Note: for a less-technical version, see: Clinical trials

Clinical trials

Clinical trials vary but the basic idea with most is that clinicians and scientists monitor patients with and without some new treatment to figure out: whether a treatment is safe; whether it works (has efficacy); whether it works better than the current “standard of care”; and/or what if any side effects it causes.

Trial arms

Arm-ed you glad you asked? The groups of patients receiving different treatments are sometimes referred to as “arms” – e.g. a group of patients receiving the drug is referred to as a “therapeutic arm” and they’re compared to a “control arm” where patients don’t get the treatment, get a fake (sham) treatment, or get the common “standard of care” (whatever would typically given to a patient were they not in the trial).

Some trials have multiple therapeutic arms, so they can compare multiple treatment strategies (different drugs, different doses, etc.). It’d be great to have a lot of arms, but it’s difficult in part because you need to keep the study size high – you need a large “n” (number of patients) in each group in order for any result to be statistically significant.

Trial phases

Did it work? Endpoints

How does one determine if a trial is “successful”? When setting up a trial, scientists set out particular “endpoints” – which are the things that they measure in order to see if they meet the “objectives” the study sets out. For example, you might measure the endpoint of days of required hospitalization to see if you meet an objective of a 50% reduction in hospitalization time in the treatment group compared to the control group. 

Primary endpoints are the main things measured, but “secondary endpoints” are monitored as well. For example, they might initially (e.g. in Phase 1 studies) look only to safety as a primary endpoint, but also add secondary endpoint(s) to see if it’s actually having a therapeutic effect. They might also have secondary endpoints in later phases for various reasons, but these shouldn’t be allowed to substitute for the primary ones.

Accelerated approval: In some cases, such as cases where disease symptoms progress over years, or if there’s a pressing need for a treatment, it can be hard to know in a reasonable amount of time if a treatment actually has clinical efficacy (does it actually help people). In such cases, and with regulatory okay, scientists may instead look to “surrogate markers” or “surrogate endpoints” which are (typically molecular) indications, sometimes in the form of “biomarkers” that are believed to correlate with clinical efficacy (e.g., lowering of levels of a misfolded protein or increase in levels of a wanted protein).

The companies are then supposed to continue following patients and/or do additional studies to confirm the treatment actually is effective, but these are not always completed (this is explained nicely in Jerry Avorn’s book, Rethinking Medications).

Avoiding bias

Both conscious and unconscious factors can influence the findings and/or the analysis of trial results, so there are a number of measures taken to avoid it.

Interim analysis: Even in blinded/masked studies, an “independent” Data Monitoring Committee (DMC), aka a Data Safety and Monitoring Board (DSMB), in addition to monitoring patient safety throughout the trial, a “independent” data monitoring committee looks at the data midway through to see if it would be unethical to proceed either because the treatment is causing severe side effects or because the treatment is super effective so it’s unfair not to give it to more people.

“Positive” results tend to get published much more than “negative” results, and “confirmatory” or “replication” findings less than “novel” findings. This makes the published literature biased. To prevent some of this bias, the FDA introduced laws that require the pre-registration of clinical trials, including the trial design (including endpoints and statistical methods to be used). They must then report their findings to be posted on clinicaltrials.gov

Gaining regulatory approval

The FDA regulates drugs and biologics in the US, with regulatory oversight broken up into different departments.

• Center for Drug Evaluation and Research (CDER) – oversees conventional small molecule drugs as well as most biologics including recombinant proteins and nucleic acids
• Center for Biologics Evaluation and Research (CBER) – oversees most vaccines, blood products, and cell-based products

The overall process to regulatory approval in the US is:

• For conventional drugs, as well as oligonucleotides and peptides (≤ 40 amino acids):
  • Pre-clinical investigation → IND (Investigational New Drug) application → clinical trials → NDA (New Drug Application) or ANDA (Abbreviated New Drug Application (for generics) → approval → NME (New Molecular Entity (for conventional drugs and small biologics)
• For biologics:
  • Pre-clinical investigation → IND (Investigational New Drug) application → clinical trials → BLA (Biologics License Application) or abbreviated BLA (aBLA) (for biosimilars) → approval → Licensed Biologic or Biosimilar
  • 351(a) is the approval pathway for a biologic in the US. It involves: Clinical safety and efficacy studies for each indication; clinical pharmacology; and animal/nonclinical studies; product quality studies.
  • 351(k) is the approval pathway for a biosimilar in the US. It’s abbreviated compared to the 351(a) required for the original biologic. It does not require clinical safety and efficacy studies for each indication (with the assumption proof of biosimilarity to the reference product will ensure the results would be similar to those from the reference product), but it may require additional clinical studies, clinical pharmacology studies, comparative analytical assessment (CAA), and product quality studies.

Note: More on biologics, generics, and biosimilars below.

