Biosimilars Raise Manufacturing and Regulatory Challenges

Published on: 
BioPharm International, BioPharm International-07-01-2018, Volume 31, Issue 7
Pages: 44–46

FDA seeks more efficient testing to spur development of less costly biotech therapies.

A central strategy for enhancing access to more affordable medicines for the Trump administration, Congress, and FDA involves smoothing the pathway for the development and approval of high-quality biosimilars and interchangeable biotech therapies. Yet, only three biosimilars are on the market-of 11 approved products-eight years after enactment of legislation authorizing follow-ons. Recent entries include Pfizer’s Retracrit, the first approved alternative to Amgen’s widely used anemia treatment Epogen (epoetin alfa), and Fulphilia (Pegfilgrastim) from Mylan and Biocon, a competitor to Amgen’s Neulasta. But if current trends continue, it may be months or years before Americans gain access to these less costly therapies.

 In the United States, biosimilars must overcome lengthy patent challenges and difficult reimbursement policies that block product marketing. Testing and production of biosimilars costs from $100 million to $250 million per program, much more than the $10 million involved in developing a conventional generic drug. Consequently, biosimilars come to market at prices only 15–20% below the innovator, which often is not enough difference to drive prescribing and industry investment in the field.

Manufacturing problems also continue to cause delays, as experienced by both

and Mylan last year (1,2). Celltrion also received FDA complete response letters for biosimilar applications for rituximab (Rituxan) and for trastuzumab (Herceptin) due to violations at its South Korea facility involving aseptic practices, which it says are now corrected (3). Other firms have run into delays in FDA approval related to technical and quality production issues.

Streamlining development

At FDA, Commissioner Scott Gottlieb, MD, is encouraging biosimilar development with initiatives to provide greater scientific and regulatory clarity for sponsors, a more efficient review process, and tools for using modern analytical techniques to make biosimilar development more predictable and less costly. With more than 60 biosimilar development programs to 31 different reference products in the pipeline, the Center for Drug Evaluation and Research (CDER) is working to better integrate policy and review functions to smooth the pathway to approval (4). FDA has finalized seven guidance documents since 2015 that spell out a range of procedures and policies for demonstrating biosimilarity to reference product, reports CDER Associate Director for Therapeutic Biologics Leah Christl. Now the agency is moving to prepare and revise advisories on several contentious issues, including biosimilar labeling, managing post-approval manufacturing changes, and demonstrating interchangeability with a reference product. Although FDA cannot change the legal standard for interchangeable biosimilars, Christl explained at the April 2018 Medicines for Europe Biosimilar Medicines Conference in London, the agency is examining possible revisions in data elements necessary to support an interchangeability designation (5).

FDA recently announced it would start over with guidance on statistical approaches for evaluating analytical similarity to better accommodate new scientific tools to streamline the studies required for comparisons between biosimilars and reference products (6). The aim is to clarify where natural variance in production lots for biologics occurs over time and how to incorporate this process into procedures for copying such variable products. FDA is examining innovative methods that may help manufacturers measure and control for routine lot differences, with an eye to addressing where it may not be necessary for a biosimilar to show comparability to a full range of variance in reference products.


Another concern for FDA is evidence that innovators may delay biosimilar testing by blocking access to supplies of reference products needed for comparability testing and clinical trials. FDA has published lists of brand drugs subject to such complaints from generic-drug makers and has its eye on restrictive contracting and distribution strategies that similarly may affect biosimilar sponsors and create barriers to the submission of biosimilar applications.

To encourage greater uptake of biosimilars, FDA also is doing more to educate clinicians and patients on product safety and efficacy and to address misconceptions that foster reluctance to prescribe and use these therapies. Biosimilar advocates are urging the agency to further explain its standards and policies to build public confidence that biosimilars are equally safe and effective as brand biologics. FDA recently expanded its educational materials on the development and approval of biosimilars and interchangeable products for healthcare professionals and patients (7). Biosimilar makers also anticipate that an efficient path for demonstrating product interchangeability with brands will help build prescriber and patient confidence in switching to the new products.

