Emerging Global Leaders in Biosimilar Development: Regulatory Guidance and Cost Impact


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Rakesh Chopra, MD

Rakesh Chopra, MD

Gilberto Lopes, MD

Gilberto Lopes, MD

BIOLOGICS PLAY A KEY ROLE in cancer treatment and are the principal components of many therapeutic regimens.1 However, they require complex manufacturing processes, resulting in high cost and occasional shortages in supply, limiting the accessibility of cancer treatment for many patients, more so in developing countries where health-care resources are limited. At the time of their launch, most biologics are patented for several years. 

Patent monopoly of biologics may be strengthened by the provisions of agreements such as the Trans-Pacific Partnership Agreement.2 The Trans-Pacific Partnership is a proposed trade deal between 12 Asia-Pacific countries (no longer including the United States, which withdrew from the agreement in July 2017) that would expand and protect patent rights. This may further impact access to affordable health care.3 

The encouraging news, however, is that several key oncology biologics are nearing their patent expiration, triggering research interest in the development of alternatives such as biosimilars. Biosimilars, which have biologic activity comparable to their corresponding reference drugs and are often more cost-effective, have the potential to enhance treatment accessibility for patients and provide an alternative for decision-makers. Many oncology biosimilars have demonstrated similar efficacy to their reference drugs in clinical4,5 and real-world settings.6 Such studies have prompted regulatory bodies to adopt a more positive opinion of biosimilars even in highly regulated markets, paving the way for the future inclusion of biosimilars in oncology therapy.7 

Regulatory Guidelines 

ACCORDING TO A RECENT ANALYSIS, the leading biosimilar specialists in the world are located in the United States, Europe, and Israel, with other important players being India, China, and Brazil.8 We take a closer look at the regulatory guidance for biosimilar development in these nations. 

Approval of biosimilars by the U.S. Food and Drug Administration (FDA) uses a risk-based “totality of evidence” approach requiring a detailed structural and functional characterization of the biosimilar and the reference biologic.1,9 Extrapolations to different indications are permitted if the mechanism of action and receptors involved for different indications are the same. Any differences do not necessarily preclude extrapolation and are considered in the context of “totality of evidence.” The guidelines further require that the reference drug be licensed by the FDA. Interchangeability is permitted, provided specific guidelines for interchangeability are met. 

“As biosimilars have the potential to revolutionize biologic therapies for cancer and other diseases, every opportunity should be tapped for the benefit of patients, caregivers, health-care providers, payers, and manufacturers.”
— Rakesh Chopra, MD, and Gilberto Lopes, MD

The European Medicines Agency (EMA) recommends a stepwise approach, including a detailed structural and functional characterization of the biosimilar so as to establish similarity between the biosimilar and its reference and ensure previously proven safety and efficacy of the reference biologic applies to the biosimilar.10 Extrapolations to other indications are permitted based only on the availability of appropriate comparability data. The guidelines mandate that the reference drug be registered in the country where approval for the biosimilar is being sought. There is no provision for interchangeability in most European Union countries. The guidelines further recommend that if there are significant differences between the proposed biosimilar and its reference, stand-alone development of the product should be considered. 

Currently, India is the world’s second largest supplier of vaccines and fourth largest supplier of pharmaceuticals11 and is emerging as a global leader in the manufacturing of biosimilars. Consequently, comprehensive regulatory guidelines are in place to monitor the development and approval of biosimilar products in India.12 Conduct of analytic and quality characterization studies, nonclinical studies (pharmacodynamic, cell-proliferation, immunogenicity, and at least one repeat-dose toxicity), and clinical studies (pharmacokinetic/pharmacodynamic, comparative, immunogenicity) is required for biosimilar approval. For clinical studies, the guidelines recommend equivalence study design over noninferiority.12,13 If the reference drug is not marketed in India, then it should have been approved/licensed and marketed in a country belonging to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.14 

Indian regulatory authorities now require specific postmarketing single-arm safety studies to be conducted on at least 200 evaluable patients, followed by comparison of results to historical data on the reference drug.14 These phase IV studies should be completed within 2 years of marketing approval and should have safety as their primary endpoint, with efficacy and immunogenicity as secondary endpoints.15 Extrapolations to different indications are permitted if the mechanism of action and receptors involved for different indications are the same and similarity to the reference biologic has been shown. The guidelines require that the reference drug be licensed in India and should be an innovator drug. There are currently no recommendations on interchangeability. 

