Challenges in the global clinical - PPD

22

Biosimilar medicines

Challenges in the global clinical

development of biosimilar products Authors Joan Boren, Manager Regulatory Affairs, and Costantino Congiatu, Principal Regulatory Affairs Specialist, PPD, Cambridge, UK. Keywords Biosimilar; Clinical trials; Guidelines; Reference medicinal product (RMP); Quality; Efficacy; Safety; Comparability; European Medicines Agency (EMA); US FDA; Japan; China; Russia; Canada; India; Brazil; Colombia; Mexico; Turkey; Germany; France.

Abstract The past five years have witnessed a growth in the development of specific guidelines for biosimilar products by different regulatory authorities worldwide. The so-called overarching guidelines established in the EU in 2005 underwent significant revisions in 2013, with the main goal of facilitating the global development of biosimilars. The World Health Organisation (WHO) published its own guidelines in 2009 and these, together with the European provisions, are being used as a reference in many countries from Latin America (LA), Asia Pacific (APAC) and the Middle East. The number of agencies that have adopted key principles from the US and/or EU guidances is steadily increasing. The common principles underpinning these provisions are effectively contributing to the global alignment on the development of biosimilars, with LA becoming a key market for pharmaceutical and biotechnology companies. However, until specific guidelines are established in other major markets such as Russia and China, it will continue to be difficult for manufacturers to define a truly global development strategy. This article focuses on the latest challenges impacting the global clinical development of biosimilar products. For regulatory professionals, early awareness and a quick reaction to change in a wide range of national laws, including interchangeability, substitution and implementation of technology-transfer legislation, could help developers to move faster into key markets.

Introduction With an estimated US$67 billion worth of patent rights on biological products expiring before 2020 and governments under increasing pressure to reduce the rapidly rising costs of healthcare,1 biosimilars represent a major opportunity for the pharmaceutical industry. Since 2006, 21 marketing authorisation applications (MAAs) have been filed at the European Medicines Agency (EMA), five of which were approved in the past year alone.2 Biosimilar products also have been

Regulatory Rapporteur – Vol 12, No 5, May 2015

registered in Australia, Canada, India, Japan and South Korea. Three biosimilar applications were filed during 2014 at the US FDA under the new 351(k) route by Apotex (pegfilgrastim), Celltrion (infliximab) and Sandoz (filgrastim). In March 2015, Sandoz received the first approval for a biosimilar from the FDA for the same indications as the reference medicinal product (RMP). Evidence of the growing interest in biosimilars is shown by the approximately eightfold increase in the number of clinical trials that have taken place between 2007 and 2014 (see Figure 1). Contributing to the increase in the number of clinical trials was the release of specific guidelines by regulatory authorities worldwide. The EMA was the first authority to address the gap in the regulatory landscape for biosimilars by issuing ad hoc guidelines that came into effect in 2005.3 The introduction of the “similar biological medicinal products” approach and comparability exercise requirements for quality, safety and efficacy clearly defined the distinction between the development of biosimilars and generics. These were followed by guidelines on nonclinical, clinical and quality issues, as well as product-specific guidance. The 2005 guidelines have been updated to better define principles and facilitate global development.4 With clinical benefit already established for the RMP, the main aim of the development programme is to prove similarity between a proposed biosimilar and the originator. In cases where similarity in safety and efficacy cannot be established, or superiority claims are made, the standard development route for new biologics must be used. In the US, the 2009 Biologics Price Competition and Innovation Act (BPCI) provided a legal framework for the 2012 FDA draft guidelines. As previously seen in the European Economic Area (EEA), the FDA has also proposed a step-wise approach for comparability, as well as recommendations for an early engagement with the agency for the review of analytical data and development plans. Data demonstrating biosimilarity to an RMP must derive from analytical, preclinical and clinical studies, including pharmacokinetic (PK), pharmacodynamics (PD) and immunogenicity assessments.5 As outlined in Table 1, several countries have issued specific guidelines for biosimilars. In general, these are broadly in line with the EMA (Australia and Malaysia have adopted the EMA guidance) and WHO principles, requiring full quality information on the biosimilar with side-by-side characterisation with the RMP. In addition, the biosimilar guideline released in February 2015 by the Chinese Regulatory Authority (CFDA) shares similar principles with EMA, FDA and WHO.6 However, key differences exist among countries with regard to the choice of the RMP and extrapolation of indications from the innovator. Furthermore it is worth noting that some countries refer to biosimilar products differently: “subsequent entry biologics” (SEBs) in Canada, “biological products” (as opposed to “new biological products” for innovators) in Brazil or “biocomparables” in Mexico.

www.topra.org

Biosimilar medicines Figure 1: Number of biosimilars clinical trials started between 2007 and 2014.

