The new-india-biosimilar-guidelines

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The new-india-biosimilar-guidelines

  1. 1. Christopher Ohly The New India Guidelines on Similar Biologics The New India Guidelines On Similar Biologics Regulatory and Market Authorization Requirements By, Christopher Ohly, Partner, Schiff-Hardin. October 8, 2012 Overview1Biological products are any virus, therapeutic serum, toxin, antitoxin, vaccine, bloodcomponent or derivative, allergenic product, protein (except any chemicallysynthesized polypeptide) or analogous product applicable to the prevention, treatmentor cure of diseases or injuries of man.2 Biological products are generally produced usinga living system or organism, but increasingly may be synthesized using chemical andcomputational techniques.3 While “small molecule” drugs have well-defined chemicalstructures that can be readily and fully characterized, and are “are ideal for replicationas generics,”4 biological pharmaceutical products are not yet as readily replicable inidentical forms. Biological pharmaceutical products are usually large, complexmolecular structures, whose chemical composition and conformation are important toactivity, effectiveness and toxicity.Biologic products are both therapeutically and economically important. In contrast toother therapeutic agents, such as chemotherapies, biologic products, particularlymonoclonal antibodies, are highly selective, offering effective treatments againstdreaded diseases with fewer side effects.5 More than 150 “reference product” biologicshave been approved for marketing in the United States. There are more than 370biopharmaceutical drug products and vaccines in clinical trials targeting more than 200diseases including cancer, Alzheimers disease, heart disease, multiple sclerosis, AIDS,and arthritis.Of the top 10 pharmaceutical products in 2011, by global sales, three (Humira, Enbreland Remicade) were biologics. 6 In 2010, the combined sales of the top 12 biologicproducts in the U.S. approached $30 billion.7 Biologic products are expensive. In theUS in 2011, it was estimated that the average cost of a biologic product was $16,000 peryear, with the costs for biologic therapies for treatment of some cancers costing as muchas $10,000 a month.8 According to one prediction, by 2014, seven out of the top tenbest-selling drugs will be biologic drugs, with sales exceeding $50 billion.9 The trend 1
  2. 2. Christopher Ohly The New India Guidelines on Similar Biologicswill continue, with biologic products increasingly replacing “small molecule” productsas 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” buttherapeutically 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 notwithstandingminor differences in clinically inactive components” and that “there are no clinicallymeaningful differences between the biological product and the reference product in termsof the safety, purity, and potency of the product.”10 Biologics and Biosimilars in IndiaAccording to a 2010 report, more than 40 biologics are marketed in India, of which 25are 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 thebiopharmaceutical market in India, but “only 7-10 companies are involved in themanufacture of recombinant products.”11 Although, in the short term, some Indiancompanies 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 pharmaceuticaland biologic manufacturers enter the growing Indian market, sometimes in competitionand sometimes in joint ventures (or mergers) with Indian pharmaceuticalmanufacturers:In 2001 India liberalized foreign direct investment (FDI) norms for the pharmaceuticalsector. As a result, 100% FDI was allowed through the automatic route (without priorpermission) in pharmaceutical manufacturing (except in sectors using recombinantDNA technology). *****In recent years there have been a number of high-profile MNC acquisitions of Indianpharmaceutical companies, starting with the takeover of Matrix Laboratories by USgeneric manufacturer Mylan Inc in 2006. This was followed by the Japanese corporationDaiichis acquisition of Indias largest pharmaceutical company Ranbaxy. At timesMNCs offered purchase prices which were many times higher than the actual sales 2
  3. 3. Christopher Ohly The New India Guidelines on Similar Biologicsturnover of the acquired firms. For instance, Abbott paid $3.7 billion for PiramalHealthcare, whose sales revenue was reported to be approximately $400 million. …The same period witnessed a series of strategic alliances between MNCs and Indianpharmaceutical companies. … Generally speaking, these strategic alliances take place inany one of the following areas: research and development (R&D), marketing andcontract manufacturing. Of the three categories, the dominant form is in the field ofcontract manufacturing.12The impact of these market changes in India is uncertain, particularly as litigation overpatents covering important and expensive products, including biologics, works its waythrough the Indian courts.13 Nevertheless, it is inevitable that Indian manufacturers willenter the burgeoning global biosimilars market, and that foreign manufacturers willcontinue to penetrate the growing Indian market for biologic drugs.14 India’s New Biosimilar GuidelinesOn June 20, 2012, at the BIO2012 conference in Boston, India’s Department ofBiotechnology (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."15India’s new guidelines describe a regulatory pathway for a similar biologic claiming tobe similar to an already authorized reference biologic. They address pre-marketregulatory requirements including the “comparability exercise” for quality, preclinicaland clinical studies and describe detailed post market regulatory requirements. Theyalso contain requirements relating to manufacturing processes and quality control.These requirements are themselves similar in many respects to comparable regulatoryguidelines in the United States and the EU. 16 While harmonization is far fromcomplete, it appears that, at least in his area, science will dominate and bring differentregulatory systems into significant conformity.17 3