Registrations of the biosimilar with the FDA, EMA, Canada, Australia, New Zealand, Japan, or the Swiss Agency for Therapeutic Products (Swissmedic) may constitute a basis for registration in Israel,16 and other countries have comparable regulatory schemes. In Israel, extrapolation to indications for which the biosimilar was not clinically tested is permitted, provided the reference drug is registered for such indications and on the basis of the totality of available information, including quality, safety, and efficacy data, with emphasis on the mechanism of action. As with the other guidelines, the reference drug must be registered in Israel for the biosimilar to obtain registration. Interchangeability is allowed on a physician’s discretion after consultation with the medical institution. 

Biosimilars … have the potential to enhance treatment accessibility for patients and provide an alternative for decision-makers.
— Rakesh Chopra, MD, and Gilberto Lopes, MD

Regulatory authorities in China require the conduct of analytic and quality characterization studies, nonclinical studies (pharmacokinetic/pharmacodynamic, immunogenicity), and clinical studies (pharmacokinetic/pharmacodynamic, immunogenicity); extrapolations are to be considered on a case-by-case basis.13 The reference drug must be approved by the Chinese regulatory agencies and should be an innovator drug; a biosimilar, even if approved, cannot be considered as a reference drug. The guidelines further require the amino acid sequence of the biosimilar and its reference to be the same. There are currently no recommendations on interchangeability. 

As in China, Brazilian authorities also require the conduct of analytic and quality characterization studies, nonclinical studies (pharmacodynamic and cumulative toxicity), and clinical studies (pharmacokinetic/pharmacodynamic, comparative, immunogenicity) for approval.13 Extrapolations are permitted only if the mechanism of action and receptors involved for different indications are the same and safety and immunogenicity have been sufficiently characterized. The guidelines require the reference drug to be registered in Brazil or in another country whose regulatory requirements are similar to those of Brazil. No recommendations are available on interchangeability. 

Pharmacoeconomic Impact 

IN DEVELOPING COUNTRIES such as India, nearly 70% of the population pay for their own health care.17 Most often, the cost of cancer treatments exceeds the average per capita income many times over. Until a few years ago, market analysts expected that biosimilars would cost up to 30% less than their reference drugs.18,19 In recent years, however, cost savings as high as 70% have been observed with the use of biosimilars. 

GLOBAL LEADERS IN BIOSIMILAR DEVELOPMENT

  • The world’s leading biosimilar specialists are located in the United States, Europe, and Israel, with other key players in India, China, and Brazil.
  • Analytic and nonclinical data requirements are similar across nations.
  • Guidelines for extrapolation to indications for which a biosimilar has not been clinically tested vary from country to country.

For example, in Norway, an infliximab biosimilar was initially offered at a 39% discount over the originator drug, but it failed to gain a significant proportion of the market. Subsequently, it was discounted by nearly 70%, and it now represents more than 50% of drug sales.20,21 A similar 70% discount was recently offered for the same biosimilar in Denmark.22 In India and Peru, a rituximab (Rituxan) biosimilar (Reditux) was introduced for the same indications as the originator drug at a 50% lower price.23 

A recent cost-benefit analysis of various biosimilars was performed assuming a year-on-year originator growth of 10%, an increase in the share of originator sales exposed to biosimilar competition from 10% in year 1 to 20% in year 10, biosimilar market penetration of 60%, and a biosimilar price discount due to competition of 35%. Results indicated that potential direct cost savings of $44.2 billion (USD) were expected over a 10-year period from 2014 to 2024.24 These trends illustrate the potentially massive impact of biosimilars on oncology care at the patient and pharmaceutical industry levels. 

Closing Remarks 

REGULATORY AGENCIES in most countries have laid out specific stepwise guidelines for biosimilar development. Analytic and nonclinical data requirements are more or less similar across nations. Since most countries are still debating over interchangeability and extrapolation, it is important that the guidelines are closely reviewed, clearly understood, and implemented. As biosimilars have the potential to revolutionize biologic therapies for cancer and other diseases, every opportunity should be tapped for the benefit of patients, caregivers, health-care providers, payers, and manufacturers.■ 

Acknowledgment: Medical writing assistance was provided by Dr. Disha Dayal from Cactus Communications. 

DISCLOSURE: Drs. Chopra and Lopes reported no conflicts of interest. 

REFERENCES 

1. Abraham J: Developing oncology biosimilars: An essential approach for the future. Semin Oncol 40(suppl 1):S5-S24, 2013

2. Office of the U.S. Trade Representative: The Trans-Pacific Partnership: Leveling the playing field for American workers and American businesses. Available at ustr.gov/tpp. Accessed January 16, 2017

3. Public Citizen: The Trans-Pacific Partnership Agreement threatens access to affordable medicines. Available at www.citizen.org/documents/1-pager%20final%20draft.pdf. Accessed August 17, 2017. 

