BioProcess Blog |

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 On February 9, 2012 FDA issued three draft guidance documents, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Quality Considerations in Demonstrating Biosimilarity to a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.

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.

By Julie Dishman  (jdishmanbptccom)   and Howard Levine  (hlevinebptccom)  

It’s hard to believe fall is already upon us and we all know what that means – cool crisp mornings, changing leaves, football tailgate parties, and the annual BioProcess International Conference. At this year’s meeting, BPTC President and Principal Consultant Dr. Howard Levine  (hlevinebptccom)   will chair an important keynote session on Tuesday, Nov. 1 featuring representatives from FDA and EMA as well as industry discussing the regulatory and technical challenges of bringing biosimilars to the market. Dr. Steven Kozlowski, FDA will present an update on FDA’s impending regulations for biosimilars while Dr. Esa Heinonen, Fimea, will review the recent EMA guidelines for biosimilar monoclonal antibodies. The session will end with Dr. Jay Stout, Merck, discussing the technical, clinical, and manufacturing challenges in developing biosimilars.

In the October Issue of the IBC Insider, Dr. Levine shared his insight on the emerging global biosimilars market in the following Q&A.

1. How long will it take for biosimilars to secure a competitive market share?

It is likely to take significantly longer for biosimilars to gain market share in established Western markets. In fact, the relatively long development times (8-10 years) for biosimilars coupled with the lack of interchangeability and the need to market directly to physicians will make it very difficult for biosimilars to gain market share from established innovator products. Additionally, the price difference between the originator and biosimilar product, a key factor in the success of small molecule generics, is likely to be much lower for biosimilars, reducing the incentive to switch. In non-Western markets, such as Asia and Latin America, where the innovator products have not established themselves, biosimilars are more acceptable and will gain market share much faster. In India, for example, 25 of the 40 approved biologics are biosimilars. Acceptance of these products is quite high, especially since substitution is automatic. It will be interesting to hear from Dr. Esa Heinonen, Fimea, how EMA intends to deal with this issue as they refine their guidelines on biosimilar monoclonal antibodies.

2. What are the greatest obstacles biosimilar products will face in Western markets?

Obstacles for growth of biosimilar products in Western markets range from the technical challenges of demonstrating comparability to the originator product to the high cost of development and manufacturing, the anticipated high marketing costs, and the lack of substitutability. Until substitution is allowed for biosimilars, it will be very difficult for these products to grow. Additionally, there are a substantial number of companies, including traditional generics companies, big pharmaceutical companies, and a host of new companies developing biosimilar products for the largest biopharmaceutical products, so competition is likely to be fierce. Two other key elements of the Biologics Price Competition and Innovation (BPCI) Act that pose significant barriers to entry for biosimilar products in the US are the exclusivity provision giving the innovator 12 years plus an additional 12 years for changes in primary structure or modifications leading to change in safety or potency and the provision requiring biosimilar manufacturers to share their full dossier with the originator company. I am looking forward to hearing from Dr Steven Kozlowski, how FDA will address these significant issues in his keynote address "Overview of Approval Pathway under Biologics price Competition and Innovation Act of 2009."

3. What is the greatest factor that will drive the biosimilar market? Why?

The greatest factor that will drive the biosimilar market is their rapid acceptance in markets where the current biopharmaceutical products are not widely used. The opportunity to bring these products to these markets at prices lower than the current innovator prices will be a significant driver for their acceptance. These lower prices in new markets will put additional pressure on the innovator companies to lower prices in established markets as well. While margins for biopharmaceutical products are quite high, although not as high as traditional branded pharmaceuticals, and because there will be multiple biosimilar products available, prices for biosimilar products will eventually decline to the point where they will gain market share. I am looking forward to hearing Dr. Jay Stout, Merck, explain how the "technical, clinical, and manufacturing challenges will need to be overcome" to enable competition in the biosimilars market and result in reduced cost and improved patient access.

Susan Dana Jones  (sjonesbptccom)  , Vice President and Senior Consultant and Julie Dishman,  (jdishmanbptccom)   Manager, Sales and Marketing, will also attend BPI, touching base with BPTC’s current client portfolio and meeting with companies to explain how BPTC’s broad expertise and vast experience can help companies develop and implement practical and efficient CMC strategies and fulfill their process development, manufacturing, outsourcing, and quality control requirements without adding costly headcount and infrastructure.

