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Communication Strategies. Case Studies. Applied Knowledge.
Hear from leaders around the globe as they share insights about their experiences and lessons learned throughout their certification journey.
Raymond A. Huml, MS, DVM, RAC • Jill Dawson, PhD • Oxana Iliach, PhD • Charu Manaktala, MD, MBBS • Nigel Rulewski, MD
Feature Articles | 25 June 2018 | Citation
This article discusses innovative approaches to expediting biosimilar drug development. As sponsors of biosimilars seek additional efficiencies to get to the market more quickly, it behooves regulatory professionals to become aware of the different tactics and options that biosimilar drug developers can employ to bring copies of expensive biologics to the global market not only more quickly, but more broadly and less expensively.
The biosimilars market continues to expand with $19 billion of current biotech spending predicted to be exposed to biosimilar competition for the first time in 2018. With at least 240 biosimilars in development, further growth is forecast. The European Union continues to lead the way, with more than 400 million patient days of positive clinical experience to date. Biosimilars have promise in expanding patient access to biologics. For example, in five countries in the EU alone (France, Germany, Italy, Spain and the UK), biosimilars increased patient access by 44% between 2006 and 2014. To increase patient access further, this article provides regulatory professionals an overview of current trends in biosimilars and discusses novel ways to expedite their development.
In his speech on 28 March 2018, US Food and Drug Commissioner Scott Gottlieb, MD noted that he does not foresee an imminent solution to the stagnation that biosimilar developers are facing in the US other than to note that, “It’s going to be a slow build.” 1 At present, nine biosimilars have been approved in the US,2 with at least 40 approved in the European Union,3 at least seven in Canada,4 13 in Australia,5 and 10 in Japan.6 In 2018, $19 billion of current biotech spending was forecast to be exposed to biosimilar competition for the first time in one or more of the developed markets, significantly more than the $3 billion that became exposed in 2017, and adding to the $26 billion already facing competition, according to the IQVIA Institute (January 2018).7 “The new exposure to competition in 2018 is the largest single-year change to date and signals the start of the next large wave of biosimilars,” according to the IQVIA Institute (Figure 1). Looking ahead, “a rich pipeline with over 240 biosimilars in development (including only those which are announced publicly) will mean that launches will be coming with increasing frequency and there will greater competition within each molecule,” notes an IQVIA white paper.8
More than 400 million patient days of positive clinical experience have been generated since the first biosimilar was launched in Europe in 2006.10 The post-marketing evidence acquired over 10 years of clinical experience shows that biosimilars approved through EMA can be used as safely and effectively in all their approved indications as other biological medicines, according to the EMA’s website.11
Regulatory professionals should note that the 50 or so new biosimilars in clinical development (in the US and EU) are forecast to extend patient access based on price competition across Europe and the US through 2020, once necessary policy measures are in place. Since their EU launch, biosimilar medicines increased patient access by 44% in five EU countries (France, Germany, Italy, Spain and the UK) between 2006 and 2014. 12
Currently, approved biosimilars are shown in Figure 2. In general, their US Summary Basis of Approval documents (or Scientific Advice in the EU) can be used by regulatory professionals to “reverse engineer” a likely regulatory pathway for second or later in class biosimilars, though it should be noted that all protocol designs should be fully vetted by the regulators prior to implementation.
Long awaited by regulatory professionals, US interchangeability guidelines for biosimilars were issued in April 2017. These require demonstration of pharmacokinetic (PK) equivalence, which makes the clinical trials very demanding for patients, as well as being long and expensive. The question remains as to whether confirmation of interchangeability provides any advantage for sponsors whose products are not first to market. At present, US insurance companies are requiring patients to use biosimilars when they are available and refusing to pay for use of the innovator product—essentially assuming the biosimilar is interchangeable with the innovator product.
Key elements in the guidelines include:
Multiple questions were raised at a recent DIA Biosimilars Conference (24-25 October 2017; Bethesda, Maryland) about whether there would always be a need to conduct Phase 3 comparative trials for biosimilars. Delegates also questioned whether there is enough confidence in the predictive value of the Chemistry, Manufacturing and Controls (CMC) package to assure equivalence. Responses from the regulatory agencies indicated changes in these areas, in the near future, are highly unlikely.
Interestingly, in Colombia, in an effort to get affordable medicines on the market, new proposed legislation sets out a controversial ‘abbreviated comparability route’ which reduces the requirement for comparative data (except for immunogenicity testing).16 Under this proposal, the reference biologic would not need to be approved in Colombia.
