New Drug

Application

The Food and Drug Administration's (FDA)

New Drug Application (NDA) is the vehicle
in the United States through which drug
sponsors formally propose that the FDA
approve a new pharmaceutical for sale
and marketing.[1][2] Some 30% or less of
initial drug candidates proceed through the
entire multi-year process of drug
development, concluding with an approved
NDA, if successful.[1]

A new drug application in the 1930s

for sulfapyridine to the United States
Food and Drug Administration

The goals of the NDA are to provide

enough information to permit FDA
reviewers to establish the complete history
of the candidate drug.[3] Among facts
needed for the application are:[2]

Patent and manufacturing information

Drug safety and specific effectiveness
for its proposed use(s) when used as
 directed
Reports on the design, compliance, and
conclusions of completed clinical trials
by the Institutional Review Board
Drug susceptibility to abuse
Proposed labeling (package insert) and
directions for use

Exceptions to this process include voter

driven initiatives for medical marijuana[4] in
certain states.

Before trials
To legally test the drug on human subjects
in the U.S., the maker must first obtain an
Investigational New Drug (IND) designation
from FDA.[5] This application is based on
nonclinical data, typically from a
combination of in vivo and in vitro
laboratory safety studies, that shows the
drug is safe enough to test in humans.[5]
Often the "new" drugs that are submitted
for approval include new molecular
entities[6] or old medications that have
been chemically modified to elicit
differential pharmacological effects or
reduced side effects.

Clinical trials
The legal requirement for approval is
"substantial" evidence of effectiveness
demonstrated through controlled clinical
trials.[7] This standard lies at the heart of
the regulatory program for drugs. Data for
the submission must come from rigorous
clinical trials.[5]

The trials are typically conducted in three

phases:[5]

Phase 1: The drug is tested in 20 to 100

healthy volunteers to determine its
safety at low doses. About 70% of
candidate drugs advance to Phase 2.
Phase 2: The drug is tested for both
efficacy and safety in up to several
hundred people with the targeted
disease. Some two-thirds of candidate
drugs fail in Phase 2 clinical trials due to
the drug not being as effective as
anticipated.
Phase 3: The drug is typically tested in
several hundred to several thousand
people with the targeted disease in
double-blind, placebo controlled trials to
demonstrate its specific efficacy. Under
30% of drug candidates succeed
through Phase 3.
Phase 4: These are postmarketing
surveillance trials in several thousand
people taking the drug for its intended
purpose to monitor efficacy and safety
of the approved marketed drug.[5]
The legal requirements for safety and
effectiveness have been interpreted as
requiring scientific evidence that the
benefits of a drug outweigh the risks and
that adequate instructions exist for use,
since many drugs have adverse side
effects.

Many approved medications for serious

illnesses (e.g., cancer) have severe and
even life-threatening side effects. Even
relatively safe and well understood OTC
drugs such as aspirin can be dangerous if
used incorrectly.
The actual application
The results of the testing program are
codified in an FDA-approved public
document that is called the product label,
package insert or Full Prescribing
Information.[8] The prescribing information
is widely available on the web, from the
FDA,[9] drug manufacturers, and frequently
inserted into drug packages. The main
purpose of a drug label is to provide
healthcare providers with adequate
information and directions for the safe use
of the drug.
The documentation required in an NDA is
supposed to tell "the drug’s whole story,
including what happened during the clinical
tests, what the ingredients of the drug are,
the results of the animal studies, how the
drug behaves in the body, and how it is
manufactured, processed and
packaged.” [2] Currently, the FDA decision
process lacks transparency, however,
efforts are underway to standardize the
benefit-risk assessment of new
medicines.[10] Once approval of an NDA is
obtained, the new drug can be legally
marketed starting that day in the U.S.
Of original NDAs submitted in 2009, 94 out
of 131 (72%) were in eCTD format.[11]

Once the application is submitted, the FDA

has 60 days to conduct a preliminary
review, which assesses whether the NDA is
"sufficiently complete to permit a
substantive review." If the FDA finds the
NDA insufficiently complete (reasons can
vary from a simple administrative mistake
in the application to a requirement to re-
conduct testing), then the FDA rejects the
application by sending the applicant a
Refuse to File letter, which explains where
the application failed to meet
requirements.[12] Where the application
cannot be granted for substantive reasons,
the FDA issues a Complete Response
Letter.