  4. 4. Christopher Ohly The New India Guidelines on Similar Biologics Basic PrinciplesThe Indian guidelines define a “similar biologic” as a “biological product/drugproduced by genetic engineering techniques and claimed to be ‘similar’ in terms ofsafety, efficacy and quality to a reference biologic, which has been granted a marketingauthorization in India by DCGI on the basis of a complete dossier, and with a history ofsafe use in India.” 18 This definition is not substantively different from definitionsoffered in US and EU laws and regulations. Unlike US law, neither Indian nor EUguidelines or law distinguish between a “biosimilar” and an “interchangeable” product,leaving choice about therapeutic substitution of a biosimilar for a reference product tophysicians and their patients. Unlike US law, neither Indian nor EU law or regulationsprovide any a period of market or data exclusivity to a biosimilar manufacturer that isable to demonstrate that its product may be freely “switched” for a reference product inany given patient,” without increasing “the risk of using the reference product withoutsuch alternation or switch.”19 Analytical StudiesLike the “stepwise approach” taken in the US and EU, India has adopted a “sequentialapproach” to its consideration of applications to market biosimilars.20According to India’s biosimilar guidelines, “[s]imilar biologics are developed through[a] sequential process to demonstrate the similarity by extensive characterizationstudies revealing the molecular and quality attributes with regard to the referencebiologic.” 21 Through this stepwise approach, “extensive structural and functionalcharacterization of both the proposed product and the reference product” using advanceanalytical techniques to identify and compare “physico-chemical and biological properties,such as higher order structures and functional characteristics,” not only of “the drugsubstance of a protein product, but also excipients and product- and process-relatedimpurities,” serves as the “foundation of a biosimilar development program.”22The India Guidelines set forth specific and highly technical requirements for “routineanalytical tests” to be employed in a “comparability exercise,” including analyticalmethods for determination of structural and physicochemical product properties,biological activity, immunological properties, characterization of impurities, andstability testing.23 Taking this sequential approach, the India Guidelines suggest that theresults of such analytical testing may reduce the potential requirement of human andanimal clinical testing of biosimilars candidates: 4
  5. 5. Christopher Ohly The New India Guidelines on Similar BiologicsAlthough the extent of testing of the similar biologic is likely to be less than thatrequired for the reference biologic, it is essential that the testing of the similar biologicbe sufficient to ensure that the product meets acceptable levels of safety, efficacy andquality to ensure public health.Generally, a reduction in data requirements is possible for preclinical and/or clinicalcomponents of the development program by demonstration of comparability of product(similarity to authorized reference biologic) and the consistency in production process, whichmay vary depending on the characteristics of the already authorized referencebiologic.24Correspondingly, the India Guidelines, like the US and EU guidances, leave ultimaterequirements to science, defined by discussions between product sponsors andregulators. Clinical TestingUnder US procedures, after evaluating results of analytical testing that characterizesboth the reference product and a proposed biosimilar, the FDA will then determine on acase-by-case basis how much animal and clinical data are required and evaluate theapplication based on the totality of the evidence. 25 Under the India Guidelines, someinformation is provided about potential animal studies to be conducted with theapproval of India’s Institutional Animal Ethics Committee (IAEC), if such approval isavailable. The guidelines clearly state that, when characterizing the “immunologicalproperties” of a proposed biosimilar product, “evaluation by animal studies should beperformed.”26In case of in vivo toxicity studies, at least one repeat dose toxicity study in a relevantspecies is required to be conducted. The duration of the study would be generally notless than 28 days with 14 days recovery period. However the duration may varydepending on the dosage and other parameters on case by case basis.Regarding the animal models to be used, the applicant should provide the scientificjustification for the choice of animal model(s) based on the data available in scientificliterature. However if the relevant animal species is not available and has beenappropriately justified, the toxicity studies need to be undertaken in two species i.e. onerodent and other non rodent species, as per the requirements of Schedule Y with duepermission from the RCGM.27 5
  6. 6. Christopher Ohly The New India Guidelines on Similar BiologicsHuman clinical testing will ordinarily follow analytical and clinical testing.28 Underthe India Guidelines a biosimilars applicant must submit an application to conduct aclinical trial in accordance with previously published CDSCO guidelines.29 Once suchan application is approved, a biosimilar sponsor will be required to conduct severalstudies designed to establish comparative safety and efficacy in relevant patientpopulations.30Comparative pharmacokinetic studies should be conducted “in healthy volunteers orpatients to demonstrate the similarities in pharmacokinetic characteristics betweensimilar biologic and reference biologic on case to case basis.” Such PK(pharmacokinetic) studies must be performed using dosages “within the therapeuticdose range of reference biologic.” The India Guidelines continue:A parallel arm design is more appropriate for biologics with a long half life or forproteins 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 scientificjustification. *****Multiple-dose, comparative, parallel arm steady state PK studies are required for asimilar biologic that is used in a multiple dose regimen, where markedly higher orlower concentrations are expected at steady state than that expected from single dosedata PK measurements, and where time-dependence and dose-dependence of PKparameters cannot be ruled out. 31Similarly, the India Guidelines require human pharmacodynamic studies:Comparative, parallel arm or cross-over, PD study in most relevant population (patientsor healthy volunteers) is required for detecting differences … If PD marker is available inhealthy volunteers, PD in healthy volunteers can be done. … The relationship betweendose/exposure, the relevant PD marker(s) and response/efficacy of the reference biologicshould be well established and used to justify the design. The acceptance ranges for thedemonstration of similarity in PD parameters should be predefined and appropriatelyjustified.32Such PD studies are “recommended” when “the PD properties of the reference biologicare well characterized with at least one PD marker being linked to the efficacy of themolecule.”33 6