Other countries are also adopting aggressive strategies, with the UK National Health Service (NHS) advising rheumatologists to use biosimilars,17 Finland considering an approved biosimilar to be automatically interchangeable with the innovator product,18 and Australia viewing biosimilars as ‘preferred’ for treatment-naïve patients.19
Presently, the first step in clinical development of a biosimilar is to demonstrate PK equivalence between the proposed biosimilar and both the EU and US marketed products. Experts are proposing this requirement for both regions is unnecessary, calling for the acceptance of “global reference comparator,”22 when certain criteria are met:
In Japan, biosimilars are regulated under the 2009 Guideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products.25 Specific requirements for biosimilar development center around the selection of a reference product, consultation with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) and inclusion of Japanese patients in clinical trials. Operational difficulties include patient recruitment and marketing strategy.
Guidance on biosimilars was finalized by the China Food and Drug Administration (CFDA) in 2015,26 clarifying biosimilars will follow the new drug approval pathway and are defined as being similar to reference products approved in China or overseas. The final text also says manufacturers should source samples used in comparative tests from the same production plant. The CFDA is understood to be committed to reducing timelines for clinical trial approvals and to streamlining regulations.
The World Health Organization (WHO) has launched a pilot prequalification program for biosimilars for cancer treatment.27 The WHO describes the effort as “a step toward making some of the most expensive treatments for cancer more widely available in low- and middle-income countries.” If the agency finds the biosimilars submitted for prequalification are comparable to originator products in terms of quality, safety and efficacy, the medicines will be listed by the WHO and become eligible for procurement by United Nations agencies.
The WHO also announced plans to review its 2009 Guidelines on the evaluation of similar biotherapeutic products to ensure that this guidance to national regulatory authorities reflects recent evidence and experience.28
Regulatory professionals should be aware that a staggered parallel approach can be used to expedite clinical development timelines (Figure 7).
Raymond A. Huml, MS, DVM, RAC, is vice president of IQVIA’s Biosimilars Center of Excellence and Head of Global Biosimilars Strategic Planning. He works with IQVIA’s experts to provide an end-to-end biosimilars solution to the biopharmaceutical industry. Huml has almost 30 years of experience in the healthcare industry and formerly led the global due diligence group for Quintiles Corporate Development. Huml earned his Doctor of Veterinary Medicine at North Carolina State University and Master of Science in biology at East Stroudsburg University. He holds RAPS US Regulatory Affairs Certification (RAC). He can be contacted at Raymond.Huml@IQVIA.com.
Jill Dawson, PhD, has been a consultant to the IQVIA Corporate Communications team for more than 10 years, collaborating across the organization to develop and execute external and internal initiatives. Dawson directs all aspects of corporate communications, including major pharmaceutical programs, social and traditional media relations, writing and editing. She has a PhD in life sciences from Imperial College London (UK). She can be contacted at firstname.lastname@example.org.
Oxana Iliach, PhD, advises on the development of global regulatory strategy and biosimilars CMC. She has provided regulatory support for multiple biosimilar products. She has more than 15 years of experience in the healthcare industry in North America and Russia, including the last 10 years in regulatory affairs at pharmaceutical and biotechnology companies. She holds a PhD in pharmaceutical science from St. Petersburg Chemical and Pharmaceutical Academy and a MS in physical chemistry from St. Petersburg State University, Russia. She can be contacted at Oxana.Iliach@IQVIA.com.
Charu Manaktala, MD, is senior medical director and head of the Asia Pacific Biosimilars Centre of Excellence and Head of Clinical Strategy, Strategic Drug Development-Asia at IQVIA. With more than 20 years of healthcare industry experience, Manaktala has expertise across clinical development and post authorization lifecycle management. She holds an MD in pediatrics from the University of Delhi, India. She can be contacted at Charu.Manaktala@IQVIA.com.
Nigel Rulewski, MD, is vice president, strategic drug development and head, Biosimilars Center of Excellence at IQVIA. In this role, he works with companies around the world advising on drug development strategies. His experience spans multiple therapeutic areas, particularly oncology, respiratory medicine and biosimilars. Rulewski earned his medical degree from St. Bartholomew’s Medical School, University of London. After completing his training in pediatrics and obstetrics and gynecology, he practiced in the UK, in both London and Guildford. He can be contacted at Nigel.Rulewski@IQVIA.com.
The authors wish to thank Tracy Stewart, director and therapeutic strategy lead for IQVIA, for her help creating the slides in Figure 3.
Cite as: Huml R A, Dawson J, Iliach O, Manaktala C and Rulewski, N. “Trends in Biosimilars: Innovative Approaches to Expediting Development.” Regulatory Focus. June 2018. Regulatory Affairs Professionals Society.