Investigational new drug

SUBMITTED BY-
SANTHOSH KUMAR T S
M.PHARM
1ST YEAR
PRESENTATION ON :
INVESTIGATIONAL NEW DRUG [IND]
KARNATAKA COLLEGE OF PHARMACY
BANGALORE
FACILITATED TO-
Dr. C. SREEDHAR SIR
HEAD OF THE DEPARTMENT
(PH. ANALYSIS)

CONTENTS
1. Introduction
2. Classification
3. Content and format of IND
4. Laws, regulation and policies
5. IND application process

PHARMACEUTICALS MAY MOVE ACROSS STATE LINES DURING
TWO STAGES OF HUMAN USE
• Research prior to “approval”
e.g., New Drug application
– Requires research permit: New Drug Exemption (IND)
e.g., Investigational application
• Marketing after “approval”
– Requires marketing permit: Application (NDA)

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.”

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.

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.

DRUG-DISCOVERY, DEVELOPMENT & ITS APPROVAL
It takes 12-15 years on an average for an experimental drug to travel from the lab to the patients. Only 5 in
5000 compounds that enter the pre-clinical testing stage, make it to the human-testing stage. One of these 5
tested on people is approved.
Discovery/
Pre-Clinical
Testing
Phase I Phase II Phase III FDA Phase IV
Years 5 - 6.5
File
IND
at FDA
1.5 2 2.5
File
NDA
at FDA
1.5- 2
Test
Population
Laboratory &
Animal Studies
20 to 100
healthy
volunteers
100 to 500
patient
volunteers
1000 to 5000
patient
volunteers
Review
&
Proposal
Process
Additional
Post-
Marketing
testing
required
by FDAPurpose
Assess safety,
biological activity
& formulation
Determine
safety &
dosage
Evaluate
effectiveness,
look for side-
effects
Confirm
effectiveness
monitor
adverse effects
from long-time
use
Success
Rate
5000
compounds
evaluated
5 EnterTrials
1
Approved

INVESTIGATIONAL NEW DRUGAPPLICATION (IND)
• An Investigation New Drug Application (IND) is a submission to Food & Drug
Administration (FDA) requesting permission to initiate the study of New drug
product
• In many ways, the investigational new drug (IND) application is the result of a
successful preclinical development program.
• The IND is also the vehicle through which a sponsor advances to the next stage of
drug development known as clinical trials (human trials).
• During a new drug's early preclinical development, the sponsor's primary goal is to
determine if the product is reasonably safe for initial use in humans, and if the
compound exhibits pharmacological activity that justifies commercial development.
• The standard for approval is evidence of safety and efficacy
• The IND exemption is granted for purposes of clinical investigation (research)

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

• 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)
TYPES OF IND

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.

EMERGENCY USE IND
• 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

TREATMENT IND
• The treatment IND [21 CFR 312.34 and 312.35] is a mechanism for providing eligible
subjects with investigational drugs for the treatment of serious and life-threatening
illnesses for which there are no satisfactory alternative treatments.
• 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 access programs

WHO CAN APPLY FOR IND????
• Applicant (Drug Sponsor)
• An applicant, or drug sponsor, is the person or entity who
assumes responsibility for the marketing of a new drug, including
responsibility for compliance with applicable provisions of the
Federal Food, Drug and Cosmetic Act and related regulations.
• The "sponsor" Is usually An individual, partnership, corporation,
Government agency, manufacturer or scientific institution.

• The IND application provides FDA with data necessary to decide whether the new drug
& the proposed Clinical trial pose a reasonable risk to human subjects participating in
the study.
• The IND application allows the company to initiate & conduct the clinical studies of
their new drug Product.
• The safety of the Clinical trial Subjects is always the primary concern of FDA.
• When preparing the IND & throughout the Drug development process the primary
goal of the Sponsor should be to demonstrate to the FDA that the
-new drug
-proposed trial
-entire clinical development plan described in the IND is designed to minimize the risk
to the trial subjects.

WHEN DO WE NEED AN IND?
• An IND would be required to conduct a Clinical trial if the drug is –
-A new chemical entity not approved for the indication under
Investigation in the new dosage form.
- being administered at the new dosage level.
-In combination with another drug & the combination is not approved.

CONTENT AND FORMAT OF THE IND
21 CFR 312.23
• All available information impacting on SAFETY!
• Animal studies
• Pharmacology (ADME)( Absorption, Distribution, Metabolism, Elimination )
• Toxicology (Lethal Dose, Short, long, genotoxicity etc)
• Previous clinical experience
• Foreign and domestic sources
• Scientific literature

• 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

GENERAL PRINCILPLE OF IND
• Toassure safety and rights of the subject.
• To assure Scientific quality of
investigation
the
will yield data Capable of
statutory Standards for marketingmeeting
approval
• The central Focus should be on general
investigational plan & protocol which should be supported by
additional information including animal toxicological studies

REQUIREMENTS OF AN IND
• A sponsor shall submit an IND to FDA who intends to conduct a clinical
investigation.
• Investigation is not supposed to begin without prior written
authorization of FDA
PHASES OF INVESTIGATION
• Phase 1 -- ADME (20- 80)healthy subjects
• Phase 2 – effectiveness in particular indication (several hundred patients)
• Phase 3 – safety andeffectiveness ( 100- 1000) subjects.

