ICTR DDRS: IND Application Guidance and Template for Biological Products
Version 1.0
IND Application for an Investigational Biologic:
Investigational New Drug Application Guidance and Template
for Biological Products (Somatic Cell Therapy*)
(*Excluding genetically modified somatic cell therapy products)
ICTR Navigators
April 10, 2012
Version 1.0
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
1.0
Table of Contents
Section
1.0 Table of Contents
2.0 Abbreviations
3.0 Definitions
4.0 FDA Websites
5.0 Introduction
6.0 Guidance and Instructions
6.1 Template Comments
6.2 Regulations and Guidance documents
6.3 Number of Copies to be submitted
6.4 Application Header and Footer
6.5 Binding
6.6 FDA Mailing Addresses
6.7 Website Address Hyperlinks
6.8 Questions and Additional Information Contact
7.0 Application Template Guidance
2.0
IND
CFR
FDA
CDER
CBER
CDRH
CMC
GCP
GLP
GMP
BLA
PMA
IDE
3.0
Page
2
2
2
3
4
4
4
5
5
5
5
7
7
7
8
Abbreviations
Investigational New Drug
Code of Federal Regulations
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Center for Biologics Evaluation and Research
Center for Devices and Radiological Health
Chemistry, Manufacturing, and Controls
Good Clinical Practices
Good Laboratory Practices
Good Manufacturing Practices
Biologic License Application
Pre-Market Application
Investigational Device Exemption
Definitions
Biological product
Section 351 of the Public Health Service (PHS) Act defines a biological product
as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component
or derivative, allergenic product, or analogous product, applicable to the
prevention, treatment, or cure of a disease or condition of human beings.” FDA
regulations and policies have established that biological products include bloodderived products, vaccines, in vivo diagnostic allergenic products,
immunoglobulin products, products containing cells or microorganisms, and
most protein products. Biological products subject to the PHS Act also
meet the definition of drugs under the Federal Food, Drug and Cosmetic
Act (FDC Act). Note that hormones such as insulin, glucagon, and human
growth hormone are regulated as drugs under the FDC Act, not biological
products under the PHS Act.
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Human Cell, Tissue/Product
HCT/P (―351 Product‖)
Human cell, tissue, cellular and tissue based products that require regulation
beyond the basic considerations of preventing the introduction, transmission
and spread of communicable disease. These products require an IND. Four
basic criteria used to identify HCT/P 351 products include:
 More than minimally manipulated such that relevant biologic
characteristics are altered by the processing;
 Intended for Non-Homologous use such that the basic function in the
recipient will not be the same as in the donor;
 Systemic effect dependent upon metabolic activity (unless autologous
use, allogeneic use in first or second degree relative or reproductive
use);
 Clinical effect is systemic or dependent upon the metabolic activity of
the cells for its primary function;
 Combined with a device, drug or biologic (unless it‟s a sterilizing,
preserving or storage agent with no new clinical safety concerns).
Somatic cell
therapy
4.0
Per the FDA Guidance for Industry entitled Guidance for Human Somatic Cell
Therapy and Gene Therapy (March 1998), the term „somatic cell therapy‟ refers
to „the administration to humans of autologous, allogeneic, or xenogeneic living
non-germline cells, other than transfusable blood products, for therapeutic,
diagnostic, or preventive purposes‟.
FDA Websites
A list of several FDA websites containing useful information for investigators using an investigational
biological product is provided below. It is strongly suggested that these websites be reviewed before
submitting an IND application to the FDA.
FDA Forms website:

http://www.fda.gov/aboutfda/reportsmanualsforms/forms/default.htm
FDA Title 21 Regulations Search Engine (e.g., IND regulations 21CRF312) website:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm
FDA Running Clinical Trials website:

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm
FDA - Sponsor-Investigator IND website

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAp
plications/InvestigationalNewDrugINDApplication/ucm071098.htm
FDA CBER - Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER)

http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDe
viceExemptionIDEProcess/default.htm
FDA CBER - Clinical Investigator Information

http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDe
viceExemptionIDEProcess/ucm094294.htm
FDA CBER - Guidance, Compliance & Regulatory Information (Biologics)
 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
5.0
Introduction
The enclosed information is intended to provide a general process overview and a template for an
Investigational New Drug (IND) application submission for biological products reviewed by the FDA
Center for Biologics Evaluation Research (CBER). The document is written from the perspective that
the person submitting the IND application is a Sponsor-Investigator. A Sponsor-Investigator is
someone who is both 1) responsible for initiating the studies conducted with the investigational
biological product and 2) who conducts the studies.
The contents of this document are based on the FDA regulations governing investigational biological
products, 21CFR312, 21CFR600, 21CFR210, 21CFR211, 21CFR1271, 21CFR600, 21CFR610, FDA
guidance documents, and personal experience. However, each biological product and associated
clinical trial may have unique features or circumstances that are not addressed by this document or
the reference guidance documents cited herein. In such cases, the Sponsor-Investigator should
consult with the ICTR-DDRS and are strongly encouraged to consider a pre-IND meeting with the
FDA. A guidance and template for pre-IND meeting requests is available through the ICTR-DDRS.
While there are numerous regulations, guidance documents and other references pertaining to IND
applications for biological products, those provided in this document are those most commonly used
and/or most widely applicable.
The following references will give the Sponsor-Investigator a general overview of the basic IND
application content and format for a somatic cell therapy.
FDA Regulation 21CRF312 Subpart B--Investigational New Drug Application (IND)
FDA Regulation 21CRF600 Subchapter F—Biological Products
FDA Guidance
Content and Format of Investigational New Drug Applications (INDs) for
Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic,
Biotechnology-derived Products
FDA Guidance
Guidance for Human Somatic Cell Therapy and Gene Therapy
6.0
Guidance and Instructions
6.1
Template Comments
The enclosed template guidance is a suggested format based on federal regulations, guidance
documents, and previous experience. Within each section of the application template are references
to applicable FDA regulations, web addresses to FDA guidance documents, comments/instructions,
web addresses to FDA forms, and suggested formatting and/or language. These instructions outline
what should be included or inserted into a particular section and may also address special
considerations. As this is a basic template and each IND is unique, best judgment should be used
concerning the information to be included in the submission. The sponsor-investigator may use this
format or adapt it as appropriate for the particular investigational biological product being evaluated.
Each section of the application should begin on new page because as you see in the binding
instructions, you should use index tabs to mark each section of the application. Thus, each section in
this document starts on a new page. A blank template with just the cover letter, title page, and
suggested section headings and subheadings is available for download at the DDRS website.
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
6.2
Regulations and Guidance documents
Throughout this document are a number references to regulations and guidance documents. These
references have been included to provide the Sponsor-Investigator with direction and guidance when
completing an IND application.
The references will not address every situation that may be encountered. If the applicant has
questions after reviewing the references provided, they should contact the ICTR Research Navigators
for assistance.
6.3
Number of Copies to be submitted
One original copy and two photocopies of the IND application must be sent with the initial
submission. Of note: Once the FDA receives the application and begins the review process, they
may ask for additional desk copies.
6.4
Application Header and Footer
The following is the suggested format of document headers and footers to be used with the initial IND
submission. Note: Headers and footers are not included in the template and must be inserted
manually and may be modified as appropriate.
Header:
[Left Hand Side]
IND Application Date: [INSERT DATE]
[INSERT Biological Product Name]
[Right Hand Side]
IND Number: pending
Serial Number: [1571 Serial #]
Footer:
[Left Hand Side]
John Hopkins University
[INSERT: Sponsor-Investigator Name]
Confidential and Proprietary
6.5
[Right Hand Side]
Page [##]
Binding
If a project manager has been assigned to the IND application being prepared for submission
or if contact information is available for a project manager within the Office/Division that will
review the IND application, it is suggested that the Sponsor-Investigator contact the project
manager to review how the IND materials should be bound.
If a project manager has not yet been assigned, the following binding guidance information
may be used. CBER does, however, request uniformity in the manner in which the information
is bound. This information is from CBER and may be found at the FDA‟s website in a
document entitled, “SOPP 8007: DCC Binding Procedures for Regulatory Documents‖.
If the Sponsor-Investigator chooses to use a different type of binder than suggested, the
binders should be labeled as suggested below.
6.5.1
FDA CDER Guidance Recommendations
Archive - ACCO Gray Stock Number 25974 or Smead Stock Number 81552 or Oxford
Stock Number ESS-129005 or similar type.
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Duplicate (or First Review Copy) - ACCO Executive Red Stock Number 25079 or
Smead Red Stock Number 81752 or similar type.
Second and additional review copies - Second and additional review copies - Any
color pressboard report binder except Gray or Red.
6.5.2
Identification of binders
Required on front folder in a clear, sharp, permanent-type print in BLACK ink Permanent adhesive labels may be used in a clear, sharp print - Printing must
withstand a "Scotch Tape Test" which consists of pressing a strip of "Scotch" tape
firmly on the printed area and removing - There should be NO transfer of the printed
area on the tape
Binders are identified with the following label:
VOL._____OF______VOLS.(total volumes in this submission)
NOTICE OF CLAIMED INVESTIGATIONAL EXEMPTION FOR A NEW DRUG
IND. NO.____(For the initial submission of the new application leave blank)_____
SPONSOR NAME
NAME OF INVESTIGATIONAL AGENT
6.5.3
Inadequate binding
If submissions are received loose or are inadequately bound, they may be
returned to the sponsor or applicant for further handling and processing. If the
submission is returned, the submission will be date-stamped when resubmitted
adequately bound.
If the application is sent in boxes, “Banker Boxes” should be used.
6.5.4
Information about ACCO Folders
Note: The vendor information listed below is provided as an example of where these
items may be purchased and is not intended as an endorsement of the vendor or a
mandatory vendor to be used to purchase the folders.
Archive (original copy) Gray (ACCO Gray Stock Number 25974 or Smead Stock
Number 81552 or Oxford Stock Number ESS-129005 or similar type)
i. Example Vendor
GovGroup.com:
http://www.govgroup.com/pressguard-binder-cover-smd81552-2183502prd1.htm
Duplicate (or First Review Copy) – Red (ACCO Executive Red Stock Number 25079
or Smead Red Stock Number 81752 or similar type)
i. Example Vendor
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Office Depot:
http://www.officedepot.com/a/products/934380/ACCO-60percent-RecycledPressboard-Binder-With/
Second and additional review copies - Any color pressboard report binder
except Gray or Red.
i. Example Vendor
Office Depot:
http://www.officedepot.com/a/products/193664/ACCO-Presstex-60percentRecycled-Binder-Side/
6.6
FDA Mailing Address
Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center,
HFM-99, Suite 200N
1401 Rockville Pike
Rockville, MD 20852-1448
6.7
Website Address Hyperlinks
All hyperlinks to websites included in this document are operational as of the date of this
version. If any non-functional hyperlinks are identified in this document, please contact the
ICTR Research Navigators via the contact information below so that the links may be updated.
6.8
Questions and Additional Information Contact
For questions regarding any of the information presented or use of the template, please
contact the ICTR Research Navigators at ICTR_Navigators@jhmi.edu or via telephone at 410614-5383.
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
7.0
Application Template Guidance:
Application Section
Cover Letter
Cover Page
Section 1: Form FDA 1571
Section 2: Table of Contents
Section 3: Introductory Statement
Section 4: General Investigational Plan
Section 5: Investigator‟s Brochure
Section 6: Clinical Protocol
Section 7: Chemistry, Manufacturing, and Controls
Section 8: Pharmacology and Toxicology
Section 9: Previous human experience
Section 10: Additional Information
Section 11: Relevant Information
Section 12: Bibliography
Section 13: Appendices
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Cover Letter
[INSTRUCTIONS: The suggested format for the cover letter that accompanies the IND application
may be found below. If the Sponsor-Investigator has already had a pre-IND meeting with the FDA,
then the pre-IND number and meeting date should be referenced in the cover letter.]
[INSERT: Sponsor-Investigator letterhead or address]
[INSERT: DATE]
Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center,
HFM-99, Suite 200N
1401 Rockville Pike
Rockville, MD 20852-1448
RE: New IND Application submission
Dear Reviewers,
Pursuant to 21 CFR 312, I am submitting an original, Sponsor-Investigator Investigational New Drug
(IND) application.
The IND is being submitted to [INSERT: Supply short description of experimental treatment/drug and
protocol]. [INSERT: If pre-IND meeting was held, then insert text referencing the pre-IND (PIND)
number and the date of meeting.]
[INSTRUCTIONS FOR ACCO BINDERS: Use the following text if submitting the application in ACCO
binders, per above guidance information. “Enclosed are the original application (red binders), first
copy of the application (green binders), and the second copy (light blue binders).”]
If you have any questions about the material included in this IND, please do not hesitate to contact me
at [INSERT: phone number of Sponsor-Investigator], by email at [INSERT: email address of
Sponsor-Investigator], or by fax at [INSERT: Sponsor-Investigator fax] any time during your review.
[COMMENT: If there is another person designated to interact with the FDA on behalf of the SponsorInvestigator, then state “{INSERT: name} is authorized to interact with the FDA on my behalf and
{INSERT: name‟s} contact information is {INSERT: phone, email, and fax}.”]
Thank you in advance for your consideration.
Sincerely,
[INSERT: Sponsor-Investigator Name]
[INSERT: Title]
[INSERT: Affiliation]
Enclosure:
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Cover Page
[COMMENTS: A suggested format for the title page to the IND application is provided below.]
Investigational New Drug
Application
DATE
IND Application Title:
Biological Product:
Serial Number:
Initial submission is “0000”
Sponsor-Investigator: Provide name and full contact
information
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ICTR DDRS: Sponsor-Investigator IND Guidance and Template for Drugs
Version 3.0
Section 1: Form FDA 1571
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[Regulatory Reference: 21CFR312.23(a)(1)- Cover sheet (Form FDA-1571) An FDA Form 1571 is a
required cover sheet for the application containing the following:
(i) The name, address, and telephone number of the sponsor, the date of the application, and the name of
the investigational new drug.
(ii) Identification of the phase or phases of the clinical investigation to be conducted.
(iii) A commitment not to begin clinical investigations until an IND covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in
part 56 will be responsible for the initial and continuing review and approval of each of the studies in the
proposed clinical investigation and that the investigator will report to the IRB proposed changes in the
research activity in accordance with the requirements of part 56.
(v) A commitment to conduct the investigation in accordance with all other applicable regulatory
requirements.
(vi)The name and title of the person responsible for monitoring the conduct and progress of the clinical
investigations.
(vii) The name(s) and title(s) of the person(s) responsible under 312.32 for review and evaluation of
information relevant to the safety of the drug.
(viii) If a sponsor [Sponsor-Investigator] has transferred any obligations for the conduct of any clinical study
to a contract research organization a statement containing the name and address of the contract research
organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations
governing the conduct of the study have been transferred, a general statement of this transfer--in lieu of a
listing of the specific obligations transferred--may be submitted.
(ix) The signature of the sponsor [Sponsor-Investigator] or the sponsor's [Sponsor-Investigator‟s] authorized
representative. If the person signing the application does not reside or have a place of business within the
United States, the IND is required to contain the name and address of, and be countersigned by, an
attorney, agent, or other authorized official who resides or maintains a place of business within the United
States.
1. Form FDA 1571
[INSERT TEXT: “Please see the signed and dated Form FDA 1571 next.”]
[WEB ADDRESS TO FDA FORM AND FORM INSTRUCTIONS
 FDA form 1571:
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083533.pdf

