FDA’s Plan for Showing Total Biosimilarity Seen Workable

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By John T. Aquino

The FDA’s roadmap for drug companies seeking a profitable “interchangeable” designation for their lower-cost biosimilar products isn’t perfect but it’s workable, stakeholders said.

The Food and Drug Administration’s long-awaited draft guidance sets a path for proving a biosimilar, a highly similar version of an original brand-name biologic drug, can be swapped for the brand drug without a physician’s approval. The designation is designed to ease patient access to biosimilar drugs, which are expected to cost 15 percent to 30 percent less than the brand biologic.

Biopharma attorneys’ initial reaction to the draft guidance when it was released Jan. 17 focused on its occasional vagueness and contradictions ( 11 LSLR, 1/20/17 ). Patient groups expressed similar concerns.

The draft guidance recommends that companies seeking an interchangeability designation undertake “switching” studies, in which patients alternate or switch between the original drug and the biosimilar.

Early Reactions

Barclays analysts suggested in Jan. 17 client communications that the FDA may have raised the bar for interchangeability so high that it might delay biosimilars from coming to market.

But Elizabeth Krutoholow, a Bloomberg Intelligence analyst, told Bloomberg BNA in a Jan. 25 e-mail: “The guidance is generally in-line with expectations in terms of what is required and should be achievable. Some biosimilar makers have already designed studies with switching and are on the right track.”

Alan Klein, a partner at Duane Morris LLP, Philadelphia, who represents biosimilar developers, wrote in a Jan. 25 e-mail to Bloomberg BNA, “While the FDA draft guidance remains open-ended and inconclusive on some key points, it is a welcome addition to a series of biosimilar guidances issued by the FDA. [It] sets high barriers for companies seeking to introduce such products into the marketplace.”

The FDA requested comments on the draft guidance by March 20.

More Biosimilars in 2017

A biosimilar is a biologic drug product that is highly similar to an FDA-approved biologic, also known as a brand biologic or a reference product (RP). The Biologics Price Competition and Innovation Act (BPCIA) provides an abbreviated approval pathway for biosimilars that partly relies on data submitted for FDA approval of the RP. Relying on the RP’s data can reduce the cost of developing the biosimilar.

Under the BPCIA, the applicant can seek additional review by the FDA that the product is interchangeable with the RP, canceling the requirement that pharmacists get physician authorization before switching the patient to the biosimilar drug.

So far, the FDA has approved four biosimilars: Sandoz’s Zarxio (filgrastim-sndz), a biosimilar of Amgen’s cancer treatment Neupogen; Pfizer and Celltrion’s Inflectra (infliximab-dyyb), a biosimilar of Johnson & Johnson’s arthritis treatment Remicade; Sandoz’s Erelzi (etanercept-szzs), a biosimilar of Amgen’s arthritis drug Enbrel; and Amgen’s Amjevita (adalimumab-atto), a biosimilar to AbbVie’s Humira (adalimumab) for multiple inflammatory diseases. None has yet been designated as interchangeable.

In a Jan. 18 posting, Krutoholow noted there is potential for an increase in biosimilar approvals in 2017: Coherus Biosciences’ biosimilar of Amgen’s Neulasta (pegfilgrastim) for treating the consequences of chemotherapy and Amgen-Allergan’s biosimilar of Genentech’s cancer treatment Avastin may receive decisions in 2017. The interchangeability draft guidance may fuel the continued development of biosimilars, Krutoholow wrote in her post.

Biosimilar Makers Supportive

Klein noted the high barriers in the draft guidance include that the supporting data must be robust and demonstrate the absence of immunogenicity through at least two switching clinical trials in which patients receive first the existing brand product, and then its interchangeable counterpart. “Likewise, the interchangeable product generally must be compared to a brand biologic approved for use in the U.S., although, with sufficient scientific justification, the agency may approve the use of a foreign-approved biologic for this purpose,” he said.

Biosimilar manufacturers tended to support the FDA’s draft interchangeability guidance.

