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
Figure 1. Developed Markets’ top 10 Biotech Medicines Spending and Expected First Biosimilar9
Current Trends in Biosimilars
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.
Figure 2. Biosimilar Approval Status (9 March 2018)13
US Interchangeability Guidelines
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:
- One or more switching studies should be carried out to demonstrate that patients can alternate between the originator and the biosimilar two or more times without diminished efficacy or safety.
- Sponsors may use extrapolated data to support interchangeability for multiple indications if there is adequate scientific justification.
- Sponsors conducting switching studies are strongly recommended to use a US-licensed originator product.
- Sponsors should carefully consider their product presentation, including the delivery device and container closure system, because differences in presentation compared with that of the originator may affect the FDA's determination of interchangeability.
Supreme Court Decision Erodes ‘Patent Dance’
In another important step, in June 2017, US Supreme Court ruled that biosimilar sponsors need not wait 180 days after FDA approval before launching their products.14
In a unanimous verdict, the Supreme Court justices ruled that the notice period could begin prior to FDA approval—effectively eroding the ‘patent dance’ that is a unique feature of the US market. Sandoz and Amgen, the two parties involved in the case, had been battling since 2014 over conflicting interpretations of the Biologics Price Competition and Innovation Act (BPCIA
Amgen (and others) argued that requirement for 180 days’ notice before marketing should begin at time of FDA approval, essentially providing innovator with a six-month patent extension.
Changes to Phase 3 Trial Requirements Unlikely
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
Strategies for Blocking Biosimilar Development
Innovators have used various strategies to prevent biosimilar availability, including changing the route of administration and developing of a ‘biobetter’ which offers improvements over the reference biologic. For example, AbbVie developed a patented formulation change for adalimumab from 40mg/0.8mL to 40 mg/0.4 mL with the claim there is less injection site-related pain compared with the previous formulation.20
This raises questions about which formulation biosimilar developers should use as a reference product, particularly if the earlier formulation is removed from the market. Some companies are going ahead with using the patented new formulation as the reference product, while others are concerned that this new patent will block them from entering the market.
Switching Concerns Allayed
Initially, biosimilars tended to be used only in treatment-naïve patients, with clinicians expressing reluctance to switching patients to biosimilars when they were already established on an innovator product. A recent systematic literature review conducted by authors in Eastern Europe and the Netherlands has concluded that concerns about switching clinically stable patients from an originator to a biosimilar are “overhyped.”21
The authors reviewed 58 papers (12 empirical papers, five systematic reviews and 41 non-empirical papers). They concluded that “preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access.”
Potential to eliminate costly bridging studies?
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:
- The selected reference biologic is approved in a jurisdiction that has formally adopted the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on comparability.
- The selected reference biologic and the locally licensed reference product share the same pharmaceutical form, route of administration, content of active pharmaceutical ingredient and composition of excipients. If there are excipient differences, data must show these differences do not have any clinical effects.
- There is publicly available evidence that the selected reference biologic and the locally licensed product have been approved based on essentially the same original clinical safety, effectiveness and other data.
Markets Outside the EU and US
Currently, 19 biologics with expiry dates between 2013 and 2019 are being targeted for biosimilar development (Figure 3
), along with a further 18 biologics with patent expiries between 2020 and 2013 (Figure 4
Figure 3. The Current Biosimilars Pipeline (Biologic Patent Expiries in 2013-19)23
Figure 4. The Predicted Biosimilars Pipeline (Biologic Patent Expiries in 2020-30)24
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
Expediting Biosimilar Development Using Secondary Data Sources
An estimated 511 biosimilars are currently in development.29
Biosimilar development continues for the ‘first wave’ of biologics despite the risk of market saturation (Figure 5
Figure 5. Biosimilars in Development for ‘First Wave’ of Biologics30
Most of the ‘second wave’ biosimilars are in early stages of development (Figure 6
Figure 6. Biosimilars in Development for the ‘Second Wave’ of Biosimilars31
Sponsors are advised by regulatory professionals and feasibility experts to select countries that support accelerated startup and enrollment, with features including: acceptance of interim safety data, motivated patients (high disease prevalence and unmet need), limited study competition, short start-up timelines, indication experience and high randomization rate.
Regulatory professionals should be aware that a staggered parallel approach can be used to expedite clinical development timelines (Figure 7).
Figure 7. A Staggered Parallel Approach32
Finding Patients in the US
In a case example, IQVIA set out to identify patients and experienced physicians for a clinical trial of a biosimilar to Lucentis® (ranibizumab). In the US, more than 3,000 physicians that see study-targeted patients (treatment naïve patients with wet age-related macular degeneration or w-AMD, aged 50+) in one year; of these, more than 250 are experienced investigators (black markers on the map (Figure 8
Figure 8. Sample Patient Density Heat Map and Investigator Locations
shows levels of health insurance coverage in the US. The fact that coverage is generally weaker in southern states makes this region potentially more favourable in terms of recruitment.
