The Government of India has recently announced certain guidelines regulating the approval of 'similar biologics' also known as bio-similars. The bio-similar market is going to be a huge market opportunity for the generic drug industry. Given the complexity of the products themselves, the regulatory regime for bio-similars is also rather complex. Since none of us on the blog had a detailed understanding of the guidelines, we invited our frequent guest blogger Mr. Christopher Ohly to write us a guest post on the topic. Mr. Ohly, a Partner at Schiff Hardin LLP is a seasoned American litigator in several fields including IP and regulation. As you can see from below Mr. Ohly, has done an exhaustive analysis of the guidelines in contrast to the position in the U.S. He has prefaced that discussion with a brief introduction to the idea of bio-similars and their importance to India.
Since it is difficult to run footnotes on blogger, I've removed all of them from this post but readers who want to read the entire article, footnotes included can download the same from our website over here.
The New India Guidelines
On Similar Biologics
Regulatory and Market Authorization Requirements
By, Christopher Ohly,
October 8, 2012
Biological products are any virus, therapeutic serum, toxin, antitoxin, vaccine, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide) or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man. Biological products are generally produced using a living system or organism, but increasingly may be synthesized using chemical and computational techniques. While “small molecule” drugs have well-defined chemical structures that can be readily and fully characterized, and are “are ideal for replication as generics,” biological pharmaceutical products are not yet as readily replicable in identical forms. Biological pharmaceutical products are usually large, complex molecular structures, whose chemical composition and conformation are important to activity, effectiveness and toxicity.
Biologic products are both therapeutically and economically important. In contrast to other therapeutic agents, such as chemotherapies, biologic products, particularly monoclonal antibodies, are highly selective, offering effective treatments against dreaded diseases with fewer side effects. More than 150 “reference product” biologics have been approved for marketing in the United States. There are more than 370 biopharmaceutical drug products and vaccines in clinical trials targeting more than 200 diseases including cancer, Alzheimer's disease, heart disease, multiple sclerosis, AIDS, and arthritis.
Of the top 10 pharmaceutical products in 2011, by global sales, three (Humira, Enbrel and Remicade) were biologics. In 2010, the combined sales of the top 12 biologic products in the U.S. approached $30 billion. Biologic products are expensive. In the US in 2011, it was estimated that the average cost of a biologic product was $16,000 per year, with the costs for biologic therapies for treatment of some cancers costing as much as $10,000 a month. According to one prediction, by 2014, seven out of the top ten best-selling drugs will be biologic drugs, with sales exceeding $50 billion. The trend will continue, with biologic products increasingly replacing “small molecule” products as the largest generators of sales revenues, if not the preferred therapeutic method.
These market and therapeutic opportunities have led to development of “biosimilars,” or “follow-on biologics,” which are produced by cellular means, not “identical” but therapeutically equivalent (in safety and efficacy) to reference products, and, hopefully, made and sold at substantially lower cost. Current U.S. law defines biosimilarity to mean “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”
Biologics and Biosimilars in India
According to a 2010 report, more than 40 biologics are marketed in India, of which 25 are biosimilars manufactured in India, including insulin, epoetin, filgrastim, streptokinase, and rituximab. Another 25 biosimilar products are in development. The same report states that there “are more than 130 companies in the biopharmaceutical market in India, but “only 7-10 companies are involved in the manufacture of recombinant products.” Although, in the short term, some Indian companies are reportedly targeting unregulated and “semi-regulated” markets, including India itself, price advantages will lead to entry in highly regulated markets, including the EU and United States.
At the same time, changes are coming in the Indian market, as larger pharmaceutical and biologic manufacturers enter the growing Indian market, sometimes in competition and sometimes in joint ventures (or mergers) with Indian pharmaceutical manufacturers:
In 2001 India liberalized foreign direct investment (FDI) norms for the pharmaceutical sector. As a result, 100% FDI was allowed through the 'automatic route' (without prior permission) in pharmaceutical manufacturing (except in sectors using recombinant DNA technology).
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In recent years there have been a number of high-profile MNC acquisitions of Indian pharmaceutical companies, starting with the takeover of Matrix Laboratories by US generic manufacturer Mylan Inc in 2006. This was followed by the Japanese corporation Daiichi's acquisition of India's largest pharmaceutical company Ranbaxy. At times MNCs offered purchase prices which were many times higher than the actual sales turnover of the acquired firms. For instance, Abbott paid $3.7 billion for Piramal Healthcare, whose sales revenue was reported to be approximately $400 million. …
The same period witnessed a series of strategic alliances between MNCs and Indian pharmaceutical companies. … Generally speaking, these strategic alliances take place in any one of the following areas: research and development (R&D), marketing and contract manufacturing. Of the three categories, the dominant form is in the field of contract manufacturing.
