or, How I Learned to Stop Worrying and Love My Own Definition.

Recently I posted on “biologic drugs” which were approved in 2019. All was well in my little scientific universe, until I received this in an email:

“You recently reported “14 novel biologic drugs,” referring to ‘novel’ biopharmaceuticals approved CDER. But, … You also include several synthetic drugs, which are clearly not biopharmaceutical/biologics.

-Reasonably authoritative figure on the internet

Wait, what? Synthetic drugs are clearly not biopharmaceutical/biologics?  Sure, the siRNA drug, Givlaari, and the antisense oligonucleotide, Vyondis 53, are both technically made by chemical synthesis.  But not considering these RNA-based drugs “biologic drugs” just felt… wrong.

It got me thinking – what is the definition of a biologic drug, anyway? I immediately started my research the way any good, card-carrying scientist does — I punched it into the Google:

Figure 1. How all good scientific research starts.

and looked at the most authoritative source that popped up:

Figure 2. How most good research ends.

Though Wikipedia delivers good answers to probably 90% of my questions, I knew this definition was incomplete – nobody considers natural products like penicillin “biologic drugs.” Not wanting to spend the rest of my Sunday night reading FDA guidance documents, I did instead what any good millennial does – I asked social media.

Figure 3. How a millennial gathers scientific data.

The results were split,1 with many on both LinkedIn and Twitter agreeing that the terminology is confusing. As one comment points out, the term “biologic” itself is anachronistic, coming from a time when chemistry and biology were considered distinct (i.e. before chemists started getting upset about Nobel Prizes in Chemistry going to “biologists” ????).  The Biologics Control Act, which first gave the US government control over the processes to make biological products, was passed in 1902 – long before it was clearly established that proteins are polymers of amino acids and that genetic information is stored chemically in nucleobases.

Digging Deeper

Based on the lack of strong consensus, I decided this was a topic worth diving further into (Figure 4).

Figure 4. How a drug discovery scientist with mild OCD wastes Saturday morning.

Readers likely remember that “biologic” became a charged term in the 2000’s, due to expensive biologic products like filgrastim and epoetin alfa, approved under Biologic License Applications (BLAs) rather than New Drug Applications (NDAs).  Since the abbreviated generic drug approval process (ANDA) only applied to originals filed under NDAs, there was no way to create a “generic” biological product without repeating expensive and lengthy clinical trials. This loophole led to the creation of the abbreviated follow-on biologicals approval pathway (aBLA) through the 2009 Biologics Price Competition and Innovation Act (BPCI).

So how are the adjectives, “biologic” or “biological,” legally defined in the US Code of Laws after BPCI in 2009? Turns out, they’re not. The term “biological product,” is legally defined only with examples, not properties:

“The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

42 U.S. Code § 262. Regulation of biological products.

With no basis in the text for determining what an “analogous product” is, no definition of what exactly makes a product “biologic” or “biological,” and with, of all things, arsphenamine (or any other trivalent organic arsenic compound) being the only explicitly spelled out example, no wonder everyone is confused. The FDA and the industry spend an enormous amount of resources deciding new registrants on a case-by-case basis, which was part of the justification for a recent change in the definition.

A Legal Update on Synthetic Processes

It gets better.  The Further Consolidated Appropriations Act, 2020, signed into law in December 2019, amended this definition by removing the phrase “(except any chemically synthesized polypeptide)”:

“The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

New legal definition of “biological product” after the Further Consolidated Appropriations Act of 2020.

The recent FDA press release on the change states that the purpose of the amendment is to allow for the possibility that a manufacturer may chemically synthesize a biologic product.  Under the old definition, if an original biologic product was licensed under a BLA, a new chemically synthesized biologic follow-on could not be licensed through an abbreviated aBLA pathway, since it was made by a synthetic process, but also could not be licensed through an ANDA, since the original was not filed under an NDA.

In the end, what this demonstrates is that there are at least two simultaneous uses of the term “biologic” in the industry – an arbitrary regulatory definition to decide what drugs are licensed under BLAs vs. NDAs, and a scientific colloquialism which most of us use on a day-to-day basis. As Figures 5 and 6 show, neither definition is clear and unambigious, and no single criterion (e.g. chemical process) universally captures all cases.

Figure 5. A rough sketch of how the US government decides to regulate molecules. This is not meant to be taken as legal advice. Consult your regulatory affairs or legal representative with your case.
Figure 6. A rough sketch of how most scientists probably decide whether a drug is “biologic” or not.

Biolognas, Anybody?

Having both uses at the same time is confusing enough to make you want to give “synthetic biologics” a different name without “biologic” in it.  But what would we call them?  Biologishes?  Biolognas?  I guess I have a year to think about it before 2020’s Biologic Drug Approvals post.

But back to my original question on social media – since oligonucleotide drugs are all filed under NDA’s, they’re regulated more like most small molecules than most biologics. But just because they’re filed under NDA’s, doesn’t mean we can’t still call them biologics (e.g. insulins are all filed under NDAs). Anyway, all this makes me very glad that we have a lot of brilliant professionals working in our very important Regulatory Affairs departments, though I’m glad it doesn’t include me!

Explore drughunter.com for more.

  1. Interestingly, people on LinkedIn tended to favor not calling them biologics, though with a smaller sample size and probably a greater bias towards people I know in CMC.