A debate is intensifying within the biotech industry over how the Food & Drug Administration should handle copycat versions of protein-based drugs, or biologics. Fights over testing requirements, data exclusivity, and even how to name these so-called biosimilars, or follow-on biologics, are delaying the agency from putting an approval process in place.
FDA received the authority to create an abbreviated pathway for approving biosimilars under the controversial health care reform act signed by President Barack Obama in March. The bill, called the Biologics Price Competition & Innovation Act, aims to lower the cost of biological drugs such as monoclonal antibodies and other complex proteins, which can cost up to $200,000 per year for one patient.
FDA now has to decide how much testing is necessary to show that a biosimilar is as safe and effective as the original product. Analytical methods for protein characterization will undoubtedly be a critical part of that testing, and the agency is likely to require some number of animal toxicology studies and human clinical trials. But there is much disagreement over exactly how much clinical testing FDA should require.
Biologics are much more challenging to regulate than chemically synthesized small-molecule drugs because they have highly complex structures and are made inside living cells. As a result, two biologics are rarely ever identical. Even slight changes in manufacturing processes can lead to modifications in a biological product and potential adverse reactions in patients.
Because of the complexity of protein-based drugs, FDA is finding it difficult to strike the right balance between the desire for low-cost biologics and the need for careful evaluation of safety and efficacy. To get input from all stakeholders on how to proceed with establishing a biosimilars approval pathway, FDA held a two-day public hearing earlier this month. Dozens of representatives from patient advocacy groups, academia, drugmakers, analytical instrument companies, and legal firms provided the agency with vastly different perspectives.
On one side of the debate are the biotech companies and patient groups, which insist that the complexity of biological products makes animal toxicology studies and human clinical trials essential for establishing safety and efficacy.
“A typical batch of a biological is made by billions of ‘cloned’ cells. Each cell produces millions of copies of the therapeutic molecule by a process that can take thousands of steps,” Joe Miletich, senior vice president of R&D at Amgen, testified at the hearing. “A biosimilar product will invariably be made up of a different mixture of related molecules than the product it is attempting to copy. The challenge with biosimilars is knowing which structural variations matter clinically and which do not.”
In its 30-year history of making biologics, Amgen has been “humbled by unexpected clinical outcomes after analytical and nonclinical studies had predicted success,” Miletich pointed out. He added that “minor changes in structure, formulation, or impurities can have a significant impact on patients that cannot always be anticipated with analytical studies.”
On the other side of the debate are the generic drug manufacturers that claim that clinical testing for biosimilars is redundant and unethical because it has already been performed on the original products. “Every unnecessary test or study imposed by FDA to establish biosimilarity not only leads to ethical problems but also compounds the cost of development, raising useless yet prohibitive barriers to potential competition,” emphasized Rasmus Rojkjaer, vice president and head of global biologics R&D at Mylan Inc., in Pittsburgh. Rojkjaer was speaking on behalf of the Generic Pharmaceutical Association, a trade group for the generic drug industry.
Rojkjaer argued that if biosimilars producers have confirmed that their product is “highly similar” to a reference biologic with state-of-the-art analytical tools, then that biosimilar “should be subject to clinical study requirements only to the same degree as is expected for originator products making manufacturing changes.” Such requirements typically do not involve clinical testing.
Massachusetts-based instrumentation company Waters Corp. came to the hearing to give regulators a refresher on what can and can’t be done with respect to protein characterization using today’s analytical instrumentation.
Waters has teamed up with Northeastern University to launch a biopharmaceutical analysis training laboratory. The partnership aims to teach both regulators and pharmaceutical workers about protein characterization methods. The lab is expected to be up and running in the summer of 2011, according to Jeff Mazzeo, director of biopharmaceutical business operations at Waters.
The training lab will focus on methods for analyzing posttranslational modifications, three-dimensional molecular structures, and protein aggregation. It will also demonstrate more routine analyses, such as peptide mapping, to confirm the primary sequence of the protein, Mazzeo tells C&EN.