Figure 9. Health Insurance Coverage in the US
Modeling Tools to Optimize Biosimilar Clinical Trial Protocol Design
The scale and complexity of today’s healthcare data is quite simply unmatched, with 530 million patient records, more than countries including deep clinical Electronic Medical Records (EMR) and claims, and 14.3 million healthcare professionals (Figure 10
). Against this backdrop, trials are more complex, and target patient populations are more tightly defined—and harder to find.
Figure 10. Healthcare Data
This is driving a need to apply real-world insights and advanced analytics before protocol approval to avoid the risk of recruitment issues and amendments (Figure 11
). These tools can be used in conjunction with advice from regulatory professionals. For example, those regulatory professionals savvy in both biosimilars and rare diseases may be able to advise on ways to reduce patient burden and eliminate “nice to have” protocol design features or academically oriented elements of protocol design in favor of recommending only those design elements required by regulators in the geographic market of interest (e.g., decreasing the number of blood draws, making sure that each laboratory test supports or informs a clinical trial endpoint, etc.), thus saving the sponsor, money, and the patient, an unnecessary burden.
Figure 11. Validating and Optimizing a Study Protocol
Data analytics, machine learning and predictive modelling are being used successfully to accelerate study start-up and patient enrolment (Figure 12
). These approaches are applied to delivery strategy to ensure an optimal country mix, selection of the most appropriate patients and sites, minimize risks to quality and meet project timelines.
Figure 12. Enabling Faster Study Start-up and Patient Enrolment
As FDA’s Dr. Scott Gottlieb correctly pointed out, there is no one way to solve the challenges faced by sponsors wishing to market biosimilars. However, important steps forward are being made. The publication of US interchangeability guidelines for biosimilars provides regulatory clarity for sponsors in areas including requirements for switching studies. Another key move was the June 2017 US Supreme Court decision in the case between Sandoz and Amgen. The Supreme Court ruled that biosimilar applicants could provide their 180-day notice of commercial marketing either before or after receiving FDA approval for the biosimilar—thus eroding the ‘patent dance.’ Outside the US, several countries are adopting aggressive strategies, including the UK, where the NHS advises rheumatologists to use biosimilars, Finland, where an approved biosimilar is automatically interchangeable with the innovator biologic and Australia, where biosimilars are a ‘preferred’ for treatment-naïve patients.33
Uncertainties about switching between innovator biologics and biosimilars are increasingly being resolved, with a recent systematic literature review concluding that concerns about switching clinically stable patients from an originator to a biosimilar are “overhyped.” Taken together, these trends hold promise delivering the patient benefits promised by this class of therapies.
- Feuerstein A. “In bid to Lower Prices, Gottlieb Says FDA Will Take new Action to Speed Approval of Biosimilars.” STAT. 28 March 2018. https://www.statnews.com/2018/03/28/gottlieb-biosimilars-fda/. Accessed 21 June 2018.
- Siegel J F and Royzman I. “US Biosimilar Approvals Soar in 2017.” Biologics Blog. 18 December 2017. https://www.biologicsblog.com/us-biosimilar-approvals-soar-in-2017. Accessed 21 June 2018.
- Siegel J F and Royzman I. “Update on Biosimilar Approvals and Pending Applications in Europe and the US. Biologics Blog. 19 May 2017. https://www.biologicsblog.com/update-on-biosimilar-approvals-and-pending-applications-in-europe-and-the-u-s. Accessed 21 June 2018.
- Iliach O and Huml R A. “An Update on the Regulatory Progress of Biosimilars in Canada, the EU and the US.” Canadian Association of Professionals in Regulatory Affairs. https://capra.ca/en/blog/an-update-on-the-regulatory-progress-of-biosimilars-in-canada-the-eu-and-the-us.htm. Accessed 21 June 2018.
- GaBI Online. TGA Approves Three Biosimilars but Fewer Generics in 2017. 2 February 2018. http://gabionline.net/Reports/TGA-approves-three-biosimilars-but-fewer-generics-in-2017. Accessed 21 June 2018.
- Invest Japan. Market Report Biopharmaceuticals and Biosimilars. December 2017. https://www.jetro.go.jp/ext_images/en/invest/attract/pdf/mr_bio_en201712.pdf. Accessed 21 June 2018.
- Press Release: IQVIA Institute for Human Data Science Study: 10 Predictions for Innovation, Spending Drivers and Societal Value of Medicines that Will Transform Global Healthcare in 2018 and Beyond. 13 March 2018. https://www.iqvia.com/newsroom/2018/03/iqvia-institute-for-human-data-science-study-10-predictions-for-innovation. Accessed 21 June 2018.
- Kent D, Rickwood S and Di Biase S. “Disruption and Maturity: The Next Phase of Biologics.” QuintilesIMS White Paper. 2017. https://www.iqvia.com/-/media/iqvia/pdfs/nemea/uk/disruption_and_maturity_the_next_phase_of_biologics.pdf. Accessed 21 June 2018.
- IQVIA Institute: 2018 and Beyond—Outlook and Turning Points. March 2018. https://www.iqvia.com/institute/reports/2018-and-beyond-outlook-and-turning-points. Accessed 21 June 2018.