Instructions for form 1571:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAp
plications/InvestigationalNewDrugINDApplication/ucm071098.htm#form1571]
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Section 2: Table of Contents
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[Regulatory Reference: 21CFR312.23(a)(2)- Table of Contents.]
[INSTRUCTIONS: The IND Table of Contents should list all sections of the application broken down
by volume and section number. Additionally, the Table of Contents should include a list of all tables,
figures, and attachments found within the application. The Table of Contents should be accurate and
easy to follow so that the FDA reviewers can find the sections they need to review quickly and easily.
Before submitting the IND application, double check to make certain that the Table of Contents
matches the content, title, page numbers, and volumes, of the final version of the IND application.]
[COMMENT: The Table of Contents below is provided as an example and is based on the
requirements set forth in 21CFR312.23 – IND content and format
Changes may be made to the Table of Contents provided based on the needs of individual IND
applications.]
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
2.0 Table of Contents
Volume 1
Section
1.0
FDA Form 1571
2.0
Table of Contents
3.0
3.1
3.1.1
3.1.2
3.1.3
3.1.4
3.1.5
3.1.6
3.2
3.3
Introductory statement
4.0
4.1
4.1.1
4.1.2
4.2
4.3
4.4
4.5
4.6
General investigational plan
5.0
Investigator’s brochure
6.0
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
Protocol
Title
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Page
ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Volume 2
Section
Title
7.0
Chemistry, Manufacturing, and Controls
7.1
7.2
7.3
7.4
7.5
7.6
8.0
8.1
8.2
Pharmacology and toxicology data
9.0
Previous human experience
10.0
10.1
10.2
10.3
10.4
Additional information
Drug dependence and abuse potential
Radioactive drugs
Pediatric studies
Other information
11.0
Relevant Information
12.0
Bibliography
13.0
Appendices
Page
LIST OF TABLES
Volume #
Section
Title
Page
Title
Page
Table 1
Table 2
Table 3
Table 4
Table 5
Volume #
Section
Table 6
Table 7
Table 8
Table 9
Table 10
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
LIST OF FIGURES
Volume #
Section
Title
Page
Title
Page
Title
Page
Title
Page
Figure 1
Figure 2
Figure 3
Volume #
Section
Figure 4
Figure 5
List of Attachments
Volume #
Section
Attachment 1
Attachment 2
Volume #
Section
Attachment 3
Attachment 4
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Section 3: Introductory Statement
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. Some of the information included may not be applicable to all applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(3)(i-iii)
(3)Introductory statement and general investigational plan
(i) A brief introductory statement giving 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).
(ii) 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).
(iii) 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.]
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
3.0
Introductory Statement
[INSTRUCTIONS: A brief introductory statement including a description and the name of the
investigational biologic and all active ingredients, 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) should be provided here. If a particular heading provided below is not applicable or
the information is not known/available at the time of the IND submission, then state “not applicable” or
provide an explanation stating that the information is not known or available. NOTE: If a pre-IND
meeting was already held with the FDA, the pre-IND number, meeting date, and outcomes
should be referenced here.]
3.1
Objectives (Suggested text to follow.)
[SUGGESTED TEXT: This Investigational New Drug Application (IND) is submitted to
study_________________
The protocol submitted in serial # 0000 of this application is for a Phase ____ trial entitled
“_____“. This study is designed to evaluate__________.
The overall objectives of this trial are:
This study was designed in response to the need__________.]
3.2
Drug Name, Pharmaceutical Properties, Formulation and Administration
[ADDITIONAL INSTRUCTIONS: List all known names of the investigational drug including, but not
limited to, the proprietary name, generic name, chemical name, and any other names of the drug.]
3.2.1
Pharmaceutical properties
[INSTRUCTIONS: Insert description of pharmaceutical properties here. If not known, explain why
it is not known.]
3.2.2
Structural and Chemical Formula
[INSTRUCTIONS: Insert both the chemical and structural formula of the final product. If not
known, explain why it is not known.]
3.2.3
Formulation of Dosage Form
[INSTRUCTIONS: Insert a succinct description of the formulation including dosage amounts of
each active ingredients of the drug product.]
3.2.4
Route of Administration
[INSTRUCTIONS: Insert a description of the route of administration.]
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
3.3
Broad Objectives and Planned Duration of the Proposed Clinical Investigation(s).
[INSTRUCTIONS: Provide description of the objectives of the clinical investigation(s) being proposed
as part of this application and how long you expect the investigation(s) (clinical trial) to last. If more
than one is being proposed, then insert appropriate subheading so the FDA can clearly distinguish
what information pertains to which trial.]
3.4
Preclinical Studies
3.4.1
Mechanism and Efficacy
3.4.2
Safety
3.5 Previous Human Experience
[INSTRUCTIONS: A brief summary of previous human experience with the biologic, 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) should be provided here. This should be
a high-level summary of the information provided in Section 9 – Previous Human Experience.]
3.6
3.5.1
Efficacy
3.5.2
Safety
Withdrawn From Investigation or Marketing in any Country
[INSTRUCTIONS: 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 should be provided here.]
3.7
References
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
Section 4: General Investigational Plan
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. Some of the information included may not be applicable to all IND
applications. General instructions and comments on the format and content of this section of
the IND application, along with a list of guidance documents and additional regulation
references, are provided. Within each subheading of this section are additional instructions,
comments, suggested text, web addresses for forms, web addresses for specific guidance
documents, and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(3)(iv)A brief description of the overall plan for investigating the drug product for the following year should be provided
here. The plan should include the following:
(a) the rationale for the drug or the research study;
(b) the indication(s) to be studied;
(c) the general approach to be followed in evaluating the drug;
(d) the kinds of clinical trials to be conducted in the first year following the submission (if plans are not
developed for the entire year, the sponsor should so indicate);
(e) the estimated number of patients to be given the drug in those studies; and
(f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data in
animals or prior studies in humans with the drug or related drugs.]
[PLEASE NOTE: Specifically for the pilot or Phase I trials, the goal of this section is to place your
developmental plans for the experimental drug in perspective and allow FDA to anticipate your needs
as the sponsor. The average total length of Sections 3 and 4 combined is 2-3 pages.. You are not
obligated to supply responses when the information is not available or is unknown. In these
instances, state here that the requested information is unknown or not available.] (Per FDA
Guidance for Industry entitled „Content and Format of Investigational New Drug Applications
(INDs) for Phase 1 Studies of Drugs, Including Well- Characterized, Therapeutic,
Biotechnology-derived Products)‟
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4.0
General investigational plan
[INSTRUCTIONS: In this section, provide a brief overview of the investigational plan for the first year
the drug is being studied. Be sure to include/address the information requested in each of the
subsections of section 4.]
4.1
Rationale for Drug and Study
[INSTRUCTIONS: In this section, state the rationale for using the investigational drug and/or
conducting the research study. Include background information on the science that supports the use
of the investigational drug and/or the research study. Note: This information can either be split into
two sections, as illustrated here (4.1.1. and 4.1.2., or included all together under 4.1). Use your best
judgment as to which style is more appropriate for your application.]
4.1.1
Rationale for Drug
[INSTRUCTIONS: See above instructions for 4.1.]
4.1.2
Rationale for Study
[INSTRUCTIONS: See above instructions for 4.1.]
4.2
Indications to be Studied the First Year
[INSTRUCTIONS: State the indication(s) to be studied during the first year of the IND here.]
4.3
General Approach to be followed in Evaluating the Drug
[INSTRUCTIONS: State the general approach to be followed in evaluating the drug here.]
4.4
Clinical Trials to be Conducted First Year
[INSTRUCTIONS: Provide an overview of the clinical trial(s) that are planned to be conducted during
the first year of the IND here. If the plans are not yet developed for the first year of the IND, indicate
this here.]
4.5
Estimated Number of Subjects to be Administered Experimental Drug in First Year
[INSTRUCTIONS: Provide an estimate of the number of total participants to be given the
investigational drug in the proposed clinical trial(s) to be conducted during the first year of the IND. If
the drug is to be given to multiple populations, i.e., healthy volunteers and patient populations, be sure
to provide an estimate for each individual population.]
4.6
Anticipated Risks of Particular Severity or Seriousness
[INSTRUCTIONS: Provide an overview of all risks of particular severity or seriousness anticipated on
the basis of the toxicological data in animals and/or prior studies with the investigational drug or
related drugs in humans here. Also include any study procedures that carry anticipated risks of
particular severity or seriousness in this section.]
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Section 5: Investigator‟s Brochure
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(5) - Investigator's brochure. If required under
312.55, a copy of the investigator's brochure, containing the following information:
(i) A brief description of the drug substance and the formulation, including the structural formula, if
known.
(ii) A summary of the pharmacological and toxicological effects of the drug in animals and, to the
extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if
known, in humans.
(iv) A summary of information relating to safety and effectiveness in humans obtained from prior
clinical studies. (Reprints of published articles on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be anticipated on the basis of prior experience
with the drug under investigation or with related drugs, and of precautions or special monitoring to be
done as part of the investigational use of the drug.]
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5.0
Investigator’s brochure
[INSTRUCTIONS:

