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Addressing the Unique Challenges of Running Biosimilar Clinical Trials
John Patava
Quintiles, Asia

The opportunity and the reality

While there is enormous potential for development of biosimilars, the actual outputs to date have been meager: only 14 successful biosimilar product approvals in the European Union (EU) and only three biological follow-on biological medications in the United States. In spite of this the biopharmaceutical industry is planning and undertaking very significant investment in the development of these products over the next three to five years.

Biosimilars in Asia

What of Asia? While the EU, US and other Western nations have adopted a cautious approach to the process of regulating and registering biosimilar products, countries in Asia – particularly Korea, China and India – have been aggressive in enabling the registration of copy biological molecules.

Companies such as LG Life Sciences and Daewoong Pharma in South Korea; CPGJ in China; and Dr. Reddy’s Laboratory, Zydus and Wochardt in India, have all been very active in developing, registering and marketing products based on originator products developed in the US and Europe. While the regulatory framework under which these products were developed were not in keeping with the EU guidelines introduced in the mid-2000s for the development of biosimilar drugs, they have met the requirements of the local regulatory agencies in place at the time – thus enabling the introduction of biosimilars in local markets at costs lower than the originator branded products.

In some cases, the originator products’ market share gets eroded with the introduction of biosimilars by indigenous suppliers, with multiple reasons at play. Price competitiveness, access to distribution networks and time to market entry with the local manufacturer having distinct advantage to the international competitor are all key contributing factors.

Evidence suggests that the biological products that these companies have produced in the past have not had any safety concerns and have been widely used in their home markets. However, the potential for Chinese, Indian and Korean companies to market their products in the US and EU has been hampered by their inability to meet US and EU regulatory guidelines and lack of a viable commercial presence there.

The converging global regulatory environment

The EU pioneered the development of biosimilar regulations and guidelines with a legislative pathway introduced in 2004 and issuance of overarching guidance soon thereafter. These original guidelines and others introduced later on quality and product class have either been adopted, as in Australia, or adapted by local regulatory agencies in countries such as in Malaysia, Taiwan, South Korea and others (Table 1).

The US has been late in the game, publishing overarching guidelines in 2012. The commonality between the US draft guidance and EMA guidelines published in 2004 about the scientific principles on which the test product and the originator are set up is noteworthy.

The Indian Central Drug Standard Control Organization also released its biosimilar guidelines in July 2012. Although India has established a very successful and productive indigenous biosimilar development industry, launching products using an abbreviated regulatory pathway in the past, the principles of the new Indian Guidelines are largely harmonious with those of the US and EU. The publication of guidelines that are in harmony with such a broad range of markets has enabled Indian companies to map out a relatively clear pathway to registration in a broad range of markets. Their immediate challenge will be gaining access to global market with their portfolio of products registered in India prior to the issuance of the new guidelines.

Clinical development planning

The guidelines that have been published globally, in addition to the product class guidelines that have been issued by the EMA over the past decade, provide a solid framework in which developers can operate to plan a biosimilar development strategy. These guidelines direct developers of biosimilar drugs to take a stepwise approach, starting with stringent full characterization and analytical comparability studies against the reference product from the region of choice followed by in vitro and in vivo, non-clinical studies, followed by Phase I PK/PD (if applicable) analysis that finally lead to Phase III trials.

The guidelines may be well-drafted and clear regarding steps to regulatory success; however they are not static. Indeed, the EMA is in the process of redrafting their guidelines for release in 2014; these will presumably incorporate valuable lessons learned by the agency over the past 10 years. A very important part of the biosimilar development planning process therefore is to validate the plan in line with the regulators. The EMA and the US FDA both recommend and make provisions for meetings to discuss the development plan so that they can provide input on the chosen pathway.

There are many issues on which the counsel of regulatory agencies can be sought. These include selection of appropriate indication for the particular biosimilar product, patient population, the appropriate comparator medication, study endpoints covering issues such as the use of surrogate markers, statistical planning and safety assessment and follow-up. There are costs associated with obtaining this advice, but these are justified in mitigating the investment risk of the planned development.