A spokeswoman for Thousand Oaks, Calif.-based Amgen, which develops both biologics and biosimilars, told Bloomberg BNA in a Jan. 25 e-mail that Amgen was pleased with the FDA‘s draft guidance, noting that “it proposes establishing a sound, science-based approach for demonstrating interchangeability of biosimilar products with their reference products.” She said the company would be submitting formal comments to the FDA.

Pfenex, a San Diego-based biosimilar developer, said in a Jan. 17 statement that the draft guidance is “an important step in creating a robust market for biosimilars in the United States and ensuring greater patient access to medicines. This recommendation, which directs a biosimilar developer to submit data from a switching study in order to demonstrate interchangeability, signals the FDA’s support for the safety and efficacy of a biosimilar compared to a reference product.”

In a separate post, Pfenex cited the Nor-Switch study in Norway that demonstrated support for switching patients from a branded biologic to a biosimilar.

Patrick Lucy, Pfenex’s interim chief executive officer, told Bloomberg BNA in a Jan. 25 e-mail that the company is “supportive” of the draft guidance.

Barriers Need to Be High

With respect to the “stringent standards established by the FDA,” Lucy wrote: "[Because] an interchangeable product can be administered for a reference product without physician interference unless otherwise stated, it is understandable that the agency has sought to ensure an interchangeable product can be administered similarly to a reference product. The draft language, while not insurmountable, creates an added element of complexity that must be considered during initial development.”

Duane Morris’s Klein responded to Barclays’ “raised the bar high” assessment by noting that the diseases for which biologic medicines are used are serious, and in some cases, life-threatening, with development costs in most instances considerably higher than traditional pharmaceuticals.

“But the upside for successful companies is very significant,” Klein said. “That upside, both in terms of profits and filling an urgent need for cheaper biologics, will motivate many companies willing to make the investment. The FDA has encouraged the growth of this industry in the U.S., but wants to ensure that patient safety remains paramount in the finished products. These barriers are not inflexible, and the agency has always indicated its willingness to discuss and assist developers in creating successful pathways for product approvals on a case-by-case basis.”

Klein’s Duane Morris partner Kevin Nelson said in a Jan. 25 e-mail that those seeking the interchangeability designation should take particular note of the instances where FDA said it had a preference for the type of information it would like to see from an applicant.

For example, the FDA prefers the applicant “make a showing with respect to all approved indications as opposed to a subset of indications,” Nelson wrote. “As FDA is sure to take a measured and pragmatic view with respect to the first few applications seeking an interchangeability determination, and since the cost of such an initial foray into interchangeability is expected to be high, prudent applicants would be wise to pay close attention to FDA’s preferences, at least until FDA becomes more comfortable with interchangeability and approving interchangeable biosimilar products.”

Patient Groups Concerned

Patient groups, however, expressed concern about the draft guidance.

Patients for Biologics Safety and Access (PBSA) welcomed the document in a Jan. 17 statement but also raised areas where more explanation of the mechanism for designating interchangeability status is needed, including:

  •  how the FDA will adequately ensure patient safety if, as the draft allows, a product can be approved as interchangeable for a condition without clinical studies of the safety and efficacy for that condition based on extrapolation of data from other conditions;
  •  how the required switching studies will account for the fact that many patients take biologics for chronic conditions for many years and could be switched back and forth multiple times;
  •  what specific additional requirements and resources will the FDA put in place for post-marketing surveillance for biosimilars and biologics;
  •  whether the FDA should require that the population examined through clinical testing be large enough to assess rare events; and
  •  whether the FDA will require unique nonproprietary names for interchangeable products.
Leigh Purvis, director of health services research for the AARP Public Policy Institute, urged a balanced approach.

She told Bloomberg BNA in a Jan. 18 e-mail the association was pleased to see the draft guidance released, but also stressed that “AARP has long held that FDA should not elevate interchangeability to a degree that it becomes unattainable. Our overriding concern remains that the Biologics Price Competition and Innovation Act be implemented in a manner that ensures safety and efficacy without creating unnecessary barriers that defeat the purpose of the legislation.”

To contact the reporter on this story: John T. Aquino in Washington at jaquino@bna.com

To contact the editor responsible for this story: Randy Kubetin at RKubetin@bna.com

For More Information

The FDA draft interchangeability guidance is at http://src.bna.com/lse.

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