The biopharmaceutical market has seen incredible growth. In your opinion, what are the drivers for this growth? Do you see a similar expansion once biosimilars become more prevalent?
Ronak Savla, Scientific Affairs Manager, Catalent; Mike Merges, Director, Strategic Growth – Analytical, Catalent: There are a number of drivers we have seen:
First, the great unmet need to treat diseases that are not adequately treated by small molecule drugs e.g. immunological diseases such as psoriatic arthritis and inflammatory bowel disease, and genetic disorders such as familial hypercholesterolemia. Biologics are being developed for therapy areas not previously addressed, including gene therapies, regenerative medicines (cell therapy), and improved immunotherapies.
Overall, there is increased understanding of disease mechanisms and modeling targets. This better understanding of the pathophysiology and elucidation of targets has allowed diseases, once thought to be “undruggable”, to be potentially treated with orphan drugs, and companies are incentivized by regulators to develop such drugs.
Additionally, the growth in computing power and genetic engineering tools allow scientists to better design and control the architecture of biologic molecules; and to invent new scaffolds, such as bi-functional antibodies, as well as predicting biologic molecules’ characteristics such as stability and aggregation.
High throughput screening (HTS) technologies have sped up development and reduced costs, and pharmaceutical companies are heavily investing in areas such as bioconjugates, bi-specific antibodies and biosimilars. The complex structures of biopharmaceuticals offer high efficacy and fewer side effects, increasing regulatory approval numbers - in 2016, 50% of FDA approvals were for biologics.
David Elder, Independent CMC Consultant: Biologicals are typically amongst the highest costing medicinal treatments on the global market As such, commercial prospects for biosimilars are huge. Many leading biological medicines will lose their patent protections by 2020, with a total worth of in excess of $81 billion in global annual sales.1 Unlike generic medicines many large innovative pharmaceutical companies are currently developing biosimilars. Pfizer recently purchased Hospira1 for $17 billion to gain access to the smaller company’s biosimilar portfolio. In the period up to 2024, direct savings to the US exchequer from biosimilars use are estimated at $44.2 billion.2
Even when biosimilars become more prevalent, there will still be significant opportunities for ongoing expansion. This is because, unlike small molecule generics, biosimilars can still command very high premiums (ca. 40-50% of innovator price) and hence they are very attractive commercial propositions.
Daniel Peckman, MS; Senior Manager, Biochemistry Method Development, Validation and Routine Testing; Eurofins Lancaster Laboratories, Inc.: One main driver for growth in the biopharmaceutical market is the vast variety of approaches and forms of treatment that are now available. For example, advancements in gene therapies, fusion proteins and monoclonal antibodies contribute to various styles of treatment options, which provide more choices for the care giver where historically fewer options were available.
A second driver is advanced customization of the therapeutic itself. Historically, many small molecule based therapeutics treated the patient through systemic levels of a given compound. Biopharmaceuticals offer the chance to treat the illness at its source with increased specificity while limiting impact to the patient. An example of this is the antibody drug conjugate platform that works by delivering a toxin not to every cell but to the site specific antigen-antibody relationship, in essence directing delivery of the therapeutic.
The expansion of biopharmaceuticals in the market will likely continue independent of the prevalence of biosimilars. The reason for this is that biosimilars may be limited to large application populations due to the cost and expected return on the development. The variety of biopharmaceuticals that are niche products will continue to drive development and interest in what can be designed specific for the patient.
While the industry has seen incredible interest in developing biopharma products, are there any limiting factors to this growth?
Savla and Merges: Manufacturing biologics at a commercial level requires sophistication not found in small molecule manufacturing. The “machinery” that produces a biologic is a living cell that must be genetically modified, cryopreserved and then thawed prior to expansion in a bioreactor. The product must then be separated from the cells and cell debris that produced it without its destruction. Manufacturing processes get more complex when dealing with peptides, proteins, antibodies, and cellular therapy product manufacturing.
The regulatory challenges then involved in proving similarity in biosimilars versus originator molecules add further complexity, even once the manufacturing challenges have been overcome.
