The document outlines the 4 phases of clinical trials that new drugs must go through to gain FDA approval. Phase I trials test safety on a small group. Phase II trials test effectiveness on hundreds of patients. Phase III trials involve thousands of patients to further test safety and effectiveness. After Phase III, the manufacturer submits a BLA application for FDA review, which typically takes 12 months. If approved, Phase IV ongoing monitoring of the drug begins. The total estimated cost from development to approval is over $1.3 billion.

1. Phase III Clinical Trials (Large)
New chemical
entity is created by
a manufacturer.
Phase I is safety testing. In
this phase, the goal is to
determine the most
frequent side effects of
the agent, how it is
metabolized, and how it is
eliminated (excreted) from
the body.
Phase II testing involves a much
larger group of patients. The
number of patients is in the
hundreds, versus the tens of
phase I. May last approximately 2
years.
Estimated cost: $34.9 million in
2013 USD
Phase III attempts to approximate
real-world conditions. It evaluates the
drug in different types of populations,
at different dosages, and in
combination with other drugs. There
is an ongoing evaluation of safety
(established in phase I) and
effectiveness (established in phase II).
Drug Discovery,
Development
IND Application Phase I Clinical Trials
(Small)
Phase II Clinical Trials
(Medium)
Review Meeting/BLA Application
Timeline for FDA Approval of Biologics
Paul Pasco | March 4, 2022
Multiple species
of animal models
are used to
evaluate the new
chemical entity.
The chemical is
assessed for
safety (i.e.,
potential
toxicities) and
efficacy. May last
up to 5 years.
Estimated cost:
$430 million in
2013 USD
Manufacturer files an
Investigational New
Drug (IND) application
to the FDA. The
application delineates
the chemical
composition of the
drug, manufacturing
methods, the design
for proposed clinical
trials, and a protocol
for informed consent
of participants.
The staff of the Center
for Biologics
Evaluation and
Research (CBER)
division of the FDA
reviews the IND to
ensure there are
adequate processes in
place for informed
consent and safety of
participants in the
clinical trials. May last
only a few months.
Forms required: Form
FDA 356h, 1571
(IND), 1572
In vitro and in
vivo (but
non-human)
testing
Phase I testing involves only
a small number of patients.
Typically, 20 to 80 patients
are used. May last
approximately 2 years.
Estimated cost: $25.3
million in 2013 USD
Phase II tests for effectiveness.
The drug is evaluated to see if it
works in patients with a certain
disease. In clinical trials, patients
who receive the drug are
compared with similar patients
who are receiving the current
standard of care or a placebo. At
the conclusion of phase II, the FDA
and manufacturer make plans for
large-scale studies in phase III.
Phase II testing involves thousands of
patients, versus the tens of phase I and
the hundreds of phase II. May last
approximately 2 years.
Estimated cost: $54.0 million in 2013
USD
Review of Application
After the conclusion of phase III clinical
trials, the drug manufacturer meets with
the FDA before submitting a Biologics
License Application (BLA). The BLA
contains many components, including
manufacturing information, human
pharmacokinetic data from previous
testing, and proposed labeling for the
drug.
Forms required: Electronic Common
Technical Document (eCTD)
Once a BLA is received, the FDA has
60-days to file it for review. If filed, the
FDA Review team evaluates the
compendium of research generated by
the manufacturer supporting the safety
and effectiveness of the drug for the
specified indication(s).
The FDA also reviews the proposed
monograph (official labeling) of the
drug to ensure it meets appropriate
criteria and inspects the facilities where
the drug will be manufactured to ensure
they meet standards for Current Good
Manufacturing Practice (CGMPs). Full
review typically takes 12 months (6
months if priority review)
Forms required: Potentially a
prelicensing application to verify
compliance with appropriate regulations
and/or discipline review letter after
personnel have completed their review
but before the overall review is finished.
Traditional Pathway*
In phase IV, healthcare professionals and
consumers may utilize MedWatch, a
voluntary system to report adverse or
sentinel events (unexpected death or
serious injury) for many medical
products, including biologics, small
molecule drugs, and medical devices.
After FDA review, these events may be
added to the drug's official labeling or
may result in removal of the drug from
the market (e.g., Vioxx®). Unless the
drug is removed, the ongoing monitoring
is indefinite.
Estimated cost: $466 million in 2013
USD
Drug Approval
Phase IV: Postmarketing
Surveillance
Phase IV occurs after the drug has
been fully FDA-approved and has
begun sale on the market. Phase IV is
designed to detect serious adverse
events that were not apparent during
phases I to III due to their limited sample
sizes and time frames (i.e., thousands
rather than millions of patients, years
rather than decades).
Indefinite (unless drug removed from market)
Up to 12 years from initiation to full FDA-approval
*Fast track, breakthrough therapy, accelerated approval, and priority review not covered here.
Sources:
1. U.S. Food and Drug Administration. Drug Approval Process. U.S. Food and Drug Administration. Accessed February 26, 2022. https://www.fda.gov/media/82381/download
2. Combs K, Food and Drug Law Institute. Introduction to FDA Review and Approval of Biological Products. Food and Drug Law Institute; 2021. Accessed February 26, 2022.
https://www.fdli.org/wp-content/uploads/2021/03/Combs-Kellie.pdf
3. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs. Journal of Health Economics. 2016;47(47):20-33.
doi:10.1016/j.jhealeco.2016.01.012
4. The FDA Group, LLC. The Biologics License Application (BLA) Process Explained. www.thefdagroup.com. Published July 16, 2021. Accessed March 3, 2022.
https://www.thefdagroup.com/blog/2014/07/test-the-biologics-license-application-bla-process/
Total out-of-pocket cost estimate from pre-approval process to full FDA approval (per approved drug): $1395 million ($1.395 billion) in 2013 USD $466 million in 2013 USD