Biosimilars & Biologics
An insight into biosimilars & biologics in Indian Pharma. Prepared in association with Nishith Desai & Associates, a leading law firm in India, this is an extract from The Pharma Legal Handbook: India, available to purchase here for USD 99.
1. Are biosimilar medicines considered the same as generic medicines in your country?
Biosimilar medicines are not regulated in the same manner as generic medicines in India. While biosimilars and generic medicines are classified as drugs under the Drugs & Cosmetics Act 1940 (“D&C Act”) (India’s primary drug control legislation), clinical trial requirements for biosimilars are stricter than those applicable to generic medicines. Once a drug formulation has received marketing authorization from the Central Drugs Standard Control Organisation (“CDSCO”) – India’s apex drug regulator – subsequent manufacturers of the drug formulation are not required to undertake clinical trials in respect of the same drug formulation, if the drug formulation has been marketed for over four years. However, biologics such as vaccines, recombinant deoxyribonucleic acid (“rDNA”) derived products and living modified organisms are required to undergo clinical trials even if another entity has been manufacturing the same biologic. As a result, unlike generic drugs, every iteration of a biologic must undergo clinical trials.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
Biologic medicines as well as biosimilars are patentable in India (subject to certain exceptions) as long as such biologic or biosimilar (i) is novel/new (ii) involves an inventive step/is non-obvious and (iii) has utility/industrial application.
Biologics comprising living organisms that are not naturally occurring i.e. have been developed by humans may be patented. However, biologics comprised of a living organism already occurring in nature cannot be patented as the mere “discovery of any living thing or non-living substance occurring in nature” is not patentable under the Patent Act 1970. It may be noted that India does not grant patent protection to (i) the mere discovery of a new form of a known substance if it does not result in the enhancement of the known efficacy of that substance or (ii) mere discovery of any new property or use for a known substance.
Biosimilars are not eligible for product patents (as the end product is the same as an already patented/known reference biologic) but are eligible for process patents as long as the process fulfils the other criteria for patentability. However, India does not grant patent protection to the mere use of a known process unless such known process results in a new product or employs at least one new reactant.
3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country?
Yes, India has a specific regulatory framework for the marketing authorization of biosimilar medicines.
4. If yes, what is the regulatory framework for the authorization of biosimilar medicines?
Biosimilar medicines in India are regulated under:
- The Drugs & Cosmetics Act 1940;
- Drugs & Cosmetics Rules 1945 (“D&C Rules”) (framed under the D&C Act govern the process for clinical trials, import and manufacture of all drugs including biologics and biosimilars);
- New Drugs & Clinical Trial Rules, 2019 (“New Drugs & CT Rules”) (framed under the D&C Act govern the procedure for the conduct of clinical trials of all drugs including biologics and biosimilars);
- Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India, 2016 (“Biosimilar Guidelines”) (guidelines that stipulate the pre-clinical trial requirements for biosimilars);
- Rules for Manufacture, Use, Import, Export and Storage of Hazardous Microorganisms/Genetically Engineered Organisms or Cells, 1989 (“Genetically Engineered Microorganisms Rules”) notified under the Environment (Protection) Act, 1986 (applicable to manufacture, import and storage of microorganisms and gene-technological products as well as genetically engineered microorganisms, microorganisms and cells);
- Regulations and Guidelines on Biosafety of Recombinant DNA Research and Biocontainment, 2017 (“rDNA Guidelines”) (cover the regulation on biosafety of rDNA research and handling of hazardous microorganisms and GE organisms or cells);
- Guidelines for Generating Pre-clinical and Clinical Data for rDNA Vaccines, Diagnostics and other Biologicals, 1999 (“Clinical Data Guidelines”) (cover preclinical and clinical evaluations. Their objective is to generate preclinical and clinical data with respect to the safety, purity, potency and effectiveness of rDNA vaccines, diagnostics and other biologicals);
- CDSCO Guidance for the Industry, 2008 (“Guidance for the Industry”) (provides guidance to clinical trial sponsors regarding the submission of clinical trial applications under the D&C Act and GCP Guidelines);
- Guidelines and Handbook for Institutional Biosafety Committee, 2011 (“IBSC Guidelines”) (provides guidance to the Institutional Biosafety Committees (“IBSC”) that are required to be set up to oversee the preclinical trials of biologics and biosimilars in India);
- Guidance Document for Industry: Submission of Stability Data and Related Documents for Review and Expert Opinion for Granting Post-approval Changes in Shelf Life of Recombinant Biotherapeutic Products and Therapeutic Monoclonal Antibodies published by the National Institute of Biologicals 2016 (“Post-Approval Guidelines”) (provides guidance and recommendations to holders of marketing authorization of biologics who intend to make post approval changes in the shelf life of the product).
