Demographic Characteristics of the Study Participants
Out of the 107 personnel from the biopharmaceutical industry and representatives from trade associations contacted for the study, 33 agreed to take part. Of those that completed the study, 6 were from Brazil, 4 from Russia, 15 from India, 1 from China, 1 from South Africa, 1 from Turkey and 5 from Mexico. The respondents were senior level executives with a designation of Vice President and above, representing Research and Development, Regulatory, Manufacturing and Marketing divisions of biopharmaceutical companies. The demographic characteristics of the study participants are presented in Table 1.
Biopharmaceutical Industry of BRICS-TM
The study participants had varied experience in the area of biosimilars. More than 58% of the participants belonged to BRICS-TM companies that have been involved in biosimilar development for more than a decade (11 years and above), while 35% of these were engaged in biosimilar development for 6–10 years. There were only 6% of respondents whose companies had experience of < 5 years.
Thirty (90%) of the participating companies were marketing biosimilars. Of these, only 11 (37%) were marketing less than three biosimilar molecules, while most have commercialized between three and ten molecules. Four (13%) companies are marketing more than ten biosimilars in these emerging markets; 59% of these companies are developing products for commercializing in other emerging markets and 78% have an in-house biologics manufacturing facility. Therefore, the nature and characteristics of the companies that took part in this study confirmed their suitability for continuing the interview for the other parts of the questionnaire involving the challenges of biosimilar development and regulatory processes.
Biosimilar Guidelines and Approval Process
Guidelines, Evaluation and Approval Process
In response to a question on the guidelines and approval process for biosimilars, only 26% considered the guidelines to be well defined and transparent with an efficient review process. The guidelines were considered to be evolving with a tedious review process by 64% of respondents and the remaining 10% felt that there was a lack of clarity and transparency with guidelines subject to different interpretation, see Fig. 2.
In India, 13 out of 15 respondents indicated an evolving and tedious regulatory process. Participants noted that the coordination between two government bodies separately reviewing non-clinical (Department of Biotechnology—DBT) and clinical data (Central Drugs Standard Control Organisation—CDSCO) has much scope for improvement. In Mexico too, three out of five respondents indicated the evolving guidelines and tedious regulatory process for biosimilars. Notably in Brazil, four out of six respondents indicated that there were well defined, transparent guidelines and an efficient review process. This could, in part, be attributed to the fact that all meetings between industry and the Agência Nacional de Vigilância Sanitária (ANVISA—the Brazil National Health Surveillance Agency) are recorded and can be retrieved and referred to. With regards to the transparency of the regulatory review process for biosimilars, 43% of BRICS-TM respondents stated that the review process was generally transparent on the main milestones but the decision-making process for each milestone was non-transparent. However, 24% of BRICS-TM reported that the review process was non-transparent.
The participants were asked to rate (on a 5-point scale where 1 = low concern and 5 = significant challenge) the key challenges in the review and evaluation of biosimilar dossiers by the respective country’s regulatory agency. It is notable that all the identified challenges were rated 3 (moderate challenge) and above, indicating that these were all significant issues across the countries (Fig. 3). ‘Process inefficiency’ emerged as the single highest concern with a median rating of 4 and a mode value of 5. ‘Inadequate communication channel between the industry and the agency’ and ‘Lack of consultation with applicant company’ emerged as the second biggest concerns with a median rating of 3.5 and a mode value of 4 for both parameters.
Some of these challenges could be mitigated by the timely provision of appropriate scientific advice from the agency to the company. However, in response to a question on this matter, it appeared that about 60% of respondents across BRICS-TM either did not receive advice or received advice that was inadequate. This concern is more pressing in Russia where there is no possibility of interaction with the Ministry of Health (MoH) on this subject. Notably, all respondents from Brazil confirmed provision of adequacy of scientific advice from ANVISA.
Efficiency and Effectiveness of Approval Process
The approval timelines of biosimilar applications did not emerge as a significant challenge with the BRICS-TM agencies. Most regulatory agencies have an average timeline of 24 months, with CDSCO India and MoH Russia having a shorter timeline of 6–12 months. In Mexico, the average approval timelines by Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) was reported as 9–12 months by the respondents. In India specifically, the most frequent timeline was reported as being 6 months. The expected optimal approval timelines by companies were reported to be in the range of 9–12 months across the BRICS-TM countries, with 9 months being the most frequently reported. The largest gap between the agency practice and the industry expectation occurred in Brazil (12 months). The study participants representing the BRICS-TM countries highlighted an absence of an abridged review pathway, although in Mexico, 80% of respondents indicated an abridged review pathway being followed by their agency. In response to a question on fast-track approvals of biosimilars, 55% of respondents reported that such procedures exist. However very few have had success in availing of such approvals, except in the case of orphan drugs and recently in the case of medicines for the treatment of COVID-19 (e.g., itolizumab was approved by CDSCO India for restricted emergency use in Acute Respiratory Distress Syndrome [ARDS] caused by COVID-19, in July 2020. This monoclonal antibody was approved in India in 2013, and the additional indication was approved via a fast-track procedure).