Although such methods can detect structural differences between two proteins, they cannot test bioactivity. Nonetheless, several people at the hearing were in favor of scaled-back clinical testing for biosimilars. They urged FDA to consider the ethical aspects of redundant clinical trials. Among those attendees was a representative for Sen. Bernard Sanders (I-Vt.), who introduced the Ethical Pathway Act (S. 3921) in late September.
S. 3921 would eliminate the controversial 12-year data exclusivity period given to biologics innovators as part of the health care reform act. During that exclusivity period, companies cannot rely on an innovator’s data to show the safety and efficacy of a biosimilar product. Sanders’ bill mandates that biosimilars producers be allowed to rely on existing, original data, subject to paying the innovator an appropriate fee.
In a Nov. 2 letter to FDA Commissioner Margaret Hamburg, Sanders urged the agency “to pay close attention to the ethical implications of the new law” and “to recommend to Congress that this fundamental flaw be addressed legislatively as soon as possible.”
The debate over the data exclusivity period is likely to come up again in Congress next year. Sen. Sherrod Brown (D-Ohio) has pledged to introduce legislation to reduce the data exclusivity period for biologic drugs.
Many advocates of a shorter data exclusivity period are particularly concerned about a loophole in the law that allows the innovator company to get a new 12-year period of data exclusivity for each small change it makes to a biologic.
The law “leaves opportunities for manufacturers to make minor product improvements and renew their exclusivity period,” Jonah Houts, chairman of the Alliance for Affordable Medicine, noted at the hearing. FDA “should require an applicant to show significant clinical advantage in safety or efficacy based on a well-controlled clinical trial to warrant an extension of exclusivity for a structurally modified product,” he said.
Likewise, William Vaughan, a health policy analyst at Consumers Union, publisher of Consumer Reports magazine, brought up the potential for “evergreening,” or enabling repeated periods of data exclusivity. “Our nation’s system of approving generic biologics is a consumer disaster,” he said. “Unless the FDA sets very high standards for extensions, the new law is basically unworkable.”
The Biotechnology Industry Organization (BIO), a trade group representing more than 1,100 biotech firms, dismissed the concerns that biologics can get more than one 12-year period of exclusivity. “In our view, the law is extraordinarily clear that there is never a second 12-year period of exclusivity. If there is a change in safety, purity, or potency, then it’s a new product,” noted Sara Radcliffe, executive vice president for health at BIO. And new products have to undergo a full set of clinical trials, she said.
Among other difficult decisions, FDA will have to consider whether modifications, such as the addition of a sugar, to a protein’s structure constitute a new biological product. FDA is also mulling whether to require distinct names for biosimilars to aid in identifying adverse events after a biosimilar is marketed. In addition, the agency is under pressure from some drug manufacturers to allow extrapolation of biosimilar safety and efficacy data from one disease to another and to accept data that demonstrate biosimilarity to non-U.S. products, such as biologics approved by the European Medicines Agency.
FDA is also required under the health care reform law to develop a user-fee program to support the review of biosimilars applications and postmarket surveillance of adverse events. The agency has until Jan. 15, 2012, to present recommendations for such user fees to Congress.
A user-fee program for biosimilars is needed to ensure that “the review of biosimilar products does not detract from FDA’s ability to review innovator products and that innovator products continue to have a very high priority at the agency,” BIO’s Radcliffe stressed.
FDA has begun the process of establishing a biosimilars approval pathway, but observers say it will likely be several years before the agency sorts through all the challenges related to implementing the new law.
Meanwhile, prices for biological drugs will remain high. According to Consumers Union’s Vaughan, the average monthly cost for a biologic is about 31 times as much as the cost of a chemical drug. And the market for biologics is growing rapidly. “Biotechnology drugs are expected to account for more than 50% of all new approvals by 2015 and 71% by 2025,” he said.