The impact of these market changes in India is uncertain, particularly as litigation over patents covering important and expensive products, including biologics, works its way through the Indian courts. Nevertheless, it is inevitable that Indian manufacturers will enter the burgeoning global biosimilars market, and that foreign manufacturers will continue to penetrate the growing Indian market for biologic drugs.
India’s New Biosimilar Guidelines
On June 20, 2012, at the BIO2012 conference in Boston, India’s Department of Biotechnology (DBT) and its Central Drugs Standard Control Organization (CDSC) announced the release of final guidelines for approval of “similar biologics.” The guidelines became publicly available on the Internet a short time later. At BIO, DBT Secretary Maharaj Bhan stated,
"We don't want the global and local industries to be in conflict all the time, there needs to be a more harmonious relationship. It [the guidelines] will give a very clear message to everyone....that the Indian regulatory system is capable of taking a scientific view of things and not necessarily worrying about trivial advantage in one direction or the other."
India’s new guidelines describe a regulatory pathway for a similar biologic claiming to be similar to an already authorized reference biologic. They address pre-market regulatory requirements including the “comparability exercise” for quality, preclinical and clinical studies and describe detailed post market regulatory requirements. They also contain requirements relating to manufacturing processes and quality control. These requirements are themselves similar in many respects to comparable regulatory guidelines in the United States and the EU. While harmonization is far from complete, it appears that, at least in his area, science will dominate and bring different regulatory systems into significant conformity.
The Indian guidelines define a “similar biologic” as a “biological product/drug produced by genetic engineering techniques and claimed to be ‘similar’ in terms of safety, efficacy and quality to a reference biologic, which has been granted a marketing authorization in India by DCGI on the basis of a complete dossier, and with a history of safe use in India.” This definition is not substantively different from definitions offered in US and EU laws and regulations. Unlike US law, neither Indian nor EU guidelines or law distinguish between a “biosimilar” and an “interchangeable” product, leaving choice about therapeutic substitution of a biosimilar for a reference product to physicians and their patients. Unlike US law, neither Indian nor EU law or regulations provide any a period of market or data exclusivity to a biosimilar manufacturer that is able to demonstrate that its product may be freely “switched” for a reference product in any given patient,” without increasing “the risk of using the reference product without such alternation or switch.”
Like the “stepwise approach” taken in the US and EU, India has adopted a “sequential approach” to its consideration of applications to market biosimilars.
According to India’s biosimilar guidelines, “[s]imilar biologics are developed through [a] sequential process to demonstrate the similarity by extensive characterization studies revealing the molecular and quality attributes with regard to the reference biologic.” Through this stepwise approach, “extensive structural and functional characterization of both the proposed product and the reference product” using advance analytical techniques to identify and compare “physico-chemical and biological properties, such as higher order structures and functional characteristics,” not only of “the drug substance of a protein product, but also excipients and product- and process-related impurities,” serves as the “foundation of a biosimilar development program.”
The India Guidelines set forth specific and highly technical requirements for “routine analytical tests” to be employed in a “comparability exercise,” including analytical methods for determination of structural and physicochemical product properties, biological activity, immunological properties, characterization of impurities, and stability testing. Taking this sequential approach, the India Guidelines suggest that the results of such analytical testing may reduce the potential requirement of human and animal clinical testing of biosimilars candidates:
Although the extent of testing of the similar biologic is likely to be less than that required for the reference biologic, it is essential that the testing of the similar biologic be sufficient to ensure that the product meets acceptable levels of safety, efficacy and quality to ensure public health.
Generally, a reduction in data requirements is possible for preclinical and/or clinical components of the development program by demonstration of comparability of product (similarity to authorized reference biologic) and the consistency in production process, which may vary depending on the characteristics of the already authorized reference biologic.
Correspondingly, the India Guidelines, like the US and EU guidances, leave ultimate requirements to science, defined by discussions between product sponsors and regulators.
Under US procedures, after evaluating results of analytical testing that characterizes both the reference product and a proposed biosimilar, the FDA will then determine on a case-by-case basis how much animal and clinical data are required and evaluate the application based on the totality of the evidence. Under the India Guidelines, some information is provided about potential animal studies to be conducted with the approval of India’s Institutional Animal Ethics Committee (IAEC), if such approval is available. The guidelines clearly state that, when characterizing the “immunological properties” of a proposed biosimilar product, “evaluation by animal studies should be performed.”