45

Number of biosimilars trials

40 35 30 25 20 15 10 5 0 2007

2008

2009

2010

2011

2012

2013

2014

Trial start date

Source: Citeline – citeline.com

An exception to the standard comparability requirements for the approval of biosimilars has been put forward by the Colombian agency. Its draft guideline proposes an abbreviated pathway for biosimilars evaluation, in addition to the comparability pathway.7 In the absence of clear specifications on how quality, efficacy and safety requirements should be demonstrated, there is criticism that developers choosing the abbreviated pathway will not be in line with the WHO guidelines and may put patients at risk due to substandard clinical assessment. It remains to be seen whether, in addition to the less contentious comparability exercise, the abbreviated pathway still will be an option for developers aiming at the Colombian market after guidelines are finalised. To date, Russia has not developed specific biosimilars guidelines. However, steps are being taken to achieve harmonisation with global standards, particularly in terms of choice of comparator products.8 Due to the continuous evolution of the regulatory landscape, it is vital to approach regulators to validate the intended development plan.

Clinical development of biosimilars In order to support a successful MAA, comparability must be established step-wise through analytical, nonclinical and clinical assessments. The key objective of clinical trials for biosimilars is to demonstrate comparable safety and efficacy with the RMP. The extent of the clinical investigation to which a proposed biosimilar can be subjected is reduced as compared with that expected for novel biologics. Nevertheless, PK/PD and efficacy/safety trials are

www.topra.org

generally required and must be carried out sequentially. Regulators in fact anticipate PK/PD comparability data arising from a Phase I investigation to support further efficacy/safety assessments in pivotal Phase III trials. Stand-alone Phase III studies, or combined Phase I/Phase III designs without supporting PK data, are unlikely to be accepted according to current guidelines. Clinical comparability requirements may vary on a case-by-case basis subject to a risk-based approach. If a clear dose-response relationship and an accepted PD surrogate marker are available, PK/PD studies can be confirmative for clinical comparability and therefore additional Phase III efficacy/ safety studies may be avoided.9 Three-arm Phase I trials are increasingly being used to demonstrate comparability between the biosimilar and two licensed versions of the same RMP that may exist in different markets. This strategy allows developers to proceed with pivotal trials using a single version of the RMP, and due to the wider comparability shown in the three-arm Phase I trial, resulting data can still support an MAA across regions. Both the EMA and FDA agree on this approach, which was indeed Celltrion’s strategy for the filing of Remsima (infliximab).10 With its newly revised guidelines, the EMA continues to drive harmonisation and its mission to facilitate global development. For instance, an expression system different from that employed in the manufacturing process of the RMP may be used.9 Moreover, subject to robust analytical and nonclinical comparability data, there may even be opportunities for clinical programmes to be carried out exclusively with an RMP not marketed in the EEA. Restrictions on the expected number of EEA patients participating in clinical trials, or


23

24

Biosimilar medicines indeed the necessity to run clinical studies in the EEA, are no longer strict requirements for licensing.9 In terms of sample sizes, although most clinical biosimilar trials use traditional designs often exceeding 500 patients, there is no precise guidance on quantitative standards. Alternative statistical strategies such as the Bayesian method and repeated measures analysis can offer opportunities to reduce sample sizes up to 30% and thus facilitate recruitment targets.11 Due to the potential for differences between the biosimilar and the RMP, immunogenicity profiling is the primary safety aspect that needs to be assessed from the outset of the investigation. In terms of safety requirements for MAA purposes, in situations where immunogenicity has proven not to be a serious risk, the EMA may accept six-month data on the day of filing, with additional six-month data to be submitted during the review period.9 The biosimilar concept may not necessarily be familiar to clinicians and some may not be won over by the perceived lack of innovative research and consistency in quality. It can also be difficult for clinicians and patients alike to justify the potential risk of reduced efficacy, not to mention safety issues, for an investigational product that is expected to be similar to an already marketed and well-known medicinal product. The Norwegian switching study between Remicade and Remsima (NOR-SWITCH) may help address these concerns on biosimilars. The prospect of reduced cost of marketed biosimilars may also motivate patients and investigators to participate in clinical trials.

Source of the reference medicinal product Unless multiple comparators are used in pivotal trials, which can be an extremely costly solution depending on variability across markets, the selection of a common RMP that can support MAAs in different regions is an additional challenge. As previously mentioned, the recently revised EMA guidelines allow the comparison with a product authorised outside the EEA.

