In a previous video, we talked about brand name and generic drugs, but we kinda left out a major player in the world of medicine: biologic drugs.  These complicated guys probably deserve a video all to themselves.  Call them what you will, biologics, biotherapeutic medicines, or biopharmaceuticals, they're the topic of this week's Healthcare Triage.

(Intro)

Most of the medications we take on a day to day basis are small molecules that are synthesized in a lab.  In a step by step process, these compounds are built through series of chemical reactions to become the tablets and capsules we're come to know and love.  Biologics take a totally different journey altogether.  

Biologic agents are made up of or derived from proteins.  Rather than being chemically synthesized, they're produced by living organisms like yeast and bacteria.  One of the oldest and most well-known biologic products, insulin, is made by bacteria thanks to recombinant DNA technology.

Biologics still target disease processes like their small molecule cousin, but their mechanism of action is often much more complicated.  Like insulin, they may replace our own proteins, trigger certain reactions in the body, or function to disrupt a disease process.

For instance, several biologics are used to combat autoimmune diseases by mimicking indigenous cell receptors.  Diseases like rheumatoid arthritis or Crohn's disease, or Ulcerative Colitis cause pain and damage because of inflammation.  One way to reduce this inflammation is by binding up the pro-inflammatory (?~1:30), tumor necrosis factor alpha, or TNF-alpha.  Biologics used as TNF blocking agents are comprised of antibodies that have been designed to mimic parts of the receptor for TNF-alpha on the surface of cells.  Upon injection, these biologic drugs attach to the TNF-alpha, ultimately reducing inflammation.  If the TNF-alpha attaches to them, it can attach to cells.

You might have guessed that these types of medications are expensive, considering their complicated manufacturing process.  When speaking of small molecule drugs, one way to deal with the cost to consumers is to provide a generic product.  It's a little more complicated with biologics, though.  A generic biologic medicine is known as a biosimilar.  Due to the complicated way living organisms create proteins, biosimilars are almost never identical to the innovator biologic drug.  This, however, doesn't mean that a biosimilar is inferior to the innovator.  Like small molecules, they still must meet rigorous safety, purity, and potency standards before being approved for use.

Regulatory bodies like the FDA also have interchangeability standards that must be met, proving that the biosimilar product will not have significant differences in safety or clinical results, so do biosimilars work just as well as their innovator or reference products?  Spoiler alert: They do!

A recently published double-blind randomized phase III noninferiority trial compared a biosimilar of filgastim to its reference product.  Filgastim, a granulocyte colony stimulating factor, or GCSF, works by increasing the number and cytotoxicity of (?~3:05), or you know, it makes the white blood cells fight infection.  It has many indications, but it's often used to combat neutropenia caused by chemotherapy drugs.  The study examined the duratio of severe neutropenia in patients receiving biosimilar filgastim as compared to the reference product in patients being treated for breast cancer.

218 patients were split into four groups.  Two groups received either the biosimilar or a reference filgastim for six cycles of chemotherapy.  The other two groups received alternating treatments of the biosimilar and reference product with each cycle of chemotherapy in reverse order.  The outcome of interest was the duration of severe neutropenia.  

Those who got reference filgastim had severe neutropenia for 1.2 days, and those who got the biosimilar filgastim had severe neutropenia for 1.2 days.  If you don't want to do the math yourself, that's non-inferior.  There were also no significant differences in the incidences of febrile neutropenia, hospitalization due to febrile neutropenia, infections, or time to neutrophin recovery.

BIosimilars have been shown to be as safe and effective as the innovator biologic products.  Hooray!  Cost effective biosimilars for everyone!  Yeah, not so much.  First, biosimilars are still really expensive to manufacture, so a biosimilar is likely to be relatively expensive compared to a small molecule generic.  My blogmate Austin Frakt recently wrote about this at The Upshot.  He noted that as the law professors W. Nicholson Price and (?~4:31) put it, if an aspirin were a bicycle, a small biologic would be a Toyota Prius, and a large biologic would be an F-16 fighter jet.  It is 100 times more expensive to reverse engineer a modern biologic than a small molecule drug, and then there's the regulatory process of getting approval.  The cost of bringing a generic drug to market is about $2 million, which is relatively inexpensive, compared with the up to $200 million it costs for a biosimilar.

To confirm that a generic drug will perform the same as its brand-name counterpart, chemical equivalence is what matters, something relatively easy to assess. That scientific fact underpins the FDA's path for approval of generic drugs.  For biosimilars and their corresponding brand name biologics, structural equivalence is hard to achieve and verify.  Their structure and clinical performance depends on the means of production.

For example, the exact organism and other manufacturing details used to produce a biologic are crucial, but that information is not fully disclosed in patents or evident in the final product.  Therefore, a biosimilar manufacturer seeking to reverse engineer a process is likely to produce a slightly different drug and that difference may affect patients.

The first biosimilar product wasn't approved in the United States until March of 2015.  This is staggering when you consider that the European Medicines Agency, or EMA, approved its first biosimilar drug in 2006, so what's with the discrepancy?  Like all things involving money and laws, it's a complex issue.

There are the usual arguments that get batted back and forth.  Some people say that biologic manufacturers stand to make more profit in the United States if there are no relatively less expensive biosimilars so they're not trying very hard.  Others might say, well, it takes a long time to sufficiently prove safety and efficacy, so of course it took a while for the United States to get biosimilars.

While both of these ideas have some merit to them, a major reason why it took so long in the United States for biosimilars to show up has to do with laws.  The EMA has had a regulatory process in place for the approval of biosimilar drugs since 2005.  When did the United States finally realize a law that would create an abbreviated approval pathway for biosimilars?  Why, that would be the Biologics Price Competition Act, which is part of, you guessed it, the Affordable Care Act.  Thanks, Obama.

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