The challenge of biosimilar development: Finding investigators and patients

There are many reasons that clinicians participate in clinical research, including personal interest, the potential to provide new options to their patients for whom available treatments are ineffective or inadequate, or the prestige that comes from being involved in the front line of medical discovery. For the latter reason in particular, it has always been challenging to interest key opinion leaders and highly experienced investigators in participating in the research of products that follow the first-line blockbuster compound in a particular therapeutic space.

That holds equally true for biosimilars trials. The response from potential investigators we have approached to participate in biosimilar trials has been slightly less enthusiastic than for new product clinical research opportunities as a whole. Our internal research indicates numerous reasons for this dampened enthusiasm. For one, protocol requirements can be demanding of the site infrastructure and the patient, with overnight stays and highly rigorous studies to demonstrate equivalence in PK, particularly in Phase I studies. There may be numerous competing trials all trying to recruit from a particularly well characterized and narrowly defined patient population. In countries where the originator drug is reimbursed, there are concerns around consenting patients into trials of products that have not gone through the full process of registration as has the originator product.

Many Investigators and patients are not aware of the strict requirements for the stepwise development of biosimilars. Investigators have also cited lack of clarity of their country’s regulatory position and processes; a lack of understanding of the potential benefits of participating in biosimilar studies; and low interest the scientific research of a therapeutic area.

Patients may also be anxious about being administered an investigational biosimilar product. In many cases that anxiety is misplaced. Biosimilars in clinical trials are carefully evaluated through the stepwise process to ensure that it is highly similar to the originator product and the risk of exposure should be no higher than the risk of being administered the originator product.

Navigating through to success

The key to increase participation in biosimilar research is through education. Quintiles has learned that investigator interest increased with a better understanding of the value proposition for biosimilars. For this reason Quintiles has made significant investment to introduce tools to reach out to investigators in Asia and globally to increase awareness of the potential that exists in this area of research. Part of this investment involves development of educational materials to inform investigators about biosimilar products; how they differ from generic products; and how their development will impact on the provision of health care. These materials have been made available through our publicly accessible, Biosimilars Knowledge Connect Web portal.

In the end, the main driver of patient participation in these trials is likely the same as those for the investigator - access to highly specialized, effective and very expensive medicines. This is not a situation restricted to developing markets of Asia, but also to the US and other markets where private outlay for biological medications is extremely high, and where clinician interest in being involved in biosimilar studies is high as a consequence.

Many of the hurdles to successful biosimilar product development can potentially be overcome through clear identification of the potential benefits, such as increasing access to medicines by making them more affordable leading to the possibility of treating a larger number of patients with highly effective biological medicines. From a societal perspective, providing access to these medicines to a larger number of patients cannot but have a profound economic benefit for the countries in which they become more readily available. This will be a key driver of the development of these products in Asia.

That there will be many challenges for biosimilar developers to overcome and the rewards for overcoming them are potentially very high makes working in the biosimilar area a very exciting proposition.

About the Author

John Patava, Director Biosimilar Intelligence and Capabilities has 25 years’ experience in the production and clinical development of therapeutic proteins and has overseen clinical trials of biological products in the indications of oncology, renal medicine, Chron’s disease, multiple sclerosis, hematology and surgery.

In his most recent role at Quintiles John oversaw P&L for the Business Units of Drug Development Asia (DDA) with 50 direct staff in the departments of Medical Services, Site Services, Biosimilar Intelligence and Strategic Drug Development.

In addition to having 10 years’ experience in clinical operations working at Janssen Cilag and Bayer, 6 of these in country and regional manager roles in Australia and South East Asia, he has been involved in Business Development in contract research organizations undertaking Account Executive and Sales and Marketing functions during which he developed marketing campaigns for a wide range of services.

John’s first position in the pharmaceutical industry was as a fermentation engineer at a biotechnology company in Australia where he developed GMP processes for the manufacture of monoclonal antibodies and vaccines. Along the way, he obtained a PhD in Physiology from the University of Sydney.

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