BioProcess Blog |

By Patti Seymour  (pseymourbptccom)  

Not surprisingly, a biosimilar version of Remicade^® (infliximab) is the first regulatory application for a biosimilar monoclonal antibody (mAb) submitted to the EMA this month. Remicade^®, marketed in the EU by Janssen Biotech (a subsidiary of Johnson and Johnson), is a mAb against tumor necrosis factor (TNF) alpha and is approved for a whopping 16 indications. While the name of the company submitting the application wasn’t disclosed by the EMA, it is widely acknowledged to be Celltrion’s submission.

Celltrion’s infliximab clinical trials were conducted with a total of 874 rheumatoid arthritis patients at 100 sites in 19 different countries throughout 2010 and 2011. It is unknown at this point if Celltrion is requesting approval for other indications in addition to rheumatoid arthritis as EMA Guidance allows for extrapolation of clinical efficacy and safety data to other indications for which the reference mAb has been approved. It is not necessary that these indications be specifically studied during the clinical development of the biosimilar as long as there is evidence of overall biosimilarity provided by the comparability exercise with adequate justification.

Approval from the EMA to extrapolate to multiple indications will be important for Celltrion to capture a meaningful portion of the $21 billion TNF-a antagonist market. While Remicade is forecasted to be one of the top three selling drugs in 2012, it was also one of the earliest mAbs to receive regulatory approval, and as a chimeric mAb (containing both human and murine sequences), it has some safety limitations associated with immunogenicity. Over the past decade, these older products are being supplanted with newer, humanized or fully human mAb versions such as Humira^®. While biosimilar competition remains a concern, the verdict is still out as to whether Remicade’s $8 billion market is more likely to be cannibalized by biosimilars or by biobetter and next generation products, such as Janssen’s own Simponi product.

Now it is a waiting game for Celltrion as the earliest patents for Remicade do not expire until 2014 in the EU. However, Celltrion isn’t taking a ‘sit and wait’ approach – the company is preparing to file for Korean Food and Drug Administration approval this year. After that, the company plans to register their biosimilar infliximab product in emerging markets in Asia and Central/South America, where Remicade does not have patent protection.

While Celltrion was the first to file for approval of a biosimilar mAb, there are sure to be many more companies submitting biosimilar mAb applications in the near future. The first-mover advantage could be short-lived for Celltrion as more companies seek biosimilar market authorization, and branded products continue their strong market performance. This is further compounded by the fact that overall adoption of the early biosimilar products in Europe has not been as strong as anticipated or hoped even with price discounts up to 40% for some products from the branded product’s price. Samsung, clearly positioning itself to be a dominant player in the biosimilar market, predicts it will be a stronger overall competitor by selling its biosimilar portfolio at up to 50% off the innovator drug price. We believe that such price drops are achievable and will lead to significant gains in market share by Samsung and other biosimilar companies able to actually deliver on this promise. However, before steep price discounts can become a reality, products must be approved. So the questions remain – What hurdles will Celltrion face in the approval process? How easily will they be able to access other indications after approval? And of course, what kind of market penetration will Celltrion’s infliximab really achieve?

By Patti Seymour  (pseymourbptccom)   and Howard Levine  (hlevinebptccom)  

Nearly two years after the Biologics Price Competition and Innovation (BPCI) Act was passed, FDA has finally taken the big step towards defining a regulatory pathway for biosimilars in the US. On February 9, 2012 FDA issued three draft guidance documents, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, along with a Q&A summary of these documents, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, describing the Agency’s interpretation of the Act’s requirements for biosimilar product licensure.

These guidances reflect the broad framework that FDA officials have spent months outlining and are consistent with their August 2011 New England Journal of Medicine article, stating that FDA will take a “totality of evidence” approach to biosimilar approval and require extensive characterization of the biosimilar product using state of the art analytical techniques. Even with this detailed characterization, animal and human clinical studies will still be mandated for the foreseeable future. Consistent with EMA’s approach to biosimilar approval, the detailed and extensive analytical characterization will allow a reduction in the scope and extent of animal and/or human studies required.