If this is 1) a sponsor-investigator initiated 2) early phase trial 3) being conducted at a
single center, then an investigator brochure (IB) is not required. Simply state that no IB is
required as per 21 CFR 312.55 (a).
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Section 6: Protocol
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. Some of the information included may not be applicable to all IND
applications. General instructions and comments on the format and content of this section of
the IND application, along with a list of guidance documents and additional regulation
references, are provided. Within each subheading of this section are additional instructions,
comments, suggested text, web addresses for forms, web addresses for specific guidance
documents, and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(6)
(6)Protocols.
(i) A protocol for each planned study. (Protocols for studies not submitted initially in the IND should be
submitted in accordance with 312.30(a).) In general, protocols for Phase 1 studies may be less
detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be
directed primarily at providing an outline of the investigation--an estimate of the number of patients to
be involved, a description of safety exclusions, and a description of the dosing plan including duration,
dose, or method to be used in determining dose--and should specify in detail only those elements of
the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries.
Modifications of the experimental design of Phase 1 studies that do not affect critical safety
assessments are required to be reported to FDA only in the annual report.
(ii) In Phases 2 and 3, detailed protocols describing all aspects of the study should be submitted. A
protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the sponsor
anticipates that some deviation from the study design may become necessary as the investigation
progresses, alternatives or contingencies to provide for such deviation are built into the protocols at
the outset. For example, a protocol for a controlled short-term study might include a plan for an early
crossover of non-responders to an alternative therapy.
(iii) A protocol is required to contain the following, with the specific elements and detail of the protocol
reflecting the above distinctions depending on the phase of study:
(a)A statement of the objectives and purpose of the study.
(b)The name and address and a statement of the qualifications (curriculum vitae or other
statement of qualifications) of each investigator, and the name of each sub-investigator (e.g.,
research fellow, resident) working under the supervision of the investigator; the name and
address of the research facilities to be used; and the name and address of each reviewing
Institutional Review Board. {NOTE: - FDA Form 1572 and CVs}
(c) The criteria for patient selection and for exclusion of patients and an estimate of the number of
patients to be studied.
(d) A description of the design of the study, including the kind of control group to be used, if any,
and a description of methods to be used to minimize bias on the part of subjects, investigators,
and analysts.
(e) The method for determining the dose(s) to be administered, the planned maximum dosage,
and the duration of individual patient exposure to the drug.
(f) A description of the observations and measurements to be made to fulfill the objectives of the
study.
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(g) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor
the effects of the drug in human subjects and to minimize risk]
[COMMENTS: This section of the application may be written in a number of different formats.
Regardless of the format chosen, the information listed in the regulatory reference above must be
provided. If the Sponsor-Investigator is using the JHM IRB eFormA, it is strongly suggested
that the eIRB application in its entirety be submitted with in this section. This is suggested
because the eIRB application contains information that is not included in the eFormA which should be
submitted for FDA review. If the eIRB application is submitted, the appropriate subheading in this
section or in the appendices should be added. Finally, if the protocol being submitted with the IND
application is already IRB approved, the Sponsor-Investigator should include the IRB approval letter
with the IND application and the appropriate subheading in this section or in the appendices should be
added.
[FORMATS: In the format suggested below, the applicant provides a high level summary of the
requested information and references the FDA reviewers to a full version of the documents (e.g.,
protocol, eIRB application, consent, IRB approval letter) located in the appendices, including the page
number of document in which the information can be found. This format is suggested as it provides
the FDA reviewers an „easy to read‟ overview of the requested information as well as specific
references to full documents.]
[FDA GUIDANCE DOCUMENTS: Below are web addresses for a number of FDA guidance document
sites that may be useful with regard to choice of study design and drafting the protocol.

FDA Guidance Documents on Clinical Pharmacology:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064982.htm

FDA Guidance Documents on Clinical / Medical:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm

FDA Guidance Documents on Biopharmaceutics:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064964.htm

FDA Guidance Documents on Drug Safety:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064993.htm