Adequate bridging data between the non-EEA authorised comparator chosen for the clinical investigation, its EEA-authorised version and the proposed biosimilar have to be assessed on a case-by-case basis and must include analytical and clinical (PK and/or PD) results. If the RMP sourced outside the EEA is manufactured in an ICH country (eg, Japan and the US) then the EMA will look more favourably on using this RMP as a comparator in a clinical trial in EEA countries. The EMA revised guidelines are effectively operational in Europe. It should be noted that the onus is on the applicant to establish that the batches sourced from outside the EEA are representative of the RMP authorised in the EEA by conducting an extensive analytical comparison. Interestingly, the FDA has made similar provisions with regards to bridging data requirements for RMPs licensed outside its jurisdiction.12 The FDA though has stated that exclusive clinical comparison with a non-US licensed product is unlikely to constitute an adequate basis to support the additional criteria required for a determination of interchangeability with the US-licensed RMP.13 To date, Japan has not aligned with the more flexible approach adopted by the EMA and FDA, with the registration of biosimilars by the Pharmaceuticals and Medical Devices Agency (PMDA) still subject to comparability with a locally licensed RMP.14 However, it may be possible that an RMP sourced from another market can be accepted if demonstrated to be comparable to the product marketed in Japan by means of an analytical comparability exercise and publicly available information, eg, scientific literature. Elsewhere, several countries, including Argentina, Australia, Canada, Egypt, India, Peru, Saudi Arabia and South Korea, accept the use of foreign-sourced RMPs for comparability exercises, subject to having been licensed in highly regulated environments and the availability of adequate bridging data.15–19 Conversely, the Brazilian authority only accepts locally authorised products for comparability purposes; in situations where the chosen comparator is not marketed

Table 1: Countries with specific biosimilars guidelines, and year in which guideline was published in each country. Year of publication

Country with specific biosimilars guidelines

2005

European Union

2007

Australia

2008

Turkey, Malaysia, Taiwan

2009

Korea, Japan, Singapore, (World Health Organisation)

2010

Brazil, Canada, Saudi Arabia, South Africa

2011

Argentina, Cuba, India, Iran, Mexico, Peru

2012

Colombia (draft), Egypt (draft), Jordan (draft), Thailand (draft), United States (draft)

2014

European Union (revised guidelines)

2015

China


www.topra.org

Biosimilar medicines in the country, it is advisable to discuss development plans with the Brazilian agency. In addition to a locally marketed innovator, a licensed biosimilar (biocomparable) can be used as the RMP for biosimilar clinical trials in Mexico.

Regulatory challenges In countries where guidelines for the clinical development of biosimilars have yet to be established, interaction with regulators can be challenging. It is recommended to approach agencies proactively for scientific advice to pre-empt potential questions and avoid delays in clinical trial approval. In most cases reviewers need to be guided through the EMA, FDA and PMDA guidelines. This is important for the following reasons: to receive agency validation of the scientific rationale for the development programme, discuss specific issues, identification of “gaps” in the planned submission package, review of the protein characterisation exercise performed in accordance with ICH Q6B, agreement regarding the source of the RMP, and to ensure assessors are familiar with the biosimilar product before clinical trial applications (CTAs) are submitted. Biosimilars developers need to be aware of the wider regulatory landscape within a chosen country/region in addition to having extensive knowledge of any existing biosimilar approval pathway and the latest agency guidelines. For example, the new EMA quality guideline for biosimilars (EMA/CHMP/BWP/247713/2012)20 that became effective on 1 December 2014 emphasises the importance of establishing the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) during the early stages of product development. The QTPP of a biosimilar should be based on data collected on the chosen RMP, including publicly available information and data obtained from extensive characterisation of the RMP. The QTPP should form the basis for the development of the biosimilar product and its manufacturing process. Regulatory authorities requiring certificates of analysis (CoAs) for the comparator, eg, Ukraine, may pose a risk for the use of a US-marketed product in a global clinical trial. Contrary to European practice, US manufacturers do not tend to make CoAs available to parties involved in the supply chain. Since biosimilars go headto-head against the originator product, it is highly unlikely US manufacturers will support the development of a direct competitor by releasing CoAs for batches purchased for use in clinical trials. Provision of pedigree statements for the RMP is usually accepted as an alternative to a CoA. Moreover, it may also be difficult for a biosimilar manufacturer to procure multiple batches of the RMP with different lot numbers and expiration dates for the inclusion in analytical comparability exercises. Ideally ten or more batches of the RMP with different lot numbers and manufacturing dates should be used in an equivalence testing programme with ten or more batches of the biosimilar to demonstrate statistical proof of similarity.21 Due to the anticipated large patient pool and high-quality clinics, India is very appealing to pharmaceutical and biotechnology companies developing biosimilar products. Newly revised legislation, however, has limited to three the number of clinical trials an Indian investigator may be involved with at any one time. Consequently, the limit imposed can make clinical development of biosimilars even more challenging. In Brazil, the forthcoming clinical dossier of drug development (CDDD) is expected to be implemented in early 2015. The CDDD will bear similarities to the US investigational new drug (IND) filing process and help reduce approval timelines of clinical trials. New submission requirements are expected to impact

