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14 April 2016AsiaSameer Sah, Nisha Austine and Jahnvi Shah

Taking shape: biosimilar rules in India

Biologics are large, structurally complex proteins derived from living cells such as bacteria, yeasts or mammalian cells. In comparison to a small molecule or chemical drug, biologics may be 200 to 1,000 times bigger, with high molecular complexity. Biologics include therapeutic proteins and monoclonal antibodies. Biologics that are similar to each other in terms of safety, efficacy and quality to a reference biologic product are referred to as biosimilars.

Due to the complexity of their structures, the discovery process and subsequent manufacturing of biologics is a challenging affair. Even a slight alteration in the composition of a biologic can alter the resulting drug’s efficacy significantly. Comparatively, the discovery process of a biosimilar is bound to be more cost and time effective as the intention is to reproduce and create an almost the same/similar product as the reference biologic, as opposed to creating a completely new product altogether.

While both products retain their complexities in manufacturing, and require robust processes for validation and change control, the reduced expenditure on the discovery process allows biosimilars to be priced more competitively than the reference biologic.

In the last two to three years, various reference biologics have lost patent protection and several more are expected to join the club in the near future. It is currently estimated that by 2020, blockbuster reference biologics with global sales of billions of dollars—including AbbVie’s Humira (adalimumab), Bristol-Myers Squibb’s Erbitux (cetuximab), Johnson & Johnson’s Remicade (infliximab), Rituxan (rituximab), etc—will head over the patent cliff. This is bound to create opportunities for entry of biosimilars in markets across the world, including India.
In preparation, governments and authorities all over the world have set out guidelines for considering and approving biosimilars for marketing. This article will explore and provide certain salient features of the regime in India.

Marketing rules

In India, the primary legislation governing drugs and pharmaceutical products is the Drugs and Cosmetics Act, 1940 and the Drugs and Cosmetics Rules, 1945. These regulations are administered at the central level by the Central Drugs Standards Control Organisation (CDSCO), headed by the Drugs Controller General of India (DCGI). The CDSCO then supervises various state level Food and Drugs Administration departments.

All new products that have hitherto not been approved for marketing in India, or have been approved only during the last four years, are treated as new drugs (not to be confused with standards of novelty required under patent law) and must be approved by the DCGI’s office, subject to clinical and other efficacy data being submitted and analysed. The DCGI’s office refers applications to various specific organisations, including the Drugs Technical Advisory Board, before approving such products for marketing.

In 2012 the Department of Biotechnology of the Ministry of Science (DBT) and the CDSCO together released the “Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India”. They provided guidance on the entire life-cycle of a biosimilar, including early preclinical studies, animal response analysis, clinical testing, marketing approval, and post-approval pharmacovigilance.
The 2012 guidelines state that a biosimilar is to be developed only against an authorised reference biologic that has been approved in India or if the reference biologic has been licensed and marketed in India for at least four years with significant safety and efficacy data. This period of four years can be waived if the relevant disease does not have any medicines, or where the product is intended to be used in palliative therapy with no curative intent, or in case of national healthcare emergencies.

“All new products that have hitherto not been approved for marketing in India, or have been approved only during the last four years, are treated as new drugs.”

The approval process for a biosimilar involves consideration of a lot of information, including:
1. A comparison of quality, and preclinical and clinical studies showing similarity with the reference biologic are required;
2. Extensive characterisation studies to show similarity with the reference biologic; and
3. For imported products (as opposed to products that are indigenously developed), the DCGI’s office will also review data from the country of origin and other countries where the product has been approved for marketing.

A reduction in data requirements may be possible for preclinical and/or clinical aspects by demonstration of similarity to the authorised reference biologic and consistency in the production process, depending on the characteristics of the authorised reference biologic. With respect to extrapolation, in case the reference biologic is used for more than one indication, the efficacy and safety of the biosimilar has to be justified and if necessary demonstrated separately for each claimed indication. Extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies have been done) to other clinical indications may be possible only if certain conditions are met.

