India's New Biosimilar Guidelines and Their Relationship to the Rest of the World

by Dechert LLP

The Indian Ministries of Health & Family Welfare and Science and Technology have released their Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India (the “Indian Guidelines”).   These Guidelines will be implemented on August 15.  India is an important jurisdiction in the world of biosimilars (“similar biologics” in Indian parlance); not only does it have a burgeoning market for biologics, it has a vibrant pharmaceutical industry which is leading the way in biosimilar development.   Thus the Indian Guidelines may well have an impact on the global biosimilar marketplace.  Comparison between the Indian Guidelines and the U.S. and European regimes demonstrates an overall similarity and philosophy and approach, but some important differences that may differentiate the Indian biologics market.  The similarity of the requirements plus the lack of market exclusivity for first-approved products may make India a logical jumping-off point for a global approval strategy.

Unlike in the U.S., the Indian authorities have been approving Indian-produced “generic” biologics with reference products that have been approved in the U.S. or Europe under an ad hoc abbreviated approval pathway for many years. Guise and Carson, Biogeneric Regulatory Policies in China and India: A Comparison Study India has already approved about twenty biologics under this regime. In many cases the Indian regulatory authorities have approved these biologics based on phase 3 bioequivalence studies comprised of about 100 patients.

The Indian Guidelines mirror the U.S. and European emphasis on detailed structural and functional characterization of the proposed biosimilar in comparison to the reference product. To earn reduced pre-clinical and clinical data requirements, there must be no “significant differences in safety, efficacy and quality studies”:

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.

Identification of any significant differences in safety, efficacy and quality studies would mean the need for a more extensive preclinical and clinical evaluation and the product will not qualify as a similar biologic. Indian Guidelines at 3.

It is unclear whether the new Indian Guidelines were intended to make the clinical requirements more or less stringent than they have been. The Guidelines merely state that the regulatory agencies felt the need to present clear guidance going forward. Interestingly, the main thrust of the press coverage on the Guidelines has been a single section which suggests that under certain circumstances biosimilars can be approved without involved clinical trials:

The confirmatory clinical safety and efficacy 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 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

The confirmatory clinical safety and efficacy study cannot be waived if there is no reliable and validated PD marker. Id. at 16.

Without knowing what the Indian regulatory authorities will deem comparability “to a high degree of confidence” or what proof is necessary for a PK/PD study to demonstrate comparability, it is hard to say whether many biosimilars will qualify for approval without full-fledged safety and efficacy trials. Presumably, the Indian authorities will base their determinations on the complexity of the molecule as well as prior international experience with the particular drug. It must be noted that the U.S. statute also expressly provides that FDA in its discretion may find that clinical studies are “unnecessary.” 35 U.S.C. §262(k)(2)(ii). And, as evidence of its intent to maintain that discretion, the recently published U.S. Guidance also holds out the possibility that under some circumstances, the need for detailed clinical studies may be “lessened”:

In general, the clinical program for a 351(k) application must include a clinical study or studies (including an assessment of immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product, as set forth in the PHS Act. The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies. The frequency and severity of safety risks and other safety and effectiveness concerns for the reference product may also affect the design of the clinical program. 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 be scientifically justified by the sponsor. FDA Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product at 12.

The PK/PD study-only option may be unimportant in any case. If India will indeed maintain less stringent standards, Indian manufacturers may nonetheless be driven to greater stringency by the desire for approval by FDA and EMA.

One major difference between the Indian regulatory regime and that of the U.S. and Europe is the lack of regulatory market exclusivity for first-approved products. In the U.S. and Europe, biosimilars cannot be approved until 10 or more years after approval of the reference product. Without this limitation, sales of biosimilars in India are only restricted by patent exclusivity. And even patent exclusivity is less of a barrier, given their less well-developed patent regime for biologics.

There is one provision of the guidelines that will delay market entry for biosimilars in some cases. The Indian Guidelines provide that where “the reference biologic is not authorized in India, it should have been licensed and marketed for at least 4 years with significant safety and efficacy data.” Indian Guidelines at 3. Since for the foreseeable future, new biologics will be predominantly pioneered in the U.S. and Europe, there will be a number of recently-developed products that fall into this category, and will await either the approval of the reference drug in India, or the passage of four years after approval elsewhere.