BPTC is pleased to be a part of this event that brings together so many innovators in the bioprocessing industry. We look forward to meeting with long-time friends and colleagues and hearing more about the advances in technology, emerging products and companies, and current trends.

See you in Long Beach!

By Sheila Magil  (smagilbptccom)  

The biopharmaceutical industry has been waiting for guidance from the FDA on the approval process for biosimilars since the EMA published its Guideline on Biosimilar Biological Medicinal Products in 2005. Through the enactment of the Biologics Price Competition and Innovation Act of 2009, Congress directed the FDA to develop a process for approval of biosimilars. However, the Agency still has yet to publish a guideline for biosimilar approval.

Kozlowski S, et al offer a hint as to what the published pathway may look like in a recent article titled, “Developing the Nation’s Biosimilars Program,” published in the August 4th issue of the New England Journal of Medicine. Alluding to the EMA experience with approval of biosimilars, the article suggests that a “one size fits all” approach is not likely and that the FDA is unlikely to sign off on a biosimilars route that eliminates the requirement for animal and possibly human studies. It is also doubtful that the Agency will answer questions about the need for these studies without first reviewing the characterization and in vitro data for the proposed biosimilar. What the FDA appears to propose is a stronger Agency-sponsor interaction to identify any necessary animal or human testing and that the decisions will be risk-based and built on the understanding of the underlying mechanism of action. The greater the body of knowledge, the more readily the risk can be evaluated from characterization data alone.

In the end the expectation is that a biosimilar submission will have to include more than simple analytical characterization comparisons. It remains to be seen whether the effort required to gain approval for a biosimilar is reduced sufficiently to support this approach or whether it is more rational to develop a “biobetter” and have 12 years of market exclusivity.

By: Dawn M. Ecker  (deckerbptccom)  , Patti Seymour  (pseymourbptccom)  , and Susan Dana Jones  (sjonesbptccom)  

As more companies express their intent to develop biosimilar products, many have speculated on the impact of these initiatives on global manufacturing capacity. Although some believe that biosimilar development will have a noticeable impact on the need for more capacity, our data suggests a much smaller impact. Product numbers, titer and market share are only a few of the factors which we believe play a role in what we see as the minor impact biosimilars will have on the overall demand for biopharmaceutical capacity.

For there to be a major impact on demand for global biopharmaceutical manufacturing capacity, there would have to be a significant increase in the number of biopharmaceutical products – obviously the number of products on the market or in development define the capacity required to produce them. Within our Biopharmaceutical Product Database, the current biopharmaceutical market and pipeline has approximately 800 products, so for biosimilars to increase the capacity demand by 50%, we estimate that 400 biosimilar products would need to be in development. Although we are seeing an increase in the number of biosimilars in development, we are certainly not seeing the number of products that would create that magnitude of an increase. Even taking the 2018 “patent-cliff” into consideration, there are nearly 30 biologics eligible to be translated into biosimilars, inferring at least 12 biosimilars for each eligible product. For the sake of argument, if several biosimilar products were developed for every one of those “patent-cliff” products – would they gain a significant foothold in the market? This has not been the case for initial biosimilar products launched in Europe, including erythropoietin (EPO) and human growth hormone (hGH), where their market share has been relatively small. According to IMS Health, biosimilar EPO has captured nearly 60% in Germany; however biosimilar hGH accounts for only 4% of the market. Why would the US market be significantly different?

While we do not dispute that there are many companies developing biosimilars, the number of biosimilars in development is nowhere near the number necessary to significantly impact the global biopharmaceutical pipeline and in turn significantly impact the capacity demand for manufacturing. Further supporting this minimal impact on manufacturing is the trend of increasing titers. Even if there were a slight increase in titers for biosimilars, this would only lessen the capacity demand – the higher the titer, the less capacity the product requires.

BPTC understands the concern for a potential capacity shortage is real, however we do not believe that a capacity shortage will be caused by biosimilars. Who can possibly forget the shortage of manufacturing capacity that sent shockwaves through the biotech industry – Immunex’s capacity shortage for manufacturing Enbrel which caused a rationing to rheumatoid arthritis patients because of the unexpectedly high demand? A similar event is not likely to occur as a result of an increase in biosimilar development as there are relatively few biosimilar products in development compared to the number of innovator products in development, titers continue to increase and significant market share for biosimilars is questionable. So, will biosimilars really have an impact on global capacity demand? We think not.