  7. 7. Christopher Ohly The New India Guidelines on Similar BiologicsThe India Guidelines appear to mandate at least some additional human clinical trials “todemonstrate the similarity in safety and efficacy profiles between the similar biologicand reference biologic.” To establish similarity, “equivalence trials with equivalencedesigns (requiring lower and upper comparability margins) are preferred.”34 Hence, inIndia, unlike the US, it would seem to be possible, in some circumstances, to employnon-inferiority tests to establish efficacy and aspects of safety in addition toimmunogenicity.35As in the US and EU, assessment of adverse events occasioned by administration of abiosimilar product is a critical component of human clinical testing. Hence, the IndiaGuidelines state that the “nature, severity and frequency of adverse events should becompared between the similar biologic and reference biologic and should be based onsafety data from a sufficient number of patients treated for an acceptable period oftime.” These guidelines add that [e]fforts should be made to ensure that comparativeclinical studies have a sufficient number of patients treated for acceptable period of timein order to allow detection of significant differences in safety between similar biologicand reference biologic.”36The India Guidelines add specific post-market surveillance requirements that seeminglywill augment or, perhaps, substitute for extensive pre-approval human clinical testingrequirements. First, the guidelines require institution of a post-approval RiskManagement Plan, designed to monitor and detect both known inherent safety concernsand potential unknown safety signals that may arise from the similar biologics. Such arisk management plan must be submitted along with a biosimilar sponsor’s MarketAuthorization Application. 37 The Plan must include at least one non-comparativepost-marketing clinical study with focus on safety and immunogenicity, designed toconfirm that the similar biologic does not have any concerns with regards to thetherapeutic consequences of unwanted immunogenicity. However, the India Guidelinesprovide, “[i]f immunogenicity is evaluated in clinical studies, it is not mandatory tocarryout additional non-comparative immunogenicity studies in post-marketingstudies.”38The importance of shifting human clinical testing requirements to the speed of approvalof a biosimilar may be demonstrated by the experience of Dr. Reddy’s Laboratories(DRL) in approval of its Reditux® (rituximab) biosimilar product. During theNovember 2010 pre-guidance FDA hearing, a speaker for DRL reported thatpre-approval testing of DRL’s rituximab biosimilar required administration of theproposed product to a mere 67 patients, with many more reported in post-marketsurveillance. Post market surveillance did not show “a single case of immunogenic 7
  8. 8. Christopher Ohly The New India Guidelines on Similar Biologicsresponse in any patient,” with more than 1000 patients treated with DRL’s Reditux aftermarket approval, by the time of the presentation.39 ExtrapolationThe FDA guidances indicate that data derived from a clinical study sufficient todemonstrate safety, purity, and potency in an appropriate condition of use, potentiallymay be extrapolated to allow the biosimilar to be licensed for one or more additionalindications for which the reference product is licensed. 40 For example, relying onclinical testing of a Humira® or Remicade® biosimilars in patients with rheumatoidarthritis, it may theoretically be possible to obtain licensing for sale and use of suchbiosimilars in patients suffering from psoriasis or Crohn’s disease, which, likerheumatoid arthritis, are thought to be conditions associated with inflammation causedby the production of TNFα (tumor necrosis factor-α) in humans, without substantial orany additional clinical testing.The India Guidelines state that “[i]n case the reference biologic is used for more than oneindication, the efficacy and safety of the similar biologic has to be justified and ifnecessary demonstrated separately for each of the claimed indications.” They add that[j]ustification will depend on clinical experience, available literature data and whetheror not the same mechanism of action is involved in specific indications.” The guidelinesthus state that, in India, “extrapolation of the safety and efficacy data of a particularclinical indication (for which clinical studies has been done) of a similar biologic toother clinical indications may be possible,” if certain conditions are met. The list ofconditions for consideration of extrapolation is not as long as the list in US guidances,but it is similar in content. Reference ProductThe India Guidelines define a “reference biologic” as “the comparator [used] forhead-to-head comparability studies with the similar biologic in order to show similarityin terms of safety, efficacy and quality.” The definition requires that “[o]nly a productthat was licensed on the basis of a full registration dossier can serve as referencebiologic.” 41 Under the guidelines the reference biologic must be used in all“comparability exercise[s] with respect to quality, preclinical and clinicalconsiderations.”42Under the India Guidelines, the reference biologic “should be licensed in India and shouldbe innovator product.” It should be “licensed based on a full safety, efficacy and quality 8
  9. 9. Christopher Ohly The New India Guidelines on Similar Biologicsdata.” Hence, “another similar biologic cannot be considered as a choice for referencebiologic.”43While the reference biologic must be licensed in India and should be innovator product,44 itis not necessary, under the India Guidelines for the reference product even to be sold ormarketed in India. 45 The India Guidelines may simply recognize that some foreignmanufactured biologic products are simply not yet available in India, if only foreconomic reasons. The India Guidelines appear to permit use of foreign referencebiologic products in a comparability exercise, whether or not the reference product ismarketed or, under some circumstances, even licensed in India.46 The critical issue willbe whether Indian biosimilar developers and manufacturers are able to obtain sufficientquantities of a foreign reference product to enable all of the required analytical, animaland human clinical testing required by Indian regulators. While this seemingly has notbeen an extraordinary impediment to date, legal developments may make acquisition ofreference product more difficult in the future.47 ManufacturingThe India Guidelines set forth a series of quality considerations applicable tomanufacturing of biosimilar products.48 Among other things, these guidelines state thatthe “manufacturing process for similar biologic should be highly consistent androbust.” 