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Development of biosimilars creates challenges for FDA, manufacturers


FDA is developing guidelines for documenting similarity and interchangeability of copycat versions of biotech therapies, a process that is drawing considerable scrutiny from a broad spectrum of stakeholders.

Key Points

FDA is developing guidelines for documenting similarity and interchangeability of copycat versions of biotech therapies, a process that is drawing considerable scrutiny from a broad spectrum of stakeholders. There are a host of thorny issues to resolve related to reference products, interchangeability, labeling, and exclusivity. An area of agreement, though, is that producing biosimilars is vastly more complex and more costly than manufacturing conventional generic drugs, and that FDA will require broader testing to license a product as biosimilar or interchangeable. Developing a follow-on biotech therapy will require considerable investment in time, resources and expertise, running up a tab of some $75 million to $250 million and typically taking 7 to 8 years, according to experts.

Even so, the prospect of biopharmaceuticals capturing a greater share of the global drug market is drawing interest from payers and providers, as well as pharma and biotech companies. The worldwide market for biosimilars is projected to grow to $3.7 billion by 2015, up from about $250 million last year, according to Datamonitor. As more biotech patents expire and regulatory authorities clarify requirements, biosimilars development is projected to soar.

An important goal of the Biologics Price Competition and Innovation Act (BPCIA), which was approved as part of the Affordable Care Act (ACA) of 2010, is to reduce spending on prescription drugs by permitting "highly similar" versions of biotech therapies to come to market based on less-extensive nonclinical and clinical data. Health plans and providers talk of biosimilars offering discounts of 25% to 30% off branded products, but reimbursement experts say that prices that are just 10% lower will be able to gain market share, particularly for therapies with high price tags to begin with.

The challenge for FDA officials is to scope out an abbreviated process for developing biosimilars that will meet standards for product safety, purity, and potency. There should be no "clinically meaningful differences" between the follow-on and the reference product, and both should use the same mechanism of action and have the same route of administration, dosage form, and strength. A biosimilar also has to be manufactured, packaged, and stored in facilities that meet good manufacturing standards.

The potential for product naming and coding to drive coverage and reimbursement is generating heated debate on those topics. Innovator firms maintain that biosimilars should have unique names to distinguish them from reference products, an issue that the BPCIA failed to address directly. Different names can ensure traceability of adverse events, reduce confusion about interchangeability, and avoid dispensing errors.

Biosimilar advocates prefer names linked to a reference product to "make clear to prescribers and patients that the products are related," explained attorney Erika Lietzan of Covington & Burling at the "Future of Biosimilars" conference in May, jointly sponsored by the Drug Information Association (DIA) and the Food and Drug Law Institute (FDLI). Some physicians propose unique names only for non-interchangeable biosimilars, a middle ground that appears to interest the regulators.

Product coding raises related issues. Innovators want biosimilars to have their own reimbursement codes, while biosimilars makers want the same code for all drugs in the same class. A dozen human growth hormone products have the same "J-code," and thus receive the same payment from Medicare, explained attorney Laura Loeb of King & Spalding.

But even without common names and codes, Loeb predicted that it will be difficult for more expensive reference products to maintain market share. Formulary committees and state Medicaid programs, she pointed out, can drive prescribing through formulary placement, higher copays, prior authorization, and requiring step-therapy procedures for reference products. "The burden will be on the reference product to prove superiority to the biosimilar," Loeb observed, "not the other way around."


Biosimilars development will be shaped largely by the policies and testing requirements FDA sets for determining that follow-on and reference products are interchangeable. Biosimilars deemed interchangeable benefit from market exclusivity; they also are more likely to gain acceptance from patients and health professionals, along with the possibility of substitution by pharmacists and prescribers.