4. Bagal B, Gawande J, Gujral S, et al: Comparison of the efficacy and safety of rituximab (Mabtheratm) and its biosimilar (Redituxtm) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis. Indian J Med Paediatr Oncol 34:292-298, 2013

5. Blackwell K, Semiglazov V, Krasnozhon D, et al: Comparison of EP2006, a filgrastim biosimilar, to the reference: A phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol 26:1948-1953, 2015

6. Nahon S, Rastkhah M, Ben Abdelghani M, et al: Zarzio®, biosimilar of filgrastim, in prophylaxis of chemotherapy-induced neutropenia in routine practice: A French prospective multicentric study. Support Care Cancer 24:1991-1998, 2016

7. Beck A, Reichert JM: Approval of the first biosimilar antibodies in Europe: A major landmark for the biopharmaceutical industry. mAbs 5:621-623, 2013

8. Visiongain Ltd: Pharma leader series: 25 Top biosimilar drug manufacturers 2016-2026. Available at www.visiongain.com/Report/1627/Pharma-Leader-Series-25-Top-Biosimilar-Drug-Manufacturers-2016-2026. Accessed August 17, 2017. 

9. U.S. Food and Drug Administration: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM291128.pdf. Accessed August 17, 2017. 

10. European Medicines Agency: Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies. Available at www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/ WC500128686.pdf. Accessed August 17, 2017. 

11. Malhotra H: Biosimilars and non-innovator biotherapeutics in India: An overview of the current situation. Biologicals 39:321-324, 2011

12. Government of India: Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India. Available at dbtbiosafety.nic.in/ Files%5CCDSCO-DBTSimilarBiologicsfinal.pdf. Accessed August 17, 2017. 

13. Chauhan MK, Malik S: Regulatory guidelines for approval of biosimilars in India, Europe, Brazil, and China: A comprehensive overview. Int J Pharm Pharm Sci 8:7-11, 2016

14. Central Drugs Standard Control Organization: Regulatory Requirements for Marketing Authorization in India. Available at www.cdsco.nic.in/writereaddata/Proposed%20Guidelines%20for%20Similar%20Biologic%20 2016.pdf. Accessed August 17, 2017. 

15. Brennan Z: India releases new biosimilars guidance. Available at raps.org/Regulatory-Focus/News/2016/03/28/24638/India-Releases-New-Biosimilars-Guidance. Accessed August 17, 2016. 

16. Ben Dori-Alkan C, Bareket E: Biosimilars in Israel: Substantial revisions to the regulatory scheme. Available at www.rcip.co.il/en/article/biosimilars-in-israel-substantial-revisions-to-the-regulatory-scheme/. Accessed August 17, 2017. 

17. Mueller LL: An overview of biosimilars and the biosimilar pathway in India. Available at bricwallblog.wordpress.com/2014/05/21/an-overview-of-biosimilars-and-the-biosimilar-pathway-in-india/. Accessed August 17, 2017. 

18. Muller R, Renner C, Gabay C, et al: The advent of biosimilars: Challenges and risks. Swiss Med Wkly 144:w13980, 2014

19. Blackstone EA, Fuhr JP Jr: Innovation and competition: Will biosimilars succeed?: The creation of an FDA approval pathway for biosimilars is complex and fraught with hazard. Yes, innovation and market competition are at stake. But so are efficacy and patient safety. Biotechnol Healthc 9:24-27, 2012

20. Bloomberg: Bullied in Norway, Merck sees sales of blockbuster dive. Available at www.bloomberg.com/news/articles/2015-04-22/merck-gets-bullied-in-norway-with-remicade-price-war. Accessed August 17, 2017. 

21. GaBI Online: Huge discount on biosimilar infliximab in Norway. Available at www.gabionline.net/Biosimilars/General/Huge-discount-on-biosimilar-infliximab-in-Norway. Accessed August 17, 2017. 

22. FirstWord: ViewPoints: Denmark joins Norway in securing a 60 percent-plus discount for biosimilar Remicade—What impact on the rest of Europe? Available at www.fwbiosimilars.com/viewpoints-denmark-joins-norway-securing-60-percent-plus-discount-biosimilar-remicade-%E2%80%93-what-impact. Accessed August 17, 2017. 

23. Qureshi ZP, Magwood JS, Singh S, et al: Rituximab and biosimilars: Equivalence and reciprocity. Biosimilars 2013:19-25, 2013. 

24. Mulcahy AW, Predmore Z, Mattke S: The cost saving potential of biosimilar drugs in the United States. 2014; Available at www.rand.org/pubs/perspectives/PE127.html. Accessed Aug 23, 2017.



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