Messplay, J.D. and Colleen Heisey, J.D.

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The pharmaceutical industry questions

answered by Hatch-Waxman in the 1980s

have arisen all over again for biopharma.

Why is the United States behind the

rest of the world in approving generic

biopharmaceuticals?

even if it does have such authority, has science advanced sufficiently to determine whether a follow-on biologic is substantially equivalent to an innovator’s product? Until those legal and scientific issues are resolved, follow-on biologic products will not be a reality in the United States.

AMERICAN HISTORY

The generic pharmaceutical industry faced a similar issue some twenty years ago. In the 1980s, there were intense policy and legislative debates regarding generic drugs. The debates focused on the need to balance accessibility to affordable drugs while maintaining a system that rewarded innovation and provided a means for drug companies to invest in more research and development of novel thera-peutic products. Creating a legal and regulatory system to accommodate that balance was an enormous political and legal challenge. The outcome was enactment of the Drug Price Competition and Patent Term Restoration Act of 1984 (referred to as the “Hatch-Waxman” Act), which amended the Federal Food, Drug, and Cosmetic Act (FDCA) to address the patent and regulatory approval process for generic drugs.

Under the Hatch-Waxman Act, Congress set out to establish a reasonable system by which to speed generic versions of off-patent pharmaceuticals to market. Specifically, the Act created a mechanism by which a generic drug could gain regulatory approval without a full complement of clinical trials demonstrating safety and efficacy if the generic product could meet a “sameness” standard when compared against the innovator drug.

The debate hosted in the development of Hatch-Waxman resurfaced in the context of follow-on biologics. In 2004, Congressional interest turned to follow-on biologics as the Senate Judiciary Committee convened meetings on the topic to “explore some of the key issues concerning the legality, feasibility and advisability of creating a new, abbre-viated regulatory pathway at the [FDA] for the review and approval of off-patent biological products.” Echoing senti-ments emanating from Hatch-Waxman, federal lawmakers again suggested that legislation may be necessary to achieve a fair balance between incentives and interests in the biopharmaceutical industry.

DRUGS VERSUS BIOLOGICS

A principal issue in the debate over follow-on biologics is whether potential follow-on manufacturers can adequately characterize a protein product given currently available technologies. Innovator companies question whether chemical characterization of active ingredients can be adequate to assure “sameness” of the biological activity and safety. The inquiry emanates from the nature of biological products and biotechnology products as distinguished from traditional drug products.

Biologics differ significantly from traditional drugs in their size, complexity, structure, and method of manu-facture. Drug products consist of small molecules, on the order of dozens of atoms synthesized from defined com-ponents according to a prescribed production method in an environment of manufacturing processes and controls.

Biological products are much larger than drugs, made up of millions of atoms, and are manufactured from living cells through an elaborate process initiated by specifically programming a cell line to produce a certain protein in a highly controlled, sterile manufacturing environment.

Biologics consist of a complex mixture of three-dimen-sional, heterogeneous proteins as well as impurities that will affect the biological activity, efficacy, and safety of the product. The multi-dimensional aspect of biologics makes the inclusion of impurities expected, and a matter the man-ufacturer must address during the manufacturing process. The large structure also means that where contamination occurs, it may be more difficult to detect and nearly impos-sible to remove adventitious agents. Contamination of drugs, on the other hand, is more easily avoidable, detect-able, and often removable.

Immunogenicity is a major topic of debate over follow-on biologics, in part because of the difficulty in detecting small immunogenic differences between biologics. Due to their size and current scientific knowledge, drug products rarely elicit an immune response. In comparison, biolog-ics developed from living cells are capable of interacting with a human body in unforeseeable ways, thereby trig-gering immune responses. Not surprisingly, the major players in biologic product development—the Generic Pharmaceutical Association (GPhA), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the Biotechnology Industry Organization (BIO)—differ in their views on detecting immunogenicity. Respectively, the views range from suggesting that pre-approval testing of follow-on biologics should include identification of the product factors with the greatest risk for immunogenicity to beliefs that immunogenicity testing should be the same for an innovator and follow-on product.

