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India’s New Similar Biologic Guidelines: An Overview Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office Corporate Lawyer Law Firm India New Delhi Kale Law Office
he Indian Ministry of Health and Family Welfare and Science andT Technology had earlier in the month of June released their guidelines on biosimilars (similar bilologis in the Indian context) to be implemented from August 15 2012. These guidelines bring an end to the era of ad-hoc abbreviated approval pathway under which the Indian authorities hadbeen approving Indian produced generic biologics with reference productswhich were approved in the United States and Europe. There have also beeninstances, where biotechnology products were approved without conductingclinical trials on enough number of patients. The guidelines are applicable forsimilar biologics developed in India or imported into the countryThe 52-page document, titled, ‘Guidelines on Similar Biologics: RegulatoryRequirements for Marketing Authorization in India’ covers both biosimilarsdeveloped in India as well as those imported into the country. The proposednorms outline specific requirements for pre-marketing and post-marketing dataapart from guidelines for pre-clinical and clinical trials for biosimilars. TheIndian Guidance lays out the same kind of stepwise approach, starting withdetailed structural characterization of the proposed biosimilar and its referenceproduct, followed by preclinical then clinical characterizations, and makesallowances for product-specific differences in analytical techniques and clinicalendpoints.Salient FeaturesDefinition of Similar Biologics and its DevelopmentAs per the guidelines, similar In case the reference biologic is notbiologic includes: a biological authorized in India it should haveproduct or drug produced by been licensed and marketed for atgenetic engineering techniques and least 4 years with significant safetyclaimed to be "similar" in terms of and efficacy data. Under presentquality, safety, efficacy to a circumstances, these guidelinesreference innovator product, which seem to be clearly aimed athas been granted a marketing encouraging more investment inauthorization in India by a biosimilars in India, both bycompetent authority on the basis of domestic and foreign companies.a complete dossier, and with a However, in case of no medicine orhistory of safe use in India. The only palliative therapy is availabledefinition of similar biologics shows or in national healthcarethat under the regulatory regime a emergency, this period of 4 yearsproduct can be considered as may be reduced or waived off.similar biologic only if it is proven Since for the foreseeable future,to be similar, using extensive new biologics will be predominantlyquality characterization against the pioneered in the U.S. and Europe,reference biologic. there will be a number of recently- developed products that fall into 1
this category, and will await eitherthe approval of the reference drugin India, or the passage of fouryears after approval elsewhere.Clinical TrialsThe guideline suggests that under certain circumstances biosimilars can beapproved without involved clinical trials: The confirmatory clinical safety andefficacy study can be waived if all the below mentioned conditions are met: 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 referentially in‐patient measurement (including immunogenicity) for adequate period justified by the applicant and efficacy measurements iv. A comprehensive post marketing risk management plan has been post‐marketing presented that will gather additional safety data with a specific emphasis on gathering immunogenicity data The confirmatory clinical safety and efficacy study cannot be waived if there is no reliable and validated PD marker. 2
COMPARATIVE ANALYSIS1. Definition of Biosimilar (Similar Biologics)INDIA UNITED STATES EUROPE 35 U.S.C § 262 (i) Biosimilarity is not explicitly“A biological product/ Highly similar to a defined, but is situational:drug produced by genetic reference product licensed “Whether a medicinalengineering techniques under 262(a) product would be acceptableand claimed to be notwithstanding minor using the ‘similar biological“similar” in terms of differences in clinically medicinal product’ approachsafety, efficacy and quality inactive components. depends on the state of theto a reference biologic, 35 U.S.C § 262 (k)– art of analytical procedures,which has been granted a Demonstrated the manufacturing processesmarketing authorization biosimilarity to reference employed, as well as clinicalin India by DCGI on the based upon: Analytical and regulatorybasis of a complete studies to show highly experiences.” CHMP/437/04.dossier, and with a similar, Animal studies, “Comparability studies arehistory of safe use in and Clinical study(ies) needed to generate evidenceIndia.” Indian Guidelines substantiating the similarat 22. nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the chosen reference medicinal product authorised in the Community.” CHMP/437/042. Developing a BiosimilarINDIA UNITED STATES EUROPESimilar biologics are A stepwise approach to “A stepwise approachdeveloped through demonstrating should be undertaken tosequential process to biosimilarity, which can justify any differences indemonstrate the similarity include a comparison of the quality attributes of theby extensive the proposed product and similar biological medicinalcharacterization studies the reference product with product versus therevealing the molecular respect to structure, reference medicinaland quality attributes with function, animal toxicity, product in order to make aregard to the reference human pharmacokinetics satisfactory justification ofbiologic. Indian Guidelines (PK) and the potential implicationsat 5. pharmacodynamics (PD), with regard to the safety clinical immunogenicity, and efficacy of the and clinical safety and product.” effectiveness Guidance CHMP/BWP/49348/2005 “Scientific Considerations” at 5. at 2. 3
3. Reference ProductsINDIA UNITED STATES EUROPE Licensed in India or in “To obtain licensure … a No provision for non-EMA“Similar biologic can only sponsor must demonstrate licensed referencebe developed against an that the proposed product products.authorized reference is biosimilar to a singlebiologic that has been reference product thatapproved using a complete previously has beendata package in India. In licensed by FDA. . . .case the reference biologic However, under certainis not authorized in India, circumstances, a sponsorit should have been may seek to use datalicensed and marketed for derived from animal orat least 4 years with clinical studies comparingsignificant safety and a proposed product with aefficacy data.” Indian non-U.S.-licensedGuidelines at 3. product….. In such a case, the sponsor should provide“The products, where the adequate data orreference biologic is not information to scientificallyauthorized in India shall be justify the relevance of thisconsidered on a case by comparative data to ancase basis if such products assessment of biosimilarityhave been granted and to establish anmarketing approval in acceptable bridge to thecountries with well U.S.-licensed referenceestablished regulatory product.” Guidance forsystems such as US FDA, Industry ScientificEMA etc. and have been in Considerations inwider use for a minimum of Demonstratingfour years.” Id. at. 22 Biosimilarity to a Reference Product at 6 4
4. Safety and Efficacy TrialsINDIA UNITED STATES EUROPEPotential for “As a scientific matter, “Usually comparativeomission of safety comparative safety and clinical trials will beand efficacy trials. effectiveness data will be necessary to demonstrateSee quote above necessary to support a clinical comparability demonstration of biosimilarity if between the similar there are residual uncertainties biological and the reference about the biosimilarity of the two medicinal product.” products based on structural EMEA/CHMP/BMWP/4283 and functional characterization, 2/2005 at 6. animal testing, human PK and PD data, and clinical immunogenicity assessment. A sponsor may provide a scientific justification if it believes that some or all of these comparisons on clinical safety and effectiveness are not necessary.” FDA Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product at 12. 5. Exclusivity PeriodINDIA UNITED STATES EUROPEIndia provides for no A section (k) application “8+2+1.” A biosimilarmarket exclusivity period may not be filed until 4 application may not bebeyond patent rights. years after reference filed until 8 years after the product approval. A reference product approval. biosimilar may not be A biosimilar may not be approved until 12 years approved until 10 years after reference product after reference approval. approval. 42 USC 262 The market exclusivity may (k)(7). be extended by an additional year if the reference product sponsor obtains approval for a second significant new indication during the data exclusivity period. 5