Associate Editor’s Commentary: The Tao of Biosimilars

Abstract

The age of the blockbuster is over. Cost concerns are more challenging than ever, and we are struggling to understand what ‘‘personalized medicine’’ really means. We are now in the era of post-patent medicine where advances in manufacturing and molecular diagnostics are as important as new molecular entities, and safety is as important (and as improvable) as efficacy. The era of post-patent medicine is also the epoch of biosimilars. A question of interest is whether biosimilars can really be as important an element of change as many believe. Will they be a game changer, and will all the changes that they bring positively affect the advancement of the public health? Many fear the expectations that biosimilars will radically reduce costs are overstated. Others fear that safety concerns are being understated and that the risks to innovation are real. Let us address each of these concerns in order. First, consider safety. It’s always important to begin a discussion of biosimilars and safety by reminding ourselves that there is no such thing as a generic biologic. ‘‘Big’’ molecules are more than just a larger version of ‘‘small’’ ones. Biologics are created from living organisms and are not as simple to replicate as traditional drugs like aspirin and antihistamines. Biosimilar safety means something different than generic drug safety. (See Table 1 for a list of terminology.) To establish that two protein products are similar and substitutable, the sponsor of a follow-on product would need to demonstrate through de novo clinical trials that repeated switches from the follow-on product to the referenced product (and vice versa) have no negative effect on the safety and/or efficacy of the products as a result of immunogenicity. In the case of biosimilars, the most important issues facing global drug regulators are the scientific and technical factors related to a determination of biosimilarity or interchangeability. For many follow-on protein products—and in particular, the larger proteins—there is a significant potential for repeated switches between products to have a negative impact on patient safety and clinical effectiveness. Therefore, the ability to make determinations of substitutability for biosimilars may be limited. This uncomplicated and indisputable fact is, alarmingly, rarely discussed by health care systems that see biosimilars exclusively as a cost-savings mechanism. But the blinders of cost containment must never be permitted to obscure the twin therapeutic pillars of safety and efficacy. Next, consider cost. Another crucial difference between biosimilars and small molecule generics is that they are difficult and expensive to get approved, are complicated and challenging to manufacture, and have a short shelf life. The result is that the price differential between innovator biologics and biosimilars will be far narrower than between branded small molecules and their generic counterparts. Another impediment to radical price declines is that this more modest cost variance will make it economically feasible for innovator companies to compete with biosimilar competition. The European experience demonstrates that the market cost of a biosimilar is somewhere around 20% to 30% of the innovator price. So, the question becomes: Can innovator companies, post–patent-expiry, lower their prices accordingly on their ‘‘brand name’’ products and still have a profitable proposition? The answer is yes, which provides a powerful marketing weapon for the innovator brands. After all, why would a physician prescribe an unfamiliar biosimilar or health care systems prioritize one for payment when the innovator product is available for the same price? These three truths will restrict the number of classic ‘‘generics’’ companies who can play in the biosimilar space, and where there is less competition, there is less price competition. This is why people such as Jeff George, the CEO of Sandoz, predict that in the United States and elsewhere, using existing regulatory pathways (like 505(b)(2) or a BLA) to bring biosimilars to market may very well be the rule rather than the exception. There still remain many vague issues relative to intellectual property rights and litigation. According to Mr George, ‘‘The devil’s really in the details.’’ He focuses on three issues: (1) The provision for a biosimilar manufacturer to give its