Need For A Smarter Regulatory System To Ensure Access To Affordable Biologics: The Biosimilars

The global pharmaceutical industry is going through a paradigm change as biologics such as monoclonal antibodies and recombinant proteins find greater acceptance for treating a wide range of chronic diseases.


Today biologics make for up half of the top 10 best-selling drugs worldwide.

The use of biologics is fast gaining traction around the globe because they can address medical needs that conventional therapeutics cannot, including many cancers, immunological and genetic diseases. Unfortunately, the development of biologics is hugely expensive and the high cost factor makes them inaccessible to a larger patient population.

With patents for several popular biologics expiring over the next few years, ‘biosimilar’ products that offer the same level of safety and efficacy as innovator molecules can be a cost-effective alternative for patients. Biosimilars can also help governments across the world rein in their burgeoning healthcare spends.

The latest available IMS forecast for biosimilars indicates a global market size of US$ 5 billion by 2016.

The quality and regulatory requirements for biosimilars are significantly more extensive than those for generic small molecules. Conventional generics are only required to demonstrate simple bio-equivalence to the originator product in a small cohort of healthy volunteers, whereas biosimilars have to establish comparable safety and efficacy through fairly large and lengthy clinical trials in patients that make the process complex and expensive.

Governments around the world thus need to define a smarter regulatory pathway that reduces ‘cost of development’ and ‘time to market’ for biosimilars. This will ensure that such new age medicines reach a wider swathe of the population, especially the poor.

Dealing with Complexity

Biosimilars differ from conventional small-molecule generics in that they are target-specific drugs that are large and complex and have a stringent production protocol.

Chemically synthesized drugs typically have a molecular weight of less than 700 Daltons, a well-defined structure and are relatively stable. In comparison, a monoclonal antibody weighs about 150,000 Daltons, has complex physicochemical characteristics and is sensitive to heat.

A plethora of analytical tools are needed to evaluate the various quality attributes of a protein. As each tool covers only a part of a protein’s complexity, several methods and multicomponent analysis needs to be carried out to arrive at its complete structure and functional attributes.

This level of complexity means the time, effort and money needed to analyze and characterize a biologic drug is exponentially higher than a small molecule drug.

It takes about 18 to 24 months and costs between US$ 1 million and US$ 4 million to file an ANDA (Abbreviated New Drug Application) in the U.S. for a small molecule generic (refer Fig 1).                                                             

In contrast, the complex regulatory path that needs to be traversed for filing for approval of a biosimilar could take as long as five to seven years and cost anywhere between US$ 80 million and US$ 100 million based on the abbreviated pathway proposed by global regulators (refer Fig. 2). The biosimilar manufacturing process starts with fermentation, which is followed by a multi-step purification process to have the right quality product. It is from this stage that the data evaluation process kicks in. The analytical and characterization group evaluates the primary, secondary and tertiary structure of these proteins. However in the case of biosimilars, unlike generics, the development process does not end at analytics but extends to large and lengthy clinical trials , which adds to the cost of development as well as delays the launch in the market.

The high levels of complexity and expenses associated with biosimilars make a compelling case for the regulations to balance the aspects of safety and efficacy with affordability.

If regulations are made too stringent there may not be enough commercial incentive for companies to develop biosimilars. At the same time, laws should be robust enough to ensure efficacy and the safety of patients is ensured.

Unfortunately, Figure 2 which is highlighted by most regulators as the short pathway for regulatory approval of biosimilars, in reality is not a “pyramid” but a “cube” (as indicated in Figure 3).

Although the regulators have indicated that clinical data requirement for biosimilars is abbreviated, when one actually discusses the same with regulators the requirements are nowhere close to the small triangle shown in Figure 2. In reality it takes 7-9 years and costs $100-150 MM,  based on current understanding of regulatory requirements.

In fact, if one looks at the approvals of some of the innovator biologics, the sample size for their pivotal studies is smaller than the requirements for biosimilars based on current guidelines.

Demonstration of Biosimilarity One of the greatest challenges for biosimilars is to demonstrate whether or not they are substitutable with innovator products. While this is still a very contentious topic, I believe biosimilars will ultimately be substituted for branded products and become part of standard medical practice in the future. There is no company today that actually sells bioidentical products. If the same product is manufactured at  two different locations even by the innovator, there is a high probability that they will not  be “bioidentical.” We are likely to see at least some variation in most cases because the cell culture process is so complex that there are bound to be batch to batch variations. In fact, innovators making the same biologic at multiple locations are in effect  producing biosimilars. Of course, there are acceptable and unacceptable levels of variation. So the question is whether we can use the same yardstick to develop biosimilar drugs? What leeway can be given to companies that are looking to make biosimilars? The way I see it, ‘biosimilarity’ will hinge largely on comparability between the original and the follow-on product in terms of safety and efficacy. If a biosimilar and an innovator product are comparable on these two parameters it will simplify the task for companies trying to make biosimilars. Journey of New Regulatory Paradigm The world over, there is a need to create a smarter regulatory environment that not only cuts down the cost of development but also ‘time to market’, which in turn benefits consumers by improving access to affordable drugs. India can play a key role in enabling this process. An innovative regulatory pathway for biosimilars in India could do away with the need for conducting Phase III clinical trials, keeping in mind that  high resolution analytics of today provide high end characterization data than before, thereby proving the biosimilarity criteria to a large extent. In light of this, the regulator could give companies a "conditional approval" for these biosimilar drugs based on Phase I comparable Pharmaco-Kinetic (PK) data  and give them a year's time to collect "safety and efficacy" data post marketing. The final approval should be given post submission of this data (Refer Figure 4). The current biosimilars regulatory regime stretches approval times to as long as 7 to 9 years and costs to between $100 million and $150 million, a new regulatory paradigm could drastically bring down timelines to between 30 to 42 months and cut costs up to a tenth. It could thus ensure that local regulatory requirements don’t add to the cost of development and force companies to price their products at a premium. Conclusion The experience of EU with biosimilars has amply demonstrated that the presence of biosimilars enhances existing market competition, increases access to medicine to a larger set of the population and helps stabilize healthcare costs. Biosimilars have been able to command 11% of the total accessible market in EU since their introduction in 2006. The urgency for a rational set of biosimilar guidelines is being felt in developed nations. Although US has recently approved a path for biosimilar products, without dealing with issues like  interchangeability and substitutability and simplifying the patent litigations, it is unlikely that there would be a meaningful impact on costs.  India therefore should take the lead among the emerging economies to expedite the approval of biologics for use by the public while, at the same time, ensuring that high levels of safety and quality are maintained. Smart regulations and a strong patents regime can help India build an ecosystem that fosters cheaper drug development and gives drug makers the impetus to pass on the benefits to patients without having to take a hit on their bottom line.