FORMAT OF INDA
1. Cover sheet (FORM FDA1571)
2. Table of contents
3. Introductory statement and a general investigational plan
4. Investigators brochure
5. Protocols
6. Chemistry , manufacturing and control information
7. Pharmacology and Toxicology information
8. Previous human experience with the investigational drug
9. Other relevant information like no of IND submissions,
Number of copies to be submitted (1 + 2)
10. Protocol amendments, any changes in the protocol.

o Name, address, telephone of sponsor
o Identification of phases
o Commitment not to begin CT until IND approval
o Commitment by IRB- Form 56
o Commitment for conducting CT- accordance with regulations
o Name, title – Monitor
o Name, title – person(s) for reviewing
o Name, Address of CRO, if any
o Signature of sponsor
1. Cover sheet (FORM FDA 1571)

2.TABLE OF CONTENTS
- Comprehensive listing of contents of IND application broken
in volumes & page number.
- TOC should include details of -
sections, appendices, attachments, reports & other reference
material
- A well drafted TOC will facilitate the task of review & decrease
the review time.

3.GENERALINVESTIONALPLAN
a brief 3 to 4 pages note on –
- the investigational product
- Sponsors’ Investigationalplan
- Goal of the section is to –
- to provide brief description of the drug
- layout development plan of the drug

4.INVESTIGATORS BROCHURE
- key document provided to each Investigator & IRB at each of the
Clinical site.
- includes-
ALL ABOUT THEINVESTIGATIONAL DRUG
- IB is a living document & must be updated by the Sponsor.

5.PROTOCOLS
Describes how the Clinical trial would be conducted.
- It describes – the objective of the study
- the trial design
- how subjects would be selected
- how the trail is to be conducted.
- ALL ABOUT THAT HOW THE STUDY WOULD BE CONDUCTED??

6.CHEMISTRY , MANUFACTURING AND CONTROL
INFORMATION
• CMC information-
-sufficient detail on QUALITY, IDENITY, PURITY & POTENCY
of the drug product.
- manufactured in conformance with cGMP.
- CMC section includes the following –
1. Introduction CMC
2. Summary
3. information of Placebo, if any
4. Proposed clinical label
5. categorical exclusion of any environmental assessment

7.PHARMACOLOGY AND TOXICOLOGY INFORMATION
• PHARMACOLOGY & TOXICOLOGYDATA –
- Non-clinical safety data that sponsor generated to prove that the IP is safe
for clinicalstudy.
- The amount & type of data depends on- class of new drug,
duration of proposed, clinical trial patient population that will be
exposed during the trial.

8.PREVIOUS HUMAN EXPERIENCE WITH THE
INVESTIGATIONAL DRUG
integrated summary report of any human studies conducted on the investigational
drug
Relevant to the safety of the investigations to be done – Pharmakokinetic studies,
Pharmacodynamic studies observed adverse event profile

9. OTHER RELEVANT INFORMATION LIKE NUMBER OF IND
SUBMISSIONS,
No of copies to be submitted (1 + 2)
• ADDITIONAL INFORMATION – special topics
drug dependence & abuse potential Radioactive drugs
pediatric population & other information
• OTHER RELEVANT INFORMATION –
Information specifically requested by FDA
• Financial disclosure information from each Investigator
& sub Investigator.
• Drug master File ( DMF)
• Reports or journal articles
• The IND application is always submitted in 1+ 2 format i.e. 1
original & 2 additional copies of each application.

LAWS, REGULATIONS, POLICIES,
PROCEDURES
• The Federal Food, Drug, and Cosmetic Act is the basic food and
drug law of the U.S The law is intended to assure consumers that foods are
pure and wholesome, safe to eat, and produced under aseptic conditions;
that drugs and devices are safe and effective for their intended uses;
that cosmetics are safe and made from appropriate ingredients; and
that all labeling and packaging is truthful, informative, and not deceptive.

• Code Of Federal Regulations (CFR)
o The final regulations published in the Federal Register (daily published
record of proposed rules,final rules, meeting notices, etc.) are collected in
the CFR.
o The CFR is divided into 50 titles that represent broad areas subject to
Federal regulations.
o The FDA's portion of the CFR interprets the The Federal Food, Drug, and
Cosmetic Act and related statutes. Section 21 of the CFR contains most
regulations pertaining to food and drugs.
21CFRPart 312 Investigational New DrugApplication
21CFR Part314
INDAand NDAApplications for FDAApproval to Market aNew
Drug (New DrugApproval)
21CFR Part316 OrphanDrugs
21CFR Part58 Good LabPractice for Nonclinical Laboratory
[Animal] Studies
21CFR Part50 Protection of HumanSubjects
21CFR Part56 Institutional ReviewBoards
21CFR Part201 Drug Labeling
21CFR Part54 Financial Disclosure by Clinical Investigators

• CDER's Manual of Policies and Procedures (MaPPs)
(Center for Drug Evaluation and Research)
MaPPS are approved instructions for internal practices and procedures
followed by CDER staff to help standardize the investigational new
drug review process and other activities.