In case of in vivo toxicity studies, at least one repeat dose toxicity study in a relevant species is required to be conducted. The duration of the study would be generally not less than 28 days with 14 days recovery period. However the duration may vary depending on the dosage and other parameters on case by case basis.
Regarding the animal models to be used, the applicant should provide the scientific justification for the choice of animal model(s) based on the data available in scientific literature. However if the relevant animal species is not available and has been appropriately justified, the toxicity studies need to be undertaken in two species i.e. one rodent and other non rodent species, as per the requirements of Schedule Y with due permission from the RCGM.
Human clinical testing will ordinarily follow analytical and clinical testing. Under the India Guidelines a biosimilars applicant must submit an application to conduct a clinical trial in accordance with previously published CDSCO guidelines. Once such an application is approved, a biosimilar sponsor will be required to conduct several studies designed to establish comparative safety and efficacy in relevant patient populations.
Comparative pharmacokinetic studies should be conducted “in healthy volunteers or patients to demonstrate the similarities in pharmacokinetic characteristics between similar biologic and reference biologic on case to case basis.” Such PK (pharmacokinetic) studies must be performed using dosages “within the therapeutic dose range of reference biologic.” The India Guidelines continue:
A parallel arm design is more appropriate for biologics with a long half life or for proteins for which formation of antibodies is likely or if study is being done in patients. In case of short half life, cross over design may be considered with a scientific justification.
Multiple-dose, comparative, parallel arm steady state PK studies are required for a similar biologic that is used in a multiple dose regimen, where markedly higher or lower concentrations are expected at steady state than that expected from single dose data PK measurements, and where time-dependence and dose-dependence of PK parameters cannot be ruled out.
Similarly, the India Guidelines require human pharmacodynamic studies:
Comparative, parallel arm or cross-over, PD study in most relevant population (patients or healthy volunteers) is required for detecting differences … If PD marker is available in healthy volunteers, PD in healthy volunteers can be done. … The relationship between dose/exposure, the relevant PD marker(s) and response/efficacy of the reference biologic should be well established and used to justify the design. The acceptance ranges for the demonstration of similarity in PD parameters should be predefined and appropriately justified.
Such PD studies are “recommended” when “the PD properties of the reference biologic are well characterized with at least one PD marker being linked to the efficacy of the molecule.”
The India Guidelines appear to mandate at least some additional human clinical trials “to demonstrate the similarity in safety and efficacy profiles between the similar biologic and reference biologic.” To establish similarity, “equivalence trials with equivalence designs (requiring lower and upper comparability margins) are preferred.” Hence, in India, unlike the US, it would seem to be possible, in some circumstances, to employ non-inferiority tests to establish efficacy and aspects of safety in addition to immunogenicity.
As in the US and EU, assessment of adverse events occasioned by administration of a biosimilar product is a critical component of human clinical testing. Hence, the India Guidelines state that the “nature, severity and frequency of adverse events should be compared between the similar biologic and reference biologic and should be based on safety data from a sufficient number of patients treated for an acceptable period of time.” These guidelines add that [e]fforts should be made to ensure that comparative clinical studies have a sufficient number of patients treated for acceptable period of time in order to allow detection of significant differences in safety between similar biologic and reference biologic.”
The India Guidelines add specific post-market surveillance requirements that seemingly will augment or, perhaps, substitute for extensive pre-approval human clinical testing requirements. First, the guidelines require institution of a post-approval Risk Management Plan, designed to monitor and detect both known inherent safety concerns and potential unknown safety signals that may arise from the similar biologics. Such a risk management plan must be submitted along with a biosimilar sponsor’s Market Authorization Application. The Plan must include at least one non-comparative post-marketing clinical study with focus on safety and immunogenicity, designed to confirm that the similar biologic does not have any concerns with regards to the therapeutic consequences of unwanted immunogenicity. However, the India Guidelines provide, “[i]f immunogenicity is evaluated in clinical studies, it is not mandatory to carryout additional non-comparative immunogenicity studies in post-marketing studies.”
The importance of shifting human clinical testing requirements to the speed of approval of a biosimilar may be demonstrated by the experience of Dr. Reddy’s Laboratories (DRL) in approval of its Reditux® (rituximab) biosimilar product. During the November 2010 pre-guidance FDA hearing, a speaker for DRL reported that pre-approval testing of DRL’s rituximab biosimilar required administration of the proposed product to a mere 67 patients, with many more reported in post-market surveillance. Post market surveillance did not show “a single case of immunogenic response in any patient,” with more than 1000 patients treated with DRL’s Reditux after market approval, by the time of the presentation.
