IND Submission Process Flashcards
What is the IND regulation number
21 CFR 312
IND’s are exempt under 505(i) from
from the requirement of the FD&C Act that a new drug have an approved application to be introduced into interstate commerce
Application to FDA to seek permission to test a new drug (or biologic) in humans
When is an IND Required
Whenever clinical studies are initiated on a new unapproved drug or biologic product being tested in the US
Whenever clinical studies are initiated on an approved drug or biologic for any of the following:
A new indication or same indication but a different population
A new route of administration
A change in formulation that increases risk
A significant change in dosing regimen
IND can be waived for what
Can be waived for bioavailability/bioequivalence studies
Most bioequivalence studies conducted to support Abbreviated New Drug Applications (ANDA) for generic drugs do not need to be conducted under an IND
Types of INDs
Commercial IND
“Standard” IND and focus of this course
Non-standard INDs
Exploratory IND
Research INDs
Sponsor-Investigator IND
Expanded Access IND
Commercial IND
Application submitted by sponsor/company with eventual goal of FDA marketing approval of a drug or biologic product
Safety and efficacy will be evaluated under the IND
Used by FDA to distinguish from INDs for non-commercial research (e.g. for most sponsor-investigator INDs)
Exploratory IND
Phase 0 or Pre-Phase 1
Permits very limited human exposure
Has no therapeutic or diagnostic intent
May be used to assess more than one candidate for further development
e.g. microdosing or pharmacodynamic screening studies
Less nonclinical and CMC data typically expected to support this type of IND
When a candidate is selected for full development, the exploratory IND is withdrawn and replaced by a standard IND
Research/Sponsor-Investigator IND
IND sponsored by an individual investigator
Individual assumes regulatory responsibilities of both sponsor and investigator
Not intended to replace traditional sponsor INDs as a mechanism to initiate clinical trials
Regulations: 21 CFR 312.3(b)
Expanded Access IND
Four categories of expanded access use
Individual patients – emergency use
Individual patients – non-emergency use
Intermediate size populations
Treatment IND/Treatment Protocol
Data needed to support expanded access depends on seriousness of the condition and how many patients will be treated
Expanded access cannot interfere with development
Regulations: 21 CFR 312.300 (Subpart I)
FDA Guidance on eSubmissions
Providing Regulatory Submissions in Electronic Format —Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (R7 –February 2020)
Comprehensive Table of Contents Headings and Hierarchy (on FDA website)
This maps from the IND and NDA regulations and traditional format to the CTD format
IND Requirements
The chemistry, manufacturing and controls information must support all drug product(s) being used in the proposed study(s), including comparator and placebo
The nonclinical section must also support the proposed dosing (frequency, duration and amount)
As additional study protocols are filed this information is filed as IND amendments
IND Form Numbers
Form FDA 1571 AND 3674
What is from 3674
to satisfy requirements for registering trials on clinicaltrials.gov if clinical trial information is included in that submission
Form 1571
This form must accompany all IND submissions
Make sure you are using the most current version
The pdf fillable form must be used
Metadata about submission is coded
Allows parsing of information for distribution
IND Study Registration Requirements
IND Acknowledgement will cite additional requirements:
You are also responsible for complying with the applicable provisions of sections 402(i) and (j) of the Public Health Service Act (PHS Act) [42 USC §§ 282 (i) and (j)], which was amended by Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law No, 110-85, 121 Stat. 904).
This means registering trial if applicable on www.clintrials.gov
Item 2 Table of Contents
For non-eCTD Submissions use a WORD/pdf TOC
When using eCTD the XML backbone will serve as the Table of Contents
eCTD Submission Standards must be followed:
https://www.fda.gov/media/93301/download
Construction of a Table of Contents is useful for sponsor as a planning tool for IND preparation
Form FDA 3674 INFO
New version Jan2020
Certification of Compliance with Requirements of ClinicalTrials.gov Data Bank
Applies to certain IND, NDA, ANDA, BLA and medical device submissions
Under Section 9, check
Box A if no clinical trials referenced in submission
Box B if requirements to register on ClinicalTrials.gov do not apply
Box C if requirements to register do apply. Include NCT (National Clinical Trial) number
Item 3 Introduction
A brief introductory statement giving the following:
the name of the drug and all active ingredients, the drug’s pharmacological class, the structural formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of administration, and the broad objectives and planned duration of the proposed clinical investigation(s).
A brief summary of previous human experience with the drug, with reference to other IND’s if pertinent, and to investigational or marketing experience in other countries that may be relevant to the safety of the proposed clinical investigation(s).
If the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, identification of the country(ies) where the drug was withdrawn and the reasons for the withdrawal
Item 4: General Investigational Plan
Provided in initial IND and annual reports
Rationale for drug/clinical research
Indications to be studied
General approach to be followed in evaluating the drug
Kinds of clinical trials to be conducted in the next year
Anticipated risks
Item 5: Investigator’s Brochure
Serves as a “label” and is a summary of all data known to sponsor
Supplied to investigators and IRBs
Regulatory references to be used:
21 CFR 312.23(a)(5)
ICH E6 (GCP Guideline) includes information on format and content of Investigator’s Brochure
Items 3 & 9: CTD Module 2 Summaries
Introductory Statement
M2.3 Quality Overall Summary (QOS)
M2.4 Nonclinical Overview
M2.5 Clinical Overview
Previous Human Experience
Benefits-Risk statement regarding investigational use
Item 6: Protocol(s) and Investigator Information
Information resides in Module 5
Protocol content and format is per 21 CFR 312.23(a)(6) and ICH E6 (GCP Guideline)
Investigator information
Investigator’s Curriculum Vitae
Form FDA 1572 (signed copy)
Facilities information (Site and Lab), IRB Information
NOTE: Submission of 1572 itself is not required; information can be provided on cover sheets but often it is more convenient to submit the 1572
What is from FDA 1672
Statement of investigator
Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs: Frequently Asked Questions - Statement of Investigator (Form FDA 1572)
Item 7: Chemistry, Manufacturing and Controls
Information resides in Module 3
Chemistry, manufacturing, and control information & summary
Drug substance (DS)
Drug product (DP)
Comparators: Active and placebo
Per 21 CFR 312.23(a)(7)(a)(b) and (c)