FDA Guidance Documents on International Conference on Harmonisation – Efficacy:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065004.htm]
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6.0
Protocol(s)
[INSTRUCTIONS: Provide FDA reviewers with the clinical protocol here.]
[SUGGESTED TEXT: “The clinical protocol begins on the following page.”]
6.1
Investigator and Facilities Data
[INSTRUCTIONS: Needed here are the name, address, and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each investigator as well as the name of each
sub-investigator (e.g., research fellow, resident) working under the supervision of the investigator.
Also needed are the name(s) and address(es) of the research facility(ies) to be used as well as the
name and address of each reviewing Institutional Review Board (IRB).
The information needed for this section is provided to the FDA on the FDA Form 1572 (see below for
additional guidance) along with copies of the Sponsor-Investigator‟s CV, medical license, and financial
disclosure forms (FDA Form 3454 and FDA Form 3455; see below for additional guidance). While not
required, the Sponsor-Investigator may also provide copies of the CVs, medical or other professional
licenses (if applicable), and financial disclosure forms (FDA Form 3454 and FDA Form 3455) for all
subinvestigators listed in Box 6 of the 1572. If the Sponsor-Investigator chooses not provide the
subinvestigators‟ information in the application, the applicant MUST maintain copies of this
documentation in their IND regulatory binder. Additional guidance on the completion of the FDA
forms for this section as well the website where fillable PDF forms can be found are provided below.
The FDA forms, CVs, and licenses may either 1) be placed after the appropriate subheading in this
section or 2) placed in the appendices.]
6.1.1
Form FDA 1572
[1572 INSTRUCTIONS and GUIDANCE: Please review the FDA 1572 FAQs guidance document
before completing the 1572. Both the FAQs and FDA Form 1572 may be downloaded from the
following links: Form FDA 1572 and FDA Guidance on 1572 (FAQs)]
[SUGGESTED TEXT: “Please see the signed and dated FDA Form 1572 on the next page.” OR
“Please see the signed and dated FDA Form 1572 in appendix ##.”]
6.1.2
Sponsor-Investigator Credentials
[SUGGESTED TEXT: “The Sponsor-Investigator‟s CV and Medical License may be found on the
next page.” OR “Please see the Investigator‟s CV and Medical License in appendix ##.”]
6.1.3
Subinvestigator(s) Credentials
[SUGGESTED TEXT:
“The CVs and medical licenses (if applicable) of the following
subinvestigators may be found on the next page.” OR “Please see the subinvestigators‟ CVs and
medical licenses (if applicable) in appendix ##.”]
[COMMENT: Provide a list of subinvestigators in the order that the CVs and licenses appear and
place the documents after this subheading or if you may place the documents in the appendices.]
[EXAMPLE TEXT (May be used here or in appendix):
“The CVs and licenses (if applicable) of the subinvestigators listed below may be found on the
next page.
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John L Doe, MD, PhD
Lisa M. Name, PhD”]
6.1.4 Disclosure of Financial Interests
[Regulatory reference: 21CFR54
Sec. 54.1 Purpose
(a) The Food and Drug Administration (FDA) evaluates clinical studies submitted in marketing
applications, required by law, for new human drugs and biological products and marketing
applications and reclassification petitions for medical devices.
(b) The agency reviews data generated in these clinical studies to determine whether the
applications are approvable under the statutory requirements. FDA may consider clinical studies
inadequate and the data inadequate if, among other things, appropriate steps have not been
taken in the design, conduct, reporting, and analysis of the studies to minimize bias. One potential
source of bias in clinical studies is a financial interest of the clinical investigator in the outcome of
the study because of the way payment is arranged (e.g., a royalty) or because the investigator has
a proprietary interest in the product (e.g., a patent) or because the investigator has an equity
interest in the sponsor of the covered study. This section and conforming regulations require an
applicant whose submission relies in part on clinical data to disclose certain financial
arrangements between sponsor(s) of the covered studies and the clinical investigators and certain
interests of the clinical investigators in the product under study or in the sponsor of the covered
studies. FDA will use this information, in conjunction with information about the design and
purpose of the study, as well as information obtained through on-site inspections, in the agency's
assessment of the reliability of the data.
Sec. 54.2 Definitions
For the purposes of this part:
(a)Compensation affected by the outcome of clinical studies means compensation that could be
higher for a favorable outcome than for an unfavorable outcome, such as compensation that is
explicitly greater for a favorable result or compensation to the investigator in the form of an equity
interest in the sponsor of a covered study or in the form of compensation tied to sales of the
product, such as a royalty interest.
(b)Significant equity interest in the sponsor of a covered study means any ownership interest,
stock options, or other financial interest whose value cannot be readily determined through
reference to public prices (generally, interests in a non-publicly traded corporation), or any
equity interest in a publicly traded corporation that exceeds $50,000 during the time the clinical
investigator is carrying out the study and for 1 year following completion of the study.
(c)Proprietary interest in the tested product means property or other financial interest in the
product including, but not limited to, a patent, trademark, copyright or licensing agreement.
(d)Clinical investigator means only a listed or identified investigator or subinvestigator who is
directly involved in the treatment or evaluation of research subjects. The term also includes the
spouse and each dependent child of the investigator.
(e)Covered clinical study means any study of a drug or device in humans submitted in a marketing
application or reclassification petition subject to this part that the applicant or FDA relies on to
establish that the product is effective (including studies that show equivalence to an effective
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product) or any study in which a single investigator makes a significant contribution to the
demonstration of safety. This would, in general, not include phase l tolerance studies or
pharmacokinetic studies, most clinical pharmacology studies (unless they are critical to an efficacy
determination), large open safety studies conducted at multiple sites, treatment protocols, and
parallel track protocols. An applicant may consult with FDA as to which clinical studies constitute
"covered clinical studies" for purposes of complying with financial disclosure requirements.
(f)Significant payments of other sorts means payments made by the sponsor of a covered study to
the investigator or the institution to support activities of the investigator that have a monetary value
of more than $25,000, exclusive of the costs of conducting the clinical study or other clinical
studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or
retainers for ongoing consultation or honoraria) during the time the clinical investigator is
carrying out the study and for 1 year following the completion of the study.
(g)Applicant means the party who submits a marketing application to FDA for approval of a drug,
device, or biological product. The applicant is responsible for submitting the appropriate
certification and disclosure statements required in this part.
(h)Sponsor of the covered clinical study means the party supporting a particular study at the time it
was carried out.
Sec. 54.3 Scope
The requirements in this part apply to any applicant who submits a marketing application for a
human drug, biological product, or device and who submits covered clinical studies. The applicant
is responsible for making the appropriate certification or disclosure statement where the applicant
either contracted with one or more clinical investigators to conduct the studies or submitted
studies conducted by others not under contract to the applicant.
Sec. 54.4 Certification and disclosure requirements
For purposes of this part, an applicant must submit a list of all clinical investigators who conducted
covered clinical studies to determine whether the applicant's product meets FDA's marketing
requirements, identifying those clinical investigators who are full-time or part-time employees of
the sponsor of each covered study. The applicant must also completely and accurately disclose or
certify information concerning the financial interests of a clinical investigator who is not a full-time
or part-time employee of the sponsor for each covered clinical study.
Clinical investigators subject to investigational new drug or investigational device exemption
regulations must provide the sponsor of the study with sufficient accurate information needed to
allow subsequent disclosure or certification. The applicant is required to submit for each clinical
investigator who participates in a covered study, either a certification that none of the financial
arrangements described in 54.2 exist, or disclose the nature of those arrangements to the agency.
Where the applicant acts with due diligence to obtain the information required in this section but is
unable to do so, the applicant shall certify that despite the applicant's due diligence in attempting to
obtain the information, the applicant was unable to obtain the information and shall include the reason.
(a) The applicant (of an application submitted under sections 505, 506, 510(k), 513, or 515 of the
Federal Food, Drug, and Cosmetic Act, or section 351 of the Public Health Service Act) that relies
in whole or in part on clinical studies shall submit, for each clinical investigator who participated in
a covered clinical study, either a certification described in paragraph (a)(1) of this section or a
disclosure statement described in paragraph (a)(3) of this section.
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(1) Certification: The applicant covered by this section shall submit for all clinical investigators
(as defined in 54.2(d)), to whom the certification applies, a completed Form FDA 3454
attesting to the absence of financial interests and arrangements described in paragraph (a)(3)
of this section. The form shall be dated and signed by the chief financial officer or other
responsible corporate official or representative.
(2) If the certification covers less than all covered clinical data in the application, the applicant
shall include in the certification a list of the studies covered by this certification.
(3) Disclosure Statement: For any clinical investigator defined in 54.2(d) for whom the
applicant does not submit the certification described in paragraph (a)(1) of this section, the
applicant shall submit a completed Form FDA 3455 disclosing completely and accurately the
following:
(i) Any financial arrangement entered into between the sponsor of the covered study and
the clinical investigator involved in the conduct of a covered clinical trial, whereby the value
of the compensation to the clinical investigator for conducting the study could be influenced
by the outcome of the study;
(ii) Any significant payments of other sorts from the sponsor of the covered study, such as
a grant to fund ongoing research, compensation in the form of equipment, retainer for
ongoing consultation, or honoraria;
(iii) Any proprietary interest in the tested product held by any clinical investigator involved
in a study;
(iv) Any significant equity interest in the sponsor of the covered study held by any clinical
investigator involved in any clinical study; and
(v) Any steps taken to minimize the potential for bias resulting from any of the disclosed
arrangements, interests, or payments.
(b) The clinical investigator shall provide to the sponsor of the covered study sufficient accurate
financial information to allow the sponsor to submit complete and accurate certification or
disclosure statements as required in paragraph (a) of this section. The investigator shall promptly
update this information if any relevant changes occur in the course of the investigation or for 1
year following completion of the study.
(c) Refusal to file application. FDA may refuse to file any marketing application described in
paragraph (a) of this section that does not contain the information required by this section or a
certification by the applicant that the applicant has acted with due diligence to obtain the
information but was unable to do so and stating the reason.
Sec. 54.5 Agency evaluation of financial interests
(a)Evaluation of disclosure statement. FDA will evaluate the information disclosed under
54.4(a)(2) about each covered clinical study in an application to determine the impact of any
disclosed financial interests on the reliability of the study. FDA may consider both the size and
nature of a disclosed financial interest (including the potential increase in the value of the interest
if the product is approved) and steps that have been taken to minimize the potential for bias.
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(b)Effect of study design: In assessing the potential of an investigator's financial interests to bias a
study, FDA will take into account the design and purpose of the study. Study designs that utilize
such approaches as multiple investigators (most of whom do not have a disclosable interest),
blinding, objective endpoints, or measurement of endpoints by someone other than the
investigator may adequately protect against any bias created by a disclosable financial interest.
(c)Agency actions to ensure reliability of data. If FDA determines that the financial interests of any
clinical investigator raise a serious question about the integrity of the data, FDA will take any
action it deems necessary to ensure the reliability of the data including:
(1) Initiating agency audits of the data derived from the clinical investigator in question;
(2) Requesting that the applicant submit further analyses of data, e.g., to evaluate the effect of
the clinical investigator's data on overall study outcome;
(3) Requesting that the applicant conduct additional independent studies to confirm the results
of the questioned study; and
(4) Refusing to treat the covered clinical study as providing data that can be the basis for an
agency action.
Sec. 54.6 Recordkeeping and record retention
(a)Financial records of clinical investigators to be retained. An applicant who has submitted a
marketing application containing covered clinical studies shall keep on file certain information
pertaining to the financial interests of clinical investigators who conducted studies on which the
application relies and who are not full or part-time employees of the applicant, as follows:
(1) Complete records showing any financial interest or arrangement as described in
54.4(a)(3)(i) paid to such clinical investigators by the sponsor of the covered study.
(2) Complete records showing significant payments of other sorts, as described in
54.4(a)(3)(ii), made by the sponsor of the covered clinical study to the clinical investigator.
(3) Complete records showing any financial interests held by clinical investigators as set forth
in 54.4(a)(3)(iii) and (a)(3)(iv).
(b)Requirements for maintenance of clinical investigators' financial records
(1) For any application submitted for a covered product, an applicant shall retain records as
described in paragraph (a) of this section for 2 years after the date of approval of the
application.
(2) The person maintaining these records shall, upon request from any properly authorized
officer or employee of FDA, at reasonable times, permit such officer or employee to have
access to and copy and verify these records.
[COMMENT: The Sponsor-Investigator must have documentation on file for each investigator and
subinvestigator who is involved in the clinical trial(s) under this IND which states whether or not
the individual has any type of financial interest which could be perceived as potentially influencing
the outcome. This documentation must be maintained in the IND regulatory files and updated as
needed.]
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[GUIDANCE DOCUMENTS: The FDA, NIH, and JHU have guidance documents concerning
financial conflicts of interest which should be reviewed in order to verify that the SponsorInvestigator and project team are in compliance. Web addresses for these guidance document
websites are listed below.
Guidance Documents:
JHM IRB Guidelines and Policies: 103.11 Organization Policy on Committee on Outside
Interests (COI) and the JHM IRB
JHU Conflict of Interest Policy
JHU Research Administration Conflict of Interest (Compliance)
FDA Guidance: Financial Disclosure by Clinical Investigators (2001)
FDA Draft Guidance Financial Disclosure by Clinical Investigators (May 2011)
Department of Health and Human Services-OHRP Financial Relationships and Interests
in Research Involving Human Subjects: Guidance for Human Subject Protection
6.1.4.1 Form FDA 3454
[FORM FDA 3454 INSTRUCTIONS/COMMENTS:
The Form FDA 3454 provides
documentation to the FDA that the Sponsor-Investigator, other clinical investigator(s), and/or
subinvestigator(s) DO NOT have any financial interests that may influence the outcome of the
study. Form FDA 3454
[SUGGESTED TEXT: “The completed Form FDA 3454 may be found on the next page.” OR
“Please see the completed Form FDA 3454 in appendix ##.”]
6.1.4.2 Form FDA 3455
[COMMENTS:
Reportable Disclosures:
If the Sponsor-Investigator, other clinical investigator(s), and/or subinvestigator(s) have any
financial conflict of interest(s) that is/are being managed per JHU policies, each conflicted
individual must complete and submit a Form FDA 3455 with attached copy of the conflict
management plan with the IND application. If this is not applicable, then delete this section
and delete from table of contents.
No Reportable Disclosures:
The DDRS has been informed that during FDA inspections/audits, the FDA has cited
investigators for not having a completed Form FDA 3455 as part of the IND‟s regulatory
documentation. Therefore, even if there are no reportable disclosures, any time a Form FDA
3454 is being submitted a Form FDA 3455 should also be submitted. When completing the
Form FDA 3455, all sections of the form should be completed except you do not check off any
of the boxes describing reportable financial disclosures. Form FDA 3455 ]
[SUGGESTED TEXT: “A completed Form FDA 3455 can be found on the next page.” OR
“Please see the Form FDA 3455 for the Sponsor-Investigator in appendix ##.”]
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6.2
Informed Consent document(s)
[INSTRUCTIONS: Provide FDA reviewers a copy of all informed consent documents being used
for the trial. If not yet IRB approved, state here that the documents being provided are drafts.]
6.3
IRB Approval
[INSTRUCTIONS: Provide FDA reviewers a copy of the IRB approval letter(s) for the clinical
trial(s) being submitted with this IND. If not yet IRB approved, state here that the study is under
IRB review with approval decision pending.]
6.4
Clinical Trial Registration
[COMMENTS: Per Title VIII of the Food and Drug Administration Amendments Act of 2007 or
FDAAA (U.S. Public Law 110-85) clinical trial registration and reporting requirements, all
applicable trials must be registered at clinicaltrials.gov, and results reported as required. As part
of this requirement, the FDA created the Form FDA 3674 to certify compliance with registration of
trials. Below are a number of resources that provide additional guidance and information
concerning this requirement. If the Sponsor-Investigator needs additional guidance, please contact
the ICTR Research Navigators. Even if the protocol being submitted is not required to be
registered at ClinicalTrials.gov, the Sponsor-Investigator must check the appropriate box in
section 9 of the form and submit the Form FDA 3674, entitled „Certification of Compliance, under
42 U.S.C § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C § 282(j))‟,
with the IND application.]
[GUIDANCE/INFORMATION RESOURCES FOR TRIAL REGISTRATION:
FDA Guidance Document re: registering trials at ClinicalTrials.gov
Clinicaltrials.gov Protocol Registration System Information Website
NIH Grantees Clinicaltrials.gov and FDAAA Policy Site
JHM IRB Policy and Guideline
Organizational ClinicalTrials.gov Registration Policy
Organizational ClinicalTrials.gov Registration Guideline
FORM FDA 3674 Website to download PDF fillable form
Form FDA 3674 Instructions
6.4.1
Form FDA 3674
[SUGGESTED TEXT: “The signed and dated Form FDA 3674 can be found on the next page.”
OR “Please see the signed and dated Form FDA 3674 in appendix ##.”]
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Section 7: Chemistry, Manufacturing, and Controls (CMC)
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. Some of the information included may not be applicable to all IND applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents, and/or
regulations. This section must be written by a person or organization familiar with the
manufacture of biologic products.]
[REGULATORY REFERENCE: 21CFR312.23(a)(7):
(i) As appropriate for the particular investigations covered by the IND, a section describing the
composition, manufacture, and control of the drug substance and the drug product. Although in
each phase of the investigation sufficient information is required to be submitted to assure the
proper identification, quality, purity, and strength of the investigational drug, the amount of
information needed to make that assurance will vary with the phase of the investigation, the
proposed duration of the investigation, the dosage form, and the amount of information otherwise
available. FDA recognizes that modifications to the method of preparation of the new drug
substance and dosage form and changes in the dosage form itself are likely as the investigation
progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed
on the identification and control of the raw materials and the new drug substance. Final
specifications for the drug substance and drug product are not expected until the end of the
investigational process.
(ii) It should be emphasized that the amount of information to be submitted depends upon the
scope of the proposed clinical investigation. For example, although stability data are required in all
phases of the IND to demonstrate that the new drug substance and drug product are within
acceptable chemical and physical limits for the planned duration of the proposed clinical
investigation, if very short-term tests are proposed, the supporting stability data can be
correspondingly limited.
(iii) As drug development proceeds and as the scale or production is changed from the pilot-scale
production appropriate for the limited initial clinical investigations to the larger-scale production
needed for expanded clinical trials, the sponsor should submit information amendments to
supplement the initial information submitted on the chemistry, manufacturing, and control
processes with information appropriate to the expanded scope of the investigation.
(iv) Reflecting the distinctions described in this paragraph (a)(7), and based on the phase(s) to be
studied, the submission is required to contain the following:
(a) Drug substance. A description of the drug substance, including its physical, chemical, or
biological characteristics; the name and address of its manufacturer; the general method of
preparation of the drug substance; the acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the drug substance; and information
sufficient to support stability of the drug substance during the toxicological studies and the
planned clinical studies. Reference to the current edition of the United States Pharmacopeia-National Formulary may satisfy relevant requirements in this paragraph.
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(b) Drug product. A list of all components, which may include reasonable alternatives for
inactive compounds, used in the manufacture of the investigational drug product, including
both those components intended to appear in the drug product and those which may not
appear but which are used in the manufacturing process, and, where applicable, the
quantitative composition of the investigational drug product, including any reasonable
variations that may be expected during the investigational stage; the name and address of the
drug product manufacturer; a brief general description of the manufacturing and packaging
procedure as appropriate for the product; the acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the drug product; and information sufficient
to assure the product's stability during the planned clinical studies. Reference to the current
edition of the United States Pharmacopeia--National Formulary may satisfy certain
requirements in this paragraph.
(c) A brief general description of the composition, manufacture, and control of any placebo
used in a controlled clinical trial.
(d) Labeling. A copy of all labels and labeling to be provided to each investigator.
(e) Environmental analysis requirements. A claim for categorical exclusion under 25.30 or
25.31 or an environmental assessment under 25.40]
[REGULATORY REFERENCE: 21CFR 211 CURRENT GOOD MANUFACTURING PRACTICE FOR
FINISHED PHARMACEUTICALS]
[GUIDANCE DOCUMENTS: Links for various guidance documents concerning the CMC are
listed below.