The authorities responsible for overseeing the approval process are:
- Institutional Biosafety Committee (a committee that is required to be constituted by every organisation engaged in research, handling and production activities related to genetically modified organisms (“GMO”). The IBSC is the nodal point for interaction within an organisation for implementation of the biosafety regulatory framework);
- Review Committee on Genetic Manipulation (“RCGM”) (a regulatory/approval committee established under the Genetically Engineered Microorganisms Rules to monitor the safety related aspect in respect of on-going research projects or activities involving hazardous microorganisms, GMOs and cells and products thereof);
- Genetic Engineering Appraisal Committee (“GEAC”) (a body established by the Ministry of Environment, Forest and Climate Change (“Environment Ministry”) to appraise activities involving large scale use of hazardous microorganisms, GMOs or cells in research, industrial production and experimental field trials); and
- The Central Drugs Control Standards Organisation (the apex regulatory body with respect to clinical trials, import and manufacture of all drugs in India including biologics and biosimilars).
5. What kind of data package is needed to obtain approval for a biosimilar drug?
The approval process for biosimilar drugs is divided into pre-clinical trial, clinical trial and post clinical trial stages with each stage having different data package requirements. Data packages may also differ based on the risk classification assigned to the GMOs) under the Genetically Engineered Microorganisms Rules, as prior authorisation from the IBSC and subsequent approval of the RCGM is required for conducting experiments involving LMOs classified in risk categories 3 or higher.
In addition to RCGM permission, the approval of the GEAC is also required for activities involving large scale use of hazardous microorganisms and recombinants in research and industrial production. The GEAC is also responsible for approval of proposals relating to release of GMOs and products into the environment including experimental field trials.
Pre-clinical Trial Stage
Data packages must demonstrate the consistency of process and product, product characterisation, and product specifications to comply with RCGM requirements. The application to the RCGM should be accompanied by approval of the IBSC and the approval of the Institutional Animal Ethics Committee (“IAEC”) along with details of the personnel involved such as study director, principal investigator, pathologist, other investigators and quality assurance officer.
The information in the data package may include the following.
Basic Information about Reference Biologic
- Information about drug, route of administration, absorption and elimination rate, therapeutic index, dose, vehicle, mode of administration, dose response etc.
- Bioequivalence range, if available,
- Tissue-specific localisation, if available,
- Available toxicity data on reference biologic, and
- Mode of action.
Basic Information about the Similar Biologic
- Known/proposed clinical use,
- Target population (age, sex, pregnancy, lactating, children etc.),
- Dosage units (frequency and intervals),
- Route/alternate routes of administration,
- Final formulation of adjuvants and additives including toxicity data of such adjuvants and additives,
- Diluents, and
- Presentation e.g. pre-filled syringe, cartridge, vial.
To establish similarity, the quality attributes of a biosimilar may be considered in two categories:
- Critical Quality Attributes (“CQA”): these attributes have a direct impact on the clinical safety or efficacy. All attributes that directly impact the known mechanism(s) of the molecule fall in this category.
- Key Quality Attributes (“KQA”): are those attributes which are not known to impact clinical safety and efficacy but are considered relevant from a product and process consistency perspective.
Attributes that do not impact the known mechanism(s) of action of the molecule fall in this category. While KQAs must necessarily be controlled within acceptable limits, it may be acceptable to have slight differences in comparison to the reference biologic.
- Details of pharmacodynamic study design (both in-vitro and in-vivo studies). The in-vitro studies should establish comparability between the reference biologic and the biosimilar.
- Details of toxicology study design such as in vivo toxicity studies on a pharmacologically relevant animal involving three levels of doses (1X, 2X and 5X of human equivalent dose) for repeat dose toxicity studies.
- Immune responses in animals i.e. antibody response, immune toxicity.
- Safety pharmacology, reproductive toxicity, mutagenicity and carcinogenicity studies are not generally required unless warranted by the results of repeat dose toxicological studies.