49 They set standards for cell lines used in the biosimilar manufacturingprocess,50 as well as standards for fermentation and downstream process development,analytical methods, product characterization, stability and specifications. 51 Theguidelines generally require that “three consecutive standardized batches which havebeen used to demonstrate consistency of the manufacturing process should be used” inthe quality comparability study. 52 The guidelines mandate that “[h]ead-to-headcharacterization studies are required to compare the similar biologic and the referencebiologic 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 similarbiologic and additional characterization studies may be necessary.” 53 The IndiaGuidelines provide that such a “quality comparison … should employ state-of-the-artanalytical techniques, including the analytical methods that are sensitive enough todetect the possibilities of changes to the product,” providing a list of routine analyticaltests to be included in the quality comparability exercise.54 9
  10. 10. Christopher Ohly The New India Guidelines on Similar Biologics Concluding CommentsThe India Guidelines represent a major step forward in establishing a rigorous,science-based regime for approval of biosimilars pharmaceutical products, especiallyfor sale and therapeutic use in India. The guidelines mirror similar efforts in the USand EU and, like those “regulated market” guidances, consciously rely upon otherguidance documents issued by the International Conference on Harmonization, with aview toward encouraging the manufacture of safe and effective biologic products inIndia, 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 willcontribute to harmonization efforts, perhaps ultimately resulting in a globally consistentapproach to biologic development and manufacture, reducing the need for redundantclinical trials. The guidelines will likely also contribute enabling certainty to the effortsof both Indian drug manufacturers and others who may enter the burgeoning Indianmarket, 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 theglobal market for biologic medicines, both as suppliers of biosimilar products and, soonthereafter, of “biobetters” and innovative new medicines. That contribution to globalhealth, whether encumbered or unencumbered by disputes over exclusivities andpatent protection, will be welcomed by all. 10
  11. 11. Christopher Ohly The New India Guidelines on Similar Biologics ANNEX 1: Other India Guidance DocumentsAccording to the India Guidelines, similar biologics are regulated in India under theDrugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945; Rules for themanufacture of hazardous and genetically engineered organisms or cells, 1989 (Rules,1989); and several additional guidelines, including:Schedule Y: Requirements and Guidelines for Permission to Import and/or Manufactureof New Drugs for Sale or to Undertake Clinical Trials. Recombinant DNA Safety Guidelines, 1990 Guidelines for generating preclinical and clinical data for rDNA vaccines,diagnostics and other biologicals, 1999CDSCO guidance for industry, 2008, on Submission of Clinical Trial Application forEvaluating Safety and Efficacy; Requirements for permission of New Drugs Approval;Post approval changes in biological products: Quality, Safety and Efficacy Documents;and Preparation of the Quality Information for Drug Submission for New DrugApproval: Biotechnological/Biological Products Guidelines and Handbook for Institutional Biosafety Committees (IBSCs), 2011The India Guidelines state that, for “establishment and characterization of the cell banks,the guidelines issued by the International Conference on Harmonization of TechnicalRequirements for Registration of Pharmaceuticals for Human Use, i.e., ICH Q5A, Q5Band Q5D.”The guidelines add that “methods used to measure quality attributes for batch release,stability studies and in-process controls should be validated in accordance with ICH Q2,Q5C, Q6B.”The India Guidelines provide that “[s]tability studies on drug substance and drugproduct should be carried out using containers and conditions that are representative ofthe actual storage containers and conditions, according to, e.g., ICH Q5C and WHO TRS822,” and that [a]ssays should be calibrated against an international or nationalreference standard, where available and appropriate. If no such standards are available,an internal reference standard must be established under ICH guidelines.” 11
  12. 12. Christopher Ohly The New India Guidelines on Similar BiologicsThe India Guidelines also cite other references as pertinent to consideration of biosimilarsmarketing applications, including: i. EMEA guideline on similar biological medicinal products containing biotechnology derived proteins as active substance: non-clinical and clinical issues. London, 2006 (CHMP/BMWP/42832) ii. EMEA guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins London, 2007 (CHMP/BMWP/14327) iii. ICH guideline on preclinical safety evaluation of biotechnology-derived pharmaceuticals (S6), 1997 iv. Guideline for Safety Study of Biological Products, (KFDA, 2010) v. World Health Organization (WHO) Guidelines on Evaluation of Similar Biotherapeutic Products (SBP), 2009 12
  13. 13. Christopher Ohly The New India Guidelines on Similar Biologics ANNEX 2: DRL Slide on Reditux Testing 1 The views, positions and opinions expressed in this article are those of the authoralone 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 legaladvice. No attorney-client relationship is established by virtue of this article. 2 21 C.F.R. § 600.3(h). 3 “Synthetic biologics” may be said to be biologically based or inspired materials thatare newly designed and created from “scratch,” combining laboratory chemicals, typically withcomputer assistance, to carry out novel tasks. See, e.g., What is Synthetic Biology?,http://www.synbio project.org/topics/synbio101/definition/. 4 Rep. Anna Eshoo (D-Calif.), H.R. 1548 better than alternatives on new drug class,http://thehill.com/special-reports/the-economy-of-healthcare-july-2009/49603-hr-1548-better-than-alternatives-on-new-drug-class 5 See Mayo Clinic Staff, Monoclonal antibody drugs for cancer treatment: How they work,http://www.mayoclinic.com/health/monoclonal-antibody/CA00082/METHOD=print (“In 13