www.topra.org

particularly on the quality and manufacturing data package. Similarly, implementation of the new European clinical trials regulation in 2016 will affect the way applications for interventional trials are managed in the EEA. As a preventive action to avoid gaps in the application package impacting on MAA review timelines, the regulatory authority in Mexico has recently been requesting that a positive opinion from the “Comité de Moléculas Nuevas” (New Molecules Committee, CMN) be received as part of the CTA approval process for biosimilars. Clinical trial sponsors are required to attend a meeting with the CMN to discuss in detail quality, nonclinical and clinical information available for the proposed biosimilar, as well as the intended clinical development plan. It should be noted that to date no official guidelines on the additional CMN review have been released and thus developers should factor in extended timelines for clinical trial approval in Mexico. Pharma and biotech companies should evaluate the feasibility of routes to market when considering participation of key countries in clinical trials. Regulations and laws to favour local businesses exist in emerging markets and, therefore, approval for the execution of clinical trials may not necessarily be conducive to successful marketing. In order to exploit these markets to their full potential, developers may require partnerships with local companies. The provisions made in the Brazilian Productive Development Partnership (PDP) legislation and those by the Scientific and Technological Research Council of Turkey (TUBITAK) regulate the technology transfer from foreign to local companies and the joint development between public institutions and private entities. In return, developers joining these national schemes will benefit from an expedited regulatory process, access to restricted funding and, most importantly, exclusive access to public tenders. Conversely, companies outside the PDP and TUBITAK are locked out of public tenders and thus confined to sell only to the retail market in Brazil and Turkey. Innovative conversion and development of the local pharmaceutical industry also is being supported by the “Pharma 2020” strategy in Russia. Favourable conditions to local development play also a major role in China. Based on the analysis of the European public assessment reports (EPARs) for biosimilar products approved by the EMA from 2006 to November 2014,2 the number of clinical studies required to support marketing authorisation varies greatly depending on the product. Minimally, a Phase I study and a Phase III study must be included in the MAA. When the RMP has been approved for multiple indications, claims for the same indications must be justified based on safety and efficacy data. In cases where claimed indications were not part of the biosimilar clinical programme, extrapolation may be accepted. In the EEA, extrapolation claims are possible as long as similar mechanisms of action and receptors are common across indications and studies involve the most sensitive population. However, if differences exist in the mechanism of action, the EMA tends to weigh residual uncertainties against the totality of the data available. This holistic approach has been taken for the approval of Inflectra and Remsima, for which full extrapolation from rheumatoid arthritis and ankylosing spondylitis clinical data was considered sufficient to also support claims on Crohn’s disease, psoriasis, psoriatic arthritis and ulcerative colitis indications.22,23 Health Canada, despite reviewing the same data package, did not allow extrapolation claims for Crohn’s disease and ulcerative colitis. For these indications, additional clinical data were requested.


25

26

Biosimilar medicines As indicated throughout this article, early engagement with regulatory authorities is highly recommended for the development of biosimilars.

