India is revising regulatory guidelines for biosimilars with an objective to broaden its scope and coverage. India’s efforts come in the wake of emerging clarity regarding a pathway for guiding and regulating the generic equivalents of complex biologic products across global markets.

The Central Drugs Standard Control Organization (CDSCO), India’s apex drug regulator, along with the Department of Biotechnology (DBT) has worked out the draft “Guidelines on Similar Biologic” and released it for the stakeholder review.

It was in 2012 DBT launched regulatory guidelines for similar biologics for the first time. The brief set of rules outlined the procedure for the evaluation of generic biologic products already marketed in India and elsewhere for over four years.

The new 58-page document details the procedures for preclinical and clinical studies using similar biologics in India. With emphasis on manufacturing quality, the draft proposals lay down the framework for continuously monitoring the safety of the products effectively utilizing post-marketing surveillance and pharmacovigilance for adverse drug reporting.

The rules state that quality comparison between similar biologic and reference biologic—the innovator product—is essential. It mandates head-to-head characterization studies to compare the similar biologic and the reference drug at active drug product level.

The manufacturer can consider product development only after the similarity of the biosimilar is demonstrated in quality to a reference product. The applicant needs to explain the rationale for the choice of the reference biologic to the regulator. And the reference biologic should be used in all the comparability exercises with respect to quality, preclinical and clinical considerations.

Safety first
The guidelines list the data requirement for preclinical studies, Phase I trials, measuring the pharmacokinetics and pharmacodynamics. The document also makes clear the specifics for extrapolation of efficacy and safety data to other indications, while elaborating on the data needs for market authorization, package insert submission and so on.

Confirmatory clinical safety and efficacy studies, however, can be waived off on certain grounds such as in cases where structural and functional comparability of biosimilar and reference product can be characterized to a high degree of confidence by physicochemical and in vitro techniques.

The roadmap document dedicates a whole section for post marketing data. It says, “Similar biologic is authorized based on a reduced preclinical and clinical data package, it is important to establish a formal Risk Management Plan to monitor and detect both known inherent safety concerns and potential unknown safety signals.” It requires manufacturers to submit Phase IV protocol along with marketing authorization application for approval.

The market for similar biologics is expected to expand further as biotherapeutics worth over $67 billion go off patent in the next couple of years.

India today has a well-delineated biosimilar segment with nearly two-dozen players operating in the space. India’s estimated $900 million generic biologics market is presently witnessing a fierce battle with competing brands as most of the firms have similar product lines.

To spur CROs?
The new regulations are expected to give a boost to the outsourcing sector, especially the CRO and manufacturing industries. Indian companies, with moderate to big pipelines, would beef up development and production capabilities for biosimilars, experts say.

Companies continue exploring overseas not only for technology partnerships but manufacturing as well. Dr. Reddy’s partnered with TR-Pharm of Turkey in March to develop and manufacture three biosimilars. The Hyderabad-based firm, which launched pegfilgrastim, rituximab and darbepoetin in India, is reportedly working on trastuzumab and bevacizumab, among others.

Intas Pharma of Gujarat, which launched a version of ranibizumab in June last year priced at one-fourth of Lucentis, said the company was aggressively pursuing cancer drugs listing EU and U.S. as target markets. Other firms from this western state, including Zydus Cadila and Torrent, also had a few launches in recent years.

Zydus introduced adalimumab in 2014. Claiming an active pipeline of around two-dozen biologics, Zydus said the focus of the company would be on domestic markets for now. Meanwhile, Torrent, which has been marketing darbepoetin alpha, entered into an exclusive deal with Reliance Life Sciences for commercializing its adalimumab, rituximab, and cetuximab in India.

Biocon, Lupin, Hetero, Cipla are among other leading players betting big on similar biologics. MNCs in India are also eager to grab a piece of this lucrative market. Roche’s tie up with Indian generic player Emcure for trastuzumab (Herceptin) is an example.