Will the pathway to approval of biosimilars run smoothly?

It has been four years since the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was enacted to create an abbreviated licensure pathway for biological products. Two years ago, FDA issued draft guidance on biosimilar product development. As of July 24, Sandoz became the first to file for approval of a biologic under the biosimilar pathway.

Sandoz announced FDA acceptance of its Biologics License Application for filgrastim, which the company noted as the first step in providing U.S. patients access to affordable, high-quality biologics. The reference product is Amgen’s Neupogen, which is indicated for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppresive anticancer drugs associated with severe neutropenia and fever.

May draft guidance: CDER outline

The most recent guidance discussed some of the overarching concepts related to clinical pharmacology studies for biosimilar products, approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials (see sidebar).

Stephen King, a public affairs specialist with FDA’s Center for Drug Evaluation and Research (CDER), has said that Congress deliberately set a very high bar for approval of biosimilar products, stating that manufacturers must demonstrate that their products are highly similar to and differ in no clinically meaningful way from the reference products in terms of safety, purity, and potency. “In fact, only minor differences in clinically inactive components are allowable in biosimilar products,” he said.

According to CDER, the clinical pharmacology assessment of a proposed biosimilar product is designed to address uncertainty regarding any clinically meaningful difference between the proposed biosimilar product and the reference product.

The evaluation will study potential differences between pharmacokinetic (how, in terms of absorption and distribution, a body affects a specific drug after it is administered) and pharmacodynamic (the biochemical and physiological effects of a drug on the body) measures.

“This draft guidance provides information to help sponsors design clinical pharmacology studies in support of applications submitted under the pathway,” King said.

Does it go far enough?

James Shehan“The new draft guidance is clearer than its predecessor and focuses more on pharmacology,” said James Shehan, counsel, Hyman, Phelps and McNamara PC, a law firm in Washington, D.C. “Although FDA is providing a high level of detail on demonstrating biosimilarity and on how to design appropriate pharmacology studies, it is slow in deciding what it takes to bring a biosimilar to market.”

Shehan notes that while the 2014 guidance expands upon much of what was outlined in 2012, it also repeats much of what was described. In a recent blog post, he criticized FDA for not finalizing 2012 guidance, but instead issuing additional recommendations, and added that the agency has not included what it will issue next pertaining to the biosimilar approval process.

“I support guidance, but it has been four years since the first U.S. statute related to biosimilars, and eight years since Europe brought its first biosimilar to market,” he said.

He also questioned whether the new stepwise process under the new draft guidance might move the date of the first biosimilar approval even further out.

Lawmakers weigh in

In May, four U.S. senators - Lamar Alexander (R-Tenn.), Richard Burr (R-N.C.), Johnny Isakson (R-Ga.) and Orrin Hatch (R-Utah) - expressed their concern over the new draft guidance to FDA Commissioner Margaret Hamburg. The issues they highlighted include lack of differentiation on the FDA website between draft and final guidances, undercutting the importance of public comment; untimely review, finalization or withdrawal of guidance; and guidance that does not seem to take into account recommendations from the scientific community.

Stephen King at CDER said that draft guidance typically leads to final guidance after the FDA reviews and considers all comments submitted to the docket. 

“Because guidances are not regulations or laws, they are not enforceable, either through administrative actions or through the courts,” King said. “An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.” 

Clear definitions needed

Salvatore GiorgianniSal Giorgianni, president and consultant pharmacist, Griffon Consulting Group Inc., in Ft. Myers, Fla., and a member of the Drug Topics editorial advisory board, has said that FDA needs to define “meaningful clinical difference” more clearly. A biosimilar should undergo sufficient rigorous analysis to support its similarity, he said.

Of particular concern to Giorgianni, a strong patient advocate, is the importance of ensuring that physicians understand what drugs are deemed appropriate for prescribing.

According to Giorgianni, the draft guidance provides a vast improvement over earlier guidance in its conceptual framework for the important considerations connected with bringing biosimilars to market and targeting more valuable metrics. He believes, however, that the measures are not tight enough, especially in critical situations with little margin for error, such as cancer treatment.

“The new guidance begins to go down the necessary pathway of moving from concept to qualitative to fundamental quantitative to sophisticated quantitative guidelines for industry,” Giorgianni said.

He emphasized the effect that biosimilars will have upon every aspect of pharmacy education and practice over the decades to come, not to mention their positive impact on patients.  Giorgianni said he is confident that the 2014 draft guidance will not be the end of FDA’s recommendations on biosimilars.

Despite the progress to date, Giorgianni expressed some skepticism over insufficient post-marketing surveillance, real-world exposure, and broadly monitored exposure in varied populations that could lead to unanticipated adverse and salutary effects.

“The assertion that small molecular differences between biosimilar products are inconsequential is simply not yet proven,” he said in a January letter to Commissioner Jon Leibowitz of the Federal Trade Commission.

Vocabulary of guidance

For his part, Shehan noted in his blog that the FDA recommends that “extensive and robust comparative structural and functional studies” precede clinical pharmacology studies - guidance that echoes the 2012 suggestions.

He described FDA’s recommendation that the attributes of the biosimilar and the reference product be compared through use of a “meaningful fingerprint-like, analysis algorithm” intriguing, because although it is quite descriptive, it is unusual for such language to appear in an FDA communication.

