Paving Approval Pathway for Biosimilars Presents Unique Challenges for FDA

April 20, 2011 10:54 am

Originally published in the April 2011 NABP Newsletter

With several patents on biologics scheduled to expire in the coming years, the need to establish an approval pathway that will ensure the safety and efficacy of follow-on biologic products is becoming more pressing. Certain complexities associated with innovator biologic products, make challenging the establishment of a Food and Drug Administration (FDA) approval process for follow-on biologics. The degree to which follow-on biologics can be equivalent to their reference biologic counterparts is in fact the question; thus, the products are often dubbed biosimilars and the developing approval process will likely be more complex than the approval pathway for generic versions of innovator pharmaceutical products.

FDA has taken its first steps toward establishing an approval pathway for biosimilars, with a public meeting held in November 2010, and a subsequent open comment period, highlighting in the process the hot-button issue of potential trade-offs between health care affordability and patient safety. The process to create the approval framework for follow-on biologics is directed by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), signed into law as part of the landmark Patient Protection and Affordable Care Act signed by President Obama in March 2010. As evidenced by their comments to FDA and in public media, many consumer advocates and other stakeholders hope that establishing a biosimilars approval pathway will introduce competition to the biological pharmaceuticals market, bringing down prohibitive costs and increasing accessibility. The complex nature of biologics, however, raises patient safety concerns which seem likely to scuttle hopes of achieving the same degree of savings accomplished by the introduction of generics in other parts of the pharmaceutical marketplace.

Biosimilars vs Generics

The appeal of creating “generic” versions of biologics is clear: Allow market forces to act as a brake on prohibitive drug prices. Biologics cost an average of 22 times as much as ordinary drugs, and are expected to make up 50% of sales from the pharmaceutical industry’s top 100 products by 2014, according to an editorial published by public policy and health experts Anthony D. So, MD, and Samuel L. Katz, MD, in The New York Times.

Often representing cutting-edge research, biologics, according to FDA, “in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available.” Their desirability is clear – but consumer advocates note that, with potential costs to patients of up to tens or even hundreds of thousands of dollars per year for a medication, fewer patients are able to afford potentially life-saving or life-changing treatment, treatment adherence drops, and overall health care costs continue to skyrocket.

While generic drugs have introduced competition and offered some cost relief for non-biologic drugs, thus far, no comparable generics exist for biologics due to the unique nature of these products. What most consumers think of as “typical” drugs are manufactured through chemical synthesis, using the principles of organic chemistry, and generally feature a well-defined chemical structure that can be analyzed in a laboratory to determine its components. To receive FDA approval for these “small-molecule” generic medications, a drug must have the same active molecule in the same strength, dosage form, and route of administration as its reference product, and must be bioequivalent. Different manufacturing processes can produce the same results. The approval process does not require additional clinical trials on humans. (See “FDA’s ANDA Review Process Designed to Ensure Safety and Efficacy of New Generic Medications,” NABP Newsletter, June-July 2008.)

Biologics, on the other hand, typically are derived from living organisms. FDA defines them broadly: “Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues.” Biologics can pose unique challenges. They work by causing an immunologic reaction in the patient; different physiological responses may be seen, particularly among certain patient populations, and immunogenicity (stimulation of antibody production in patients, sometimes with the danger of neutralizing the medication and the body’s own protein) can be an issue.

As the Biotechnology Industry Organization (Bio) describes it, biologics are “made by genetically engineering living cells to become miniature factories producing the desired molecules (proteins).” The greater variability inherent to living cells means that small changes in process (including temperature changes) or materials (a particular cell line, for example) can produce very different results. “[I]t is important to emphasize that minor differences in primary amino acid sequences can cause significant alterations in protein molecule’s secondary and tertiary structures, resulting in a biosimilar protein with vastly different effects,” said Gregory Schimizzi, a practicing rheumatologist representing the Coalition of State Rheumatology Organizations (CSRO), at FDA’s November public hearing.

According to Bio, current technology does not yet allow a determination of equivalency in the laboratory. “[T]he complexity of biologics currently makes it impossible to show in the laboratory that a follow-on biological product will work the same as another in patients,” states Bio. And while a number of biosimilars have been approved in the European Union since 2006, the United States has hitherto lacked a legal framework to approve such products.