Most countries require pricing approval for biosimilars before commercialization. This process is not unduly long with timelines ranging from 2 to 6 months.
Reference Biologic Product (RBP) Selection
The BRICS-TM agencies provide clarity in terms of the RBP to be used for each biosimilar development and the list of countries from which sourcing of a foreign acceptable comparator (FAC) is admissible.
While the industry may have clarity around the reference product and the country from which it is expected to be sourced, sourcing of the RBP remains a key challenge.
Multiple Lots of RBP
In order to meet the requirement for statistical justification of analytical similarity of the biosimilar with the original biologic, multiple lots of the reference product need to be sourced, as reported by 29 (88%) of the participants. The exact number of batches are often not specified and may vary from case to case, and it is open to industry interpretation. Individual responses from within countries vary widely but the frequency analysis revealed a mode of 3–10 batches of different ages except South Africa, where it was indicated there was no expectation for multiple batches. The sourcing of multiple batches of the RBP is a significant challenge for industry, as indicated by 70% of the companies. Content analysis of the participants’ comments showed that concurrent availability of multiple lots of the RBP in the market at any given point of time is a key hurdle.
Quantity of RBP
Even if available, the quantity of product required per batch for various tests and studies (characterizations, comparability studies, clinical studies) can be difficult to source. Large quantities of RBP required to perform comparative clinical safety and efficacy studies increases the overall cost of development.
RBP from a Single Drug Substance
The innovator usually manufactures the drug substance on a large scale. Therefore, multiple product batches can come from a single drug substance, which complicates the efforts of biosimilar developers to get drug product batches from different drug substances. Sourcing multiple batches of the same biological substance leads to limited variation in analytical results, which in turn complicates the justification for product specifications with the regulator. In order to remedy such a situation, the biosimilar manufacturer often has to set up stringent analytical specifications, which subsequently results in manufacturing difficulties, such as non-compliance to stringent standards.
Change in Manufacturing Process of RBP
If the innovator decides to change the manufacturing process and obtains approval for the same, a fresh development process with new batches needs to be initiated by the biosimilar manufacturer.
RBP Non-Availability in Open Market
In Russia, a specific issue is that all biologics are procured directly by the government from the distributors, resulting in no availability of the product in the open market for procurement. Consequently, all these factors result in sizable time and cost escalation for the companies developing biosimilars.
Criteria for Biosimilarity
Criteria for biosimilarity encompasses comparative physico-chemical and biological characterization, in vitro non-clinical studies, in vivo safety data and confirmatory clinical safety and efficacy studies.
In response to a question on challenges to prove biosimilarity, the study participants from BRICS-TM rated ‘confirmatory clinical safety and efficacy study’ as their highest concern with a mean rating of 2.4 on a scale of 1 to 3. The most frequent rating value was 3 with 22 of 33 respondents rating this as a ‘significant challenge’. The mean rating of other parameters included ‘comparative physico-chemical and biological characterization (quality)’; and ‘in vitro or in vivo non-clinical study’, which were rated as 2 (i.e., moderate challenge), but not as high as ‘confirmatory clinical safety and efficacy study’ (Fig. 4).
In terms of efficacy and safety studies, the study participants reported that the cost of trials, large sample size for trials, lead time for patient recruitment and significant drop out rates were some of the major operational issues in conducting clinical studies for biosimilars. Companies also face lack of expertise to develop in-house bioassay methods for biosimilars.
Naming of Biosimilars
The BRICS-TM regulatory agencies mandate the same international non-proprietary name (INN) for biosimilars as the RBP, as reported by 30 (90%) of the companies participating in the study. This is different from the approach followed by the US FDA, which expects the nomenclature to be in accordance with ‘Guiding Principles for Coining United States Adopted Names for Drugs’  for each biologic and biosimilar  (Table 2).
As reported earlier in this article, non-clinical studies for biosimilars were not rated as a significant challenge by the study participants from the BRICS-TM countries. Further details from the responses indicated that though non-clinical studies data are mandatory as part of the application, no regulatory agency mandates that studies be performed locally. Content analysis of the free-text comments proposed that the regulatory agencies should move towards a step-wise approach to development and mandate non-clinical data only if absolutely required.
