Title: Investigational New Drug Application (INDA)
1Investigational New Drug Application (INDA)
PRESENTED BY- Dillip Kumar Jena
Dept of pharmaceutics pharmaceutical
Technology LMCP
2WHAT I WILL TELL
- INTRODUCTION
- REGULATORY ASPECT
- TYPE OF IND
- REQUIERMENT IND
- CONTENT OF IND
- IND AMENDMENT
- ANNUAL REPORT OF IND
- CONCLUSION
3General introduction
- this data and information is generated and
gathered from three broad areas - Animal Pcology Toxicology studies
- Manufacturing information
- Clinical Protocols Investigator Information
4Regulation
- The regulations in 21 CFR 312 cover procedures
and requirements for Investigational New Drug
Applications (INDs) - These regulations define the roles and
responsibilities of FDA reviewers, IND sponsors,
and clinical investigators
5Definitions
- Sponsor
- A sponsor is an individual, company, institution,
or organization that takes responsibility for and
initiates a clinical study (21 CFR 312.3(b),
312.50)
6Sponsor
- A sponsor is responsible for
- Selecting qualified investigators
- Ensuring study monitoring
- Maintaining an effective IND, and
- Ensuring AE risk information is provided to the
FDA and investigators
7Definitions
- Investigator
- An investigator is an individual under whose
immediate direction the study drug is
administered or dispensed. If a team is involved,
the leader is the investigator other team
members are sub-investigators - (21 CFR 312(b), 312.60)
8Investigator
- An investigator is responsible for
- Ensuring the study is conducted according to the
plan - Protecting the rights, safety and welfare of
subjects, and - Control of drug under investigation
9Definitions
- Sponsor-Investigator
- A sponsor-investigator is an individual who both
initiates and conducts a study and under whose
immediate direction the study drug is
administered or dispensed. This person must
follow the requirements pertaining to a sponsor
and those pertaining to an investigator - (21 CFR 312(b))
10IND Requirements
11IND Requirements (contd)
- For a lawfully marketed product, no IND
submission is required if three specific
conditions apply (21 CFR 312.2) - The study is not intended to support a new
indication or labeling change - The study does not intend to support a change in
advertising - The study does not involve a route, dosage or
patient population, etc. that increases risk
12NOTE!
- The FDA may be aware of other studies that may
affect evaluation of potential risk, and - the FDA is subject to confidentiality
requirements and by law can not share this
specific information with others
13TYPE OF IND
- Commercial IND
- Emergency use IND
- Treatment IND
14Objective
- To focus FDAs attention during early phase of
clinical research on assuring the safety of human
test subjects. - To provide sponsors with a greater measure of
flexibility in conducting Phase 1 trials. - To facilitate consultation between FDA
sponsors, especially after there is an indication
that the new drug is safe and efficacious in
humans.
15IND Content Requirements21 CFR 312.23
- Cover Sheet (Form FDA 1571)
- Table of Contents
- Introductory Statement General investigational
plan - Investigators Brochure
- Protocols
- Chemistry, Manufacturing Control Information
- Previous Human Experience with the
Investigational Drug - Additional Information
16Cover Sheet (form FDA 1571)
- The form is provided for basic information like
name of drug, submission date, sponsor
identification, phase of proposed clinical
investigation, sponsor commitments,
identification of clinical monitor and safety
evaluator, information regarding transfer of
responsibilities to a contract research
organization.
17 Table of Contents
- Drug Name
- IND table of contents
- Item title
volume/page - Introductory statement
- general investigational plan
- (i) Introductory statement.
- (ii) summary of previous human experience
- with drug.
- (iii) If the drug has been withdrawn from
- Investigation/Marketing
18iv) General Investigational Plan.. 5
Investigators Brochure. 6 Protocol.. 7
Chemistry, Manufacturing Control Information
(a) Drug substance (b) Drug
Product. (c) Placebo (if applicable)
(d) Labeling. (e) Environmental
Analysis . 8 Pharmacology Toxicology
Information.