Clinical Trial Stage
Based on successful evaluation of pre-clinical study reports, the RCGM may recommend that the Drugs Controller General of India (“DCGI”) (head of the CDSCO and apex drug regulator of India) allow the sponsor to conduct appropriate phase of clinical trial as per CDSCO requirements. A clinical trial typically takes place over four stages. The New Drugs & CT Rules, which have replaced the erstwhile clinical trial rules under Part X-A and Schedule Y of the D&C Rules, govern the conduct of clinical trials in India. The clinical trial data requirements for biosimilars are the same as for drugs apart from a few differences.
Overview of Clinical Trial Regulation
While a clinical trial is typically conducted over four phases, the DCGI is empowered to expedite the approval process with respect to a drug taking into account the severity, rarity and prevalence of the disease. For instance, the requirement for submission of studies relating to animal toxicity, reproduction, tetrogenic, perinatal, mutagenicity and carcinogenicity may be waived if the CDSCO is satisfied that there is adequate published evidence regarding the safety of the drug.
Additionally, a local clinical trial may not be required at all if the new drug is approved and marketed in countries specified by the CDSCO and if:
- No major adverse events have been reported,
- There is no probability or evidence of difference in (a) the enzymes or gene involved in the metabolism of the new drug, (b) pharmacokinetics (“PK”) and pharmacodynamics (“PD”), safety and efficacy of the new drug between the Indian population and the population the drug was tested on,
- The applicant has undertaken to conduct Phase IV clinical trials (post-marketing studies) to establish and effectiveness of the new drug as per study design that has been approved by the CDSCO.
Additional Data Requirements for Biosimilars
- Comparative PK and PD studies: PK and PD studies are conducted in the first phase of the clinical trial. PK studies should be conducted to demonstrate comparability in both single dose and multi-dose PK studies. For biosimilars that is proposed to be used in a multi-dose regimen, multiple-dose, comparative, parallel arm steady state PK studies are required. Comparative PD studies are also recommended when the PD properties of the reference biologic are well characterised with at least one PD marker validated for a clinical outcome of the molecule.
- Confirmatory safety and efficacy studies: In order to eliminate any residual risk, a comparative safety and efficacy study (typically conducted in the third phase of the clinical trial) are required. The requirement of safety and efficacy study may be waived only in exceptional cases if there are no uncertainties left after comparing the biosimilar and reference biologic at the analytical, non-clinical and PK/PD level and if a comprehensive post-marketing risk management plan has been presented to the CDSCO. Wherever, phase III trial is waived, the immunogenicity that should have been gathered in the PK/PD study will also need to be generated during post-approval phase IV study.
Post-Clinical Trial Stage
Post-marketing surveillance is particularly important in the case of biosimilars, as a biosimilar is approved based on a reduced pre-clinical and clinical trial data package. Therefore, a formal Risk Management Plan must be established to monitor and detect both known inherent safety concerns and potential unknown safety signals that may arise from the biosimilar. A comprehensive pharmacovigilance plan must also be put into place which shall include the submission of periodic safety update reports (“PSUR”).
In the event phase III clinical trials are not carried out, immunogenicity studies must be conducted in phase IV. Additional safety data may need to be collected after market approval through a pre-defined single arm study of over 200 evaluable patients. The study should preferably be completed within 2 years of receipt of marketing permission/manufacturing license unless otherwise justified.
6. Is this any different to the requirements for the original Biologics drug?
The data package requirements for biologics drugs are similar to those of biosimilars. The notable differences are:
- The data collected for an original biologics drug will not be in reference to a pre-existing product. For instance, the PK/PD data collected will not be in reference to another product but will be directed towards assessing the PK/PD of the original biologics drug.
- Phase III clinical trial must be conducted as the original biologic will be licensed on the basis of a full safety, efficacy and quality data as opposed to the reduced data package employed when licensing a biosimilar.
7. What are the requirements for the choice of the reference comparator product?
The requirements for choice of comparator product are as follows:
- reference comparator product should be licensed / approved in India or a country that follows the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (“ICH”)
- reference comparator productshould be the innovator’s product asanother biosimilar cannot be the reference biologic as the comparator product should be licensed based on a full safety, efficacy and quality data.
8. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
The comparator product can be imported from another regulatory jurisdiction regardless of whether such product is beingmarketed in India. The only requirement is that the comparator product be approved in an ICH country. However, the acceptance of an innovator product as comparator product for evaluation of a biosimilar does not imply approval for the use of such comparator product in India.
9. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
The Drugs (Prices Control) Order 2013 (“DPCO”) governs pricing for both original biologics and biosimilars in the same manner. The National Pharmaceutical Pricing Authority (“NPPA”) is empowered by the DPCO to fix ceiling prices of drugs (including biologics) that are listed in the schedule to the DPCO (“Scheduled Formulations”). The Scheduled Formulations include biologics such as vaccines and sera. The DPCO clarifies that all biologicals irrespective of variation in source, composition and strengths and all the products of the same vaccine/sera/immunoglobulin considered as part of the schedule to the DPCO.
10. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
India currently does not have a mechanism for reimbursement of biologics or biosimilar medicines. Out-of-pocket-expenditure is the primary source of healthcare financing in India as India suffers from a low level of both private and government insurance penetration. In addition to the above, the Indian government runs schemes that provide free or highly subsidized care to Indian citizens. There are also Non-Governmental Organisations that provide free medication to patients who are otherwise unable to afford them. All of these methods are however, applicable for all drugs, biologics and medical devices.
11. Does biosimilar competition impact the reimbursement policy of the originator reference products?
India does not have a reimbursement policy in place.
12. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original Biologics drug?
In India, doctors are required to prescribe all drugs, including biologics by their chemical names i.e. the name of pharmaceutical formulation. There is no difference in requirements for prescribing or dispensing an original biologic and a biosimilar.
A valid prescription shall:
- Be in writing and be signed by a medical practitioner registered under the Indian Medical Degrees Act, 1916, the Indian Medical Council Act, 1956 or the Dentists Act, 1948 among others (“Registered Medical Practitioner”),
- Specify the name and address of the person for whose treatment it is given, and
- Indicate the total amount of medicine to be supplied and the dose to be taken.
Biologics or biosimilars can only be dispensed by registered pharmacists on the basis of a valid prescription signed by a registered medical practitioner.
13. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
Pharmacy level substitutions of a biosimilar for a biologic are possible as doctors in India are required to prescribe medicines using their chemical name. Moreover, a biosimilar can be approved for all the clinical indications the reference biologic has been approved if:
- Similarity with respect to quality and preclinical assessment has been proven to reference biologic,
- Clinical safety and efficacy is proven in one indication,
- Mechanism of action is same for other clinical indications,
- Involved receptor(s) are same for other clinical indications.
14. What are the post – authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?
Entities marketing biosimilars are obliged to undertake pharmacovigilance for a period of four years from the launch of the drug. Under the pharmacovigilance system, the marketer must have a risk management plan in place which provides brief details of safety concern and necessary action taken by the marketer to mitigate these safety concerns. PSURs must be submitted to the CDSCO every six months for the two years after the biosimilar has been granted approval. Thereafter, the PSUR must be submitted annually for two more years.
Post-approval studies for biosimilars must be conducted in more than two hundred patients in continuation to demonstrate comparability between the biosimilar and the original biologic. In the event permission was obtained to not undertake safety and efficacy study, immunogenicity data that should have been gathered in the PK/PD study will need to be generated in the post-approval phase. However, if pre-approval immunogenicity studies were conducted on more than 100 patients, then the number of patients in the post-approval study may be modified such that safety data (from both immunogenicity and post-approval study) is derived from a minimum if 300 patients treated with the similar biologic.
15. Are there specific policies and requirements in terms of biosimilar medicines labelling in the event of second medical use patents? Is this any different to the requirements for the original Biologics drug?
India does not recognise second medical use patents as the Patents Act, 1970 (“Patents Act”) – India’s patent regulatory framework- excludes the discovery of a new use for a known substance from the definition of invention.
16. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)
The Delhi High Court held that the predecessor to the Biosimilar Guidelines published in 2012 is enforceable in law in the case of Roche Products (India) Pvt. Ltd. & Ors v. Drugs Controller General of India & Ors. [MIPR 2016 (2) 217] (“Roche Judgement”). The court held that guidelines are in the nature of directions issued by the government and as long as the guidelines are not in contradiction but merely in addition to already existing rules and regulations, the guidelines will have legal validity. Even though the Roche Judgement was in context of the previous version of the Biosimilar Guidelines, the same principle should apply to the current Biosimilar Guidelines as well.
17. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?
There are currently no proposals for reform or significant change to the legal, regulatory or procurement framework of biosimilars.