The combination of an established biosimilar regulatory pathway which is similar to the major markets plus the lack of market exclusivity suggests a global biosimilar strategy for both Indian manufacturers and the big multinational players that begins in India. In order to hasten approval worldwide, first seek approval in India, which may be possible long before other jurisdictions, then use the same data package, plus long-term pharmacovigilance data gathered from sales in India and required post-marketing studies as the basis for approval elsewhere at the first moment possible. In this way, the regulatory package for other markets will be “paid-for” by sales in India, plus the likelihood of worldwide approval will be enhanced by a long history of safety in India.

Given the widely reported rush of international investment in Indian biosimilar manufacturers, it looks like India will be right at the center of the continued evolution of the biosimilar industry.


The following is a comparison of some of the features of the Indian Guidelines to the U.S. and European regimes:

Definition of Biosimilar

The Indian authorities use the term “similar biologic” rather than “biosimilar” but like the U.S. and Europe, similarity is assessed by structural and functional comparisons to an approved reference product.




“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.” Indian Guidelines at 22.

35 U.S.C § 262 (i)

Highly similar to a reference product licensed under 262(a) notwithstanding minor differences in clinically inactive components.


35 U.S.C § 262 (k)– Demonstrated biosimilarity to reference based upon: Analytical studies to show highly similar, Animal studies, and Clinical study(ies)

Biosimilarity is not explicitly defined, but is situational:

“Whether a medicinal product would be acceptable using the ‘similar biological medicinal product’ approach depends on the state of the art of analytical procedures, the manufacturing processes employed, as well as clinical and regulatory experiences.” CHMP/437/04.


“Comparability studies are needed to generate evidence substantiating the similar 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/437/04

Stepwise Approach to Demonstrating Biosimilarity

The Indian Guidance lays out the same kind of stepwise approach, starting with detailed structural characterization of the proposed biosimilar and its reference product, followed by preclinical then clinical characterizations, and makes allowances for product-specific differences in analytical techniques and clinical endpoints.




Similar biologics are developed through sequential process to demonstrate the similarity by extensive characterization studies revealing the molecular and quality attributes with regard to the reference biologic. Indian Guidelines at 5.


A stepwise approach to demonstrating biosimilarity, which can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness Guidance “Scientific Considerations” at 2.

“A stepwise approach should be undertaken to justify any differences in the quality attributes of the similar biological medicinal product versus the reference medicinal product in order to make a satisfactory justification of the potential implications with regard to the safety and efficacy of the product.” CHMP/BWP/49348/2005 at 5. 

Origin of the Reference Product

Indian manufacturers will be particularly interested in basing biosimilars off drugs that have been previously approved in other jurisdictions. The Indian Guidelines permit well-studied foreign-approved reference products.




Licensed in India or in

“Similar biologic can only be developed against an authorized reference biologic that has been

approved using a complete data package in India. In case the reference biologic is not authorized in India, it should have been licensed and marketed for at least 4 years with significant safety and efficacy data.” Indian Guidelines at 3.


“The products, where the reference biologic is not authorized in India shall be considered on a case by case basis if such products have been granted marketing approval in countries with well established regulatory systems such as US FDA, EMA etc. and have been in wider use for a minimum of four years.” Id. at. 22. 

“To obtain licensure … a sponsor must demonstrate that the proposed product is biosimilar to a single reference product that previously has been licensed by FDA. . . . However, under certain circumstances, a sponsor may seek to use data derived from animal or clinical studies comparing a proposed product with a non-U.S.-licensed product….. In such a case, the sponsor should provide adequate data or information to scientifically justify the relevance of this comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product.” Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product at 6. 


No provision for non-EMA licensed reference products.

Requirement for Safety and Efficacy Trials




Potential for omission of safety and efficacy trials. See quote above.

“As a scientific matter, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about the biosimilarity of the two products based on structural and functional characterization, 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.

“Usually comparative clinical trials will be necessary to demonstrate clinical comparability between the similar biological and the reference medicinal product.” EMEA/CHMP/BMWP/42832/2005 at 6.


Exclusivity Period




India provides for no market exclusivity period beyond patent rights.

A section (k) application may not be filed until 4 years after reference product approval. A biosimilar may not be approved until 12 years after reference product approval. 42 USC 262 (k)(7).

“8+2+1.” A biosimilar application may not be filed until 8 years after the reference product approval. A biosimilar may not be approved until 10 years after reference approval. The market exclusivity may be extended by an additional year if the reference product sponsor obtains approval for a second significant new indication during the data exclusivity period.




DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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