COMPETING ACTS

Aggravating the scientific debate over follow-on biologics is the fact that there are different approval mechanisms in place for drugs and biological products. Currently, there is no agreement as to whether a regulatory pathway exists that would provide for generic approval of a biological product. FDA has asserted that the FDCA governs the approval of drugs and most biological products because the term “drug” is set forth broadly in the Act, defined as “articles intended for use in the diagnosis, cure, mitigation, treat-ment, or prevention of disease ...; and articles (other than food) intended to affect the structure or any function of the body ... .” However, biological products are defined under the Public Health Services Act (PHSA), not the FDCA. Under the PHSA, a “biological product” means “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, ... applicable to the prevention, treatment, or cure of a disease or condition of human beings.” To market a biological product, a manufacturer must obtain a license under the PHSA by demonstrating that the biological prod-uct is “safe, pure, and potent” and that “the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biologi-

44 BioExecutive International MAY 2006

cal product continues to be safe, pure, and potent.”

Under the FDCA, a generic drug manufacturer may submit an abbreviated new drug application (ANDA) for approval to market a generic drug product. The ANDA process is intended to minimize the costs associated with duplicative and costly animal and clinical research on products FDA has already determined to be safe and effective. Approval of a generic drug under FDA regulations is based on a “sameness” standard under 505(j) of the FDCA. A generic drug meets the sameness standard by establishing several criteria: the drug must contain the same active ingredient as the innovator drug; it must have the same strength, dosage form, and route of administration; it must have the same conditions of use; it must be bioequiv-alent; and it must be manufactured according to current good manufacturing practices. No analogous sameness stan-dard exists explicitly under the PHSA.

A generic drug manufacturer may also rely on FDA’s determination of safety and effectiveness of an innovator drug when seeking approval of a drug that is different in certain limited respects from the innovator drug. In such cases, the generic manufacturer must provide additional research and data related to the differences between the innovator and modified drug in an application as described under Section 505(b)(2) of the FDCA. Both an ANDA and a 505(b)(2) application, by definition, rely on an innovator’s intellectual property rights in seeking approval and require the applicant to acknowledge patents listed with the FDA by the innovator at the time of approval. Follow-on biologic proponents often cite the 505(b)(2) process as an adequate regulatory mechanism for approval of a generic biological product.

BIOSIMILARS IN THE EUIn the midst of FDA’s inaction regarding follow-on biologics, other governments, notably the European Union (EU), have moved forward in developing approval mechanisms based on their own scientific justifica-tion. EU has advanced further than the United States in developing and implementing an approval pathway

for follow-on biological products. Indeed, it appears that such an EU approval is imminent. Regulatory and scientific guidance documents developed by the European Agency for the Evaluation of Medicinal Products (EMEA) have helped position the EU as the first major governmental body to authorize a biosimilar prod-uct. In May 2004, the EU established the procedures for authorizing and supervising the regulatory approval of generic biological products. Since that time, the EMEA has produced sev-

eral guidelines, draft guidelines, and concept papers regarding the compara-bility of biosimilar products.

According to European guidelines, manufacturers of a new therapeutic protein product may rely on the marketing authorization of a thera-peutic protein already on the market. However, the manufacturer must substantiate the quality, safety, and efficacy of the product. These three elements represent the main sections of a new drug application necessary for any therapeutic product authorization in the EU. Each section of the dossier must rely on the same innovator product as the relevant reference.

The quality assessment for a biosimilar product must be a com-prehensive comparison against the innovator product. The application may be abbreviated in that the spon-sor may not be required to repeat all efficacy and safety studies if the physi-cochemical and in vitro characteristics of the two products can be evaluated. The biosimilar product sponsor must also demonstrate the two products’ chemical comparability. However, the

EMEA guidelines are quick to point out that there will be some situations in which satisfactory equivalence cannot be demonstrated due to the complexity of the protein’s structure, the manufacturing process, and the effect of product differences on quality, safety, and efficacy. In such situations, a full complement of clinical and pre-clinical data are necessary to support a therapeutic product dossier. Regardless of the practical outcome for an indi-vidual product, the reality of the EU guidelines means there is a potential for regulatory approval of a biosimilar therapeutic protein.

FDA UNDER PRESSURE

As noted above, the United States has been unable to develop a mechanism for approval of follow-on biologics. The pressure being placed on the agency to take action is building, par-ticularly in light of the international movement on biosimilar products. FDA faces pressure to announce a policy on the “approvability” of generic biologics from a number of sources. In early 2006, following the CHMP recommendations on Valtropin and Omnitrope, Senator Orrin Hatch (R-UT) and Representative Henry Waxman (D-CA) sent a letter to act-ing FDA Commissioner Andrew von Eschenbach urging the FDA to issue guidance documents already drafted for follow-on insulin and human growth hormone (HGH) products. The two Congressmen have consis-tently encouraged FDA to establish a regulatory pathway for follow-on biologics, using their positions to urge development of a framework that would allow generic biologics to enter the marketplace and thereby help curb increasing healthcare expenditures.