Revised guidelines

The CDSCO released revised draft guidelines on March 26, 2016, and has invited public comments until April 30. Although the proposed guidelines have not been substantially modified vis-à-vis the 2012 guidelines, these yet-to-be-approved guidelines do reflect some important changes. One such major change proposes that if the reference biologic is not authorised in India, it should have been approved/licensed and marketed in an International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) country.

The proposed changes further include collecting additional post-marketing safety data, where such a study is to be completed preferably within two years of the marketing permission/manufacturing licence. Other proposed changes concern when a confirmatory clinical safety and efficacy study can be waived as well as non-comparative safety and efficacy studies where, if certain conditions are met, the clinical trials requirements may be abbreviated. The proposed changes are intended to fast-track the approval process for biosimilars and prioritise patient safety.

As the global regulatory guidelines require biosimilars to demonstrate a stringent similarity to the reference biologics at several stages, innovator companies are expected to closely monitor the approval of biosimilars. Further, although biosimilars are to enter the market after the patent covering the reference biologic expires, it is possible that the reference biologic may be part of other patents’ claims such as manufacturing processes, formulation or packaging patents. Given the competing economics, there is bound to be friction and disputes.

A clear example of this came in the Roche v Biocon/Mylan dispute. Biocon and Mylan sought and received approval from the DCGI to market biosimilars of Roche’s product, Herceptin (trastuzumab). Despite Roche’s having slashed the price of the product by 50%, the biosimilar variants would still be cheaper than the slashed price of Herceptin. Roche initiated legal proceedings against the manufacturers and against the DCGI alleging irregularities in the biosimilar approval process.

The Delhi High Court, after considering Roche’s objections, issued an injunction against Biocon and Mylan preventing them selling the biosimilar. Roche and its subsidiary Genentech have also challenged Reliance’s Herceptin biosimilar along similar lines and the Delhi High Court again held Reliance back from proceeding with its product. This litigation is unlikely to be a one-off and heralds future litigation between innovators and biosimilars manufacturers.

The patent dance

Another potential arena of litigation is patent infringement. In this context, the US has enacted the Biosimilars Price Competition and Innovation Act , which provides an expedited approval pathway involving a multi-step procedure for exchange of patent-related information between a biosimilar manufacturer and an innovator (also referred to as the ‘patent dance’).

However, there has been some controversy around whether the patent dance is indeed mandatory. Sandoz and Amgen have already visited the courtroom around this issue as Sandoz declined to comply with all the patent dance requirements, and notified Amgen of its intention to market the relevant biosimilar.

Amgen, however, reasoned that the patent dance had not been completed and sought an injunction restraining Sandoz from marketing the product. The court ruled that this patent dance procedure is not mandatory. As a concept, this process could provide certainty and visibility to the biosimilars manufacturer about whether to expect patent litigation or not. It remains to be seen whether such a process can be introduced in India.

These are interesting times for biosimilars globally. India, which is one of the largest generic markets in the world, has a ballooning biosimilar sector. Zydus Cadila is expected to start selling a type of trastuzumab in India under the brand name Vivitra. An expert committee of the government approved the Vivitra drug in October 2015 after suggesting specific changes in the product specifications. Intas Pharmaceuticals, one of the largest local developers of biosimilars in India, has launched several biosimilars over the years. Biocon is also developing biosimilars along with Mylan.

Price competition and price control threaten companies’ top line and therefore the only way to improve profitability is to introduce products with a low bottom line. High costs and uncertainty over success discourage these companies from taking risks and developing next-generation biologics. Biosimilars therefore offer a good alternative.

Indian guidelines and regulations will have to be gradually developed into more sophisticated approaches to ensure continued availability of affordable healthcare options. In the near future jurisprudence in this area will take shape.

Sameer Sah is an associate partner at  Khaitan & Co. He can be contacted at: mumbai@khaitanco.com

Nisha Austine is a senior associate at Khaitan & Co. She can be contacted at: mumbai@khaitanco.com

Jahnvi Shah is an associate at Khaitan & Co. She can be contacted at: mumbai@khaitanco.com

All views are personal and are not attributable to the firm.

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