BioNJ is pleased that a regulatory pathway for biosimilars was included in the Health Care Reform Act. Our position prior to its inclusion and passage appears below.
From its inception, the biotechnology industry has been driven by the application of cutting-edge science and innovative approaches and technologies that has resulted in the discovery, development and commercialization of hundreds of novel medicines and therapies to treat unmet medical needs, improve human health and save lives.
The great strides in the medical progress the industry has already achieved – and can continue to achieve – and the enormous benefits to patients and society that this progress brings, rests on the industry’s ability to be seen as a major commercial opportunity that continues to attract significant private capital investment, which is the lifeblood of the biotechnology industry.
It is within this context, that the BioNJ Board of Trustees recommends that discussions regarding the introduction of biosimilars to the medical landscape be considered.
Specifically, the Board recommends that any initiative to introduce biosimilars into the U.S. marketplace be measured against:
- The need to provide reliable and effective regulatory criteria and guidelines that ensure patient safety and product efficacy.
- The need to reward true innovation as the driver for therapeutic and diagnostic advances.
- The need to provide incentives that ensure U.S. competitiveness.
Patient Safety and Efficacy
- Require that all biosimilars demonstrate both safety and effectiveness through comparative clinical testing that includes an assessment of immunogenicity and long-term safety.
There are a multitude of reasons why biologics (large and complex molecules) discovered and developed by the biotechnology industry, differ from conventional pharmaceuticals (small molecules). At their most basic, biologics are complex products produced utilizing fermentation, or cell culture, while small molecule drugs are chemical entities originating from conventional molecular design and synthesis. It is important to also note that there is a wide range within biologics ranging from small proteins such as growth hormones or insulin to very large proteins such as monoclonal antibodies or Factor IIX.
Therefore, it is essential to acknowledge, when considering the introduction of biosimilars to the medical landscape, that biologics are far more complex than small molecular entities and because of this complexity, biologics cannot be scientifically characterized to the same degree as traditional pharmaceuticals. Hence, it is generally agreed that bio-equivalence (the standard for approval of small molecule generic drugs) is not feasible for biosimilars, and therefore any approval pathway must rely strongly on robust clinical testing.
For small molecules, it is understood that even subtle changes in composition and/or molecular structure, such as a single isomeric form, can have major consequences for safety and efficacy. Regulatory agencies have, therefore, created rules for determining bio-equivalence based on identical chemical and molecular features that can be determined analytically.
The analytical techniques available today are sometimes inadequate to detect subtle changes with the much more complex biological molecules. Minor changes in composition, and in addition, potential changes in the three dimensional folding pattern (tertiary structure) affect the biological function critically. The complex methods that are required to manufacture a biologic can give rise to such subtle changes. For example, a biologic manufactured utilizing different cell lines, different nutrient sources or environmental conditions, or subject to a slightly different downstream purification process can alter the product features without necessarily showing up in analytical differences. This can result in differences in efficacy and/or toxicity. Hence, in the absence of reliable test methods to predict efficacy or safety, clinical testing for both efficacy and safety is a must.
With that being the case, the practices and procedures associated with the approval and production of small molecule generic pharmaceuticals cannot be applied to biologics. In the approval process for a generic chemical entity, a manufacturer needs to show that its product is chemically identical and bioequivalent based on a pharmacokinetic study in humans that merely establishes the time course of distribution (i.e. what the body does to the drug). Otherwise, the manufacturer relies on the innovator product’s safety and efficacy data to substantiate the safety and efficacy of the generic product.
In conclusion, reliable guidelines will have to be developed by the U.S. Food and Drug Administration (FDA) that incorporate these concerns and that rely on adequate clinical testing of biosimilars for efficacy and safety.
The issues surrounding the potential safety of a biosimilar also apply to its potential effectiveness unless exact clinical effectiveness and interchangeability can be demonstrated:
• Biosimilars should be assigned a non-proprietary name that readily distinguishes the biosimilar from the innovator product.
• Regulations should require that patients are not given a biosimilar unless clearly stated on the prescription by the physician that substitution is allowed.
In many states, small molecule generic drugs may be dispensed interchangeably with innovator products without physician knowledge. The FDA, however, has stated that it “has not determined how interchangeability can be established for complex proteins.” Until a method to determine interchangeability is identified and proven, it is in the best interests of patients to ensure that treatment decisions remain in the hands of the physician.
