Does Interchangeability Really Matter for Biosimilars?

The answer is perhaps not that much, according to some biosimilar developers, as well as payers and health plans. Biosimilar marketers anticipate that favorable placement of their products on formularies, with lower costs and co-pays, will drive prescribing and uptake, even if physicians are leery of switching to therapies they don’t fully understand. While waiting for the Food and Drug Administration to issue much-anticipated guidance on how to test and gain approval of interchangeable therapies, biosimilar makers acknowledge the need to educate doctors and pharmacy benefit managers (PBMs) on how biosimilars are equally safe and effective as their reference products, and offer better value.

With one approved biosimilar on the U.S. market, and dozens more in development or under review at the FDA, there’s a growing sense that these competitive therapies are moving forward, albeit though too slowly for some parties. FDA has received six biosimilar applications to reference products, and has approved one – Sandoz’ Zarxio (filgrastim-sndz). Of equal importance, some 57 biosimilar products for 16 reference drugs were enrolled in FDA’s Biosimilar Product Development program as of mid-September, and sponsors are seeking preliminary advice on another 27 projects.

Interchangeability elusive

Generic drugs have taken over much of the U.S. prescription drug market based on substitution of identical medicines at the pharmacy level, and the conventional wisdom is that biosimilars will need similar “interchangeability” status to gain widespread market acceptance. But the real drivers in biosimilar uptake, according to participants at the October “Biosimilars 2015” conference sponsored by the Drug Information Association (DIA), will be payers looking to manage rising outlays for increasingly costly biotherapeutics, partly by expanding use of the new comparative products coming to market.

Sandoz did not seek interchangeability from FDA due to a higher hurdle to achieving that status, explained Mark McCamish, global head of biopharm & oncology injectables development at Sandoz International. But he expects formularies will push lower-priced products, despite efforts by innovator firms to label biosimilars as lower quality because they’re not interchangeable. Parexel vice president Cecil Nick commented that it’s not clear if it’s important to payers for biosimilars to have interchangeability status, noting that hospital P&T committees will be important in encouraging use of the new, less expensive therapies. He considers product distribution, reimbursement policies, and the response of the innovator to competitor price cuts key to constraining or accelerating biosimilar uptake.

Interchangeable status, however, may be important in overcoming concerns about biosimilar safety and quality, observed Jim Roach, senior vice president at Momenta Pharmaceuticals. But that designation won’t be meaningful without FDA naming and labeling policies that indicate a high degree of similarity of an interchangeable biosimilar to the reference product, as well as coding and reimbursement policies that encourage biosimilar use. Roach also seeks policies that support extrapolation to all approved indications of the reference product for interchangeable therapies to avoid “redundant and unethical” clinical trials. He emphasized that the scientific capabilities of his firm and other leading biosimilar makers to use “reverse engineering” to develop products with “fingerprint-like similarity” will support interchangeable status and product substitution at the pharmacy.

Financial analyst Ronny Gal of Sanford Bernstein considers investment in biosimilars very attractive economically and predicted gradual, but complete U.S. market penetration, as physicians become more comfortable with these products and deeper discounts emerge. While prescribers now have concerns about using a “non-gold-standard” therapy, and counter-detailing by innovators may slow biosimilar adoption in the U.S., Gal expects these barriers will weaken in five years. Interchangeable status can help overcome such impediments, he noted, although it will add to development costs and take longer to recoup investment.

Just how long and expensive will be the testing to document interchangeability should become clearer from FDA guidance, which is expected to outline a program of switching studies to support interchangeability. These recommendations will be part of the agency’s “totality of evidence” approach that relies on extensive product characterization and analytics as the basis for documenting similarity to a reference product. But FDA has concerns that a patient being treated with a reference drug could have adverse immune responses if switched to a new therapy, or to multiple different products over time.

Global alignment

While U.S. policies governing biosimilar development are similar to many requirements established in Europe, interchangeability and substitution involve different approaches. The European Union has authorized nearly 20 biosimilars since 2006, but these do not include recommendations on interchangeability with reference medicines, leaving that decision to members states. Finland, for example, has determined that biosimilars are interchangeable with their reference products under the supervision of a health care person, explained Niklas Ekman of the Finnish Medicines Agency, at the DIA conference. Automatic substitution at the pharmacy level is not part of any recommendation, as is the case in most European countries, yet national health plans are shifting prescribers and patients to biosimilars, a trend expected to accelerate as all parties gain more experience and comfort with these less costly products.

Meanwhile, the globalization of drug development is encouraging regulatory authorities to seek common standards and regulatory proposals to facilitate biosimilar development in multiple regions. Sponsors look to utilize data generated in one market to support product development in additional countries, raising questions at FDA about whether a biosimilar application may rely on data produced in other regions or use a non-U.S.-licensed comparator in studies to support U.S. licensure, reported Leah Christl, associate director for therapeutic biologics in CDER’s Office of New Drugs (OND).

These and other issues are being examined by the Biosimilars Cluster, which meets several times a year to seek “scientific alignment” of policies and development issues related to biosimilar oversight by FDA, the European Medicines Agency (EMA), Health Canada and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Similarly, the Biosimilars Working Group of the International Pharmaceutical Regulators Forum (IPRF) periodically discusses issues and challenges in regulating biosimilars in these countries as well as South America, Asia and other regions. Biosimilar sponsors may seek “parallel scientific advice” from FDA and EMA, Christl adds, noting that full program “harmonization” may be difficult to achieve.

The adequacy of funding to support FDA’s resource-intensive biosimilar development program will be examined in the coming months as part of the process for reauthorizing biosimilar user fees in 2017. FDA is holding an initial public meeting in December to launch negotiations on the fee structure and other aspects of the program. To continue to provide extensive agency assistance to sponsors on shaping R&D programs, FDA may be looking for manufacturers to pay upfront an even larger portion of the biosimilar application fee, a unique feature of this program.