Biosimilar drugs, are a new buzz in India, as the market offers a new growth opportunity. The 2016 market of $186 million is expected to reach $1.1 billion in 2020 (Business Standard 19 Feb 2017). As many of the leading biologic products face patent expiry in US and Europe, it is estimated that the global biosimilar market may reach as high as $20 billion by 2020. However, the entry and expansion in biosimilar market are not as easy as entering a chemical generic market. The drug development path for establishing biosimilarity is fraught with multiple challenges – regulatory requirements, preclinical, clinical trials, interchangeability, extrapolation of indications, competition, pricing, medical perceptions etc – posing challenges for industry and prescription dilemma for doctors. The article briefly reviews these issues.
Development challenges
Biosimilar drug development is long, arduous and risky, because of the complex nature of biologic drugs and stringent regulatory requirements to assess biosmilarity.
Biological drugs are therapeutic proteins, and are manufactured from natural sources, including living host systems, such as human and animal cells, yeast, and bacteria. Biological drugs are large size complex structure entities, manufactured by complex processes. They are difficult to characterize, sensitive to storage and handling conditions, and carry high risk of immunogenicity (Table 1). Hence biosimilar development is not just creation of a generic version of biologic. And biosimilar development requires deep expertise, and deep experience in the field. Analysis of marked biosimilar shows difficulties of establishing biosimilarity. Analysis of several biosimilar erythropoietin brands showed large variations in potency 70 to 200 per cent with several brands failing to meet the specifications (European Journal of Hospital Pharmacy Science 2005).
US FDA regulations require that a biosimilar should be highly similar to the reference biologic product notwithstanding minor differences in clinically inactive components. It should be similar in safety, purity, and potency, with no clinically meaningful differences between reference and biosimilar. The drug development process should be stepwise, with consideration of critical importance of analytical and preclinical data (Fig 1). The critical processes are:
1) analytical studies – preclinical structural and functional comparison using state-of-the-art technology
2) animal studies – pharmacokinetic, pharmacodynamic, toxicity, and immunogenicity
3) clinical pharmacokinetic / pharmacodynamic studies
4) additional clinical studies- clinical efficacy, safety, and immunogenicity assessment.
At each step, the sponsor should evaluate the level of residual uncertainty about the biosimilarity of the proposed biosimilar product to the reference product and identify next steps to address that uncertainty. European Medicines Agency (EMA) also considers the critical importance of rigorous analytical testing of biosimilars supported by relevant confirmatory clinical evidence to evaluate the clinical impact of minor changes in structure compared with the reference biologic. EMA refused to approve a recombinant human interferon alpha-2a as the biosimilar product displayed differences in impurity profile, clinical pharmacokinetics and clinical efficacy compared to reference biologic. (Cancer Medicine 2014).
To meet these rigorous regulatory requirements, the company should have robust science-based and data-intensive development process, state-of-the-art technology, and highly sensitive analytical techniques. (Sandoz Development of Biosimilars). The clinical trials to show similarity with reference product should be conducted in population which is sensitive to detect differences in relevant pharmacodynamic activity based endpoints. Such trials should include statistically valid sample size, which can demonstrate equivalence / similarity between reference biologic and biosimilar e.g. for Trastazumab biosimilar clinical trial 806 patients are included. Hence, biosimilar drug development could cost up to $100 to $200 million. (Cancer Medicine 2014).
Indian regulations for biosimilars are not as demanding as FDA or EMA regulations. There is less emphasis on demonstration of biosimilarity during preclinical development, and sample size requirement for clinical trial is not driven by statistical considerations but is fixed - around 100 patients. This has allowed many Indian companies to enter Indian biosimilar market. For developed country markets, the Indian brand would not be accepted as biosimilar, as it has not undergone strict development process required for US or EMA regulatory approval. Hence Indian biosimilar brands are unlikely to have much export potential to US and Europe.
Safety monitoring
Safety of biosimilars is challenging as multiple biosimilars brands are available on Indian marketed. Small differences in biosimilar development and manufacturing process can cause structural changes that can influence safety e.g., immunogenicity. A manufacturing change in Eprex (erythropoietin alfa) was associated with an increase in the incidence of antibody-mediated pure red cell aplasia (PRCA). Kikuzubam®, a biocopy of rituximab was taken off the market in March 2014 due to several reports of anaphylactic reactions when patients switched from the original biologic to this biomimic.