19- 9)Previous Human Experience with the
Investigational Drug. - (i) Summary of Previous Human Experience.
- (ii) If the drug is a combination of drug
- previously investigated/marketed.
- (iii) If the drug has been marketed outside
the - United States
- 10 Additional Information (as applicable for
- radioactive drugs or drugs with dependence
or abuse potential).
20Introductory Statement General Investigational
Plan
- It consists of four subsections
- 1st subsection (introductory statement)
- Name of drug
- Pcological Class
- Structural formula
- Route of administration
- Broad objectives
- Planned duration of the proposed clinical
investigation
21- 2nd subsection
- Brief summary of any previous human experience
with the drug, including investigational or
marketing experience in other countries - 3rd subsection
- It is a statement as to whether or not the drug
has been withdrawn from investigation or
marketing in any country for any reason of safety
or efficacy
22- 4th subsection
- Brief description of overall investigational plan
for drug during the following year like
Indications to be studied, kinds of clinical
trials to be conducted in first year
23Investigators Brochure (IB)
- Sponsor must provide to all clinical
investigators, not required for sponsor
investigators (21 CFR 312.55). It must include - Brief product description
- Pharm/tox summaries
- Previous human experience
- Description of anticipated risk and any special
monitoring needs - Updates as appropriate
24- Drug Name
- Investigator's Brochure
- Table of contents
- Page
- Introduction..
- Chemistry.
- Physical Properties
- How Supplied.
- Pharmacology.
- Specific Effect Studies
- General Studies.
25- Toxicology..
- Acute Toxicity.
- Multidose Toxicity.
- Special Toxicity Studies
- Reproductive Studies
- Mutagenicity Studies.
- Pharmacokinetics
- Preclinical.
- Clinical.
- Clinical Trial.
- Phase 1
- Phase 2/3 .
26- Safety/Efficacy Overview
- Safety..
- Efficacy..
- Possible Risks and Side Effects
- References.
27Introductory Content Elements
- Cover Sheet (Form FDA 1571)
- Table of Contents
- Introductory Statement (description of product,
formulation, route, broad study objectives,
relevant previous use, foreign experience) - General Investigational Plan (rationale,
indication, general approach, anticipated studies
including number of subjects and possible risks)
285 Protocols
- Phase 1 protocol provides an outline of
investigation by specifying information such as
estimated number of test subjects,
inclusion/exclusion criteria and dosing plan - Phase 2 and Phase 3 protocols are detailed,
describing all aspects of the studies, such that
any deviation in a design if required, it can be
established in the protocol from the beginning.
29- All the protocols are required to contain the
following elements - Statement of the objectives and purpose of the
study - Patient inclusion/exclusion criteria
- Estimate of number of patients to be studied
- Description of study design
- Dosing information including planned maximum
dosage and duration of individual patient
exposure to the Drug - Description of the observations and measurements
planned to fulfill the study objectives
30CMC Information
- Emphasis in Phase I is on identification and
control of raw materials and new drug substance,
including information on any placebo as well - Even for Phase I, need enough information to
assess safety - Extent of expected information increases as drug
development proceeds - Throughout product development, good
documentation of all manufacturing and testing
steps is essential - Deficiencies in CMC information can result in
clinical hold
31Pharm/Tox Information
- Animal studies may be conducted to obtain proof
of concept or tox information - Studies should support proposed clinical dose and
regimen - Best to get CBER concurrence on pivotal tox
protocols prior to initiation - Need to submit complete study reports for tox
studies, including summary and individual animal
data
32Other IND Items
- Previous human experience needs to be included
(if applicable) - Additional information such as pre-IND meeting
minutes or critical references should be included
as well - Serial numbering of pages of an IND is required
(21 CFR 312.23(11)(e)) as this facilitates
reference if the FDA has questions
33IND Protocol Amendments
- 21 CFR 312.30
- A new protocol
- Safety or design related changes to an existing
protocol - New investigator (notification is required within
30 days of being added) - These should be submitted to the FDA prior to
implementation - IRB approval is needed prior to implementation
34IND Information Amendments
- 21 CFR 312.31
- Information amendments advise the FDA of
- New tox, CMC or other technical information
- Notice of discontinuance of a clinical study
35IND Safety Reports
- If a sponsor notify any unexpected fatal / life
threatening experience associated with the use of
the drug requires to notify the FDA by telephone
no later than 3 working days after receipt of the
information, followed by a written report within
10 days.