According to Shehan, the agency expects that this comparative analytical characterization will lead sponsors to one of four conclusions about their biosimilar products: not similar, similar, highly similar, or highly similar with fingerprint-like similarity. The guidance makes sense, he said, in that it will give drug sponsors an idea of which drugs would gain approval and which ones would require additional clinical studies.

What’s in a name?

In his letter to the FTC, Giorgianni also expressed strong support for the need to name biosimilars and their reference products differently, and for the creation of a new International Nonproprietary Name (INN) for follow-on drugs - a stance to which the Generic Pharmaceutical Association (GPhA) is opposed.

According to GPhA, biosimilars have no clinically meaningful difference from their reference products, so the addition of a new INN makes little sense. The organization filed an official petition last year, stating this position.

The World Trade Organization does not require small molecular generics to adopt a different INN.

Giorgianni believes that unique names given at the onset of a product’s introduction into the marketplace will provide “essential, broad-based, real-life clinical experiences to use in determining whether the hypothesis of biotherapeutic equivalency for a biosimilar is correct or not correct.” Without such a measure, he said, he is worried that valuable information about a biosimilar will be lost forever.

AMCP analyzes ADEs

Last year, the Academy of Managed Care Pharmacy (AMCP) created a Biosimilars Collective Intelligence Task Force to document biosimilar safety and efficacy, deriving its reference points from continuous analysis of available data for innovator specialty drugs.

Mary Jo Carden“The consortium is designed to give us a scientific basis for understanding adverse drug events resulting from biosimilars,” said Mary Jo Carden, senior director of regulatory affairs, AMCP. “We are able to leverage the data of managed care organizations and the 30 million patients they cover.”

“The data will enable us to compare the innovator drug with the biosimilar and discern any negative outcomes,” said Bernadette Eichelberger, AMCP’s director of pharmacy affairs. “When a biosimilar product hits the marketplace, data will provide more assurance to P&T committees of a drug’s efficacy.”

Carden emphasized the research promise that use of biosimilars could realize $250 billion in savings, which in turn could help subsidize the high cost of specialty drugs.

Eichelberger points out, however, that there are too many gray areas in the way the BPCI Act has been structured, necessitating further guidance. “The lack of clarity discourages drug manufacturers from developing biosimilars,” she said.

Giorgianni agreed that lack of clarity in the draft guidance could make manufacturers cautious about continuing to invest in expensive research and development without an understanding of what is necessary.

Some manufacturers might choose to pursue the standard biologics license application (BLA) - a more expensive and lengthy process - if the new pathway remains ambiguous about the studies required for approval. In addition, he said, the BLA affords 12-year patent protection.

Catching up with Europe

The lack of clear direction for manufacturers is one of the reasons the United States has been much slower than Europe in bringing biosimilars to market, said Shehan. He notes that Europe stepped up to the plate more quickly, providing a pathway in 2003. The European Medicines Agency (EMA) approved its first biosimilar in 2006 - Sandoz’s Omnitrope (somatropin), a growth hormone.

As of January 2014, EMA has approved 20 biosimilars within the classes of human growth hormone, granulocyte colon-stimulating factor, erythropoietin, and TNF inhibitor. Two, however, have since been withdrawn.

Although no biosimilars have yet been approved in the United States, King said, CDER continues to meet with sponsors interested in developing biosimilars, but that federal law and regulations prevent the agency from discussing existing or potential drug applications.

Besides the latest draft guidance, new and revised draft guidances planned by CDER for publication in 2014 include additional questions and answers regarding implementation of BPCI; considerations demonstrating interchangeability to a reference product; labeling for biosimilar biological products; and reference product exclusivity for biological products filed under the pathway for biosimilars.

Mari Edlinis a freelance writer in Sonoma, Calif.

Key concepts from the new draft guidance

According to CDER, the draft guidance discusses three key concepts:

1.    Exposure-response assessment. Well-designed clinical studies in a biosimilar development program evaluate the similarities and differences between a proposed biosimilar and a reference product. Evaluating a person’s response when exposed to a biological product helps determine safety, purity, and potency, and may highlight potential differences between two products that are clinically meaningful. With a biological product, to determine the response to exposure is particularly challenging, because the active product is not a single chemical or its active metabolites; instead, it is a mixture of closely related, complex biological substances that make up the active component.

2.    Evaluation of residual uncertainty. While evaluating an application that supports a demonstration of biosimilarity, FDA will use a risk-based approach to consider the data and information submitted as a whole. When evaluating clinical pharmacology, FDA looks closely at pharmacokinetics, pharmacodynamics, and safety data obtained in conjunction with the clinical pharmacology studies. These data should be collected in steps throughout the clinical pharmacology evaluation. FDA will assess the need for additional studies at each step of the evaluation by determining the remaining degree of uncertainty about similarity between the proposed biosimilar product and the reference product.

3.    Assumptions about analytical quality and similarity. During the biosimilarity assessment period, sponsors should conduct structural and functional comparative studies that are extensive and robust, in order to evaluate whether the proposed biosimilar product and the reference product are highly similar. Among other things, a meaningful assessment depends on the capabilities of available state-of-the-art analytical tools to assess the product. The sponsor should describe the capabilities and limitations of the methods used in the analytical assessment. An extensive analytical characterization may reveal differences between the proposed biosimilar product and the reference product. Clinical pharmacology studies may be used to address the relevance of any analytical differences on potential clinically meaningful differences.