How exactly does a medicine get approved? (Part 2 of 5)

Episode 2: The Saga Continues

Last time we reviewed the overall framework of FDA regulation. Today we’ll dive into the details of how products are categorized.


Drugs, Devices, and Biologics

Pop quiz: are medical maggots a drug, a device, or a biologic product in the US? (Maggots are exceptionally skilled at removing dead tissue from a wound without touching living tissue, so they are occasionally used to debride and clean complex wounds.)

Hint: the FDA has cleared medical maggots “for debriding chronic wounds such as pressure ulcers, venous stasis ulcers, neuropathic foot ulcers and non-healing traumatic or post surgical wounds.” Is debridement a chemical, mechanical, or biological action?

Answer: medical maggots are considered a device for this indication.

Medical products are those which are intended to treat, diagnose, or prevent abnormal health conditions, or to alter the normal structure or function of human anatomy. Thus a product that is intended to prevent a disease (such as a vaccine) is a medical product, whereas a product that is intended to support immune health (a vague and nonspecific concept) is not. This is why nutritional supplements carry such vague statements as “to support a healthy immune system.” This is also why 23andme got into such trouble with the FDA: they were promoting their service as able to determine the risk of a disease and/or susceptibility to a given medication, which are diagnostic actions. As such, the product was a medical device subject to FDA regulation, yet they had never obtained FDA approval.

It’s important to note that medical products are cleared or approved for a given indication, i.e. the end use that the manufacturer or seller openly intends. Drugs and devices can be marketed for a particular use if they have demonstrated sufficient safety and efficacy profiles and received approval from regulatory authorities, but promotion of any other “off-label” use is not allowed. Physicians may opt to prescribe the product for off-label use as part of their licensed practice, but the manufacturer may not promote the product for such. This becomes tricky when a body of scientific literature suggests that an existing product may have utility in a new condition, or when a manufacturer becomes aware that an off-label use is becoming commonplace. Occasionally, manufacturers have been forced to study the safety and efficacy of these alternate applications and apply for FDA approval.

Ultimately, medical products are regulated based upon their intended Primary Mode of Action (PMoA). If the product will operate via chemical means, it is generally a Drug; if mechanical/electromagnetic, it is generally a Device; if biological, it is a Biologic. Hence acetaminophen, paclitaxel, and penicillin are drugs as they operate by chemical means, whereas a vascular stent, x-ray machine, or wound debridement product is a device. Biologics can be tricky, as they often operate via multiple activities, and as such often become Combination products, subject to review from multiple Centers within the FDA.



Drugs are all put on essentially the same level playing field, and all new drugs must undergo similar evaluation via Phase I (basic safety), Phase II (expanded safety and basic efficacy), Phase III (full or “pivotal” safety and efficacy), and occasionally Phase IV (postmarket) study. These Investigational New Drugs (INDs) hope to eventually obtain New Drug Approval (NDA) upon submission and review of safety and efficacy data. Very rarely, a drug will demonstrate such unequivocal safety and efficacy, or will demonstrate acceptable safety and efficacy in a uniquely vulnerable population with an urgent need, that it receives accelerated review and approval.

Generic forms of a drug can be approved under an abbreviated NDA which does not require new clinical data. As long as the generic manufacturer can demonstrate that they are producing the same Active Pharmaceutical Ingredient (API) (typically a single molecule such as acetaminophen, ibuprofen, paclitaxel, levothyroxine, etc.), and are not making any meaningful changes to the excipients (the gel, syrup, capsule, pill, etc. used to deliver the API), then they can eventually obtain approval, subject to certain restrictions (more on that in a moment). (Very rarely these different excipients cause variable efficacy or allergic sensitivity in certain patients, and hence some people must take the brand-name product. For the vast majority of us though, generics are cheaper and just as effective.)

Recent estimates put the total cost of developing a novel drug at $2.6 billion, though this value has been contested. New drugs typically require three to four separate clinical trials and a $2,335,200 filing fee ($1,167,600 for generic drug submissions), plus an annual fee of $569,200 per manufacturing site and $110,370 per product*. The review cycle for new drugs often takes over a year with continuous dialog between the manufacturer and the regulatory body. Add in the 2-5 years of bench study and preclinical evaluation and the 2-10 years of clinical study, and suddenly a 20 year patent doesn’t offer much protection time to recoup a multi-million (or billion) dollar development effort.

Development times from initial discovery to product launch are commonly ten to twenty years. With patents expiring 20 years after filing, this can leave a very brief window for the manufacturer to recoup the cost of research and development. This is in part why the Hatch-Waxman Act was passed in 1984, providing for three to seven years of market exclusivity after drug approval. Under Hatch-Waxman, the FDA is forbidden from approving a generic form of a drug during the exclusivity period, regardless of patent status. If new clinical data for a new indication is presented, the exclusivity can be renewed (typically for three years). Some companies have used this option to string together exclusivities, running new clinical studies sequentially. Others have benefitted from circumstances beyond their control: when CFC propellants were banned, oral asthma inhalers had to be reformulated, and the new formulation was considered a new drug, triggering exclusivity and bumping generic competitors off the market.

(Note I’m not defending pricing schema for drugs; I’m only pointing out the expense side of the equation, with no consideration of the revenue side. That’s a whole other situation to tackle.)

*The annual manufacturing site and product fees are used to pay for routine–typically bi-annual–audits of the manufacturer.


Tune in next week for more fun and excitement!




Topher is a nerd, scientist, bioengineer, photographer, costumer, dog trainer, beer brewer, and a lot of other nouns. He has too many degrees and too many hobbies because it’s all fun and interesting, and … squirrel!

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