- Biosimilar News. 28 April 2016. 10 Years of Biosimilar Medicines in Europe: Transforming Healthcare. http://www.biosimilarnews.com/10-years-of-biosimilar-medicines-in-europe-transforming-healthcare. Accessed 21 June 2018.
- European Medicines Agency and European Commission. Biosimilars in the EU. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf. Accessed 21 June 2018.
- Op cit 10.
- IQVIA Biosimilars Global Database and gabionline.net.
- Sandoz Press Release: US Supreme Court Rules in Favor of Sandoz in Biosimilars Case, Enabling Earlier Access to Potentially Life-Saving Medicines. 13 June 2017. https://www.sandoz.com/news/media-releases/us-supreme-court-rules-favor-sandoz-biosimilars-case-enabling-earlier-access. Accessed 21 June 2018.
- McCaffrey K. Amgen, Sandoz Argue Biosimilar Patent Case to the Supreme Court. MM&M. 27 April 2017. https://www.mmm-online.com/legalregulatory/amgn-nvs-biosimilar-supreme-court-amgen-novartis-zarxio/article/653227/. Accessed 21 June 2018.
- Bruce F. “Row Erupts Over “Third Way” for Biosimilar Approvals in Colombia.” The Pink Sheet. 13 October 2017. https://pink.pharmaintelligence.informa.com/PS121753/Row-Erupts-Over-Third-Way-For-Biosimilar-Approvals-In-Colombia. Accessed 21 June 2018.
- Commissioning Framework for Biological Medicines (Including Biosimilar Medicines). NHS England. 12 September 2017. https://www.england.nhs.uk/wp-content/uploads/2017/09/biosimilar-medicines-commissioning-framework.pdf. Accessed 21 June 2018.
- Brennan Z. “Are Biosimilars 'Interchangeable' in the EU? A New Perspective.” RAPS Regulatory Focus. 31 March 2017. https://www.raps.org/regulatory-focus™/news-articles/2017/3/are-biosimilars-interchangeable-in-the-eu-a-new-perspective. Accessed 21 June 2018.
- The Center for Biosimilars. Australian Medical Association Questions Government's Approach to Biosimilars. 23 October 2017. http://www.centerforbiosimilars.com/news/australian-medical-association-questions-governments-approach-to-biosimilars-. Accessed 21 June 2018.
- Healio Rheumatology: New Adalimumab Formulation Associated With Less Injection Site-Related Pain. 20 July 2016. https://www.healio.com/rheumatology/rheumatoid-arthritis/news/online/%7B670022ff-9e2a-43f7-a513-b51f3a575735%7D/new-adalimumab-formulation-associated-with-less-injection-site-related-pain. Accessed 21 June 2018.
- Inotai A, Prins C P J, Csanádi M, Vitezic D, Codreanu C and Kaló Z. “Is there a reason for concern or is it just hype? A Systematic Literature Review of the Clinical Consequences of Switching From Originator Biologics to Biosimilars.” Expert Opin Biol Ther. 2017 Aug;17(8):915-926. Epub 26 June 2017. https://www.ncbi.nlm.nih.gov/pubmed/28650704. Accessed 21 June 2018.
- Webster C J and Woollett G R. “A 'Global Reference' Comparator for Biosimilar Development.” BioDrugs. 2017 Aug;31(4):279-286. https://www.ncbi.nlm.nih.gov/pubmed/28526943; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541093/. Accessed 21 June 2018.
- Therapy areas targeted for clinical trials were predicted based on publicly available information in the databases such as clinicaltrials.gov and IQVIA experience in biosimilar clinical development; sales are reported from IMS MIDAS 2016.
- Japan Pharmaceutical and Medical Devices Agency: Guideline for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics. 4 March 2009. https://www.pmda.go.jp/files/000153851.pdf. Accessed 21 June 2018.
- 26. Taylor N P. “Asia Regulatory Roundup: China's New Biosimilars Guideline and Price Controls.” RAPS Regulatory Focus. 10 March 2015. https://www.raps.org/news-articles/news-articles/2015/3/asia-regulatory-roundup-china-s-new-biosimilars-guideline-and-price-controls-(10-march-2015). Accessed 21 June 2018.
- World Health Organization News Release: WHO to Begin Pilot Prequalification of Biosimilars for Cancer Treatment. 4 May 2017. http://www.who.int/mediacentre/news/releases/2017/pilot-prequalification-biosimilars/en/. Accessed 21 June 2018.
- Analysis by IQVIA Biosimilars Center of Excellence Using Public Sources of Information, Including Company websites (October 2017).
- First Wave (up to 2019): Earliest Patent Expiry Either in the US and EU is Considered. Analysis by IQVIA Biosimilars Center of Excellence Using Public Sources of Information, Including Company websites (October 2017).
- Second Wave (2020-2025): Earliest Patent Expiry Either in the US and EU is Considered. Analysis by IQVIA Biosimilars Center of Excellence Using Public Sources of Information, Including Company websites (October 2017).
- Analysis Based on IQVIA Feasibility Experience.
- Op cit 19.
About the Authors
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 email@example.com.
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.