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FDA advisory committee unanimously recommends approval of biosimilar to Humira
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The FDA Arthritis Advisory Committee today voted 26-0 in favor of recommending the approval of ABP 501, Amgen’s proposed biosimilar to AbbVie’s Humira.
The company is seeking licensure for rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis and plaque psoriasis.
However, committee members expressed a number of concerns after the vote regarding extrapolation to indications not evaluated in clinical trials, nonmedical switching or interchangeability, and the lack of mandated postmarketing surveillance.
The biosimilar candidate’s active ingredient is an anti-TNF-a monoclonal antibody with the same amino acid sequence as Humira (adalimumab), and also the same pharmaceutical dosage form, strength and administration route. The FDA has set a Biosimilar User Fee Act target action date of Sept. 25, 2016, according to a press release from Amgen.
The recommendation for licensure follows the committee’s review of analytical, nonclinical and clinical data demonstrating ABP 501’s biosimilarity to adalimumab, as required by the FDA’s abbreviated licensure pathway for biosimilars.
These included safety and efficacy data from two phase 3 comparative studies in moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis. The primary endpoints showing clinical equivalence to adalimumab were met in these studies, and comparable safety and immunogenicity were also demonstrated.
Further analysis of a subgroup of psoriasis patients who transitioned from adalimumab to ABP 501 showed similar rates of binding and neutralizing anti-drug antibodies, although some committee members noted that because of the study’s small sample size, the fact that these antibody levels were numerically higher is concerning.
“The totality of evidence supports the licensure of ABP 501 as a biosimilar,” Richard Markus, MD, PhD, vice president of global biosimilars development at Amgen, said during the meeting. “The analytical characterization showed a highly similar product with the same amino acid sequence and potency, and similar effector functions, similar toxicology profile, similar pharmacokinetics, and finally two separate clinical studies both showed similar efficacy, safety, and immunogenicity. So the data show that ABP 501 is highly similar to adalimumab with no clinically meaningful differences.”
After reviewing these data, the FDA agreed with Amgen’s interpretation that the evidence shows ABP 501 is analytically highly similar to adalimumab, that there are no clinically meaningful differences based on the RA and psoriasis trials, and that there is adequate scientific justification for extrapolation across the other proposed indications.
“The agency believes that it is reasonable to extrapolate data to support a demonstration that there are no clinically meaningful differences for [the proposed indications] between ABP 501 and U.S.-licensed Humira,” Nikolay P. Nikolov, MD, from the FDA’s Office of Drug Evaluation II, said during the meeting. “In summary, the totality of the data submitted by the applicant supports the demonstration that ABP 501 is highly similar to U.S.-licensed Humira and there are no clinically meaningful differences between [the two].”
However, committee members expressed concerns about using analytical data to justify extrapolation to clinical indications, particularly in pediatric populations and in patients with inflammatory bowel disease.
Amgen’s analytical data showed TNF binding, adalimumab’s primary mechanism of action, was similar across RA, psoriasis and IBD patients, and concluded that ABP 501 is therefore expected to have the same activity as adalimumab in all extrapolated indications.
Scott A. Waldman, MD, from Thomas Jefferson University Hospitals, questioned this conclusion, arguing that IBD may have additional mechanisms of action.
“Neutralization of TNF alpha may not be sufficient to be clinically active in IBD, so in absence of clinical comparison in IBD, do we have enough information to jump from in vitro analysis to clinical efficacy?” he said.
Jeremy Adler, MD, from CS Mott Children’s Hospital, University of Michigan, agreed, saying his main concern was lack of clinical data on IBD and pediatric patients.
“That said, the evidence still was strong enough for me to vote yes," he said. "I still feel given this lack of clinical evidence that it’s important to have a specific, deliberate, prospective postmarketing surveillance study.”
Several committee members also noted that mandated postmarketing studies would be appropriate as the presented studies were underpowered to detect safety signals. The FDA will not require these studies, but said the same postmarketing surveillance efforts of any approved biological product would be expected of biosimilars.
Finally, concerns about nonmedical switching or interchangeability were expressed by several committee members and by a number of stakeholders during the open public hearing. The FDA said it is still deliberating on its policy regarding interchangeability of biosimilars with the originator product.
“Interchangeability is an extreme concern to clinicians as this moves forward in the marketplace,” June K. Robinson, MD, from Northwestern University Feinberg School of Medicine, said during the meeting.
“I struggled a little bit, but I thought the totality of the evidence, particularly for the indications that had small clinical trials, was very convincing,” Sarah Streett, MD, from Stanford University School of Medicine, said during the meeting. “I agree there are other issues we weren’t charged to tackle but remain floating about and remain paramount, and I hope we are more empowered to explore them going forward.”
This is the third proposed biosimilar application under the biosimilar pathway to be discussed by an FDA advisory committee, and the first proposed biosimilar to adalimumab, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said during the meeting. The fourth, a biosimilar to Enbrel (etanercept, Sandoz) will be discussed tomorrow, she added.
“We are continuing to write basically the early history of a new class ... of products regulated by FDA,” she said. – by Adam Leitenberger
Perspective
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Stephen B. Hanauer, MD, AGAF, FACG
“We are continuing to write basically the early history of a new class ... of products regulated by FDA,” Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, stated at the recent FDA Advisory Board reviewing Amgen’s biosimilar product to AbbVie’s Humira. Of note to gastroenterologists, similar to the recent Advisory Board and subsequent approval of the biosimilar to Janssen’s Remicade, the clinical trials supporting the approval did not include patients with either ulcerative colitis or Crohn’s disease. Members of both advisory panels were disturbed by the notion of “extrapolation” without evidence in individual disease states.
It must be understood that the concept of extrapolation is foundational to biosimilar approval and development where the developmental triangles from analytics to clinical trials is reversed (eg, there is more emphasis on analytical demonstration of similarity than clinical trial data).
If a biosimilar product is required to undergo testing in every approved indication for the innovator product there would be no cost savings to develop biosimilars and, hence, no cost-savings for these expensive therapies.
Another point that gastroenterologists need to understand is that the comparative clinical testing for biosimilar products vs. originators has used the same criteria for efficacy that were used in the original trials leading to approval. While there have been few changes, thus far, in rheumatologic trials, trials in IBD, particularly Crohn’s disease are evolving. The original trials with infliximab and adalimumab were short-term and used the Crohn’s disease activity index of 70 points as “response”. Frankly, the field has moved on from these trials and we recognize that a CDAI 70 is not a strong endpoint with a high placebo response. Even the FDA is eliminating the CDAI as an endpoint such that there may not be appropriate guidance as to how to study comparability of a biosimilar to an originator in Crohn’s disease. We have moved on to look at higher dosing of the originators and using therapeutic drug monitoring that are outside of regulatory approvals.
The biggest issue remaining to everyone is “interchangability” regarding development of immunogenicity. There are likely to be several (or many) biosimilars compared with each originator but not compared to each other. It remains to be determined whether the small differences between biosimilars and originators are amplified between different biosimilars. Thus far the FDA has not provided guidance regarding interchangability, which is probably why Dr. Woodcock notes that the agency “… is continuing to write (regulations) … for this new class.”
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