FDA Guidance Document
Guidance for FDA Reviewers and Sponsors: Content and Review of CMC Information
for Human Somatic Cell Therapy INDs

FDA Guidance Document
Content and Format of Investigational New Drug Applications (INDs) for Phase 1
Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived
Products

FDA Guidance Documents
Chemistry, Manufacturing, and Controls (CMC)


FDA Guidance Documents
CMC and GMP for Vaccines, Blood, and Biologics
FDA Guidance Documents
Microbiology (Chemistry, Manufacturing, and Controls)

FDA Guidance Documents
International Conference on Harmonisation – Quality

21 CRF25
Environmental Impact Considerations
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[GENERAL COMMENTS:
For all phases of clinical trials (per 21CFR 312.23):
1. Sufficient information must be submitted to assure proper identification, quality, purity, and
strength of the investigational drug.
2. Stability data is required at all phases of the trial. However, scope of data depends on the
phase of the investigation (i.e. limited data for very short-term studies)
3. When product manufacturing shifts from smaller to larger scale production, any changes in the
manufacturing process must be submitted to the FDA as information amendments to the IND.
4. If submitting a Phase 1 study, the following guidance should be reviewed:
 CGMP for Phase 1 Investigational Drugs
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7. Chemistry, Manufacturing, and Controls
[INSTRUCTIONS: At the beginning of this section, the sponsor-investigator should state whether
he/she believes: 1) the chemistry of either the drug substance or the drug product, or 2) the
manufacturing of either the drug substance or the drug product, presents any signals of potential
human risk. If so, these signals of potential risks should be discussed, and the steps proposed to
monitor for such risk(s) should be described, or the reason(s) why the signal(s) should be dismissed
should be discussed.
In addition, sponsors should describe any chemistry and manufacturing differences between the drug
product proposed for clinical use and the drug product used in the animal toxicology trials that formed
the basis for the sponsor's conclusion that it was safe to proceed with the proposed clinical study.
How these differences might affect the safety profile of the drug product should be discussed. If there
are no differences in the products, that should be stated.]
7.1 Facility Information
[INSTRUCTIONS: Include the name(s) and address(es), FDA registration number if available,
and other pertinent organizational information for each manufacturer responsible for any
portion of the manufacture or testing operations (e.g., the processing, packaging, labeling, or
control operations) for the biological substance (e.g., performs the isolation, purification,
testing, processing, packaging, or labeling). This may include contractors or other company
subsidiaries serving as contractors, or other location/sites owned and operated by the
applicant. Include a brief description of the operations(s) performed by each party and the
responsibilities conferred on each party by the applicant.]
7.1.1
Names and Addresses of Manufacturers
[INSTRUCTIONS: For each manufacturing location, a floor diagram should be included that
indicates the general facilities layout. This diagram need not be a detailed engineering
schematic or blueprint, but rather a simple drawing that depicts the relationship of the subject
manufacturing areas, suites, or rooms to one another, and should indicate other uses made of
adjacent areas that are not the subject of the application. This diagram should be sufficiently
clear that the reviewer may visualize the flow of production of the biological substance and
would be able to identify areas or room "proximities" that may be of concern for particular
operations, e.g., segregation of operations. Room numbers or other unique identifiers should
be provided; however, the location of processing equipment within rooms and areas is not
necessary. Reference can be made to manufacturing flow information presented in previous
sections or in the establishment description section.
[SUGGESTED TEXT:
A blue print for the facility is shown in (Figure _____/ on page ___).
The organizational chart for the facility is shown in (Figure _____/ on page ___).]
7.1.2
Location of Manufacturing and Testing
[INSTRUCTIONS: For all areas in which operations for the preparation of cell cultures and cell
processing are performed, the following information concerning precautions taken to prevent
contamination or cross-contamination should be provided:
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The air quality classification of room or area in which operations are performed as validated
and measured during operations.
A brief, narrative description of the procedures and/or facility design features for the control of
contamination, cross-contamination and containment (air pressure cascades, segregation of
operations and product, etc.) - this is of particular importance for multi-use areas or for
different lots of the same product.
General equipment design description, e.g. does the design represent an open or closed
system or provide for a sterile or non-sterile operation.
A description of the in-process controls performed to prevent or to identify contamination or
cross contamination.
The manipulation of more than one cell culture product or two different products in a single
area or piece of equipment, either concurrently or on a campaign basis, should be indicated or
measures to ensure prevention of cross contamination should be discussed.
Reference other sections as appropriate.]
7.1.3
Other Manufactured Products
[INSTRUCTIONS: A comprehensive list of all additional products or different lots of the same
product to be manufactured or manipulated in the areas used for the product in question
should be provided.
The applicant should indicate in which rooms the additional products will be introduced and the
manufacturing steps that will take place in the room. An explanation should be given as to
whether these additional products will be introduced on a campaign basis or concurrently
during production of the product which is the subject of the application. Indication should also
be given as to which additional products may share product contact equipment with the
product in question (dedicated vs. multi-use equipment/areas should be delineated for each
process step, in this section or other appropriate sections of the application). A brief
description should be provided as to the type and developmental status of the additional
products.]
7.1.4
Quality Assurance Audits
[SUGGESTED TEXT: A summary of the quality assurance/quality control program for the
facility is included in Attachment ______.]
7.2 Product Manufacturing-Components and Materials
[INSTRUCTIONS: A list of all components used in the manufacture (i.e., collection,
processing, isolation and culture) of the biological substance, and the tests and specifications
or reference to official compendia should be provided. For purchased raw materials,
representative certificates of analysis from the suppliers and the manufacturer's own
acceptance testing results should be included in the submission. Process gases (e.g., air,
carbon dioxide) and water are considered raw materials. Include a list with tests and
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specifications of all special reagents and materials used in the manufacture of the biological
substance, e.g., culture media, buffers, sera, antibiotics, preservatives. In some cases a
detailed description of their preparation and characterization may be required.
Submit a description of the tests and specifications for materials of animal source that may
potentially be contaminated with adventitious agents, such as Bovine Spongiform
Encephalopathy agent (BSE) for bovine derived products and other adventitious agents of
human or animal origin. Information (validation data) or certification supporting the freedom of
reagents from adventitious agents should be included in the submission.
[SUGGESTED TEXT: This section contains a list of …(Identify components you are listing in
the manufacture of your drug)…… used in the manufacture of ….(Identify the drug you are
describing the manufacturing for). Copies of raw material specification sheets and certificates
of analysis for reagents used in production are shown in Attachment _______. Manufacturer
information is found on specification sheets.]
7.2.1
Cells
7.2.1.1 Autologous Cell Components
[INSTRUCTIONS: Describe the following information:






cell source
tissue and cell type (e.g., colon, hematopoietic, neuronal, T-cells)
mobilization protocol (if applicable) documenting whether or not donor cells
are mobilized or activated in vivo in the donor
collection or recovery method: state the procedure used to obtain cells (e.g.,
surgery or leukapheresis indicating the device used if possible)
name and location of the collection facility
transport conditions (if shipped to a processing facility for further
manufacturing)
[NOTE: A donor eligibility determination and/or donor screening is not required for
cells and tissues for autologous use (21 CFR 1271.90(a)(1)). However, the
sponsor-investigator should determine whether manufacturing procedures increase
the risk of propagation of pathogenic agents that may be present in the donor. If so,
the sponsor-investigator should document whether the donor is reactive for specific
pathogens and should describe precautions to prevent the spread of viruses or
other adventitious agents to persons other than the autologous recipient.]
7.2.2
Reagents
[INSTRUCTIONS: List in the IND any reagents used in manufacturing the product (21 CFR
312.23(a)(7)(iv)(b)). For the purpose of this guidance, reagents are those materials that are
used for cellular growth, differentiation, selection, purification, or other critical
manufacturing steps but are not intended to be part of the final product. Examples include
fetal bovine serum, trypsin, digestion enzymes (e.g., collagenase, DNAse) growth factors,
cytokines, monoclonal antibodies, antibiotics, cell separation devices, and media and
media components. These reagents can affect the safety, potency, and purity of the final
product, especially by introducing adventitious agents. For monoclonal antibodies, refer to
the guidance on “Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use” for further information.
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7.2.2.1. Tabulation of Reagents Used in Manufacture
[INSTRUCTIONS: FDA recommends that the following information be provided for all
reagents used during product manufacturing:
• Concentration of the reagent at the manufacturing step at which it is used
• Vendor/supplier
• Source:
Human: If human albumin is used, have procedures in place to ensure that no
recalled lots were used during manufacture or preparation of the product. If
using human AB serum, ensure serum is obtained from an approved blood
bank and meets all blood donor criteria. For all other reagents that are human
derived, identify whether it is a licensed product, or clinical or research grade,
and provide a COA or information regarding testing of the donor and/or reagent.
Porcine: If porcine products are used, a COA or other documentation that the
products are free of porcine parvovirus.
Bovine: If a reagent is derived from bovine material, identify the bovine
material, the source of the material, information on the location where the herd
was born, raised, and slaughtered, and any other information relevant to the
likelihood that the animal may have ingested animal feed prohibited under 21
CFR 589.2000. It may be that bovine material is introduced at different points in
production of a reagent; the information described above should be provided for
all bovine materials used. For more information see, “Proposed Rule: Use of
Materials Derived from Cattle in Medical Products Intended for Use in
Humans and Drugs Intended for Use in Ruminants,” (72 FR 1581; January
12, 2007. In addition, provide a COA to document that bovine materials are
compliant with the requirements for the ingredients of animal origin used for
production of biologics described in 9 CFR 113.53.
• Reagent quality:
FDA recommends use of FDA-approved or cleared, or clinical grade reagents
whenever they are available. Document whether each reagent is an FDAapproved product. Refer to the guidance on "Points to Consider in the
Manufacture and Testing of Monoclonal Antibody Products for Human
Use" for examples of expected information.