Elder: Some barriers to growth include a changing regulatory climate (particularly risk-based approaches), patient and physician awareness, understanding and changing perceptions of biosimilars, lack of long-term clinical data and an evolving science base.3
In addition to biosimilars, there are also “non-comparable biotherapeutic products (NCBPs)”, sometimes referred to as “biobetters”, which are available on the global market. NCBPs have typically not undergone the same comprehensive comparability exercises based on quality, safety, and efficacy as biosimilars and this may cause confusion and necessitate greater overall regulatory control.4
Peckman: One of the major limitations to biopharma product development is the regulatory oversight of therapeutics as they progress towards commercialization. Biopharma products have multiple components, or modalities, that will increase the complexity of accurate and comprehensive characterization. As the products become more specialized and require advanced characterization, the regulators must keep pace with determining what is critical to their oversight, and what is not, while understanding the potency and end impact. To make this determination, it is important for both the regulators and the sponsors to interact closely to confirm both parties are in agreement on critical attributes and how to test for them earlier in the product to market timeline.
As the pharmaceutical industry has become more global – what are some concerns pharma companies have in developing and marketing biopharmaceutical and biosimilar products worldwide?
Savla and Merges: The industry is growing rapidly and it is proving difficult to find trained individuals to develop new products, improve the manufacturing and testing processes, and then build enough capacity to manufacture these materials to provide for an increasingly global market.
Clinical development timelines are accelerating, meaning CMC is often a critical path to product approval. Companies need to increase development speed of the most innovative products without sacrificing quality.
The growing demand for biologic medicines is stretching the biopharma industry by adding complexity to operations and supply chain. This complexity is likely to continue growing as new classes (bi-functional antibodies, anti-drug conjugates, and cell and gene therapies) advance and each require unique manufacturing, supply, and quality approaches.
From a regulatory standpoint, if the manufacture of a product is spread across multiple sites to meet global demand, developers need to be concerned about transferring processes and ensuring uniformity. High capital investment is required to build manufacturing facilities, and although single-use technology reduces costs and shortens timelines to build facilities, there is still capital at risk if a product fails or a competitor reaches market first.
With these potential risks in mind, innovators are starting to outsource more services to CDMOs, who can maximize facility utilization and are efficient and effective at taking a drug through development and commercialization.
Elder: The costs of developing biosimilars can be two orders of magnitude greater than for corresponding generic molecules; i.e. $75 to $250 million versus around $2 to $3 million for a generic medicine.1 However, outsourcing of biopharmaceutical development to India and China in an effort to cut costs is unlikely to see large scale take-up, due to significant concerns around sterile quality in these regions.
As biopharmaceutical products become more prevalent do you see their acceptance from patients growing? Do developers of biopharma products have an obligation to consider “patient-centricity” as a key element in their drug development scale-up?
Savla and Merges: With good education provided by primary care physicians, patients see and then experience the benefits from biologic treatments. High efficiency and reduced side effects often translate to one dose in the case of some regenerative medicine therapies, or only a few doses for other biologics; a very desirable patient situation.
‘Patient centricity’ must remain a focus for biopharma developers, despite often being one step away from direct interaction with patients - with doctors and payers in between.
Biologic medicines have become more commonplace in treatment regimens and this has led to greater patient knowledge and acceptance. Biologic medicines now offer a choice where none may have existed previously, and it takes time to increase familiarity - look at the number of diabetes patients who now take ownership of treatment through injected insulin.
Administration of biologic medicines is often complex compared to small molecule drugs. Developers need to evaluate “patient profiles” and assess where and how medicines will be administered; and by who.
Typically, a biologic drug is administered using a device (syringe/ reservoir and needle) and numerous studies have been carried out assessing patients’ experience and acceptance. Manufacturers have developed auto-injectors and on-body infusion pumps to alleviate concerns of needle-phobia, improve patient experience, and ensure the efficacy of the biologic medicines.
Elder: Even when biosimilar molecule(s) have established safety, effectiveness, quality and cost-effectiveness profiles, there is an additional hurdle of clinician and patient acceptability, the so called “fifth hurdle”.5 However, patient outcomes in one country/territory are not directly applicable to others as a result of differences in national proscribing practices, payment schemes, patient values, and regulatory oversight.2
We are still at an early stage of the “evidence based development for biosimilar molecules”, particularly in the US. As such there are pressing needs for high quality clinical, regulatory, and oftentimes analytical comparative data,4 as well as economic information, for all interested parties.5
It has taken regulators almost a decade to fully understand biosimilars and provide guidance on the regulatory expectations, particularly in the field of “analytical similarity”. However, no meaningful thought has been given to physician/patient expectations or trying to explain why the molecules they are being proscribed aren’t “biosame” rather than biosimilar. As such, biosimilars have raised a number of questions and concerns with patients, ranging from the approval process to safety, efficacy and risk (particularly the immunogenic risk factors).6
What do you see as the major industry critical issues over the next five years in regards to biopharmaceutical/biosimilar product development?
