The new drug approval process involves several phases of laboratory and clinical testing that can take over a decade and cost hundreds of millions of dollars. Only about 1 in 1000 compounds that enter pre-clinical testing are approved for human testing. After pre-clinical animal testing, companies submit an Investigational New Drug (IND) application to the FDA to request permission for human clinical trials. If approved, the drug then enters three phases of clinical trials involving several hundred to thousands of human subjects to evaluate safety, efficacy, and proper dosing. If phase 3 trials are successful, companies submit a New Drug Application (NDA) to the FDA for review and potential approval allowing marketing and post-market safety surveillance.

1. New Drug Approval Process and
Investigational New Drug (IND)
Application

2. The FDA Drug Approval Process

3. New Drug Approval
• It takes 12-15 years and hundreds of million
dollars to get a new drug from the laboratory
onto the pharmacy shelf.
• Once a company develops a drug, it undergoes 3
½ of laboratory testing,
• Then an application is made to the U.S. Food and
Drug Administration (FDA) to begin testing the
drug in humans.
• Only 1 in 1000 of the compounds that enter
laboratory testing ever make it to human testing.

4. Probability of Success and Duration
of Drug Development

5. New Drug Approval Timeline

6. New Drug Approval Process
• : Abandoned Investigational
New Drug Applications
Case 1
•Advisory Committee
MaterialsCase 2
• FDA Advisory Committee
Member Conflict-of-Interest
Statements
Case 3
• Data about Disapproved
UsesCase 4
• Abandoned NDAs
Case 5
• Phase IV Protocols
Case 6

7. Pre-clinical testing
• When new drugs show
promise in lab testing, studies
are designed to evaluate
them further.
• These studies in animals are
referred to as “pre-clinical
studies.”

8. Pre-clinical testing
• Pre-clinical studies help establish boundaries
for safe use of the treatment if/when human
studies begin. (Animal Models :- to test drugs & side effects)
• Many new drugs and treatments are
abandoned at this step because they are
proven unsafe.

9. Clinical research and development
• The application to the FDA to request
permission to begin human testing is called an
Investigational New Drug application, or IND.
• The IND permits the use of an investigational
new drug for the sole purpose of conducting
clinical trials.

10. What is an IND ?
• IND is not a marketing application
• An exemption from the law which otherwise
requires that a drug (biologic, device) be
approved before it can be transported across
state lines
• The standard for approval is evidence of safety
and efficacy
• The IND exemption is granted for purposes of
clinical investigation (research)

11. Importance of the IND
• Affirms a body of knowledge about the
manufacturing, pharmacology, and toxicology
of the drug to support its use in human testing
• Requires that the clinical investigation(s) be
performed in accordance with Good Clinical
Practice (GCP)
• Provides an additional level of protection
through FDA oversight

12. Investigational New Drug (IND)
• There are three IND types:
Investigator IND
Emergency Use IND
Treatment IND
• There are two IND categories:
Commercial(Ultimate goal is to achieve
marketing approval for new product)
Research (non-commercial)

13. Investigator/Sponsor IND
• An Investigator IND is submitted by a physician who both
initiates and conducts an investigation, and under whose
immediate direction the investigational drug is administered
or dispensed .
• A Research IND is to be submitted for proposed study of
Unapproved drug
Approved product for
» New indication
» New patient population
• Motivation is not necessarily commercial in nature

14. Emergency Use IND
21 CFR 312.36
• It allows the FDA to authorize use of an experimental drug in
an emergency situation that does not allow time for
submission of an IND in accordance with 21CFR , Sec.
312.23 or Sec. 312.34
• It is also used for patients:
 who do not meet the criteria of an existing study protocol
 or if an approved study protocol does not exist.
 Reserved for life-threatening situations
 No standard acceptable treatment is available

15. Treatment IND
• Experimental drugs showing promise in clinical testing-safety
and efficacy.
• After completion of Phase I and II
Used for the treatment of serious or life threatening
conditions
• No alternate treatments available
• AIDS, Cancer
 Made available while final clinical testing is completed and
reviewed by the FDA
 Reduce reluctance of people to participate in expanded drug