Beyond documenting biosimilarity based on molecular structure and in vitro assays, a demonstration of equivalence will involve non-clinical pharmacology and toxicology studies, plus pharmacokinetic (PK) and pharmacodynamic (PD) testing in humans. Additional clinical studies generally will be needed to document equivalent efficacy in at least 1 approved indication. However, generics-makers oppose broad requirements for clinical switching studies to compare biosimilars to reference products, something that is not required for innovator manufacturers to document comparability following post-approval changes.

Yet, innovators emphasize that clinical studies in multiple populations with different risk-benefit profiles are necessary to document that there are no greater risks of safety problems or efficacy differences with product switching. Amgen Vice President Anthony Mire-Sluis maintained that head-to-head studies are needed to compare immunogenicity between reference and follow-on biotechnology products, and that different assays can yield different rates of immunogenicity. He also wants product labels to state explicitly the approved indications of a therapy and whether a biosimilar is interchangeable for that use.

However, even innovator firms acknowledge that an appropriate biosimilar pathway would involve less-extensive animal toxicity testing and reductions in dose finding and phase 2 clinical trials. Equivalence and non-inferiority trials would utilize active controls and not placebos, for ethical as well as practice reasons.

FDA began the formal guidance development process for evaluating biosimilars at a November 2010 public meeting. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), recently indicated that general guidance should appear this year, and that requirements for human testing will vary according to how well a biosimilar can document sameness to the innovator product.

FDA also is moving forward with a user fee schedule for biosimilars applications. The agency proposes to set fees similar to those for innovator drugs and biologics, but with a new approach to help finance FDA's extensive involvement in steering sponsors through the development process. The plan is for manufacturers to pay a product development fee of $150,000 with submission of an investigational new drug application and annually thereafter; those upfront payments then would be subtracted from the eventual application fee.

In devising guidance, FDA has to tackle some very basic issues, such as which products fall under the new regulatory program. The BPCIA extends the definition of biologics to most proteins beginning in March 2020. That raises questions about how the change will affect manufacturers of human growth hormones and other proteins, and how they should proceed during the 9-year transition period.

A thorny subject is whether FDA can approve a biosimilar based on a reference product that is approved overseas, but not in the United States. The BPCIA says that reference products have to be licensed by FDA, but biosimilar makers want flexibility to permit comparison to a biologic licensed by a foreign regulatory body under certain circumstances.

Another contentious topic is whether biosimilars manufacturers can extrapolate data from a clinical study to other indications of the reference product. European regulatory authorities permit this if the added indication involves the same mechanism of action and same receptor, and if extrapolation of immunogenicity data applies to a lower-risk population or route of administration. Biosimilar sponsors say that extrapolation may be appropriate if supported by open-label safety studies for each indication.


Although the BPCIA authorized 12 years data exclusivity for innovator biologics, a period when FDA cannot approve a product based on innovator studies, that has not ended the debate over what period of protection is needed to support biotech innovation. Biotech companies consider 12 years exclusivity vital for encouraging investment in R&D, but critics claim that it's too long. The Obama administration recently proposed reducing exclusivity to 7 years to accelerate access to less-costly medicines. A related aim is to minimize the impact of patent "evergreening," which refers to the practice of biotech manufacturers seeking an additional period of protection for products that are modified enough to qualify as "new." FDA has to define what changes would sufficiently impact a product's safety, purity, or potency to warrant extended exclusivity.

As with conventional generics, everyone is bracing for extensive legal maneuvering over patent and exclusivity issues. The legislation's highly complex resolution system for patent disputes calls for makers of biosimilars to turn over dossiers to the reference product firm, which would then identify patents that the innovator might consider infringed. This process was designed to promote early agreement on which patents will be disputed, but the new policy seems to please no one. Biosimilar makers fear that too many parties will gain access to their confidential regulatory filings, while innovators stand to lose protection if they miss a deadline.

If this and other policies make the new biosimilars pathway too costly and treacherous, sponsors may avoid the new regulatory process altogether and decide to take the traditional route to market for biologics-and the reward of 12 years exclusivity.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.

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