Added efficiencies may arise from establishing a global market for biosimilars, and FDA is collaborating with regulatory authorities in Europe, Japan, and Canada to harmonize R&D requirements and share experiences in overseeing biosimilars. Such partnerships can support global economies of scale in biosimilar development programs across national boundaries, Christl noted at the London conference. Regulatory authorities from the United Kingdom and other European countries reported millions in savings from the growing uptake of biosimilars to rituximab, infliximab, and etanercept, as prescribers gain more confidence in switching patients to the lower-cost therapies.


Rebate roadblocks

In the US, though, payment and rebate practices create additional barriers to biosimilar marketing and utilization. In a speech to health insurance firms in March 2018, Gottlieb pointed to rebating and contracting schemes and “Kabuki drug-pricing constructs” that expose consumers to high out-of-pocket costs for biosimilars and discourage manufacturers from investing in producing more affordable alternatives (8). The problem is that high rebates paid by brand manufacturers encourage health plans and pharmacy benefit managers (PBMs) to favor brand therapies on formularies. In April 2018, the commissioner scolded PBMs directly about how “restrictive contracting, rebating, and distribution agreements deter coverage and reimbursement” for biosimilars (9). 

The crux of the problem, Gottlieb explained, is the “rebate trap” that permits PBMs and insurers to profit from the spread between list price and the actual rebated price for an innovator therapy. Rebates can amount to hundreds of million of dollars in annual revenues for plans and typically are tied by manufacturers to volume or preferred formulary status. This system means that PBMs and plans lose substantial rebate revenues by shifting patients from an established drug to a biosimilar.

As biologics account for an increasingly large portion of drug outlays, Gottlieb urged payers and insurers to reject such rebate arrangements and to encourage biosimilar use by lifting prior authorization requirements for biosimilars, designing formularies with biosimilars as the default option for newly diagnosed patients, and waiving co-insurance on these products. Payers must decide if they want to continue to benefit from profitable rebates, Gottlieb told the insurers, or “help generate a vibrant biosimilar market that can help reset biologic pricing.”

These rebate and contracting issues that stymie biosimilar competition, along with a range of patent, regulatory, and reimbursement challenges, are discussed in a white paper from the Biosimilars Council of the Association for Accessible Medicines (10). The group is pressing for legislation to facilitate access to test samples for generic-drug and biosimilar manufacturers, as well as policies to promote biosimilar competition at FDA and other government agencies.


1. Pfizer, “Pfizer Provides Update on Proposed Epoetin Alfa Biosimilar,”

, June 22, 2017.
2. Mylan, “US FDA Approves Mylan and Biocon’s Fulphila™ (pegfilgrastim-jmdb), the First Biosimilar to Neulasta®,” Press Release, June 4, 2018.
3. Celltrion, “Celltrion Completes Resubmission for Biosimilar Candidate to FDA for Review,” Press Release, May 30, 2018.
4. FDA, Biosimilars,
5. L. Christl, PhD, “Update: Biosimilar Program in the US,” Medicines for Europe Biosimilar Medicines Conference, April 27, 2018.
6. FDA, FDA Withdraws Draft Guidance for Industry: Statistical Approaches to Evaluate Analytical Similarity, June 21, 2018.
7. FDA, FDA Video Series about Biosimilar and Interchangeable Products,
8. FDA, Capturing the Benefits for Competition for Patients,
9. FDA, Advancing Patient Crae Through Competition,
10. The Biosimilars Council, “Breaking Through on Biosimilars,” Whitepaper.

Article Details

BioPharm International
Vol. 31, No. 7
July 2018
Pages: 44–46


When referring to this article, please cite it as J. Wechsler, "Biosimilars Raise Manufacturing and Regulatory Challenges," BioPharm International 31 (7) 2018.