The FDA guidances indicate that data derived from a clinical study sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, potentially may be extrapolated to allow the biosimilar to be licensed for one or more additional indications for which the reference product is licensed. For example, relying on clinical testing of a Humira® or Remicade® biosimilars in patients with rheumatoid arthritis, it may theoretically be possible to obtain licensing for sale and use of such biosimilars in patients suffering from psoriasis or Crohn’s disease, which, like rheumatoid arthritis, are thought to be conditions associated with inflammation caused by the production of TNFα (tumor necrosis factor-α) in humans, without substantial or any additional clinical testing.
The India Guidelines state that “[i]n case the reference biologic is used for more than one indication, the efficacy and safety of the similar biologic has to be justified and if necessary demonstrated separately for each of the claimed indications.” They add that [j]ustification will depend on clinical experience, available literature data and whether or not the same mechanism of action is involved in specific indications.” The guidelines thus state that, in India, “extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible,” if certain conditions are met. The list of conditions for consideration of extrapolation is not as long as the list in US guidances, but it is similar in content.
The India Guidelines define a “reference biologic” as “the comparator [used] for head-to-head comparability studies with the similar biologic in order to show similarity in terms of safety, efficacy and quality.” The definition requires that “[o]nly a product that was licensed on the basis of a full registration dossier can serve as reference biologic.” Under the guidelines the reference biologic must be used in all “comparability exercise[s] with respect to quality, preclinical and clinical considerations.”
Under the India Guidelines, the reference biologic “should be licensed in India and should be innovator product.” It should be “licensed based on a full safety, efficacy and quality data.” Hence, “another similar biologic cannot be considered as a choice for reference biologic.”
While the reference biologic must be licensed in India and should be innovator product, it is not necessary, under the India Guidelines for the reference product even to be sold or marketed in India. The India Guidelines may simply recognize that some foreign manufactured biologic products are simply not yet available in India, if only for economic reasons. The India Guidelines appear to permit use of foreign reference biologic products in a comparability exercise, whether or not the reference product is marketed or, under some circumstances, even licensed in India. The critical issue will be whether Indian biosimilar developers and manufacturers are able to obtain sufficient quantities of a foreign reference product to enable all of the required analytical, animal and human clinical testing required by Indian regulators. While this seemingly has not been an extraordinary impediment to date, legal developments may make acquisition of reference product more difficult in the future.
The India Guidelines set forth a series of quality considerations applicable to manufacturing of biosimilar products. Among other things, these guidelines state that the “manufacturing process for similar biologic should be highly consistent and robust.” They set standards for cell lines used in the biosimilar manufacturing process, as well as standards for fermentation and downstream process development, analytical methods, product characterization, stability and specifications. The guidelines generally require that “three consecutive standardized batches which have been used to demonstrate consistency of the manufacturing process should be used” in the quality comparability study. The guidelines mandate that “[h]ead-to-head characterization studies are required to compare the similar biologic and the reference biologic at both levels of drug substance and drug product,” adding that “[d]ifferences … should be evaluated for their potential impact on safety and efficacy of the similar biologic and additional characterization studies may be necessary.” The India Guidelines provide that such a “quality comparison … should employ state-of-the-art analytical techniques, including the analytical methods that are sensitive enough to detect the possibilities of changes to the product,” providing a list of routine analytical tests to be included in the quality comparability exercise.
The India Guidelines represent a major step forward in establishing a rigorous, science-based regime for approval of biosimilars pharmaceutical products, especially for sale and therapeutic use in India. The guidelines mirror similar efforts in the US and EU and, like those “regulated market” guidances, consciously rely upon other guidance documents issued by the International Conference on Harmonization, with a view toward encouraging the manufacture of safe and effective biologic products in India, perhaps at lowered costs, to ensure access to life-saving drugs for many.
Like their counterparts in the US, EU and perhaps elsewhere, the India Guidelines will contribute to harmonization efforts, perhaps ultimately resulting in a globally consistent approach to biologic development and manufacture, reducing the need for redundant clinical trials. The guidelines will likely also contribute enabling certainty to the efforts of both Indian drug manufacturers and others who may enter the burgeoning Indian market, that contemplate significant investment in research, manufacturing facilities, and new means of product marketing.
All of this may well lead Indian manufacturers to become effective competitors in the global market for biologic medicines, both as suppliers of biosimilar products and, soon thereafter, of “biobetters” and innovative new medicines. That contribution to global health, whether encumbered or unencumbered by disputes over exclusivities and patent protection, will be welcomed by all.
[i] The views, positions and opinions expressed in this article are those of the author alone and do not necessarily reflect the views of any of the other partners in Schiff Hardin LLP, or the views of any of the firm’s clients. Nothing in this article is intended to provide legal advice. No attorney-client relationship is established by virtue of this article.