As part of the biosimilar application, most agencies expect data from a phase I study (comparative clinical pharmacokinetic [PK], pharmacodynamic [PD] or combined PK/PD), phase III study (comparative clinical safety and efficacy) and phase IV post-marketing surveillance study (including follow-up study for immunogenicity). A comparative confirmatory clinical study (phase III) is one of the most important requirements to be fulfilled as part of the marketing authorization of the application. In Sect. 3.3.2 of the Results describing criteria for demonstrating biosimilarity, it was reported that the companies taking part in this study rated ‘confirmatory clinical safety and efficacy study’ as the highest concern for them in the development of a biosimilar product.
Mandatory Local Studies
This study needs to be performed locally in India, Mexico, Russia and China and should be comparative in nature; the reference drug needs to be used throughout the study to prove comparative efficacy of the respective biosimilar. Mostly biosimilar applicant companies combine the confirmatory clinical and immunogenicity studies.
Lack of Clarity on Study Design
There exists lack of clarity on certain aspects of these studies, such as study types, population, end points, design, paediatric population, safety pharmacology expectations and follow-up period.
The industry also faces challenges in the following areas:
Approval of clinical trial protocol by the regulatory agency.
Availability of a clinical research organization (CRO).
Lack of specific and binding scientific advice on clinical studies.
These factors were rated by the company participants (Fig. 5) across the BRICS-TM, which showed ‘Lack of specific and binding scientific advice on clinical study design’ to be the single biggest challenge with a mean value of 3.5 and a mode value of 4 (high challenge). ‘Approval of protocol by the agency’ and ‘Patient recruitment’ were rated as the next biggest obstacles. This outcome further validates earlier reported data on inadequacy of scientific advice.
Sample Size for Clinical Studies
The BRICS-TM [15,16,17,18,19,20,21] agencies require confirmatory clinical studies to be performed in two arms with a patient ratio of 1:1 for the test and reference product. The response from countries was markedly variable; however, it was reported that the minimum expectation from the regulatory agencies was 100–200 patients per arm, or based on statistical powering of the trial, whichever was highest.
Considering the time and cost involved in developing and marketing biosimilars, the companies active in this space are those that overcome steep entry barriers and are therefore typically large multi-national players. Despite this, industry players find it difficult to develop a global regulatory strategy for biosimilars covering the emerging markets, due to several hurdles. While 69% of companies indicated that they are pursuing multi-country biosimilar developments including for BRICS-TM countries, they face obstacles on several fronts (Fig. 6).
In response to a question on these challenges, the participants rated ‘Lack of harmonized guideline for biosimilar development across BRICS-TM’ and ‘Absence of common clinical trial design and approval process across BRICS-TM’ as the highest concerns, with a mean of 3.5 on a scale of 1–4 and a mode value of 4 for both. Other issues such as ‘Acceptance of reference biological product across BRICS-TM’ and ‘Acceptance of foreign patients’ data’ were also rated as a ‘significant challenge’, with 4 being the most prevalent rating, signifying all four criteria as critical barriers.
Pricing and Market Access Concern
A Quintiles and IMS Health (IQVIA) article on biosimilars and biobetters published in September 2020  reported that the rest of the world (RoW) countries accounted for US$0.1 billion sales for follow-on biologics (FOBs) including biocomparables versus US$15 billion global sales, as of second quarter 2020. It was concluded that there is an overall low coverage of biologics, and FOBs are an emerging sector where sales remain low. Further, on their own, RoW countries are unable to justify the cost of development for biosimilar projects .
This study delved into the reasons for limited access for patients and entry barriers for the industry. ‘Innovator patent term and strategy’ and ‘Higher cost of therapy of biosimilars as compared to small molecule medicines’ were rated as the highest barriers to access with a mean rating of 3.6 and 3.4, respectively. The next biggest obstacles were rated to be ‘Challenges pertaining to regulatory framework for development and approval of biosimilars’ and ‘Less numbers of active industry players in biosimilar segment’. Apart from the concerns around patent terms of original biologics, the other three challenges can be substantially mitigated by facilitating ease of development and approval of global biosimilars and enabling more competition in this space. Related to this, companies were asked about specific issues that acted as entry barriers into this space. ‘Late and unsure return on investment considering high cost involved’ and ‘Prohibitive cost of clinical trials for biosimilars’ were rated as the highest challenges with a median rating of 4.3 and 4.1, respectively. ‘Lack of in-house expertise and infrastructure in biosimilars’ and ‘Pressure on pricing from health authorities/insurers/procurement authority’ were rated as the second-highest barriers with a median rating of 3.5 and 3.4, respectively (Fig. 7).