The future regulatory landscape Defined regulatory pathways for biosimilars are slowly paving the way towards the goal that key pharmaceutical industry stakeholders have wanted for several years: namely automatic substitution at the pharmacy level. Legislators in the US and Japan have made provisions for interchangeability but, to date, the FDA has not clarified how this can be achieved, and Japan has discouraged automatic substitution. The FDA has indicated that interchangeability likely will be granted in the post-approval setting. The EMA has addressed neither interchangeability nor substitution in its guidelines, but rather it is left to individual member states to deliberate on the matter. According to Germany’s 5th Book of the Social Code (SGB V), automatic substitution is acceptable provided that production of both original and biosimilar products occurred at the same manufacturer site following the same manufacturing process. The French government has taken the approach of including less restrictive provisions in the 2014 country budget.24 Substitution will be allowed, provided (1) the prescribing physician has not marked the prescription as “non-substitutable,” (2) substitution takes place when initiating a course of treatment (or in order to allow the continuation of a treatment that started with that biosimilar) and (3) the biosimilar belongs to the same “similar biologic group” as the prescribed product as established by the French regulatory authority (ANSM). Pharmacists will be required to complete a register and inform the prescribing physician in the event of a substitution. Criteria for inclusion in the “similar biologic group” by ANSM, detailed procedure for the registration by pharmacists in the biosimilar register and more precise conditions for substitution are expected to be further defined with the implementation of the decree. Once this is rectified by its Supreme Court later in the year, France is well placed to be the first member state to effectively open the door to biosimilar substitution despite the fierce attempt by the pharma industry to derail the change.25 How quickly this will be implemented in the rest of the EEA and across the major international markets remains to be seen.

Acknowledgements The authors gratefully thank the PPD Biosimilar Development Services Group (BDSG) for its valuable comments and review; Cecile Daumas, Heba Hashem, Guoliang Liu, Anna Paula Mas, Michael Park, and Paresh Tipare for their input on specific local expertise; and Leona Fitzgerald and Elizabeth Madichie for their help with preparation and review of this article. References 1. GaBI online. 29 June 2012. (http://gabionline.net/Biosimilars/General/ US-67-billion-worth-of-biosimilar-patents-expiring-before-2020) 2. EMA. www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fl anding%2Fepar_search.jsp&murl=menus%2Fmedicines%2Fmedicines.js p&mid=WC0b01ac058001d124&searchTab=searchByAuthType&alreadyL oaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&s tatus=Suspended&status=Refused&keyword=Enter+keywords&searchTy pe=name&taxonomyPath=&treeNumber=&searchGenericType=biosimila rs&genericsKeywordSearch=Submit


3. EMA. Guideline on Similar Biological Medicinal Products, CHMP/437/04, 2005. (www.ema.europa.eu) 4. EMA. Guideline on Similar Biological Medicinal Products, CHMP/437/04 Rev 1, 2014. (www.ema.europa.eu) 5. US FDA. Guidance for Industry, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, Draft Guidance, FDA Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), May 2014. 6. CFDA. Technical Guideline for Development and Evaluation of Biosimilars, CFDA, China, 28 February 2015. 7. Ministerio de Salud y Protección Social, República de Colombia, 3rd draft, 21 January 2013. 8. GaBI online. 31 May 2013. (http://gabionline.net/Biosimilars/News/ Russia-to-harmonize-biologicals-regulations) 9. Presentation by Andrea Laslop, Scientific Office, AGES, Austria, Biosimilar Global Congress 2014 Europe, , London, UK, 17–19 September 2014. 10. Celltrion press release. 11 August 2014. http://www.celltrion.com/en/ company/notice_view.asp?idx=456&code=ennews&intNowPage=1&me nu_num=&align_year=all 11. A J Combest, S Wang, B T Healey, D J Reitsma. ‘Alternative statistical strategies for biosimilar drug development’, GaBI Journal, 3:13-20. 2014. 12. US FDA. Guidance for Industry, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, FDA Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), February 2012. 13. US FDA. Guidance for Industry, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, FDA Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), February 2012. 14. MHLW, Japan. Guideline for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics, Ministry of Health, Labour and Welfare, Japan, 2009. 15. TGA, Australia. Evaluation of biosimilars, Therapeutic Goods Administration, Australia, 2013. 16. Health Canada. Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), Health Canada, 2013. 17. MoH, Egypt. Draft Guideline for Registration of Biosimilar Products. Ministry of Health, Egypt, December 2012. 18. CDSCO, India. Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India, Department of Biotechnology, Central Drugs Standard Control Organisation, Government of India, 2012. 19. KFDA, Korea. Guidelines on the Evaluation of Biosimilar Products, Korea Food and Drug Administration, September 2010. 20. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), EMA, 22 May 2014. 21. M Blüggel. ‘CMC Analytical Comparability Methods and Strategies for Biologics, Biosimilars and Biobetters’, The Masterclass, 18–19 September 2014. 22. EPAR for Inflectra. 23. EPAR for Remsima. 24. Social Security Financial Law No 2013-1203, Journal Officiel de la Republique Francaise, 23 December 2013. 25. Fierce Pharma. (www.fiercepharma.com/story/big-pharma-tries-shortcircuit-frances-move-towards-biosimilar-substitution/2014-04-14).

www.topra.org