Assuming the FDA finds everything

acceptable, they decide if the NDA needs a
standard or accelerated review, and
communicates acceptance of the
application and their review choice in
another communication, known as the 74-
day letter.[13] A Standard Review implies an
FDA decision within about 10 months while
a Priority Review should complete within 6
months.[14]
Requirements for similar
products
Biologics, such as vaccines and many
recombinant proteins used in medical
treatments are generally approved by FDA
via a Biologic License Application (BLA),
rather than an NDA. The manufacture of
biologics is considered to differ
fundamentally from that of less complex
chemicals, requiring a somewhat different
approval process.

Generic drugs that have already been

approved via an NDA submitted by another
maker are approved via an Abbreviated
New Drug Application (ANDA), which does
not require all of the clinical trials normally
required for a new drug in an NDA.[15] Most
biological drugs, including a majority of
recombinant proteins are considered
ineligible for an ANDA under current US
law.[16] However, a handful of biologic
medicines, including biosynthetic insulin,
growth hormone, glucagon, calcitonin, and
hyaluronidase are grandfathered under
governance of the Federal Food Drug and
Cosmetics Act, because these products
were already approved when legislation to
regulate biotechnology medicines later
passed as part of the Public Health
Services Act.
Medications intended for use in animals
are submitted to a different center within
FDA, the Center for Veterinary Medicine
(CVM) in a New Animal Drug Application
(NADA). These are also specifically
evaluated for their use in food animals and
their possible effect on the food from
animals treated with the drug.

See also
Drug development
Inverse benefit law
Investigational New Drug, FDA
application to start clinical trials
 Kefauver Harris Amendment, a 1962
amendment to the Federal Food, Drug,
and Cosmetic Act (e.g. to also require
evidence of efficacy)
Regulation of therapeutic goods, rules in
different countries.

References
1. "The Drug Development Process" (https://w
ww.fda.gov/ForPatients/Approvals/Drugs/
default.htm) . U.S. Food and Drug
Administration. January 4, 2018. Retrieved
May 1, 2018.
2. "The Drug Development Process. Step 4:
FDA Drug Review" (https://www.fda.gov/Fo
rPatients/Approvals/Drugs/ucm405570.ht
m) . U.S. Food and Drug Administration.
January 4, 2018. Retrieved May 1, 2018.

3. Gad, Shayne Cox (2008). Pharmaceutical

Manufacturing Handbook: Production and
Processes (https://books.google.com/boo
ks?id=4c0Hp3AOi8UC&pg=PA39) . John
Wiley & Sons. ISBN 9780470259801.
4. Commissioner, Office of the. "Public Health
Focus - FDA and Marijuana" (https://www.fd
a.gov/NewsEvents/PublicHealthFocus/ucm
421163.htm) . www.fda.gov. Archived (http
s://web.archive.org/web/2018042816241
1/https://www.fda.gov/NewsEvents/Public
HealthFocus/ucm421163.htm) from the
original on April 28, 2018. Retrieved
April 30, 2018.

5. "The Drug Development Process. Step 3:

Clinical Research" (https://www.fda.gov/For
Patients/Approvals/Drugs/ucm405622.ht
m) . U.S. Food and Drug Administration.
January 4, 2018. Retrieved May 1, 2018.
6. "The Drug Development Process. Step 1:
Discovery and Development" (https://www.f
da.gov/ForPatients/Approvals/Drugs/ucm4
05382.htm) . U.S. Food and Drug
Administration. January 4, 2018. Retrieved
May 1, 2018.

7. Food, Drug, and Cosmetic Act, Section 505;

21 USC 355]

8. 21 CFR 201.5: Labeling Requirements for

Prescription Drugs and/or Insulin

9. "Daily Med:Current Medication Information"