Areas of Contention

Margaret A. Hamburg, MD, Commissioner of Food and Drugs, stated at the Generic Pharmaceutical Association Annual Meeting, February 18, 2011, that as FDA works “to set the scientific parameters of determining just how similar is similar enough when it comes to complex biologic products . . . we want to rely on what is known to the greatest degree possible, and avoid any unnecessary animal or human testing.” Hamburg noted that while there will be many questions initially, science will serve as the guide.

At the same time, due to the difficulties in analyzing a biosimilar’s equivalence to its reference product – as well as the potential differences in therapeutic responses to a particular biologic – some patient advocates (and current manufacturers of biologics) are emphasizing to FDA the importance of proving a biosimilar’s safety and efficacy through clinical trials, as well as vigorous post-marketing monitoring. “There simply is no substitute for testing these products given their degree of complexity and their effects,” said Schimizzi.

While all stakeholders presenting views at the FDA public meeting emphasized safety, opinions differed on the need for mandated clinical trials for all biosimilars. One argument against universal clinical trials is that biosimilars would lose much of their cost advantage (and cost-dampening effect) if FDA required clinical trials for all applications. Some stakeholders, including companies that manufacture generics, promote a more case-by-case approach, suggesting that with proper scientific justification and a thorough understanding of a biologic’s mechanism of action, some safety and efficacy data could be extrapolated.

Biosimilars or Interchangeable Biologics?

The BPCI Act specifies two possibilities for FDA approval of follow-on biologics: biosimilars and interchangeable biologic products. The latter presents a much higher hurdle to clear: FDA would have to conclude that the interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient” and that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Again, some experts doubt the current feasibility of interchangeability. The CSRO’s Schimizzi told FDA’s November panel, “Practicing rheumatologists believe that there is no sufficient scientific understanding of potential biosimilars to allow for an interchangeability of biologic products at this time.” Other experts pointed out features of biologics that could hamper interchangeability trials. For small-molecule drugs, noted Laszlo Endrenyi, PhD, professor emeritus at the University of Toronto, switchability and interchangeability are generally determined through crossover studies, in which each drug product is administered to each subject so that each subject receives more than one form of the drug, and preferably all forms being tested. Biologics often have a long half-life, however, he pointed out, rendering crossover trials potentially ineffectual. And even for those biologics without long half-lives, he noted, other factors intrinsic to biologics, including unpredictable sensitivity in patients and potential deviations, would indicate exercising caution in seeking switchability or interchangeability.

The issue of how to name biosimilars forms another area of disagreement that could ultimately affect cost. Should the non-proprietary drug name for the biosimilar be the same as the reference drug’s? The same (or very similar) name could cause confusion for patients and prescribers, some fear, risking medication error; proponents, on the other hand, argue that it would reduce confusion for patients. Moreover, different non-proprietary names would require more marketing on the part of biosimilars makers, again reducing cost savings. Current biologics makers favor different names; prospective biosimilars makers lean the other way.

Patent Exclusivity

While the BPCI Act leaves most of the scientific discretion and judgment of an appropriate biosimilars approval pathway up to FDA, it goes into greater detail as it spells out market exclusivity periods and the processes to address patent disputes between a biosimilar maker and its reference product manufacturer. Indeed, though the BPCI Act formed one of the less controversial sections of the overall health care bill, one of its most contentious aspects is its specifications for market exclusivity. The act grants reference biologics makers 12 years of marketing exclusivity; that is, FDA cannot approve a biosimilar application using the reference product’s data until 12 years after the reference product was first licensed (under the Hatch-Waxman Act that deals with non-biologic generic drug approval, exclusivity is five years), and FDA cannot accept an application for a biosimilar within four years of a reference product’s initial license. The act also specifies a 12 to 14 month exclusivity period for the first interchangeable follow-on biologic for a given reference product, depending on the date it is first marketed or the date it is licensed by FDA and whether it is the subject of patent litigation.

The BPCI Act does not establish a timeline for FDA to develop its biosimilars approval pathway, but Hamburg noted in her February speech that “It is among our highest priorities at FDA to move forward on this as quickly and effectively as possible.” A detailed analysis of the BPCI Act that appeared last year in Pharmaceutical Law & Industry Report, stressed that legal battles are anticipated, including potential challenges to FDA regulations and decisions. The authors also noted that Congress will likely face pressure to amend the law. It also is expected that, sooner or later, regulatory questions regarding biosimilars will bring themselves to the attention of the state boards of pharmacy, which typically oversee laws and rules concerning drug product selection and therapeutic substitution of medications.