16. Content and Format of the IND
21 CFR 312.23
• All available information impacting on SAFETY!
 Animal studies
 Pharmacology (ADME)
 Toxicology (LD, Short, long, genotoxicity etc)
 Previous clinical experience
 Foreign and domestic sources
 Scientific literature

17. Content and Format of the IND
21 CFR 312.23
• Test article information and proposed dosage
form
– Chemical structure
– Manufacturing and purification techniques
– Analytical testing methods
– Physical characteristics
– Stability

18. Content and Format of the IND
21 CFR 312.23
• Overall plan of study for next year (minimum)
• Proposed protocols with justification
• Patient Inclusion & Exclusion criteria
• Method of patient selection to prevent bias
• Identification & qualifications of investigators
& sub-investigators
• Assurances of investigator supervision
• Assurances sponsor monitor
• Identification of key responsible individuals

19. Content and Format of the IND
21 CFR 312.23
• Requirements
Form FDA 1571
Table of contents
Introductory statement
General investigational plan
Investigators brochure
Clinical protocols
Chemistry, manufacturing and control data
Pharmacology and toxicology data
Previous human experience

20. IND APPLICATION PROCESS
• IND contains:
– sufficient Chemistry, Manufacturing, and Control
– pre-clinical safety information and describes the proposed
human trial (Phase 1)
• Multi-disciplinary Review Team
• 30-Day Deadline for Decision
• Team Decision
– Yes? “Okay to Proceed” No? Clinical HOLD
• Communication to sponsor: What work must sponsor do
to get HOLD lifted?

21. 30-Day Safety
• Studies shall not be initiated until 30 days
after the date of receipt of the IND by the FDA
unless you receive earlier notification by the
FDA that studies may begin.

22. WHAT NEXT AFTER FILING
IND?????
CLINICAL TRIALS

23. Phase 1 trials
• Drug is tested for its
interaction with the human
body.
• Trials are conducted to
determine the appropriate
dose range with regard to
safety and toxicity (NOT
efficacy).
• Trials are conducted on a
limited number (20-80) of
normal volunteers or
patients (such as patients
with cancer or AIDS).

24. Phase 1 trials
• Phase 1 trials often takes 9 to 18 months to
complete.
• Many drugs are abandoned in Phase 1 testing
because of problems with safety or toxicity.

25. Phase 2 trials
• Small-scale, well-controlled
trials evaluate the
preliminary safety & efficacy
in 100 to 300 patients with
the disease or condition to
be treated.
• May focus on dose-response,
dosing schedule or other
issues related to preliminary
safety and efficacy.

26. Phase 2 trials (IIa, IIb)
• Often takes 1 to 3 years to
complete.
• Additional animal testing
may be conducted at the
same time to obtain long-
term safety data.
• If studies show drug to be
safe and useful, testing may
proceed to Phase 3.

27. Phase 3 trials
 The most extensive (and
expensive) testing of a
drug.
• These trials fully assess
safety, efficacy and drug
dosage in a large group
of patients with the
specific disease to be
tested.

28. Phase 3 trials
• Conducted on larger (100s
to 1000s) and more diverse
groups of patients with the
condition.
• Make comparisons between
the new treatment and a
placebo and/or the standard
treatment.

29. Phase 3 trials
• Trials help to better understand the drug’s
safety and uncover any adverse effects.
• Trials often take 2 to 5 years to complete.

30. PHASE 2 PHASE 3PHASE 1

31. WHAT AFTER
PHASE 3 ????
NDA Review
FDA Approval
Phase 4
Clinical Trials

32. Phase 4 trials (Post-marketing
surveillance)
• Companies continue clinical trials of a drug after
it has been approved for marketing.
• Phase 4 trials may be performed to learn more
about side effects and long-term risks and
benefits.
• Companies may also evaluate different
formulations of a drug (like sustained-release) or
test the drug for a different indication.

33. Phase 4 trials (Post-marketing
surveillance)
• The company must
continue to report
information about new
findings and problems
after drug approval.
• Health care providers can
report new findings to the
company or directly to the
FDA (consumers can
report information to the
FDA as well).

34. New Drug Approval Process
(Overview)