  14. 14. Christopher Ohly The New India Guidelines on Similar Biologicsgeneral, monoclonal antibody treatment carries fewer side effects than do traditionalchemotherapy treatments.”) 6 http://www.twnside.org.sg/title2/resurgence/2012/259/cover03.htm A. Bourgoin (Thomson-Reuters), WHAT YOU NEED TO KNOW ABOUT THE 7FOLLOW-ON BIOLOGIC MARKET IN THE U.S.: IMPLICATIONS, STRATEGIES, ANDIMPACT http://thomsonreuters.com/content/science/pdf/ls/newport-biologics.pdf, at 1. 8 Id. 9 http://www.fiercebiotech.com/pages/top-10-products-sales-2014;http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=188700&sectionID=&isEPVantage=yes. By 2014, it is projected that 7 of the top 10 selling pharmaceutical products willbe monoclonal antibodies (Avastin, Humira, Rituxan, Herceptin and Remicade) or recombinantprotein products (Enbrel, Lantus). 10 42 U.S.C. § 262(i)(2). US law (the “US Biologics Act”) also defines an“interchangeable” product as a biosimilars product may be substituted for the referenceproduct without the intervention of the health care provider who prescribed the referenceproduct. 42 U.S.C. § 262(i)(3). For a product to be licensed as a “interchangeable” in the U.S.,it must be demonstrated that it is biosimilar and that it “can be expected to produce the sameclinical result as the reference product in any given patient. For a biological product that isadministered more than once to an individual, it must also be shown that “the risk in terms ofsafety or diminished efficacy of alternating or switching between use of the biological productand the reference product is not greater than the risk of using the reference product withoutsuch alternation or switch.” 42 U.S.C. § 262(k)(4). 11See The opportunity for India in the global biosimilars market (June 2010),http://www.pharmaphorum.com/2010/06/21/the-opportunity-for-india-in-the-global-biosimilars-market/ 12 An unhealthy future for the Indian pharmaceutical industry?, http://www.twnside.org.sg/title2/resurgence/2012/259/cover03.htm 13Id. (“out of 3,488 product patents issued from 2005 to March 2010, 3,079 were grantedto MNCs”). See, e.g., F. Hoffman-LaRoche et al. v. Cipla Ltd., CS (OS) No.89/2008 and C.C. 52/2008(Delhi High Court September 7, 2012), http://lobis.nic.in/dhc/MAN/judgement/10-09-2012/MAN07092012S892008.pdf 14 See McKinsey & Company, India Pharma 2020: Propelling Access and Acceptance,Realizing Full Potential, at 20 (2012)(the “biologics market will also grow rapidly to become a $3billion segment [of the Indian economy] by 2020.”) http://www.mckinsey.com/~/media/ 14
  15. 15. Christopher Ohly The New India Guidelines on Similar Biologicsmckinsey/dotcom/client_service/Pharma%20and%20Medical%20Products/PMP%20NEW/PDFs/778886_India_Pharma_2020_Propelling_Access_and_Acceptance_Realising_True_Potential.aspx 15 http://www.in-pharmatechnologist.com/Regulatory-Safety/India-launches-similar-biologics-guidelines-at-BIO2012 16 See, e.g., India’s New Biosimilar Guidelines and Their Relationship to the Rest of the World,BioLawgics, July 16, 2012 http://www.biolawgics.com/fda-approval/guise-biogeneric-regulatorypdfthe-indian-ministries/ (“The Indian Guidelines mirror the U.S. and European emphasis ondetailed structural and functional characterization of the proposed biosimilar in comparison tothe reference product. To earn reduced pre-clinical and clinical data requirements, there must beno “significant differences in safety, efficacy and quality studies.”) Until the new guidelines were promulgated, India’s regulatory regime for biologicmedicines, especially biosimilars, was less well defined. See DRUGS AND COSMETICS(IIND AMENDMENT) RULES, 2005 (Schedule Y), http://cdsco.nic.in/html/schedule-y%20(amended%20version-2005)%20original.htm. The United States Food and Drug Administration issued three draft guidances in early2012, to describe its proposed approach to approval of biosimilars. See Quality Considerations inDemonstrating Biosimilarity to a Reference Protein Product (FDA Quality Considerations); ScientificConsiderations in Demonstrating Biosimilarity to a Reference Product (“FDA ScientificConsiderations”); and Biosimilars: Questions and Answers Regarding Implementation of the BiologicsPrice Competition and Innovation Act of 2009 (FDA Q&A) (February 9, 2012),http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm, and https://collaboration.fda.gov/p13473376/?launcher=false&fcsContent =true&pbMode=normal (webinar). Written and oral publiccomments were received by the FDA before and after these guidances were issued. Seehttp://www.regulations.gov/#!docket Detail;D=FDA-2010-N-0477 (before), andhttp://www.regulations.gov/#!docketDetail;D=FDA -2011-D-0618 (after). No date has been setfor issuance of the FDA’s final guidance documents. The EMA issued its first Guideline on Similar Biologic Medicinal Products in 2005.http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf. In 2012, the EMA issued a detailed Guideline on similar biological medicinal productscontaining monoclonal antibodies – non-clinical and clinical issues. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf. In November2011, the EMA issued a Concept paper on the revision of the guideline on similar biological medicinalproduct (the “overarching” guidelines). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/11/WC500117987.pdf. Comments on these new guidelines 15
  16. 16. Christopher Ohly The New India Guidelines on Similar Biologicswere received by February 29, 2012. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c#Overarchingbiosimilarguidelines. See also http://www.in-pharmatechnologist.com/Regulatory-Safety/EMA-will-accept-reference-meds-made-outside-Europe-under-biosimilars-guidelines 17 See India Calls for Science-Based Regulation for Biotech, The Hindu Business Line, October1, 2012, http://www.thehindubusinessline.com/industry-and-economy/article3954041.ece. 18 Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization inIndia, at 29, http://cdsco.nic.in/Bio%20Similar%20Guideline.pdf (“India Guidelines”). Obversely,the India Guidelines provide: “Identification of any significant differences in safety, efficacy andquality studies would [require] more extensive preclinical and clinical evaluation and the productwill not qualify as a similar biologic.” In the United States, significant improvements in efficacy willlikely disqualify a proposed biosimilar product from consideration under abbreviatedprocedures established under the US Biologics Act and the FDA’s recent guidances. The FDA guidances state that “clinical studies should be designed such that they candemonstrate that the proposed product has neither decreased nor increased activity comparedto the reference product.” They add that [d]ecreased activity ordinarily would precludelicensure of a proposed product,” and that [i]ncreased activity might be associated with moreadverse effects, or might suggest that the