The Investigational New Drug (IND) Process:
Drug developers, or sponsors, must submit an Investigational New Drug (IND)
application to FDA before beginning clinical research. In the IND application,
developers must include:
• Animal study data and toxicity (side effects that cause great harm) data
• Manufacturing information
• Clinical protocols (study plans) for studies to be conducted
• Data from any prior human research
• Information about the investigator

FDA APPLICATION PROCESS
• IND contains:
• sufficient Chemistry, Manufacturing, and other Controls
• pre-clinical safety information 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?

FDA REVIEW OF THE INDA
 Once the IND stamped as received ,it is sent to the review division
within CDER.
 On arrival at the review division , it is critically evaluated byseveral
reviewers of
Chemist
Biopharmaceutics
Medical
Stastistics
Microbiology
Pharmacology /toxicology sections

FDA’SIND REVIEW PROCESS
• Safety Review:
• Following review of an initial IND submission, CDER has 30 calendar days in which to
decide or if a clinical hold is necessary (i.e., if patients would be at an unacceptable
risk or if CDER (Center for Drug Evaluation and Research) doesn't have the data to make such a
determination).
• Generally, drug review divisions do not contact the sponsor if no concerns arise with
drug safety and the proposed clinical trials.
• If the sponsor hears nothing from CDER, then on day 31 after submission of the
IND, the study may proceed as submitted.

CLINICAL HOLD DECISION
• A clinical hold is the mechanism that CDER uses when it does not believe, or cannot
confirm, that the study can be conducted without unreasonable risk to the
subjects/patients.
• If this occurs, the Center will contact the sponsor within the 30-day initial review
period to stop the clinical trial. CDER may either delay the start of an early-phase trial
on the basis of information submitted in the IND, or stop an ongoing study based on
a review of newly submitted clinical protocols, safety reports, protocol amendments,
or other information.
• When a clinical hold is issued, a sponsor must address the issue that is the basis of
the hold before the order is removed.

• CLINICAL HOLD
a clinical hold can be –
- “complete clinical hold” – a delay or Suspension of all clinical work requested
under IND submission
- “partial clinical hold”- a delay or suspension of only part of clinical work
e.g. part of protocol.

NOTIFYSPONSOR
• Once a clinical hold is placed on a commercial IND, the sponsor will be notified
immediately by telephone by the division director.
• the division is required to send a letter within five working days following the
telephone call.
• The letter should describe the reasons for the clinical hold, and must bear the
signature of the division director (or acting division director).
• The sponsor may then respond to CDER by sending an "IND CLINICAL HOLD
RESPONSE" letter to the division. To expedite processing, the letter must be clearly
identified as an "IND CLINICAL HOLD RESPONSE" letter.

• The division then reviews the sponsor's response and decides
within 30 days as to whether the hold should be lifted.
• If the division does not reply to the clinical hold response within
30 calendar days, the division director will telephone the sponsor
and discuss what is being done to facilitate completion of the
review.
• If it is decided that the hold will not be lifted, the hold decision is
automatically sent to the office director for review.

• The office director must decide
calendar days whether or not to
within 14
sustain the
division's decision to maintain the clinical hold.
• If the decision is made to lift the hold, the division telephones the
sponsor, informs them of the decision, and sends a letter
confirming that the hold has been lifted.
• The letter will be sent within 5 working days of the telephone call.
However, the trial may begin once the decision has been relayed
to the sponsor by telephone.

SPONSORNOTIFIEDOFDEFICIENCIES
• If other deficiencies are found in an IND that the review division determines are not
seriously enough to justify delaying clinical studies, the division may either
telephone or forward a DEFICIENCY LETTER to the sponsor.
• In either case, the division informs the sponsor that it may proceed with the planned
clinical trials, but that additional information is necessary to complete or correct the
IND file, or that there are issues that need to be addressed prior to a marketing
application (NDA) submission.

STUDYONGOING
• Once CDER's 30-day initial review period expires, clinical studies can
be initiated, unless a clinical hold has been placed.

INDA ANNUALREPORTS
 Sponsors should submit an annual report that provides the FDA with
a brief update on the progress of all investigations included in the
IND.
 It should contain the following:
Individual study information.
Summary of the study.
Listing of any significant foreign marketing developments with the
drug
e.g. approval in another country.

REFERENCES:
• www.google.in
• www.slideshare.net

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