Savla and Merges: Increasing costs, complexity, and regulatory scrutiny are the three evident challenges that the industry will continue to face over the next five years on both the scientific and operational sides. The introduction of HTS tools spurred a revolution in small molecule medicines, allowing researchers to be able to synthesize and screen thousands of molecules. However, it also introduced “inflated” molecular properties, which can cause solubility and bioavailability challenges. The use of HTS tools has increased development pipelines, but it will be important to ensure this does not introduce challenges downstream.
Pressures will also continue in finding and training the scientific and engineering talent to increase capacity and meet global demand, to ensure the life-changing medicines have the resources available to ultimately reach the patient.
On the operational side, innovator companies will need to choose a strategic position. For personalized medicines, such as cell therapies, companies will need a model for quick production of small batches. The high costs and cold chain transport have been major barriers for patients in the developing world to access biologic medicines, so future development of biologic medicines for conditions such as malaria may require high volume solutions to minimize cost. Regardless of their strategies, companies will need to solve how to evolve technologies and capabilities, reduce costs, expand capacity, incorporate the strengths of CDMO organizations, and introduce products that demonstrate value to the market, patients and payers.
Elder: Analytical data comparability requirements are likely to increase.5 In addition, the ability to evaluate and trend significant volumes of analytical data generated from orthogonal methodologies that may not be fully aligned, i.e. data that can be conflicting as well as complimentary, will be challenging. Real time review of data for manufacture and release of biosimilars is also an aspirational goal.7 Analytical process control (APC) will likely become common using e.g. model predicted control (MPC) approaches.8 These are some examples of “big data” challenges that requires innovative approaches in the field of biosimilars.
Also, as indicated earlier, sterile quality is a significant challenge and regulatory expectations are likely to continue to rise, as further incidences of product recalls continue to increase. Finally, single use equipment is likely to be the common platform.
References
- Fortune, 2015. Biosimilars may one day save your life. But what are they? http://fortune. com/2015/02/06/biosimilars-what-are-they/. Accessed on 12 November 2017.
- A.W. Mulcahy, Z. Predmore, S. Mattke . 2014. Perspective: the cost savings potential of biosimilar drugs in the United States. RAND.
- J. Crespi-Loften, J.B. Skelton. 2017. The growing role of biologics and biosimilars in the United States: Perspectives from the APhA Biologics and Biosimilars Stakeholder Conference. J. Amer. Pharm. Assoc., 57(5):e15-e27.
- S. Milmo. Labeling of Biosimilars. EMA is under pressure to exert even tighter standards on biosimilars being marketed in Europe. Pharm. Tech. 39(2), 21-22. http://www.pharmtech. com/labeling-biosimilars. Accessed on 12 November 2017.
- A. Lyles. 2015. Biosimilars: patient and physician acceptability is the fifth hurdle to market competition. Generics and Biosimilars Initiative Journal (GaBI Journal), 4(1), 6-7. http:// gabi-journal.net/biosimilars-patient-and-physician-acceptability-is-the-fifth-hurdle-tomarket-competition.html. Accessed on 12 November 2017.
- D. Skingle. Biosimilars: what do patients need to consider? RMD Open, Rheumatic and muculoskeletal diseases. http://dx.doi.org/10.1136/rmdopen-2015-000141. http:// rmdopen.bmj.com/content/1/1/e000141?utm_source=trendmd&utm_medium= cpc&utm_campaign=rmd&trendmd-shared=1&utm_content=Journalcontent&utm_ term=TrendMDPhase4. Accessed on 12 November 2017.
- T. Alosi. Next Generation Biologics Manufacturing: Delivering the Vision. https://cdn. osisoft.com/osi/presentations/2017-uc-emea-london/UC17EU-D2LS04-Biogen-AlosiNext-Generation-Biologics-Manufacturing.pdf. Accessed on 12 November, 2017.
- J. Rantanen, J. Khinast. 2015. The Future of Pharmaceutical Manufacturing Sciences. J. Pharm. Sci., 104(11), 3612-3638.