proposed product should be treated as an entirelydifferent product with superior efficacy, in which case the appropriate licensure pathway wouldbe section 351(a) of the PHS Act [BLA].” FDA Scientific Considerations at 17. It is less clear whether such “biobetters” may still qualify for consideration as“biosimilars” under the India Guidelines. Relevant to this article, the guidelines also define a “comparability exercise” as“Comparison of a similar biologic with a reference biologic with the goal to establish similarityin safety, efficacy and quality.” Id., at 26. They define a drug product as a “pharmaceuticalproduct type that contains a drug substance, generally in association with excipients,” and adrug substance as the “active pharmaceutical ingredient and associated molecules that may besubsequently formulated, with excipients, to produce the drug product,” including the desiredproduct, product-related substances, and product, process-related impurities, and othercomponents such as buffers. Id., at 26 – 27. 19 42 U.S.C. § 262(k)(4). 20 The FDA Scientific Considerations, see Note 16, supra, note: “The purpose of a biosimilardevelopment program is to support a demonstration of biosimilarity between a proposedproduct and a reference product including an assessment of the effects of any observeddifferences between the products, but not to independently establish the safety and 16
  17. 17. Christopher Ohly The New India Guidelines on Similar Biologicseffectiveness of the proposed product. FDA recommends that sponsors use a stepwise approachto developing the data and information needed to support a demonstration of biosimilarity. Ateach step, the sponsor should evaluate the extent to which there is residual uncertainty aboutthe biosimilarity of the proposed product and identify next steps to try to address thatuncertainty.” Id., at 7. 21 India Guidelines at 4. 22 FDA Scientific Considerations at 5, 7. As set forth in the US guidances, a biosimilarsponsor must first “extensively characterize the proposed product and reference product withstate-of-the-art technology as the foundation for a demonstration of biosimilarity.” Theguidance sets forth the FDA’s expectation that “the expression construct for a proposed productwill encode the same primary amino acid sequence as the reference product. Minormodifications will not affect safety and effectiveness may be justified and should be explainedby the sponsor.” 23 India Guidelines at 8 – 10, 35 – 42 (Annexure 2). Test requirements are in some waysdescribed, albeit in basic terms, in greater detail in the India Guidelines than in the FDA’sguidances. For example, with respect to physicochemical and biological characterization ofantibodies, the India Guidelines set forth eleven requirements for physicochemicalcharacterization (e.g., “Purity on HPLC (RP, SEC, IEX)/MALDI (To check if preparation is free ofany impurities).”) and four requirements for biological characterization (e.g., “Neutralizingactivity in actual target host cell (at least one highly prevalent Indian variant/isolate should beused) (To compare activity of similar biologic with reference biologic in the target cell).”) Id., at41- 42 (Annexure 2D). The FDA guidances do not contain product specific requirements, although such biosimilarproduct guidelines are statutorily authorized and may be promulgated in the future. See, e.g.,FDA, Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for HumanUse, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/UCM153182.pdf. The EUhas already issued several biosimilar product specific guidance documents. See, e.g., EMA,Guideline on non-clinical and clinical development of similar biological medicinal products containingrecombinant erythropoietins (Revision), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/04/WC500089474.pdf. See also EMA,Product-specific biosimilar guidelines, http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c#Productspecificbiosimilarguidelines. 24India Guidelines at 7. Similarly, the FDA Scientific Considerations note that “[s]uch astrategy may further reduce the possibility of undetected structural differences between the 17
  18. 18. Christopher Ohly The New India Guidelines on Similar Biologicsproducts and lead to a more selective and targeted approach to animal and/or clinicaltesting.” Id., at 7. 25 The FDA Scientific Considerations state that pharmacologic activity of protein productscan be evaluated by in vitro and/or in vivo functional assays, including, but are not limited to,bioassays, biological assays, binding assays, and enzyme kinetics. They add that animal toxicitydata will be considered useful when uncertainties remain about the safety of the biosimilarproduct and need to be addressed before initiation of clinical studies in humans. They statethat animal toxicity studies will generally not be regarded as useful “if there is no animalspecies that can provide pharmacologically relevant data for the protein product (i.e., no speciesin which the biologic activity of the protein product mimics the human response …).” 26 India Guidelines at 10. The India Guidelines state that “Antibody response to the similarbiologic should be compared to that generated by the reference biologic in suitable animalmodel. The test serum samples should be tested for reaction to host cell proteins. … Forevaluating immune toxicity of the similar biologic under study, the results of local tolerance(part of repeat dose or stand-alone test) should be analyzed …” Id., at 17. 27 India Guidelines at 14 - 17. Compare FDA Scientific Considerations at 10 – 12. 28 In the US, the FDA has said, “In general, the clinical program for a [biosimilar]application must include a clinical study or studies (including an assessment of immunogenicityand PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriateconditions of use for which the reference product is licensed and intended to be used and forwhich licensure is sought for the biological product … The scope and magnitude of clinicalstudies will depend on the extent of residual uncertainty about the biosimilarity of the twoproducts after conducting structural and functional characterization and possible animalstudies. … Lessening the number or narrowing the scope of any of these types of clinical studies(i.e., human PK, PD, clinical immunogenicity, or clinical safety and effectiveness) should bescientifically justified by the sponsor.” FDA Scientific Considerations at 12. 29 India Guidelines at 17. 30 India Guidelines at 20 (“Information to establish comparative safety and efficacy inrelevant patient population is mandatory for all similar biologics.”) 31 India Guidelines at 18 - 19. The guidelines state: “Appropriate rationale for doseselection should be provided. The route of administration should be the one where thesensitivity to detect differences is the largest. Sample size should have statistical rationale …”Compare FDA Scientific Guidance at 13 (“… both PK and PD studies (where there is a relevantPD measure) generally will be expected to establish biosimilarity, unless a sponsor canscientifically justify that an element is unnecessary. … Sponsors should provide a scientific 18
