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IN OUR JUNE 2005 “FDA WATCH” column, we provided an overview of the regulatory, political, and scientific landscape for follow-on biological products in the U.S. As reported a year ago, the biogenerics debate centers around whether generic biologics are scientifically possible (i.e. can biologics be replicated in a manner that ensures their efficacy and safety?) and whether the current legal and statutory framework supports a regulatory pathway for the Food and Drug Administration (FDA) to approve a follow-on protein. The past year has not brought any clear resolution to these two fundamental issues. However, events form the past year have placed additional pressures on the FDA to advance the state of affairs. These pressures include the successful development of a biosimilar approval process in the European Union (EU), an approval by the EU of a follow-on biological, and an order from a U.S. federal court calling for action on a generic biological product application pending before FDA, as well as statements and actions by members of Congress to advance this issue. EU Advancements on Biosimilar Protein Products While FDA has not provided any additional direction for follow-on biologics in the past year, other countries, most notably the EU, have developed follow-on biological approval mechanisms.

Since May 2004, the EU has worked to establish a science-based procedure for supervising and authorizing the regulatory approval of generic biological products. During that time, the European Agency for the Evaluation of Medicinal Products (EMEA) has produced several final guidelines, draft guidelines, and concept papers regarding the comparability of biosimilar products. The EMEA’s work in developing these regulatory and scientific guidance documents has enabled the EU to be the first major governmental body to authorize a biosimilar product. Under the guidelines developed by EMEA, manufacturers may rely on the marketing authorization granted to a therapeutic protein when preparing a dossier for a biosimilar protein product. However, the guidelines establish that the manufacturer must adequately substantiate the quality, safety, and efficacy of the biosimilar product; these elements constitute the three main sections of any new drug application needed for product authorization in the EU. Each of these sections of the dossier must rely on the same innovator product. While the quality assessment for a biosimilar product is a comprehensive comparison against the innovator product, the application may be abbreviated in that the sponsor may not be required to repeat all efficacy and safety studies.
 
The applicant will not be required to repeat these investigations if the physicochemical and in vitro characteristics of the two products can be adequately evaluated. In addition, the biosimilar product sponsor must demonstrate chemical comparability between the two products, apotentially difficult task depending on the innovator protein’s complexity and other product or manufacturing attributes. In fact, the EMEA guidelines 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. Where chemical comparability is not or cannot be demonstrated, a full complement of clinical and preclinical data will be necessary to support the dossier for the follow-on therapeutic product. While the EU guidelines may be difficult to satisfy, particularly for more complex therapies, they nevertheless provide sponsors with the opportunity for obtaining regulatory approval of a biosimilar therapeutic protein through an established regulatory framework. Recently, the European
Commission, acting on a recommendation by the EMEA Committee on Medicinal Products for Human Use (CHMP) and following the established guidance documents, granted its first marketing authorization for a follow-on biologic in April 2006 to Sandoz’s generic human growth hormone, Omnitrope. Omnitrope is a follow-on version of Pfizer’s Genotropin (somatropin recombinant).
CHMP recommended that Omnitrope be authorized in the EU as an injectable therapeutic protein intended to treat growth disturbance and growth hormone deficiency, based on its finding that the information and studies submitted by Sandoz had shown Omnitrope to have a comparable quality, afety, and efficacy profile to Genotropin. Concluding that there was a favorable benefit to risk balance for Omnitrope, CHMP recommended the grant of marketing authorization.

As was expected, the European Commission adopted the CHMP position within 90 days of the recommendation being made. CHMP has further recommended that the Commission approve a generic form of a second recombinant growth hormone, Valtropin, which is BioPartner’s follow-on version of Lilly’s Humatrope (somatropin [rDNA origin] for injection). Commission action on that recommendation is considered imminent. [Shortly before press time, Valtropin was approved by the Commission. -- ed.]
According to Sandoz, the company expects to begin marketing the biogeneric product in the EU soon. The first markets for the product will be Germany and Austria, following negotiations with government health authorities regarding pricing and other regulatory matters. The biosimilar Omnitrope was previously authorized and is currently available in Australia, where the Therapeutic Goods Administration approved the product in September of 2004 for treatment of growth disorders in children.

