INNsight article by Alan Klein, October 2013

In 2009 the U.S. Congress enacted the Biologics Price Competition and Innovation Act encouraging the development of biosimilars principally by generic drug companies to broaden the availability of and lower the prescription cost of these important medicines.  Biosimilars and their biologic reference drugs are prescribed for a variety of significant therapeutic needs – human growth hormones, blood clotting factors, chemotherapy-induced neutropenia, inflammatory bowel disease, non-Hodgkin’s lymphoma and autoimmune disorders, among others.

An Emerging Global Biosimilars Market

There is a rapidly emerging demand for biosimilar drugs. The global market, estimated at $2.5 billion this year, has increased 20% over last year’s figures, but accounts for only 2% of the entire worldwide biologics market.  Because of impending patent expirations of the leading biologics and the escalating cost of health care, the biosimilars marketplace will likely expand dramatically over the next decade.  Drug companies in the U.S. and abroad such as Baxter, Hospira, Sandoz and Teva, among many others, either alone or in partnerships with smaller biopharmaceutical companies, are aggressively pursuing the development and regulatory approval of biosimilars.

The Biosimilars Regulatory Pathway

Bringing these complex molecules from development stage to product launch is a daunting and expensive process.  As biosimilars are made of living cells or living organisms, the manufacturing process for biosimilars is complex since, unlike many small-molecule drugs, they are extremely sensitive to environmental factors.

Biosimilars, not being the generic equivalent of their biologics model, can express changes during their manufacture affecting their potency, safety and efficacy.  Companies making biosimilars need to demonstrate to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) their similarity by performing side-by-side comparisons with the reference biologic drug.  Both in Europe and the U.S. a biosimilar manufacturer must establish “biosimilarity” in composition, potency and safety in clinical trials.  Both the EMA and FDA require that the biologic drug upon which a biosimilar is based has undergone a thorough review before it may serve as a reference product.  If a biosimilar is also claimed to be “interchangeable” with its biologic reference product, the FDA requires additional supporting data before approving its substitutability by healthcare providers and pharmacists.

The FDA has assisted industry by publishing four Guidance documents – three in 2012 and a fourth earlier this year, but in the U.S. final regulations delineating a definitive biosimilars pathway remain pending four years after passage of Congress’ enabling legislation.

In Europe, by contrast, the regulatory framework has been in place since 2005 to ensure the approval and availability of high quality biosimilar drugs.  Most recently, the European Commission approved Inflectra (infliximab), a lower-cost version of the blockbuster drug Remicade for the treatment of rheumatoid arthritis and other inflammatory conditions.  It was the first monoclonal antibody to receive E.U. approval.  Its approval is certain to reverberate throughout the biologics industry as some of the most profitable biologics also use monoclonal antibodies.  Two are AbbieVie’s Humira (adalimumab) and Genentech’s Avastin (bevacizumab).

Some U.S. States Restrict Biosimilar Prescriptions

As noted in an article appearing in the April issue of this publication (Dr. Vicky G. Norton, “States in the U.S. Enact Laws Restricting the Sale of Biosimilars”), leading U.S. biologic drug makers and their allies are funding efforts in state legislatures to restrict the substitution of biosimilar drugs, ostensibly to protect patient safety, but, in reality, to make market penetration of biosimilar products more difficult.

The FDA has voiced its concerns over such efforts to erode public confidence in biosimilars.  Most recently, in response to pending legislation in California to enact such restrictions, the FDA issued a strongly worded statement criticizing these lobbying activities by biologics companies and other proponents of such legislation:  “Efforts to undermine trust in these [biosimilar] products are worrisome and represent a disservice to patients who could benefit from these lower-cost treatments.”  Referencing provisions of the 2010 Affordable Care Act allowing the substitution of biosimilars for the brand name biologic reference product, the FDA alluded to the past development of generic small molecule drugs and their current widespread acceptance and use:  “Substitutability helped spur the growth of the generic drug industry at an earlier time, and is similarly essential to help foster competition in the biologic drug market... Ultimately, such competition will spur innovation, improve consumer choice and drive down medical costs.”

State legislation requiring pharmacists, for example, to promptly notify the prescribing doctor prior to substituting a biosimilar drug for its reference biologic, is almost unheard of in the use of traditional generics, which are frequently substituted by dispensing pharmacists for the brand name reference drug unless in the prescription the prescribing physician has indicated otherwise.  Opponents of such legislation, such as the Generic Pharmaceutical Association (GPhA), have complained that biologic innovators are clearly placing roadblocks in the way of biosimilar competition.  In a press release following the recent rejection of such legislation in Texas, GPhA President Ralph Neas said “While we will not rest until the last gavel bangs in the remaining state legislatures, the totality of rejection of Amgen and Genentech-sponsored provisions [in state legislatures] over the past five months shows that once legislators have all of the facts, they will block measures that would restrict future access to biosimilars.”

The Road Ahead for Biosimilars in the U.S.

The generic drug industry and FDA are working collaboratively to pave the way for biosimilars in the U.S.  The agency has received about 60 requests for preliminary meetings from manufacturers and developers to discuss about a dozen different biosimilar products.  Most meetings have occurred, and more are scheduled.  Companies have filed approximately 20 investigational new drug applications for permission to conduct clinical trials for biosimilars, and other development programs are moving ahead as well.  While some commentators believe that the FDA will set a very high regulatory bar for biosimilars marketed in the U.S., they remain optimistic that ultimately the biosimilars marketplace will thrive, increasing patient access and lowering the cost of these biopharmacotherapies.