  19. 19. Christopher Ohly The New India Guidelines on Similar Biologicsjustification for the selection of the human PK and PD study population (e.g., patientsversus healthy subjects) and parameters … ”) 32 India Guidelines at 19. 33 Id. 34 Id. at 20. The India Guidelines provide that confirmatory clinical safety and efficacystudy requirement can be waived if all of the following conditions are met, but cannot be waivedif there is no reliable and validated PD marker: “i. Structural and functional comparability of similar biologic and reference biologic can be characterized to a high degree of confidence by physicochemical and in vitro techniques ii. The similar biologic is comparable to reference biologic in all preclinical evaluations conducted iii. PK/PD study has demonstrated comparability and has preferentially been done in an in-patient setting with safety measurement (including immunogenicity) for adequate period justified by the applicant and efficacy measurements iv. A comprehensive post-marketing risk management plan has been presented that will gather additional safety data with a specific emphasis on gathering immunogenicity data.”India Guidelines at 21. 35 Under the proposed US FDA guidances and the US Biologics Act, it appears thatbioequivalence must be established for efficacy and aspects of safety other than immunogenicity.The US guidance documents indicate that two-sided clinical studies will generally be necessary toestablish that there are no other clinically meaningful differences between the biosimilar and thereference product. They state that “at least one clinical study that includes a comparison of theimmunogenicity of the biosimilar product to that of the reference product will generally beexpected.” The FDA guidances add, however, that generally it will only be “important todemonstrate that the immunogenicity of the proposed product is not increased, so a one-sided(non-inferiority) design will ordinarily be adequate to compare clinical immunogenicity of theproposed product and reference product.” Hence, under the proposed FDA guidances,improved (bio-superior) immunogenicity will not preclude approval as a biosimilar. However,as noted above, superior efficacy (biobetter) will, in all probability, require submission of a fullBiologics License Application (BLA), rather than an abbreviated application under the USBiologics Act. The EU recently issued a concept paper that recognizes the need to tackle the issue of“biobetters” and the related clinical testing requirement issue, i.e., whether a two-sided 19
  20. 20. Christopher Ohly The New India Guidelines on Similar Biologicsequivalency test must be conducted, or a simpler non-inferiority test will suffice, even for ademonstration of efficacy. See EMA, Concept paper on the revision of the guideline on similarbiological medicinal products containing biotechnology derived proteins as active substance: non-clinicaland clinical issues, at 3 (September 2011), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/10/WC500115611.pdf. See also S. Chow, et. al., Scientific factorsfor assessing biosimilarity and drug interchangeability of follow-on biologics, Biosimilars 2011:1 13–26(2011), www.dovepress.com/getfile.php?fileID=10321. Under the India Guidelines, if “non-inferiority trials are required they must be clearlyjustified and applicants are advised to consult with CDSCO prior to study initiation. Samplesizes should have statistical rationale and comparability limits should be defined and justifiedprior to conducting the study.” India Guidelines at 20 (emphasis added). 36 India Guidelines at 20. 37India Guidelines at 23. The Risk Management Plan must include, among otherthings, a Pharmacovigilance Plan designed to evaluate the clinical safety in all theapproved indications in the post-marketing phase, including requirements forsubmission of periodic safety update reports (PSURs), every six months for the first twoyears after approval of the similar biologic and annually for the subsequent two years. India Guidelines at 23 – 24. See FDA Scientific Considerations at 20 – 21 (noting 38that “robust post-marketing safety monitoring is an important component in ensuringthe safety and effectiveness of biological products, including biosimilar therapeuticprotein products, taking into account particular safety or effectiveness concernsassociated with the use of the reference product and its class.”) See also 42 U.S.C. §262(k)(4)(C) (REMS requirements for “interchangeables”). 39See Transcript of FDA Hearing, November 3, 2010, at 70.http://www.regulations.gov/#!documentDetail;D=FDA -2010-N-0477-0012. The slidereferenced in DRL’s testimony, apparently no longer available on the Regulations.gov website isdepicted in Annex 2, below. 40See FDA Q&A at 9 – 10. According to this guidance, scientific justification for suchextrapolation must be based on several factors, including a product’s mechanism of action, thetarget/receptor(s) for each relevant activity/function of the product, the binding,dose/concentration response, and pattern of molecular signaling upon engagement oftarget/receptor(s), the relationship between product structure and target/receptor interactions,the location and expression of the target/receptor(s), “PK and bio-distribution of the product indifferent patient populations; PD measures may provide important information on the MOA,”differences in expected toxicities in each condition of use and patient population, and “[a]ny 20