The product launched there in November 2005. FDA Ordered to Act on Omnitrope Application As Omnitrope’s market entry in Austria and Germany draws nearer, even the possibility of the follow-on Omnitrope product in the U.S. remains mired in FDA inaction. However, the pressure faced by FDA to make a decision regarding Omnitrope has been ratcheted up, most recently by from the judicial branch, stemming from litigation regarding the Agency’s lack of action on Sandoz’s pending U.S. application. Sandoz originally filed, and the Agency accepted for filing, a new drug application (NDA) for Omnitrope in July 2003. The NDA was submitted following considerable discussions with the Agency and contained preclinical, clinical, and comparability data, as well as literature references and reference to FDA’s decision on Pfizer’s Genotropin. In August 2004, FDA notified Sandoz that the Agency had completed its review of Omnitrope but that because of the application’s “nature and complexity,” FDA would defer its decision on whether the data submitted were adequate to support a conclusion that Omnitrope is safe and effective for the proposed indications. Following inaction on the application by FDA, Sandoz filed suit against the Agency in September 2005 in the U.S. District Court in Washington, D.C., demanding action on the pending application according to the requirements established under the Prescription Drug User Fee Act of 1992 (PDUFA). Sandoz claimed that FDA’s delay in acting within 180 days of submission of the application violated the Agency’s obligations to render product approval decisions under PDUFA. On April 10, 2006, the District Court agreed and granted Sandoz summary judgment in the matter. The District Court ordered FDA to comply with its statutory obligations to act on the application. However, as the Court noted in its opinion, this does not necessarily mean FDA must make a final decision regarding Omnitrope. FDA may opt to provide Sandoz with an opportunity for a hearing on the question of whether the application is approvable. By statute, the hearing must be conducted on an expedited basis.

Demands from Capital Hill

In addition to the international and judicial pressures, FDA has also been confronted with demands from the U.S. Congress to resolve the generic biological products issues. In early 2006, following the CHMP recommendations on Omnitrope and Valtropin, Senator Orrin Hatch (R-UT) and Representative Henry Waxman (D-CA) sent a letter to acting FDA Commissioner Andrew von Eschenbach urging FDA to issue guidance documents for follow-on insulin and human growth hormone (HGH) products. According to FDA, the Agency has had a draft of the guidance documents in final or near final form for some time. Focusing on the need to rein in increasing healthcare expenditures, the two Congressmen have repeatedly urged FDA to establish a regulatory pathway for follow-on biologics. The Congressmen’s letter explicitly reminded the Agency that, on numerous occasions, FDA officials have assured Congress and the public that the Agency was diligently considering the issues necessary to develop a regulatory mechanism for approving generic biological products.

The letter insisted that FDA “clarify” what data the Agency requires from a manufacturer seeking to market a generic insulin or HGH product and 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, “There is simply no excuse—scientific, legal, or otherwise—for FDA to continue to delay the release of these guidance documents.” According to the letter, the guidance documents have been drafted since 2002. Congress is not likely to wait indefinitely for FDA to establish a regulatory pathway. Indeed, Rep. Waxman is expected to introduce a bipartisan bill later this year that would establish a regulatory pathway for the approval of generic biologic products.

While speaking at a recent meeting of the Generic Pharmaceuticals Association (GPhA), Rep. Waxman stated that he believed generics should be allowed to enter the market to provide competition when a biologic’s patents expire, echoing his sentiments regarding generic drugs made over two decades ago in the context of the Hatch-Waxman Act.
Looking Ahead Over the past year, a number of events have placed increased pressure on the FDA to make substantive progress on developing a mechanism for reviewing and approving follow-on biologics: the development of a regulatory pathway in Europe; the authorization of a biosimilar product by the European Union; judicial intervention; and Congress sending signals
regarding its intent to take direct action if FDA does not act imminently. The momentum is clearly building toward some regulatory movement on the generic biologics issue. FDA may seek to relieve some of this pressure through some incremental action, such as development of a regulatory pathway for a certain class of biologics, like insulin products or human growth hormone products. Alternatively, the Agency may take broader action by creating a general pathway for most or all biologic products, but reserving final decisions on a specific pathway based on a product-by-product determination. The one certainty in all of this is that FDA will be taking some action on the issue of generic biologics in the not-too-distant future.

 

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