In India, pharmacovigilance reporting system is not robust enough to detect such rare and serious adverse events. Robust pharmacovigilance reporting and analysis of all biosimilars is essential to identify such adverse event signals to attribute causality to a biosimilar brand. It would be desirable to follow international practices in such reporting. EMA requires that all relevant measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report, with due regard to the name of the medicinal product and the batch number. EMA mandates that marketing authorization holders are required to include batch number, brand name, and active substance in such reports (European Medicines Agency 2012). In absence of such a robust pharmacovigilance system, the Indian patients are at risk of serious unexplained adverse event to any biosimilar. It would be necessary to create awareness amongst the prescribers about need for such unique safety monitoring requirement and reporting on biosimilars.
Interchangeability
In India, there is a common medical practice of changing prescription of generics due to cost considerations, or shortage of a brand, or commercial benefits. Interchangeability amongst chemical generics may not lead to therapeutic failure or safety issues for individual patients. However, interchangeability for biosimilar requires additional evidence would be required before a biosimilar could be approved as interchangeable with its reference product. (Cancer Medicine 2014).
Unlike generics, US FDA regulatory approval may not include interchangeability, as US FDA regulations consider a biosimilar interchangeable product if it fulfils the following conditions
n It is biosimilar to an FDA-approved reference product.
n It is expected to produce the same clinical result as the reference product in any given patient.
n Risk in terms of safety or reduced effectiveness of alternating or switching between the interchangeable product and the reference product is not greater than the risk of using the reference product without alternating or switching.
Interchangeability is a higher standard of bio-similarity. Hence, it would be prudent for Indian physicians to avoid changing prescriptions for biosimilars.
Extrapolation of Indications
Another common medical practice is prescription of a drug in off-label unapproved indications. However, this extrapolation of indication also requires regulatory approval.
The regulatory authorities e.g. US FDA could consider approval of extrapolation to an indication if the sponsor company could justify such extrapolation by submitting the following information to support extrapolation:
n Scientific justification for extrapolation
n Mechanism of action for each indication
n Target-binding characteristics, pharmacokinetics, and bio-distribution of the product in different patient populations
n Immunogenicity of the product in different patient populations
n Differences in expected toxicities in each condition of use and patient population
Price competition
In the US, the Congressional Budget Office had estimated that biosimilars will cost 20–40 per cent less than the reference products. (Cancer Medicine 2014). In Europe, the biosimilars are priced at ~10–35 per cent over reference biologic. In contrast, the generic small-molecule drugs are available at 70–80 per cent discount over innovator brand.
In India, there are no official estimates of cost reduction due to biosimilar prescriptions. The market price of recent biosimilar - Trastazumab provides some idea of the estimated cost benefits. The price of Trastazumab 440 mg vial is: Roche Rs 75,000, Biocon Rs 41,000, Zydus 64,000, and others Rs. 50,000.
In fact, when Indian Trastazumab biosimilar came to the market, Roche brought down the price of innovator from Rs 125,000 to 75,000. So, the effective cost reduction with Indian brands is 15-45 per cent. It is expected that price competition for biologics may drive the prices down, and increased patient access to biologics. The companies may create innovative cost saving and patient assistance programs for Indian patients, as most of them can’t afford the current price of biosimilars.
However, the question is: How would the Indian physicians perceive a small cost saving whilst prescribing a high price biologic for a serious condition like cancer? Would small clinical trials of biosimilar in Indian setting convince the physician about comparative safety, purity, and efficacy of biosimilar vis-à-vis the reference biologic approved by US FDA or European Medicines Agency?
Medical perspectives
For physicians, biosimilars as a new drug option, and require consideration of above issues before prescribing them to their patients. A large survey of awareness, knowledge, and perceptions of 1201 US medical specialists, who were high prescribers of biologics e.g. dermatologists, gastroenterologists, hematologist, oncologists, nephrologists, and rheumatologists highlighted a significant need for evidence-based education about biosimilars for physicians. (Adv Ther Sep 2016). The survey showed that most respondents had limited understanding of key concepts of biosimilars and regulatory pathways. There were knowledge gaps in several critical aspects such as
1) definition of biologics, biosimilars, and biosimilarity
2) understanding of regulatory approval process
3) awareness of safety and immunogenicity issues
4) understanding rationale for extrapolation of indications; and
5) recognition of concept of interchangeability.
The survey respondents prefer and trust peer-reviewed literature as the most important information source for biosimilars. Indian medical specialists are likely to have similar challenges in comprehending the new concepts of biosimilarity.
For Indian doctors the dilemma is: How similar are Indian biosimilar to reference biologic? They will require in-depth knowledge and understanding of totality of evidence for establishing biosimilarity at each step from bench to bedside before they feel confident about prescribing these high cost new treatment alternatives to their patients.
(The author is Consultant – Clinical Research & Development)