Likewise, a biosimilar should be given a name that is distinct from the innovator product to ensure that the physician and medical care professionals can distinguish between the innovator product and the biosimilar.
• Include 12 years of non-patent data exclusivity post-approval, during which time biosimilar manufacturers could not rely on FDA’s prior approval of a pioneer’s biologic to support the approval of their own product. An additional two years can be allocated for the completion of clinical trials that lead to the approval of another indication(s).
• Ensure proper patent protection.
• Continue to prioritize FDA review toward review and approval of new therapies and cures.
Proposals to introduce FOBs come at a time when the biotechnology industry is being particularly hard hit by the worldwide economic downturn. Unlike the “large-cap” pharma industry, the biotechnology industry is heavily dependent on access to significant amounts of high-cost public and private investment capital.
Statistics indicate the biotechnology industry is under duress. The amount of new capital raised by biotechnology companies fell fifty five percent in 2008 relative to 2007. Likewise, the number of biotechnology companies operating with less than six months cash on hand increased by ninety percent!
The current financing environment is highly competitive, and funds are preferentially funneled into companies and projects that produce short-term value inflection points at which time research and development can be monetized. Early innovation suffers especially, creating an innovation gap that is expected to occur in 2015 and beyond. These trends must be seen in terms of potential longer lasting losses with regard to innovative therapies and technologies deferred or abandoned, and jobs lost and jobs not created.
Therefore, because of the fledgling nature of biotechnology companies – many of which have yet to market a product, proposals to introduce biosimilars must be careful to be seen as not hampering innovation and scaring away already shaky investors.
There is a need to balance the societal/political demand for reduction in cost of health care and increase in competition in the biotechnology industry through biosimilars with the need to provide investors with a stable framework that will ensure a rationale for their investments, thus providing an environment that nurtures innovation and helps maintain the competitive edge of the U.S. biotechnology industry. Major advances in medicine have only happened in an environment that stimulated and protected entrepreneurial behavior. Understandably, that need for innovation needs, at a given point, to be balanced with accessibility of the large public to the innovation; hence the debate on biosimilars. This need for balance should not, however, go at the exclusive expense of the innovators, nor should it put innovators in the United States at a disadvantage from innovators in other countries.
Indeed, at a moment in the USA when voices are emerging that plead for a reduction in patent protection or in years of data exclusivity, other countries are in the process of stimulating intellectual property protection and considering 10 to 12 years of data exclusivity for innovators. For the U.S. biotech industry to remain competitive, biosimilar proposals must ensure adequate data exclusivity and provide an equitable framework to resolve patent disputes in order to maintain a secure and predictable funding environment.
Lastly, provisions need to be in place that will ensure that the initiation of a biosimilar process that does not hamper or slow down the FDA in approving new therapies. Increased demands of the FDA should be accompanied by increased resources.
The Board of Trustees of BioNJ believes that pathways to make biosimilars available to the large patient population must be considered.
BioNJ also strongly recommends that any proposed pathway to introduce biosimilars into the armamentarium of medical treatments be crafted so that patient safety is paramount, and that the medical effectiveness of all marketed biologics is ensured.
BioNJ also strongly recommends that innovation be preserved and enhanced, and that it should be seen in the light of substantial enhanced support and protection that is given to technology companies in a variety of countries that directly compete with the USA.
For society to continue to benefit from 21st century medical advances, the market must continue to reward innovation. Incentives must be in place to attract investors and encourage companies to put substantial amounts of money into biotechnology, diagnostics and medical device industries. Looking at this in a global context of competitiveness is the only way the United States will be able to maintain the premier position this country currently enjoys in the biotechnology industry.
In reviewing the various proposals that have been put forth, BioNJ recommends support for H.R. 1548, The Pathway for Biosimilars Act, a bi-partisan legislative proposal recently introduced by Rep. Anna Eshoo (D-CA), Rep. Jay Inslee (D-WA) and Joe Barton (R-TX), and urges members of the House of Representatives to sign on as co-sponsors.
Based on the issues discussed in this White Paper, BioNJ believes that through this legislation, a regulatory pathway for biosimilars can be created that will realize the goal of helping to manage some of the costs of healthcare, while rigorously protecting patient safety and encouraging innovation.