Like them or hate them, generic versions of conventional drugs save money for patients and the healthcare system. They have low development costs, clinical testing and approval tends to be quick and inexpensive, and there's little to no marketing. That's why third party payers unceasingly promote their use and lawmakers encourage their proliferation. It's no surprise, then, that Congress and the President have turned their sights on “generic biologics” in efforts to cut healthcare costs. But those familiar with the science note fundamental differences between conventional drugs and biologic agents. As interest in follow-on biologics grows, prescribers and patients should be prepared to understand those differences and their practical implications.

Generics vs. Follow-ons

Typically, patent protection on a conventional drug is 11.5 years, with an average time to generic competition of 13.5 years, according to the Biotechnology Industry Organization or BIO (bio.org). However, some evidence suggests this trend is shifting. According to a recent IMS Health report cited by The Wall Street Journal Health Blog (blogs.wsj.com/health/), generics can take up to 80 percent of prescription share within six months of patent loss. Generics are a lucrative business. In 2010, non-branded drugs made up 78 percent of all prescription drugs dispensed in the US, according to the same IMS report; in terms of numbers of prescriptions filled, no branded drug was in the top 10 most commonly dispensed drugs.

Biologic products in the US, by contrast, have 14-year exclusivity, BIO says. Until recently, however, their protection was virtually guaranteed beyond that point. There has been no provision for the approval of biosimilar or follow-on biologics (the term generic biologics is inaccurate, as described below). The Patient Protection and Affordable Care Act (PPACA) now has charged the FDA with outlining a process for approval of follow- on biologics in the US. This provision is intended to reduce healthcare expenses by providing cheaper alternatives to costly biologic therapies. Despite the mandate of the PPACA, follow-on biologics in the US may still be several years away. The onus is now on the FDA to determine how it will assess and approve follow-on biologics. BIO notes that, as recently as 2006, FDA explicitly stated that it had not determined a method for establishing interchangeability for complex proteins.

There are questions regarding the degree of cost savings associated with biosimilars. One reason generic versions of conventional drugs are so cheap is because manufacturers usually do not perform large clinical trials. Instead, they conduct small and relatively inexpensive studies to demonstrate bioequivalence. If the generic formulation, with the same concentration of active drug in the same dosage form as the innovator, is “bioequivalent” to the innovator, it is presumed to offer similar efficacy and safety. Biosimilars cannot copy innovator biologics and are close approximations at best. Therefore, large clinical trials will almost certainly be required to support their approval.

Defining Terms

To understand the various claims made about biosimilars, it is essential to know the terms associated with them. Conventional drugs are based on organic chemistry, which, according to Audrey Phillips, PhD, Executive Vice President, Biopharmaceutical Public Policy and Advocacy at Johnson & Johnson, can be likened to working with “recipes.” Combining certain chemicals in certain proportions will always lead to the same outcomes. “The reason generics are possible,” she says, “is because organic chemistry is, by its very nature, predictable.” While there may be clinical concerns about the influence of non-active ingredients on rates of absorption and other factors, the reality is that generic formulations chemically are copies of innovators, and the active molecules will exert the same effects on the body.

Biologics are more complex and not predictable. Biologics are protein-based, comprised of strings of amino acids derived from living cells. “Proteins are far more complicated in their structure and size compared to small organic molecules,“ Dr. Phillips says. Because the production of proteins, “depends on a whole host of factors,” she says it is impossible to create an exact copy. Among the factors that influence the formation of proteins is the laboratory itself, the materials used, and environmental controls. Many biologic products require cold storage. Most production facilities are custom designed; Sometimes different stages of production take place at different locations.

One consideration before regulators is the definition of biosimilarity, says Omar Khan, MD, Director of the Multiple Sclerosis Center and Image Analysis Laboratory at Wayne State University. Dr. Khan, who notes that the emergence of follow-on biologics will influence all areas of medicine, says that since follow-ons are not identical copies, there must be a standard for demonstrating interchangeability to a patent molecule. It is unclear what degree of deviation from the innovator would result in a biologic needing to pursue a new biologics license application (BLA) versus follow-on approval.

Dr. Phillips likens the production of biologics in some ways to fermentation of beer or wine. The same basic ingredients can go in, but a quite different product can result based on temperature and other environmental influences, the vessels in which the ingredients are combined, and even the duration of fermentation.

Dr. Khan says that the complexity of the innovator may influence the approval process. In the that interferon is a relatively simple molecule that may be more readily developed as a follow-on than, say, glatiramer acetate, which is comprised of four amino acids. Therefore, he suggests, decisions about biosimilars are expected to be carefully weighed on a case-by-case basis.

Regulatory Challenges and Clinical Concerns

As noted, the bioequivalence models used in conventional therapeutics do not translate to biologics. The FDA is not working in a vacuum. Models for the approval of biosimilars exist outside the US. “Regulatory agencies around the world have been in the same boat we are in,” Dr. Khan says, noting that follow-on biologics are available in many markets worldwide.

The most significant concern for health authorities assessing the safety of biologic therapies— innovators or biosimilars—is the issue of immunogenicity, according to Dr. Phillips. The human immune system is programmed to detect and defend against large proteins, and the possibility of antibody formation is well known among physicians and researchers.

Immune-related adverse events to biologic therapies may be rare, occurring in only one out of 5,000 patients or less frequently, Dr. Phillips suggests. With the many patient years of exposure achieved during the large clinical trials required to earn marketing approval for a BLA, there is confidence in the safety of an innovator biologic. But it is presently unclear how much testing will be required for follow-on biologics. Too little testing may not uncover a safety concern, while very large trials will be expensive and obviate the proposed cost-savings of biosimilars.

Dr. Phillips provides as an example the anemia drug recombinant human erythropoietin or Eprex, which was associated with a very rare but serious adverse event of antibody-mediated pure red cell aplasia (PRCA). The drug was on the market for a number of years in Europe and then the incidence of PRCA rose after the formulation was changed to replace human serum albumin (HSA) with a nonanimal product (polysorbate 80). A later change in the product drove the incidence of PRCA back to normal levels. This is one example of how the body's immune system can detect small differences in products and why biologic products made by different manufactures cannot be assumed to be the same.

The challenge for regulators is to assure safety and efficacy without significantly increasing the costs of developing biosimilars. Dr. Khan insists that when biosimilars reach the market, patients should expect to see them as clinically “the same” as innovators, but emphasizes that “they can't compromise on safety or efficacy.”

Anticipated Developments

The question about biosimilars at this point is not if they will come to market, but when. As FDA works on establishing protocols for approval, a cadre of interested parties will certainly be watching closely. “The situation,” Dr. Khan observes, “is evolving in real time.” Without doubt, drug developers will jump at the opportunity to market biosimilars. Though the costs of development may be high, there are profits to be made. The cost advantages for the healthcare industry remain to be seen.

General guidance for companies seeking to market follow-on biologics could be available before year's end, FDA says. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research reportedly indicated in May that human testing will ne be required for all biosimilar formulations. The agency is also seeking input on fees to be collected from biosimilar marketers.

Clinical questions loom. The issue of immunogenicity is critical, according to both Drs. Khan and Phillips. “There is the potential for products by different manufacturers to be different in a subtle way that the highly sophisticated immune system will recognize,” Dr. Phillips says. Presumably, some patients already using a biologic would be interested in switching to a less expensive followon. But, Dr. Phillps says, “No one knows what impact switching between biologics will have on the immune system.”