The letter notes the many occasions FDA officials have assured Congress that the agency was diligently consid-ering the issues necessary to develop a system for approving generic bio-logical products. Despite the agency’s reassurance, Congress has not seen any significant action on the issue. To promote movement at the agency, the lawmakers insisted that FDA “clarify” what data the agency requires from a manufacturer seeking to market a generic insulin or HGH product. The

In the European Union, the quality assessment

for a biosimilar product must be a comprehensive

comparison against the innovator product.

MAY 2006 BioExecutive International 45

Congressmen suggested that the two products could be removed from the currently stalled regulatory framework for all follow-on biologic products because they do not raise the same — scientific and regulatory issues as other, more complex biological products. The letter stated that “[t]here is simply no excuse—scientific, legal, or other-wise—for FDA to continue to delay the release of these guidance documents.”

It also appears that Congress does not intend to wait indefinitely for the FDA to enunciate a regula-tory pathway. While speaking at the annual meeting of the Generic Pharmaceuticals Association (GPhA), Rep. Waxman stated that he would introduce a bipartisan bill in 2006 to establish a regulatory pathway for generic biologic products to provide market competition when a biologic’s patents expire.

In addition, the FDA is currently embroiled in litigation with Sandoz over the non-approval of Omnitrope in the United States, adding pressure to the agency to take action on follow-on biologics. Sandoz originally filed, and the agency accepted for filing, a new drug application (NDA) for Omnitrope in July 2003 after considerable dis-cussions with the agency. The NDA contained preclinical, clinical, and comparability data as well as literature references and reference to FDA’s —decision regarding Pfizer’s Genotropin. FDA notified Sandoz of its inability to reach an approval decision on the company’s application in August 2004 but did not specify why the application could not be approved. Facing a lack of regulatory action, Sandoz filed suit against FDA in September 2005 in U.S. District Court in Washington, D.C. In its lawsuit, Sandoz demanded that the agency rule on its pending application.

On April 10, 2006, the District Court granted summary judgment for Sandoz and ordered FDA to comply with its statutory obligations to act on the application. As the Court notes in its decision, however, this does not mean that FDA must opt to provide Sandoz with an opportunity for a hear-ing on the question of whether the application is approvable. By statute, the hearing must be conducted on an expedited basis.

FDA’s lack of progress on an issue undertaken years ago and for which FDA receives numerous inquiries each year has several groups asking why the agency is unable to develop a regulatory pathway for approval of Sandoz’s Omnitrope and other—similarly situated products. Although there are significant legal, regulatory and scientific issues that FDA could rely on to either support or reject the viability of generic biological products, FDA has instead elected to remain silent. The lack of an articulated opin-ion on these issues in the face of the agency’s development of guidelines was reasonable for a period of time. However, its inaction is becoming increasingly more difficult to defend due to the regulatory and legal prog-ress made in the European Union and other nations.

GATHERING FORCE

In the past several months, a number of events have placed increased pres-sure on the FDA to make significant progress on developing a mechanism for reviewing and approving follow-on biologics: the prospect of biosimilar product authorization by the European Union has gained momentum; the FDA has been sued for its inaction on a biogeneric application; FDA officials increasingly refer to the imminent release of guidance documents that will resolve the situation; and Congress has threatened to take direct action if FDA does not act imminently. These pressures will undoubtedly result in FDA taking some stance on the bio-generic issue in the very near future.

Gary Messplay is a partner in the Washington, D.C. office of Hunton & Williams LLP, where he is head of the law firm’s Food and Drug Practice Group. Colleen Heisey is an attorney in the Firm’s Food and Drug Practice Group.

1 The Law of Biological Medicine: Hearing before the Senate Comm. on the Judiciary, 108th Cong. (2004) (Statement of Sen. Orrin Hatch).

2 21 U.S.C. §321(g)(1).

3 42 U.S.C. §262(i).

4 42 U.S.C. §262(i).

5 Letter from Congressman Waxman to Acting FDA Commissioner von Eschenbach. February 10, 2006. http://www.house.gov/waxman/pdfs/letter_fda_2.10.06.pdf

References