COA or cross-reference letters:
If using a research grade (not FDA-approved or cleared) reagent as part of the
manufacturing process, FDA recommends that the sponsor-investigator provide
information verifying the source, safety, and performance of the reagent. If the
vendor of the reagent has a regulatory file with the FDA, a cross-reference letter
from the sponsor may be provided in the IND. If a COA from the reagent
manufacturer is used, assess whether the testing performed is adequate (see
“Qualification Program” below) and provide that information in the IND.
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Reagent
7.2.3
Concentration at Use
Source
Grade
Vendor COA
Qualification Program
[INSTRUCTIONS: If the reagent is not FDA-approved or cleared, additional testing may be
needed to ensure the safety and quality of the reagent. FDA recommends establishing a
qualification program that includes safety testing (sterility, endotoxin, mycoplasma, and
adventitious agents), functional analysis, purity testing, and assays (e.g., residual solvent
testing) to demonstrate absence of potentially harmful substances. The extent of testing
will depend on how the specific reagent is used in the manufacturing process.]
7.2.3.1 Determination of Removal of Reagents from Final Product
[INSTRUCTIONS: The final product should be tested for residual manufacturing
reagents with known or potential toxicities and describe the test procedures used to
detect residual levels of these reagents in the final product. FDA recommends
determining whether a qualification study is sufficient to document their removal, or
whether lot release testing is appropriate prior to initiation of clinical trials. If there are
known or potential toxicities associated with these reagents,
the sponsor should
provide data from a validation study to document their removal prior to initiation of
clinical trials.]
7.2.3.2 Other Concerns
[INSTRUCTIONS: Because some patients may be sensitive to penicillin, FDA does not
recommend use of beta-lactam antibiotics (e.g., penicillins, cephalosporins and related
compounds) during the manufacturing of a therapeutic product for humans. If betalactam antibiotics are used, FDA recommends providing a rationale for their use and a
description of precautions to prevent hypersensitivity reactions.]
7.2.4
Excipients
[INSTRUCTIONS: An excipient is any component that is intended to be part of the final
product, such as human serum albumin or Dimethyl Sulfoxide (DMSO). List all excipients
used during manufacture of the product that are intended to be present in the final product.
(21 CFR 312.23(a)(7)(iv)(b)). Include the concentration and source of the excipients and
provide information regarding the qualification of all excipients that are present in the final
product (21 CFR 211.84(a)).
Excipient
Concentration at Use
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Source
Grade
Vendor
COA
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7.2.4
Additional Considerations
7.3 Product Manufacturing – Procedures
[INSTRUCTIONS: Include a detailed description (list or summary) of all procedures used during
the collection, production, and purification of the cellular therapy product. FDA believes that a
schematic of the production and purification process, and in-process and final product testing,
helps to provide more clearly this information.]
[SUGGESTED TEXT: The manufacture of __ is conducted according to 21 CFR 210 and 211
cGMP.]
7.3.1
Method of Cell Collection/Processing/Culture Conditions
[INSTRUCTIONS: Describe the volume and number of cells collected. Include any
mechanical or enzymatic digestion steps used, and describe the use of any cell selection
device or separation device, including density gradients, magnetic beads, or fluorescence
activated cell sorting (FACS). Provide a description of culture systems (flasks, bags, etc.)
and state whether the system is closed or open and describe any in-process testing that
will be performed during these procedures.]
7.3.2
Irradiation
[INSTRUCTIONS: If the autologous or allogeneic cell product is irradiated before injection,
provide data to demonstrate that the cells are rendered replication-incompetent, but still
maintain their desired characteristics after irradiation. Also describe the documentation of
calibration of the cell irradiator source.]
7.3.4
Final Harvest
[INSTRUCTIONS: Provide a detailed description of the final harvest. Inform FDA whether
the final cell harvest is centrifuged prior to final formulation, and if so, describe the wash
conditions and media used. Discuss whether the cells are cryopreserved after formulation
or will be formulated immediately and given to the patient. If the final harvest is stored,
describe the storage conditions and the length of storage, and provide appropriate
supporting data.]
7.3.5
Process Timing and Intermediate Storage
[INSTRUCTIONS: Report the approximate time elapsed for each step from cell collection
to final harvest. It is important to know the time limit of each step in production to determine
what, if any, in-process testing to perform. If cells are cryopreserved before injection into
patients, include this information along with any stability studies initiated. Also describe the
time and conditions of storage prior to patient administration.]
7.3.6
Final Formulation
[INSTRUCTIONS:Describe the formulation of the final product, including excipients such
as growth factors or human serum albumin (21 CFR 312.23(a)(7)(iv)(a)). State the source
of these components, identify the vendor and final concentration of these excipients and
describe the cell density or cell concentration used in the final product.
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If the final product is delivered to the clinical site frozen, include a description of how the
product will be shipped and data to show that the product can be thawed with consistent
results. In addition, if the product is shipped, provide data on product stability during
shipping.]
7.3.7
Formulation/Infusion Buffer
7.3.8
Excipients
7.3.9
Cell Density/Concentration in the Final Product
7.3.10 Storage Method Prior to Use
7.4 In-Process Testing and Criteria
[INSTRUCTIONS: FDA recommends that product testing for cellular therapies include, but not be
limited to, microbiological testing (including sterility, mycoplasma, and adventitious viral agent
testing) to ensure safety and assessments of other product characteristics such as identity, purity
(including endotoxin), viability, and potency. It is recommended that this testing be done
throughout the manufacturing process, including on the manufacture of cell banks, to evaluate the
manufacturing process itself and to ensure the quality and consistency of the product. In this
section, describe the specifications used for intermediate acceptance criteria and final product
release criteria.
Specifications are the quality standards (i.e., tests, analytical procedures, and acceptance criteria)
that confirm the quality of products and other materials used in the production of a product.
Acceptance criteria mean numerical limits, ranges, or other attributes or variables for the tests
described. Specifications should be appropriate to the stage of product development, because
release criteria should be refined and tightened as product development progresses toward
licensure.
Submit test results related to lot release, characterization testing, MCBs, and WCBs in tabular
form including the lot number or identifier, date of manufacture, test, test method, the sensitivity
and specificity of test methods and, when appropriate, release criteria.
Product testing is an integral part of ensuring control of the manufacturing process and lot to lot
consistency. Therefore, it is important to identify critical parameters in the manufacturing process
and critical product attributes to ensure the desired clinical effect of the final product. Refer to the
“FDA Guidance Concerning Demonstration of Comparability of Human Biological
Products, Including Therapeutic Biotechnology-Derived Products” for additional information.
7.4.1
Sterility Testing (Bacterial and Fungal Testing)
[INSTRUCTIONS: FDA recommends performing microbiological testing on cell banks, inprocess intermediates, and the final product, as appropriate].
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Manufacturing Steps
Where Performed
Test
Method
Criteria
Sensitivity
Specificity
Sterility
Mycoplasma
Purity (endotoxin)
Purity (other
contaminants)
Identity
Potency
Others (cell dose)
Others (cell viability)
7.4.1.1 Test Method
[INSTRUCTIONS: Suitable sterility tests include the test described in 21 CFR 610.12
and the test described in United States Pharmacopoeia (USP) <71> Sterility Tests
(23rd edition, 1995). Later versions of the USP<71> are also suitable. If using another
test method, describe its suitability. Note that under 21 CFR 610.9, prior to product
licensing, the alternative method must be shown to provide assurances of the safety,
purity, potency and effectiveness of the biological product equal to or greater that the
assurances provided by the method or process specified in the 21 CFR 610.12
method.
If antibiotics are used in manufacturing, provide documentation that the antibiotics
were removed prior to sterility testing. If the antibiotics cannot be removed from the
final product, FDA recommends assessing the validity of the sterility assay using the
bacteriostasis and fungistasis testing as described in USP <71> Sterility Tests. Use of
this assay is designed to ensure that any residual antibiotic present in the product does
not interfere with the results of sterility testing.]
7.4.1.2 Test Timing
[INSTRUCTIONS: Sponsor-investigators frequently perform in-process sterility testing
at critical points during manufacturing, such as during extended culture periods, or
after cells have undergone activation or other modification. Identify when in-process
sterility testing is performed during manufacturing and the test method used. The test
method chosen for in-process sterility testing should be adequate to provide assurance
of product sterility.
If the final product will be frozen before its use, FDA recommends performing
testing on the product prior to cryopreservation, so that results will be available before
the product is administered to a patient. However, if the product undergoes
manipulation (e.g., washing, culturing) after thawing, particularly if procedures are
performed in an open system, it may be necessary to repeat sterility testing.
Incorporate the results of in-process sterility testing into acceptance criteria for final
product specifications.
If the product has a short dating period and must be administered to patients
before sterility test results of the final product are available, then develop an
alternate approach to provide sterility assurance. As an alternative approach, FDA
recommends performing all of the following tests:
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•
•
•
in-process sterility testing on a sample taken 48 to 72 hours prior to final
harvest or after the last re-feeding of the cell cultures
a rapid microbial detection test such as a Gram stain or other procedure on the
final formulated products
sterility testing compliant with 21 CFR 610.12 on the final formulated product.
Under this alternative approach the release criteria for sterility would be based on a
negative result of the Gram stain and a no-growth result from the 48 to 72 hour inprocess sterility test. Although in this situation the results of the sterility culture
performed on the final product will not be available for product release, this testing will
provide useful data. A no-growth result will provide assurance that aseptic technique
was maintained. A positive result will provide information for the medical management
of the subject, and trigger an investigation of the cause of the sterility failure.
The sterility culture on the final formulated product and when possible the in-process
culture should be continued to obtain the full 14 day sterility test result even after the
product has been given to the patient.
In all cases where product release is prior to obtaining results from a full 14 day
sterility test, the investigational plan should address the actions to be taken in the
event that the 14 day sterility test is determined to be positive after the product is
administered to the subject. Report the sterility failure, results of investigation of cause
and any corrective actions, in an information amendment submitted to the IND in a
timely manner, within 30 calendar days after initial receipt of the positive culture test
result (21 CFR 312.31).
The investigator should evaluate the subject for any signs of infection that may be
attributable to the product sterility failure. If the patient experiences any serious and
unexpected adverse drug experience that could be from administration of the sterility
failure of the cellular product, this information must be reported to FDA in an IND
safety report no more than 15 calendar days after initial receipt of the information (21
CFR 312.32). If it is determined that an investigational drug presents an
unreasonable and significant risk to subjects, those investigations that present
the risk must be discontinued, the FDA notified, all Institutional Review Boards
notified, and all investigators (21 CFR 312.56(d))notified.
7.4.3 Mycoplasma
[INSTRUCTIONS: There are several potential sources of mycoplasma contamination. Two
major sources include animal serum products used in culture and the culture facility
environment, particularly with open culture systems. FDA recommends performing
mycoplasma testing on the product at the manufacturing stage when the test is most likely to
detect contamination, such as after pooling of cultures for harvest but prior to cell washing.
Testing should be conducted on both cells and supernatant.
FDA recommends that they be informed as to whether there is in-process testing for
mycoplasma during extended culture procedures. Due to the limited dating period of many
cellular products, it is frequently not feasible for a sponsor to perform the recommended
culture-based assay for release testing. In those cases, FDA recommends the use of
polymerase chain reaction (PCR)-based mycoplasma assays or another rapid detection assay
during product development.]
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7.4.4
Adventitious Agent Testing
[INSTRUCTIONS: As appropriate, perform and describe adventitious agent testing as per
below. For more information on adventitious agent testing, refer to “ Points to Consider in the
Characterization of Cell Lines Used to Produce Biologicals ” and ICH guidance Q5A:
“Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell
Lines of Human or Animal Origin.”
7.4.5
In Vitro Viral Testing
[INSTRUCTIONS: When cell lines are used, describe the cell lines and perform in vitro viral
testing. In vitro viral testing should be performed on the MCB, WCB, and as a one-time test on
the EOP cells. Testing should be conducted by inoculating the test sample (MCB) onto various
susceptible indicator cell lines such as the human cell line MRC-5 or Vero cells which are
primate in origin. The choice of cells used would depend on the species of origin of the product
to be tested.
An appropriate test should include monolayer cultures of the same species and tissue as that
used for production of the product, as well as a human and a non-human primate cell line
susceptible to human viruses. In addition, the test should include a measure of both cytopathic
and hemadsorbing viruses.]
7.4.6
In Vivo Viral Testing
[INSTRUCTIONS: When cell lines are used, FDA recommends performing and submitting
data on in vivo viral assays carried out by inoculating the test sample (MCB) into animals such
as adult and suckling mice and embryonated hen eggs. Consider whether to include additional
testing of guinea pigs, rabbits, or monkeys. Such studies would assess the test animals for
any indication of illness. If such additional testing is appropriate, describe and explain the
suitability of the animals used.]
7.4.7
Selected Species-Specific Testing for Adventitious Viruses
[INSTRUCTIONS: FDA recommends MCB be tested for appropriate, species-specific viruses.
In the IND, describe the testing that is performed, the different stages of manufacturing where
those tests are performed (e.g., cell banks, final product), and the test methods used. If human
cell lines are used in the therapeutic product, FDA recommends performing testing for human
pathogens (CMV, HIV-1 & 2, HTLV-1 & 2, EBV, HBV, HCV, B19), and other human viral
agents, as appropriate. FDA recommends such testing because these cells are manipulated
(cultured for extended time periods) and human pathogens can be introduced or propagated
during the extended culture periods. Human viral agents may be tested using a PCR-based
test system. Also, document whether FDA licensed/approved/cleared test kits were used.]
7.4.7.1
Selected Species-Specific Virus Testing
[INSTRUCTIONS: Rodent cell lines used during product manufacture should be tested for
rodent specific viruses, usually through detection by antibody production tests (i.e. MAP:
Murine, antibody production; RAP; Rat antibody production; HAP: Hamster antibody
production)]
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7.4.8
Tumorigenicity Testing
[INSTRUCTIONS: Continuous cell lines derived from rodents need not ordinarily be tested for
tumorigenicity. Human epithelial lines and all lines used for live virus vaccine production
should however be tested. In addition, in some special cases, cells to be used in somatic
cell or gene therapy may require tumorigenicity testing. (Refer to “Points to Consider in
the Characterization of Cell Lines Used to Produce Biologicals" for testing details)]
7.4.9
Identity
[INSTRUCTIONS: FDA recommends that verification be included in the IND of the identity of
the MCB, WCB, and the final product by assays that will identify the product and distinguish it
from other products being processed in the same facility. For the final product, identity testing
is important to ensure that the contents of the vial are labeled appropriately.
If the final product consists of one or more cell lines, FDA recommends establishing identity
tests and/or controls that distinguish between the multiple cell lines used, and describe those
tests and/or controls in the IND submission. Tests may include assays for cell surface markers
or genetic polymorphisms.]
7.4.10 Purity
[INSTRUCTIONS: Product purity is defined as relative freedom from extraneous material in
the finished product, whether or not harmful to the recipient or deleterious to the product (21
CFR 600.3(r)). Purity testing includes assays for pyrogenicity/endotoxin (see below), residual
proteins or peptides used to stimulate or pulse cells, reagents/components used during
manufacture, such as cytokines, growth factors, antibodies, and serum, and unintended
cellular phenotypes.]
7.4.10.1
Residual Contaminants
[INSTRUCTIONS: The appropriate purity testing should include assays for residual
peptides, and proteins used during production and purification, and reagents used during
manufacture, such as cytokines, growth factors, antibodies, beads, and serum. Appropriate
purity testing should include a measurement of contaminating cell types or cell debris. For
further information, refer to ICH Q3 on “Impurities”. Describe in the IND the purity testing
to be conducted and specifications for release.]
7.4.10.2
Pyrogenicity/Endotoxin
[INSTRUCTIONS: The rabbit pyrogen test method is the currently required method for
testing biological products for pyrogenic substances (21 CFR 610.13). Although the
pyrogenicity test is required, there may be specific cases where this test method cannot be
performed for release due to properties of the cellular product (i.e., short product shelf life,
toxicity of product in rabbits). Under these circumstances, a test method such as the
Limulus Amebocyte Lysate test method (LAL) may be used as an alternative method, but
prior to licensure must be shown to provide equal or greater assurances of safety, purity,
and potency (see 21 CFR 610.9). The 1987 FDA Guideline on Validation of the Limulus
Amebocyte Lysate (LAL) Test as End-Product Endotoxin Test for Human and Animal
Parenteral Drugs, Biological Products, and Medical Devices sets forth acceptable
conditions for use of LAL.
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For any parenteral drug, except those administered intrathecally, FDA recommends that
the upper limit of acceptance criterion for endotoxin be 5 EU/kg body weight/hour. For
intrathecally-administered drugs, FDA recommends an upper limit of acceptance criterion
of 0.2 EU/kg body weight/hour. Describe in the IND the pyrogenicity/endotoxin testing
conducted, and acceptance criterion for release. For further information, refer to the FDA
guidance on "Validation of the Limulus Amebocyte Lysate Test as an End-Product
Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and
Medical Devices.”]
7.4.11 Potency
[INSTRUCTIONS: Describe and justify all assays that will be used to measure potency. FDA
recommends that these assays be quantitative, but in addition, they may include a qualitative
biological assay. By the end of Phase 2, FDA recommends that the potency assays consist of
in vivo or in vitro tests that measure an appropriate biological activity. If development of a
quantitative biological assay is not possible, then a quantitative physical assay which
correlates with and is used in conjunction with a qualitative biological assay can be used. Note
that potency assays are part of lot release and should be validated prior to licensure.
FDA recommends that samples of each lot are retained to facilitate comparisons between lots
as assay development progresses.]
7.4.12 Viability
[INSTRUCTIONS: Establish and include minimum release criteria for viability. For somatic
cellular therapies, the minimum acceptable viability specification is generally set at 70 percent.
If this level cannot be achieved, FDA recommends that the sponsor-investigator submit data in
support of a lower viability specification, demonstrating, for example, that dead cells and cell
debris do not affect the safe administration of the product and/or the therapeutic effect. For
further information, see FDA Guidance for Industry: Guidance for Human Somatic Cell
Therapy and Gene Therapy. March 1998.]
7.4.13 Cell Number/Dose
[INSTRUCTIONS: Develop and include specifications for the minimum number of viable and
functional cells as part of product testing and release. FDA recommends that the sponsorinvestigator inform the FDA as to whether or not a maximum number/dose of cells to be
administered has been established and the basis for that level. ]
7.5 Product Release Specifications
NOTE: Considerations for Development of Final Product Release Criteria Specifications
Release specifications, such as those related to product safety, should be in place prior to
initiating Phase I clinical studies. Additionally, as product development proceeds, additional
specifications for product quality and manufacturing consistency are developed and implemented.
For additional information, see ICH Guideline Q6B: "Test Procedures and Acceptance Criteria
for Biotechnological/Biological Products." For additional discussion of manufacturing quality
control, see "Guidance for Industry: Guideline on the Preparation of Investigational New Drug
Products" and Guidance for Industry: "IND Meetings for Human Drugs and Biologics;
Chemistry, Manufacturing and Controls Information."]
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Proposed release acceptance criteria for the final product are based on scientific data and
manufacturing experience obtained during development of the product as described below:
Phase 1
Based on data from lots used in preclinical studies
Phase 2
Refine and tighten based on data generated during Phase 1
Phase 3
Based on information collected during product development.
Based on information collected during product development using validated
assays
Licensure
Proposed analytical procedures are based on scientific data and manufacturing experience as
described below:
Phase 1-3
Usually based on Code of Federal Regulation (CFR) methods or alternative
methods, if appropriate.
Phase 2
If an alternative to the CFR method is used, FDA recommends that the
sponsor initiate validation of the alternative method by Phase 3.
Licensure
Product specification should be in place and established under a validated
assay
[INSTRUCTIONS: The final product is the final formulated product used for administration to
human subjects. Final product release criteria testing should be performed on each lot of product
manufactured. In some situations, each dose could be considered a single lot, depending on the
manufacturing process. The results from final product release criteria testing should be available
prior to administration to a human subject. If results from final product testing will not be available
prior to release, FDA recommends that this be clearly indicated in the IND, together with the
specifications, and include a description of the reporting notification process if the acceptance
criteria are not met.
Provide, in table format, all proposed specifications (tests for safety, purity, potency, and identity,
test methods, and acceptance criteria), including test sensitivity and specificity, where
appropriate, for the final product.
Test
Method
7.5.1
Criteria
Sensitivity
Description of Test Methods
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Specificity
Results Available
Prior to Release
ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
7.6 Stability Testing
[INSTRUCTIONS: Under 21 CFR 312.23(a)(7)(ii), stability testing must be conducted in all
phases of the IND, to demonstrate that the product is within acceptable chemical and physical
limits for the planned duration of the proposed clinical investigation. If a very short term clinical
investigation is proposed, the stability data submitted may be correspondingly limited. The
sponsor-investigator should submit a stability protocol and data for both in-process material
and the final cellular product. A proposed stability protocol should include a measure of
product sterility, identity, purity, quality, and potency. For each test conducted, describe the
test method, sampling time points (there should be a zero-time point), testing temperature, and
other appropriate information, including justification of the assays used to indicate product
stability, measuring those parameters for the duration of storage required by the clinical
protocol. FDA recommends sterility testing be performed at zero-time, end of stability study,
and at an intermediate point during the study.
7.6.1
In-Process Stability Testing
7.6.1.1 Cryopreserved Cells
[INSTRUCTIONS: If cells are cryopreserved, describe the stability protocol that will be
used to ensure that the product is stable during the period of cryopreservation,
measuring the parameters, as appropriate. A comparison is often made of analyses
carried out pre-freeze and post-thaw.]
7.6.1.2 Other Intermediate Holding Steps
[INSTRUCTIONS: Describe any stability testing performed on the product during the
holding steps, such as cryopreservation of cells and storage of bulk product.]
7.6.2
Final Product Stability Testing
7.6.2.1 Product Formulation to Patient Infusion
[INSTRUCTIONS: Include in the IND any data that demonstrate that the product is
stable between the time of product formulation and infusion to subjects to aid in
establishing an expiration-dating period. We recommend that you conduct the testing
at the appropriate temperatures and at time points consistent with predicted storage.]
7.6.2.2 Shipping Conditions
[INSTRUCTIONS: If the product is shipped from the manufacturing site to the clinical
site, describe the time and shipping conditions (e.g., packaging, temperature). The
stability protocol should be adequate to demonstrate that product integrity, sterility, and
potency are maintained under the proposed shipping conditions.]
7.7 Container Closure System
[INSTRUCTIONS: Describe here the types of container and closure used, and determination
that the containers and closures are compatible with the product.
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For more information, refer to “Guidance for Industry: Container Closure Systems for
Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls
Documentation” and “Guidance for Industry: Container Closure Systems for Packaging
Human Drugs and Biologics, Questions and Answers.”]
7.8 Labels
[INSTRUCTIONS: Describe the product labeling used throughout the manufacturing process
and on the final product container. As described in 21 CFR 312.6(a), the label for an
investigational product must contain the following statement: “Caution: New Drug – Limited
by Federal law to Investigational Use.” To minimize the potential for mix-ups for products
manufactured in multi-use facilities and for patient-specific products, FDA recommends that
the product label contain:
1)
2)
3)
4)
5)
the date of product manufacture
storage conditions
expiration date and time (if appropriate)
product name
and two non-personal patient identifiers.
As HCT/Ps, labeling for somatic cell therapy products must meet the requirements in 21 CFR
1271.250. For autologous donors and other situations described in 21 CFR 1271.90(a) for
which a donor eligibility determination is not required, the applicable required labeling in 21
CFR 1271.90(b) must be included. For example, for autologous cells intended for autologous
use the product must be labeled “FOR AUTOLOGOUS USE ONLY” (21 CFR 1271.90(b)(1)),
and “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” if donor testing and screening is
not performed (21 CFR 1271.90(b)(2)).]
7.8.1
Vial Label
7.8.2
Shipping Box Label
7.8.3
Syringe Label
7.9 Product Tracking
[INSTRUCTIONS: Establish a product tracking and segregation system. An adequate system
should allow identification of the therapeutic product from collection to administration of the
product and should include procedures to ensure that the product is segregated from other
products in incubators, hoods, and cryopreservation units. Establish and maintain a system of
tracking that enables the tracking of all products from the donor to the consignee or final
disposition, and from consignee or final disposition to donor (21 CFR 1271.290(b)). In INDs for
somatic cell therapy products, typically the processor would consign the product to the
investigator, thus the investigator is the consignee.]
7.10
Environmental Exemption
[INSTRUCTIONS: A statement regarding whether or not the investigational drug product
qualifies for a categorical exclusion from or the submission of an environmental assessment
per 21CFR312.23 (a)(7)(iv)(e) belongs here.
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Usually, for an IND, a claim for categorical exclusion is requested under 21CFR25.31 or an
environmental assessment under 21CFR25.40 is provided].
Below are the links to 21CFR25.31 and 21CFR25.40 regulations.