36Annual Reports
- 21 CFR 312.33
- To be submitted within 60 days of the anniversary
of in effect date - Include enrollment, demographic and conduct
status information for each study - Adverse event summaries (safety reports, deaths,
dropouts) - Drug action information
- Preclinical study status information
37Annual Reports (contd)
- CMC change information
- Revised/updated investigator brochure with
revisions described - Foreign marketing experience
- Outstanding business with the FDA
38Annual Reporting of Adverse Events
- RECOMMENDATIONS
- For solicited events tabulate by study, study
group and severity - For unsolicited events use a line listing by
study - SAEs should be highlighted and discussed
- Include numerators and denominators
- Include cumulative cross-study, multi-year
summaries - Include all events regardless of attribution of
relatedness to study drug
39Specific Responsibilities of Sponsors
- Selecting qualified investigators and monitors
(21 CFR 312.53) - Obtaining investigator information (signed Form
FDA 1572 and CV) - Controlling shipment of drug only to
participating investigators - Obtaining clinical protocol information
- Obtaining financial disclosure information
- Providing each investigator an investigator
brochure (21 CFR 312.55) - Informing investigators of new safety
observations (see 21 CFR 312.32 on IND safety
reports)
40Specific Responsibilities of Sponsors
- Review ongoing investigations (21 CFR 312.56)
- Monitor study progress for compliance with
protocol - Dealing with noncompliant investigators
- Review and report to FDA safety and effectiveness
data (annual reports and IND safety reports)
41Specific Responsibilities of Sponsors
- Maintenance of adequate records (21 CFR 312.57)
including - Tracking of drug shipment and information
- Recording financial interest of investigators
- Keeping records for 2 years post approval or post
last IND drug shipment - Retention of reserve samples and standards for
certain tests - Providing FDA with records upon request (21 CFR
312.58) - Proper disposition of unused investigational drug
(21 CFR 312.59)
42Specific Responsibilities of Investigators
- Control administration of investigational drug
(21 CFR 312.61) - Provide qualification and study conduct
information to sponsor - Following the protocol (commitment to this
required per Form FDA 1572) - Maintenance of records (21 CFR 312.62) including
- Drug disposition
- Case histories (CRFs, ICFs, medical records)
- Keeping records for 2 years post approval or post
study discontinuation
43Withdrawal of an IND
- It is option of a sponsor to withdraw an IND at
any time without prejudice. - On withdrawn, sponsor must notify the FDA.
44Conclusions
- Two major outcomes from the IND discussion
- are
- 30 days after an IND is submitted to the FDA, if
the sponsor has not heard anything from the FDA
it can be assumed that the drug is not on a
clinical hold and clinical trials may be started - The Investigators Brochure, which will be used
during that important first clinical study and in
every clinical study thereafter, acts as the
approved labeling for the drug while it is under
an IND
45List of references
- 1.www.fda.gov/cder/about/history/time1.htm
- 2.Remington the science and practice of pharmacy,
20th edition, Lippincott,Williams Wilkins, page
no 930-943 - 3. New Drug Approval Process second Edition,
Revised and Expanded, edited by Richard A.
Guarino page no 39-64, 243-263 - 4.www.fda.gov/cder/handbook/indbox.htm
- 5.www.fda.gov/cder/handbook/ndabox.htm
- 6.www.fda.gov
46Thank You
47Specific Responsibilities of Investigators
- Reports to sponsor (21 CFR 312.64)
- Providing progress reports for IND annual report
- Promptly reporting safety concerns
- Provision of final report after study completion
- Providing financial disclosure information
- Assuring IRB review (21 CFR 312.66)
- Providing FDA with records upon request (21 CFR
312.68)