Recently, the FDA published an article in the New England Journal of Medicine outlining the requirements for a new type of drug approval: “biosimilars.” This is the kind of news that draws the attention of only a small group of wonks inside the trade, but ultimately has an enormous impact on everybody. As the authors explain in the first paragraph:
Biologic products developed over the past three decades and approved by the Food and Drug Administration (FDA) now provide important therapeutic options for a variety of serious clinical conditions (see graph). Therapeutic biologics such as genetically engineered recombinant proteins and monoclonal antibodies represent a large portion of newly approved therapies for conditions such as chronic inflammatory diseases and cancer. Biologic enzyme-replacement therapies provide clinical benefits in previously untreatable genetic disorders. Although typically more structurally complex than the small-molecule drugs more prevalent in today’s market, biologics vary in complexity from cellular therapies to small, highly purified proteins. Unfortunately, access to such products may be limited, not infrequently because of their cost.
Behind that bureaucratic understatement stands a large and growing segment of the overall pharmaceutical industry. Biologically-derived drugs such as Remicade and Procrit, to pick two off the top of my head, can be lifesavers for patients. They also represent billions of dollars in revenue for their brand-name manufacturers, or billions in costs for health insurers, depending on your perspective.
Unlike traditional small-molecule drugs, though, these “biologics” don’t usually go generic. Because they’re classified differently from small molecules, they don’t fall under the usual FDA rules that would allow generic manufacturers to release a lower-cost version after a set time period. Any new biologic drug, even one that is an exact copy of an existing one, has to go through the full set of clinical trials as if it were a new compound. That development cost means any “generic” version will end up being priced nearly as high as the brand-name drug, if anyone even bothers to try to develop it. As a result, the brand-name manufacturer of a biologic drug gets to hold a monopoly and keep the price as high as they like indefinitely.
That didn’t sit well in our budget-slashing political environment, so in 2009 Congress passed a bill telling the FDA to come up with an approval pathway for generic biologics, technically called “biosimilars” in the industry. As the new article explains, that was easier said than done.
The main problem is biology itself, which is terribly messy. A team of smart synthetic chemists can look at a small-molecule drug, such as Ritalin or Viagra, and come up with a synthesis that will produce an exact copy of that compound. They can test its purity in numerous ways, and pretty much guarantee that it’s just like the original. That’s why the FDA only requires generic drug manufacturers to demonstrate that their copy of the drug is bioequivalent to the brand-name version, meaning it’s metabolized the same way in a relatively small group of test patients. As clinical trials go, that’s a cheap and easy thing to do, and the resulting generic copy’s price reflects that.
Biologic drugs aren’t really just drugs. They’re complete procedures. If we take exactly this cultured cell line, which contains exactly that recombinant DNA sequence, grow it under exactly these conditions, and perform precisely this purification technique, we get the drug. A similar cell line in a similar facility with a similar purification process won’t produce the same result, just something that’s probably close. Whether it’s close enough is an open question. That’s why the FDA has – I think correctly – treated each biologic drug as a new entity.
We’re not completely ignorant about biology, though. A team of smart biochemists should be able to copy most aspects of a biologic drug’s production, and they shouldn’t need to repeat the entire set of clinical trials to demonstrate that it’s a reasonable facsimile of the original. There should be a middle path for these drugs that allows generic versions to get to market. However, that pathway needs to be a lot more flexible than the one for small-molecule generics.
Now the agency seems to have struck a reasonable balance, at least for a first draft. By patterning the guidelines on similar recommendations already in force in Europe, the FDA ensures that pharma and biotech companies won’t have to adapt to radically different regulatory strategies in these two big markets. At the same time, they’ve made it clear that would-be biosimilar makers will need to bring their “A” game. As John Carroll at Fierce Pharma explains:
But anyone hoping for a simple instruction manual with crystal clear goals and relatively low-cost data demands will be sorely disappointed. The regulations for developing biosimilars will come with its own complex set of customized instructions, complete with demands on animal and human data and new ground rules for initial talks with regulators.
The NEJM article is freely accessible, so anyone can go read the backstory on the coming generation of biosimilars. Or you can just wait until it comes up in a conversation with your doctor or insurer. Trust me, it will.