While the guidances cover many issues important to the overall development of biosimilars, we are encouraged by several points that are especially relevant for the CMC development of biosimilars. The current draft guidances do allow for differences in the formulation of a biosimilar product compared to its reference product. For example, FDA indicates that it may be possible for a biosimilar product formulated without human serum albumin to be considered similar to a reference product formulated with human serum albumin. We applaud this rationale and sensible position of allowing biosimilar developers to move away from potentially dangerous raw materials used in the innovator products and implement technical advances in formulation development without losing the biosimilar status of the product. We also support allowing biosimilar products to use different delivery devices or container closure systems from that used in the reference product making it possible, for example, for a biosimilar product to be approved in a pre-filled syringe or auto-injector device while the reference product may be in a conventional vial presentation.

As you may recall from our previous post on this topic, we are in favor of allowing data generated using a non-US licensed reference products in support of a biosimilar application in the US. FDA agrees with this approach and will consider the use of a non-US licensed reference product in certain studies to support biosimilarity. Since most biologic products today are sourced from a single manufacturing location, but sold globally, FDA will require the relationship between the license holder for the non-US licensed product and BLA holder for the US licensed reference product to be disclosed, including whether the non-US licensed product is manufactured in the same facility(ies) as the US-licensed reference product and whether the facility(ies) are licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA. Even if non-US licensed reference product data can be used, analytical characterization and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study must directly compare the biosimilar product with the US licensed reference product.

To help companies with the design of acceptable biosimilar development plans, FDA is encouraging them to meet with the Agency to discuss their detailed plans and share manufacturing information and preliminary comparative analytical data so that the Agency and the Sponsor can agree on the type and amount of animal and clinical data needed to support eventual licensure of the biosimilar product. According to Theresa Mullin, director of FDA’s Office of Planning and Informatics, FDA has received 31 requests for such meetings and had held 21 of these meetings as of December 2011.

These guidances are an important and meaningful first step toward full implementation of the BPCI Act. Overall, the guidances do not contain any surprises although we are pleased to find them more open to permissible deviations from the reference product than expected. The Agency is accepting public comment on the draft guidances for the next 60 days and will, hopefully issue its final guidances shortly thereafter. Now that these general guidances for biosimilar development have been published we hope FDA will turn its attention to product specific guidances as has already been done in Europe to ensure a clear and meaningful roadmap for the development and approval of biosimilar products in the US.

By Patti Seymour  (pseymourbptccom)  

With shortages of life saving medicines making headlines recently, President Obama signed an Executive Order on October 31 to ease pressure on health care providers and reverse this dangerous trend. Drug shortages, primarily involving generic sterile injectables, have been increasing in frequency and severity in recent years with roughly half of the approximately 80 manufacturers experiencing shortages in 2011.

FDA has reacted to this situation by issuing “A Review of FDA’s Approach to Medical Product Shortages,” detailing the existing drug shortage, summarizing actions FDA is taking both to prevent and respond to drug shortages, and the unique drivers causing these shortages. While the problem is complex and caused by a variety of contributing factors, quality issues at the drug manufacturing facilities seem to be a leading cause of the drug shortages, accounting for 43% of all shortages. As discussed in my previous post on this topic, FDA is focused on identifying and correcting supplier performance as part of their overall risk-based approach to inspections, which has translated into numerous 483 citations at sterile product contract manufacturers. The expectation is that Sponsors will be more proactive in managing these suppliers to ensure product quality, but clearly this is not happening. A leading manufacturer of sterile injectable oncology products, Ben Venue Laboratories, announced in August that the company was exiting the contract manufacturing business while it dealt with multiple FDA 483s at their manufacturing facility in Bedford, Ohio. Unfortunately for Sponsors and patients relying on medicines manufactured there, Ben Venue temporarily suspended all drug manufacture and distribution just before Thanksgiving, putting further pressure on already stressed supply chains.