There are several (non-exclusive) mechanisms for therapeutics to get speedier reviews by the FDA (definitions taken from FDA website):

• Fast track: “A process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.”
• Breakthrough therapy: “A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.”
• Accelerated Approval: “These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.“
• Priority Review: “Priority Review designation means FDA’s goal is to take action on an application within 6 months.”
  • Note: companies may be granted priority review vouchers for doing things like developing treatments for orphan diseases. They are then able to apply those vouchers to speed up approval of other medications or sell them to other companies. This is explained well in Rethinking Medications by Jerry Avorn.

Naming – you can actually learn a lot from a generic/nonproprietary name

Therapeutics are given both brand/trade names and “generic” (nonproprietary) names. The generic names may seem really random and opaque, but they’re actually highly formulaic (except for the first part of them, which is chosen for “any” reason)! The generic names are composed by piecing together a bunch of international nonproprietary names (INN) “stems” defined by the World Health Organization (WHO).

Biosimilars are given the same core name as their reference biologic product, but unique 4-letter suffixes are added to the end to distinguish them. For example, adalimumab-ryvk (Simlandi) and adalimumab-adbm (Cyltezo) are 2 biosimilar forms of the reference product adalimumab (Humira)

Generics and biosimilars, me-too drugs, etc.

Patents, market exclusivity, etc.

Patents and market exclusivity rights are 2 separate avenues that protect the innovations of inventors and therapeutic developers. They aim to promote and incentivize innovation, while also providing an avenue for eventual competition and thus potentially lower-cost generics, biosimilars, etc. Once a treatment’s patent(s) and/or exclusivity period expires, competitors may market generics (in the case of small molecules) or biosimilars (in the case of biologics). 

To avoid losing market share, companies may engage in practices such as making minor alterations to the treatment (with little or no added value) to seek new patents for the new version. To gain longer exclusivity times, companies may do things like apply for approval of the same treatment for additional conditions, in additional dosages, etc. And/or, they might seek approval for treating a rare/orphan disease, which provides longer exclusivity.

Patents are legal mechanisms to protect inventions and promote innovation

• Patents can be obtained (from the United States Patent and Trademark Office (USPTO)) for both formulations and processes at any phase of the therapeutic development process.
• Patents prevent competitors from using an invention without paying the patent-holder
• Patents typically expire 20 years after the date of filing (not the date of therapeutic approval!); however, patent term extensions (PTEs) of up to 5 years may be granted to make up for time spent in the approval process (this is a key component of the 1984 Drug Price Competition and Patent Restoration Act (more commonly referred to as the Hatch-Waxman Act).

Market exclusivity is a set number of years in which companies have the exclusive right to manufacture and sell a treatment they developed once approved. The length of this period depends on the type of approval.

• New Chemical Entity Exclusivity (NCE) – 5 years
  • This is what you get for your typical new drug approval.
• Reference Product Exclusivity (RPE) – 12 years, including 4 years data in which competitors can’t even file an aNDA for a biosimilar.
  • This is the exclusivity period for a new biologic.
  • Biologics get a longer exclusivity period with the rationale they’re more complicated and pricy to develop.
  • This is dictated by the Biologics Price Competition and Innovation Act (BPCIA).
• Orphan Drug Exclusivity (ODE) – 7 years
  • This longer exclusivity period is meant to incentivize development of therapeutics for indications (diseases/disorders) with a small treatable population that might not otherwise be an “attractive” target for development
• Generating Antibiotic Incentives Now (GAIN) Exclusivity – 5 years added
  • This longer exclusivity period is meant to incentivize development of much-needed antibiotics. Antibiotic development is urgently needed, but generally not very lucrative.
• New Clinical Investigation Exclusivity – 3 years
  • You get a shorter exclusivity period if the drug isn’t new, but you’ve now gotten it approved for an additional indication.
• Pediatric Exclusivity (PED) – 6 months added
  • This is to incentivize development of therapeutics for pediatrics, which can be seen as “riskier” and thus incentive-needing.
• Competitive Generic Therapy (CGT) – 180 days
  • The first generic version of a product that’s approved gets a short market exclusivity period in which other generics can’t be sold (but the brand name still can)
• Patent Challenge (PC) – 180 days
  • If the brand name manufacturer has infringed on patents or something along that lines, the first company wanting to market a generic that sues the brand name manufacturer gains some exclusivity.

The “Orange Book” has patent and exclusivity information for small molecule therapeutics and some small biologics (e.g. ASOs), whereas the “Purple Book” has information for larger and/or more complex biologics (gene therapy, cell therapy, protein therapeutics, etc.). Unfortunately, the Purple Book isn’t as informative – It has patent and exclusivity information for some entries but not others. It does, however include some useful information including allowing you to see what, if any biosimilars and interchangeable biologics are available.