Another step forward: India releases updated biosimilar guidelines

HYDERABAD, India – Following feedback from industry, health policy experts and the public, India recently updated its draft guidelines for biosimilars, narrowing down the conditions for waivers of late-stage trials and expanding some testing criteria.

"The revised guidelines have considered some stakeholder input, relative to the conduct of clinical trials and safety/efficacy studies," Ranjana Smatacek, former director general of the Organisation of Pharmaceutical producers of India (OPPI), told BioWorld Asia.

The new version narrows down the conditions for waivers for phase III trials. It also broadens the pharmacokinetic (PK) and pharmacodynamics (PD) criteria for testing biosimilar drugs and stipulates that confirmatory safety and efficacy studies are mandatory for monoclonal antibody (MAb)-based products.

"However, disappointingly, there are other important suggestions that have not been incorporated," Smatacek added. "These presently omitted suggestions would make for a scientific approach to ensure that safe, effective and quality similar biologics are developed, approved and marketed in India."

OPPI had made specific suggestions, some of which have been accepted. Those include recommendations that both the drug product and drug substance should be characterized; viral clearance should be included for confirmation of efficacy; and the study should be conducted in a sensitive and homogeneous patient population with appropriate sensitive primary points as per requirements of a phase III trial.

Other suggestions included waivers of confirmatory clinical safety and efficacy studies if the PK and PD studies have demonstrated comparability for PD markers validated for clinical outcome; and that clinical trials for large biologics – for example, MAbs – should not be waived.

However, other feedback suggestions have not been taken on board in the revised guidelines. Those include suggestions that the guidelines need to be considered as regulatory pathways linked to India's Drugs and Cosmetics Act and Rules, some of which could be modified to factor in biosimilars regulation.

Another suggestion pertains to the design of a clinical study, with scientifically well-defined margins for efficacy equivalence studies, and to prove that the biosimilars are not inferior to the original molecule.

Others include determination of sample size based on statistical considerations and taking into consideration the primary endpoint of the phase III study; the appropriate sequence of studies, with the PK data evaluation, even if conducted in patients, preceding further conduct of a large confirmatory comparative phase III study; and greater clarity, in line with evolving international guidelines, on issues relating to extrapolation of data, interchangeability of substances, automatic substitution and nomenclature.

MIXED REACTIONS

India's 2016 revised draft guidelines, first released in March, and an updated version of its previous 2012 guidelines, had drawn mixed reactions initially from the country's pharma industry that has, by and large, welcomed the increased clarity and more rigorous conditions in the revised guidelines, but drew some flak from the OPPI, comprising largely foreign pharma firms, which said the new rules could compromise patient safety.

The 2016 revised "Guidelines on Similar Biologics" have been prepared by India's Central Drugs Standard Control Organization (CDSCO) and the Department of Biotechnology (DBT). They lay down the regulatory pathway for a "similar biologic"– a biologic drug that claims to be similar in quality, safety and efficacy when compared to an already authorized "reference biologic."

The Indian guidelines address the regulatory pathways regarding manufacturing process and safety, efficacy and quality for biosimilars. The guidelines also address premarket regulatory requirements, including a comparability exercise for quality, preclinical and clinical studies and postmarket regulatory requirements for similar biologics.

The guidelines also provide detailed criteria for the selection of a reference biologic; the manufacturing process, including upstream and downstream processes; quality considerations; prerequisites for conducting clinical studies, including pharmacological and toxicological studies; data requirements for clinical trial applications; data requirements for marketing authorization; and postmarket data.

More details on postmarketing studies, with the aim "to further reduce the residual risk of the similar biologic," also are included in the new guidelines. They also specify a timeline – preferably within two years of the marketing or manufacturing license –for postmarketing safety data through a pre-defined single-arm study of more than 200 patients and compared to historical data of the reference product.

The guidelines stipulate that the "primary aim of the postmarketing phase IV studies is safety" and that the primary endpoint of those studies should be safety and secondary endpoints efficacy and immunogenicity.

Four conditions need to be met for products to receive a waiver for confirmatory safety and efficacy studies. Those include structural and functional comparability of the similar biologic and reference biologic; proven comparability in all preclinical evaluations; proven comparability in PK and PD studies in in-patient settings for an adequate period of time; and submission of a comprehensive postmarketing surveillance plan.

The guidelines, however, stipulate that also "wherever the phase III trial is waived, the immunogenicity should have been gathered in the PK/PD study and will also need to be generated during a post-approval phase IV study."

GROWING BIOSIMILARS SECTOR

India's revised guidelines come as the country's biotech companies, backed by the government, are making a strong attempt to become world-class biosimilar manufacturers.

But to achieve their ambitions, the country needs to overcome chronic problems with quality control, limited funding and the fact that making big-molecule biosimilar drugs is much more difficult than developing and making the small-molecule generics that have traditionally been the backbone of the country's pharmaceutical industry.

The number of companies in India with biosimilar portfolios is growing and now includes companies like Mumbai-based Cipla Ltd., Bangalore-based Biocon Ltd., Hyderabad-based Dr. Reddys Laboratories and Ahmedabad-based Zydus Cadilla.

Hyderabad-based Hetero Drugs Ltd. in 2015 launched its own biosimilar rituximab under the brand name of Maball. The drug is a version of Roche Holdings AG's Mabthera for non-Hodgkin's lymphoma and leukemia.

In June, two firms – Reliance Life Sciences and Hetero Drugs –launched biosimilars of Roche's Avastin (bevacizumab) that were approved by India's Drug Controller general of India. And Torrent Pharmaceuticals Ltd. announced the launch of biosimilar adalimumab by 2016 under the brand name Adfrar to treat auto-immune disorders. The originator drug is Humira from Abbvie Inc.

In recent months, multinational companies have challenged the Indian government over some of its guidelines. In May, for example, Roche attempted to block approvals of copies of bevacizumab. The company is similarly suing Biocon, U.S.-based Mylan NV and Mumbai-based Reliance Life Sciences over their biosimilars of breast cancer drug Herclon (trastuzumab), marketed by Roche as Herceptin.

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