(http://dailymed.nlm.nih.gov/dailymed/abo
ut.cfm) . Archived (https://web.archive.org/
web/20081112024512/http://dailymed.nl
m.nih.gov/dailymed/about.cfm) from the
original on November 12, 2008. Retrieved
October 10, 2007.
10. Liberti L, McAuslane JN, Walker S (2011).
"Standardizing the Benefit-Risk Assessment
of New Medicines: Practical Applications of
Frameworks for the Pharmaceutical
Healthcare Professional" (https://web.archi
ve.org/web/20120206083026/http://adiso
nline.com/pharmaceuticalmedicine/Abstra
ct/2011/25030/Standardizing_the_Benefit_
Risk_Assessment_of_New.1.aspx) . Pharm
Med. 25 (3): 139–46.
doi:10.1007/BF03256855 (https://doi.org/1
0.1007%2FBF03256855) .
S2CID 45729390 (https://api.semanticscho
lar.org/CorpusID:45729390) . Archived
from the original (http://adisonline.com/ph
armaceuticalmedicine/Abstract/2011/2503
 0/Standardizing_the_Benefit_Risk_Assessm
ent_of_New.1.aspx) on February 6, 2012.

11. Kathie Clark (December 15, 2009).

"Updates from the Regulators:FDA" (http://t
heectdsummit.com/summit/?p=630) . The
eCTD summit. Archived (https://web.archiv
e.org/web/20110716232846/http://theect
dsummit.com/summit/?p=630) from the
original on July 16, 2011.
12. "Merck KGaA Receives Refuse To File Letter
From FDA On Cladribine Tablets New Drug
Application" (http://www.medicalnewstoda
y.com/articles/172522.php) .
medicalnewstoday.com. Archived (https://
web.archive.org/web/20100305060217/htt
p://www.medicalnewstoday.com/articles/1
72522.php) from the original on March 5,
2010. Retrieved April 30, 2018.
13. "FINDINGS: Issues and Communication:
Independent Evaluation of FDA's First Cycle
Review Performance – Final Report" (http
s://web.archive.org/web/2010030803455
0/https://www.fda.gov/ForIndustry/UserFe
es/PrescriptionDrugUserFee/ucm127153.h
tm) . Food and Drug Administration.
Archived from the original (https://www.fd
a.gov/ForIndustry/UserFees/PrescriptionDr
ugUserFee/ucm127153.htm) on March 8,
2010. Retrieved February 23, 2010.
14. "Cadence Pharmaceuticals Announces
Priority Review and Acceptance of NDA
Submission for Acetavance for Treatment
of Acute Pain and Fever" (https://www.drug
s.com/nda/acetavance_090715.html) .
drugs.com. Archived (https://web.archive.o
rg/web/20170711032241/https://www.dru
gs.com/nda/acetavance_090715.html)
from the original on July 11, 2017.
Retrieved April 30, 2018.

15. "FDA, CDER Office of Generic Drugs" (http

s://www.fda.gov/cder/ogd/) . fda.gov.
Archived (https://web.archive.org/web/200
90528175742/https://www.fda.gov/cder/o
gd/) from the original on May 28, 2009.
Retrieved April 30, 2018.
16. "C&EN: COVER STORY - BEYOND HATCH-
WAXMAN" (http://pubs.acs.org/cen/covers
tory/8038/8038biogenerics2.html) .
pubs.acs.org. Retrieved April 30, 2018.

External links
Henninger, Daniel (2002). "Drug Lag" (htt
p://www.econlib.org/library/Enc1/DrugL
ag.html) . In David R. Henderson (ed.).
Concise Encyclopedia of Economics
(1st ed.). Library of Economics and
Liberty. OCLC 317650570 (https://www.
worldcat.org/oclc/317650570) ,
50016270 (https://www.worldcat.org/oc
lc/50016270) , 163149563 (https://ww
w.worldcat.org/oclc/163149563)
Chapter 11: Prescription Drug Product
Submissions in: Fundamentals of US
Regulatory Affairs, Eighth Edition 2013
(https://www.raps.org/focus-online/und
er-raps/under-raps-article/article/3694/
book-excerpt-prescription-drug-product-
submissions.aspx) Archived (https://we
b.archive.org/web/20160304054513/htt
p://www.raps.org/focus-online/under-ra
ps/under-raps-article/article/3694/book
-excerpt-prescription-drug-product-subm
issions.aspx) March 4, 2016, at the
Wayback Machine
Novel Drug Approvals for 2021 (https://
www.fda.gov/drugs/new-drugs-fda-cder
 s-new-molecular-entities-and-new-thera
peutic-biological-products/novel-drug-a
pprovals-2021)

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