  21. 21. Christopher Ohly The New India Guidelines on Similar Biologicsother factor that may affect the safety or effectiveness of the product in each indication andpatient population for which licensure is sought.” Id. 41 India Guidelines at 28. Similarly, the guidelines define an “innovator product” as “[a]medicine which has been licensed by the national regulatory authorities on the basis of a fullregistration dossier; i.e., the approved indication(s) for use were granted on the basis of fullsafety, efficacy and quality data.” Id. In both definitions, the use of the phrase ”full dossier” iscritical and dispositive. The definition suggests that another biosimilar cannot be a “referencebiologic” unless it has been licensed on the basis of full human clinical testing. In the US, the Biologics Act defines a “reference product” as “the single biologicalproduct licensed under subsection (a) [a full Biologics License Application] against which abiological product is evaluated in an application …” 42 U.S.C. § 262(i)(4). 42 India Guidelines at 5. 43 Id. 44 Among other things, the guidelines also require that the reference biologic bemaintained throughout the life cycle of the product, for purposes of further comparison. Id.This seems requirement seems to recognize that there may be differences between an initialreference product and later versions that may have “drifted” in some characteristic away fromthe initial product. Use of a single reference standard may also avoid enlargement of the scopeof bioequivalency in any one or more specific characteristics and thus somewhat narrow theranges within which a biosimilar product sponsor will be able to demonstrate comparability.See Note 39, supra. 45 The India Guidelines provide that “[i]n case the reference biologic is not marketed inIndia, the reference biologic should have been licensed and widely marketed for 4 years postapproval in innovator jurisdiction in a country with well-established regulatory framework. Incase no medicine or only palliative therapy is available or in national healthcare emergency, thisperiod of 4 years may be reduced or waived off.” Id¸ at 5. 46 The EU recently issued a statement “that it intends to accept batches of referencemedicinal products sourced from outside the EEA in certain pre-clinical and clinical studies forthe comparability exercise.” Under this approach, “it will be the applicants responsibility toestablish that the batches sourced outside the EEA is representative of the reference medicinalproduct authorised in the EEA through an extensive analytical comparison.”http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000125.jsp&mid=WC0b01ac0580533e0c. 21
  22. 22. Christopher Ohly The New India Guidelines on Similar Biologics The US Biologics Act requires comparison of a proposed biosimilar to a single referenceproduct, 42 U.S.C. § 262(k)(5)(A). Like the India Guidelines, the US Biologics Act requires thatthe reference product be “licensed under” US laws governing Biologic License Applications, 42U.S.C. § 262(i)(4)(defining a “reference product” and referring to 42 U.S.C. § 262(a)). See alsoFDA Q&A, at 7 (non-US licensed reference product may be used as comparator under somecircumstances, with “bridging” studies); and FDA Quality Considerations at 9 (commenting onthe potential use of data obtained in foreign analytical, animal and clinical studies, comparing aproposed biosimilar product to a reference product not licensed in the US). 47In the United States, a lawsuit has been recently commenced by a manufacturerseeking a declaratory judgment against two generic manufacturers, to enforce themanufacturer’s right to choose with whom it does business and to declare that themanufacturer has no duty or obligation to provide samples of its patented product to thegeneric competitors. See Actelion Pharmaceuticals, et al. v. Apotex, Inc., et al., Civil No. 1:12-cv-05743-NLH-AMD (D.N.J. September 14, 2012). 48In the US, each facility at which a biosimilars product may be manufactured must beinspected and licensed by the FDA before marketing of a product made at that facility will bepermitted. See, e.g., US Biologics Act, 42 U.S.C. §§ 262(a)(1)(c)(ii), 262(k)(2)(A)(i)(V), 262(k)(3)(B). The FDA Quality Considerations provide “guidance on analytical studies that may berelevant to assessing whether the proposed biosimilar protein product and a reference productare highly similar, which is part of the biosimilarity assessment.” Id., at 4. In part, theseguidances describe the “complete and thorough chemistry, manufacturing and controls (CMC)section that provides the necessary and appropriate information (e.g., characterization,adventitious agent safety, process controls, and specifications) for the product to be adequatelyreviewed.” Id., at 4 – 5. The FDA Quality Considerations document contemplates that the CMC submission in abiosimilar application will include, in addition to other data, the same CMC informationrequired in a BLA. See, e.g., Guidance for Industry for the Submission of Chemistry, Manufacturing,and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a MonoclonalAntibody Product for In Vivo Use (issued jointly by CDER and CBER, August 1996). Among other things, the FDA Quality Considerations guidance states that “[a]comprehensive understanding of all steps in the manufacturing process for the proposedbiosimilar product should be established during product development.” It adds that“[c]haracterization tests, process controls, and specifications that will emerge from informationgained during process development must be specific for the proposed biosimilar product andmanufacturing process.” And, it states that “[t]he use of Quality-by-Design approaches topharmaceutical development, along with quality risk management and effective qualitysystems, will facilitate the consistent manufacturing of a high-quality product.” 22
  23. 23. Christopher Ohly The New India Guidelines on Similar Biologics The FDA Quality Considerations also provides guidance about impurities, drug productstability, reference product standards and other issues relating to biosimilar products in bothlaboratory and manufacturing level scales. 49 India Guidelines at 6. 50 Id. (“If the host cell line used for the production of reference biologic is disclosed, it isdesired to use the same cell line as the reference biologic. Alternatively any cell line that isadequately characterized and appropriate for intended use can be used to develop a similarbiologic, with appropriate justification in order to minimize the potential for significant changesin critical quality attributes of the product and to avoid introduction of certain types of processrelated impurities that could impact clinical outcomes and immunogenicity. For theestablishment and characterization of the cell banks, the guidelines issued by the InternationalConference on Harmonisation of Technical Requirements for Registration of Pharmaceuticalsfor Human Use (referred to as ICH) viz. Q5A4, Q5B5 and Q5D6 should be referred for guidance.” 51Id., at 7. The guidelines list forms that used in connection the approval process, andinclude requirements for data retention. Id., at 25. 52 Id., at 11. 53 Id., at 11. 54 Id., at 11 - 12. See also Annexure-2 (2A-2D). 23

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