Unfortunately, Ben Venue is not an isolated case. When using a CMO for any part of your supply chain, it is important to ensure that the CMO is operating in full compliance of all cGMP regulations to avoid supply disruptions. This diligence begins with the initial selection of the CMO but should continue through periodic GMP compliance audits. Without question, any quality issues identified either during a Sponsor audit or a regulatory inspection should routinely be addressed immediately and the CMO monitored to ensure appropriate corrective actions have been implemented and compliance is maintained or restored. Proactive supply chain monitoring can provide early warning signs of potential supply chain issues, enabling Sponsors to implement risk-mitigation plans to head-off potential catastrophes. For all links in the supply chains, a risk-management plan which identifies all elements that could contribute to a breakdown in supply and outlines risk-mitigation strategies, such as second source manufacturing for key links in the supply chain, that will ensure continuity of supply.

While some of the current drug shortages could not have been predicted, many of them could have merely by connecting the dots through vigilant supply chain oversight and robust risk-management plans. It’s not too late to thoroughly analyze your supply chain and inspect it for any chinks or weak links that could disrupt continuity of supply. Make this your New Year’s resolution.

Howard Levine  (hlevinebptccom)  , Sheila Magil  (smagilbptccom)  , and Alex Kanarek  (akanarekbptccom)  

The EMEA (now EMA) issued its first guideline for similar biological medicinal products in 2005, followed by detailed guidelines for specific products in subsequent years. Citing such issues as the development of biosimilar monoclonal antibodies, The WHO Guidelines on Evaluation of Similar Biotherapeutic Products, and EMA’s emphasis on the 3 R principles (replacement, reduction and refinement) in animal testing, EMA issued a few weeks ago a concept paper on revising their 2005 guideline to bring it more in line with these newer guidances. Recognizing that repeat dose toxicity studies in non-human primates recommended in it’s the earlier guidelines are of little relevance, the concept paper recommends that a risk-based approach for the design of non-clinical studies be used which takes into account the results of biochemical comparability studies, the availability of sensitive in vitro functional assays which are predictive of in vivo pharmacodynamics, and the feasibility and relevance of in vivo testing in a relevant species. With regards to human clinical trials, the concept paper recommends that the biosimilar guidelines should be revised to address the need for pharmacodynamic markers in Phase 1 studies and whether or not a biosimilar product can proceed to pivotal Phase 3 clinical trials if similarity to selected PK parameters have been met but relevant pharmacodynamics markers are not available. The concept paper also recommends updating the guideline to include examples of acceptable surrogate endpoints already recommended in guidelines for specific classes of biosimilar products, defining considerations for acceptance of pharmacodynamics markers for demonstration of clinical similarity, and the possibility of using a non-inferiority design for certain Phase 3 studies.

Given the technical advancements in the development of biosimilars over the past couple of years, it is encouraging to see EMA acknowledging this rapidly changing environment and embracing the idea of updating its original guidelines. The clarification on non-clinical requirements, especially the importance of defining reliable PK/PD markers for biosimilarity, and the possibility of using non-inferiority as an end-point for clinical trials should help accelerate the development and introduction of biosimilar products. The use of non-inferiority as a criterion for approval should allow faster, smaller, and less expensive clinical trials but comes with the disadvantage that such trials may make it more difficult to demonstrate interchangeability of a biosimilar product with the original innovator product. Neither the original guideline nor the current concept paper addresses what criteria would be necessary to establish interchangeability, the holy grail of biosimilars. Our reading of the concept paper and other recent activities and announcements from EMA, as well as the US FDA, suggest we are not likely to see any meaningful pathway towards interchangeability in the US or Europe anytime soon. This is a shame since the true potential for biosimilars will not be met until we have established guidelines for using these products completely interchangeably with the original innovator product as is currently the case for small molecule generic drugs.

Dr. Sheila Magil   (smagilbptccom)  and Dr. Susan Dana Jones  (sjonesbptccom)   will be joined by Joyce Chiu of Sperian Protection to offer a short course on Ensuring Operational Excellence in Bioprocessing: PAT, QbD, DoE and Continuous Improvement – An Introductory Overview at the Bioprocessing Summit to be held from August 22-25, 2011 in Boston, MA. This short course is designed to impart the lessons learned from other industries to the application of Quality by Design, DoE, and PAT in biopharmaceutical production. Dr. Jones will also present a talk in the Optimizing Mammalian Cell Lines track of the main conference on Wednesday August 24, entitled Applying Quality by Design Principles to Candidate Selection and Cell Line Development, where she will demonstrate the advantages of evaluating product quality as early in development as feasible.