21CRF25.31:Claim for categorical exclusion (Human drugs and biologics)

21CFR25.40:Environmental assessment
7.11
Biostatistics
[INSTRUCTIONS: There are many significant design and analysis issues in the areas of
assay validation, establishing specifications, evaluation of product potency, and evaluation of
product stability. Proper statistical design and analysis information for such studies should be
provided in the CMC to assure reliable documentation of the safety, purity, and potency of the
product.
7.12
Attachments
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Section 8: Pharmacology and Toxicology
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23 (a)(8)
Pharmacology and toxicology information: Adequate information about pharmacological and
toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which
the sponsor has concluded that it is reasonably safe to conduct the proposed clinical
investigations. The kind, duration, and scope of animal and other tests required varies with the
duration and nature of the proposed clinical investigations. Guidance documents are available
from FDA that describe ways in which these requirements may be met. Such information is
required to include the identification and qualifications of the individuals who evaluated the
results of such studies and concluded that it is reasonably safe to begin the proposed
investigations and a statement of where the investigations were conducted and where the
records are available for inspection. As drug development proceeds, the sponsor is required to
submit informational amendments, as appropriate, with additional information pertinent to
safety.
(i) A section describing the pharmacological effects and mechanism(s) of action of the drug in
animals, and information on the absorption, distribution, metabolism, and excretion of the drug,
if known.
(ii)(a) An integrated summary of the toxicological effects of the drug in animals and in vitro.
Depending on the nature of the drug and the phase of the investigation, the description is to
include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on
reproduction and the developing fetus; any special toxicity test related to the drug's particular
mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology); and
any in vitro studies intended to evaluate drug toxicity.
(ii)(b) For each toxicology study that is intended primarily to support the safety of the proposed
clinical investigation, a full tabulation of data suitable for detailed review.
(iii) For each nonclinical laboratory study subject to the good laboratory practice regulations
under part 58, a statement that the study was conducted in compliance with the good
laboratory practice regulations in part 58, or, if the study was not conducted in compliance with
those regulations, a brief statement of the reason for the noncompliance.]
CITED GUIDANCES
1
FDA Guidance for Industry-Guidance for Human Somatic Cell Therapy and Gene
Therapy, March 1998
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ADDITIONAL GUIDANCE RESOURCES: Below are links for various guidance documents
and resource sites regarding nonclinical safety testing and GLP:
FDA list of International Conference on Harmonisation – Safety Guidance
Documents:
FDA Pharm/Tox guidance documents
Q & A- Content and Format of INDs for Phase 1 Studies of Drugs, Including WellCharacterized, Therapeutic, Biotechnology-Derived Products, for answers to
questions concerning pharmacology and toxicology (CDER)
Providing Clinical Effectiveness of Human Drugs and Biological Products
FDA Good Laboratory Practices
FDA Guidance for Industry – cGMP for Phase I Investigational Drugs
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8.0
Pharmacology and Toxicology
[GENERAL INSTRUCTIONS: Under each of the following headings are listed the requirements for
this section as per the regulatory reference and specific FDA guidances cited above.]
8.1
Pharmacology and Drug Distribution:
[INSTRUCTIONS: If known, provide a brief (less than 5 pages) summary describing
pharmacologic effects and mechanism of action of drug in animals; and absorption,
distribution, metabolism and excretion of the drug. The regulations do not further
describe the presentation of these data, in contrast to the more detailed description of
how to submit toxicologic data. A summary report, without individual animal records or
individual study results, usually suffices. In most circumstances, five pages or less
should suffice for this summary. If this information is not known, it should simply be so
stated.
To the extent that such studies may be important to address safety issues, or to assist
in evaluation of toxicology data, they may be necessary; however, lack of this potential
effectiveness information should not generally be a reason for a Phase 1 IND to be
placed on clinical hold.]
8.2
Integrated Toxicology Summary (showing toxicologic effects in animals and in
vitro)
[INSTRUCTIONS: Depending pending on the phase of the trial and the nature of the
drug results, here should be included acute, subacute and chronic toxicity tests; effects
on reproduction and the developing fetus; special tests related to the drug's specific
mode of administration or conditions of use; and any in vitro studies intended to
evaluate drug toxicity. When species specificity, immunogenicity, or other
considerations appear to make many or all toxicological models irrelevant, sponsors
are encouraged to contact the FDA to discuss toxicological testing.
For each toxicology study supporting the safety of the proposed clinical study, also
provide a full tabulation of data that is suitable for a detailed review.
1) Data may be submitted as an integrated summary from unaudited but completed
individual toxicologic studies.
2) Full toxicology individual, quality assured study reports and documents as well as a
final integrated summary based on final quality assured reports must be made
available to FDA (upon request for all but the final integrated summary) within 120
days of the start of the trial. Regardless of whether or not any changes are made
between the initial integrated report submission and the final quality assured
version must be stated.
3) The integrated summary is:
 10-15 pages of text with tables or other visual presentation aids (e.g., box
plots, stem and leaf displays, histograms or distributions of lab results over
time) as required
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 The sponsor's evaluation of the animal studies that support the contention that
the drug is safe for human trials. Must be updated as any new results become
available
 A brief description of the studies, any deviations from the design in the conduct
of the trials, and dates studies were performed. Reference to the study protocol
and protocol amendments may suffice for some of this information.
 A systematic presentation (proceeding through different body systems) of the
animal toxicology and toxicokinetic studies highlighting potential indications of
human risk. Again, the format of this part of the summary may be approached
from a "systems review" perspective: (e.g., CNS, cardiovascular, pulmonary,
gastrointestinal, renal, hepatic, genitourinary, hematopoietic and immunologic,
and dermal). If a product's effects on a particular body system have not been
assessed, that should be so noted. If any well documented toxicological "signal"
is not considered evidence of human risk, the reason should be given. Whether
or not the drug's effects were not studied in a particular body system and if the
toxicology findings are presented in the Investigator's Brochure must be stated.
4) The identity and qualifications of the individual who reviews the animal toxicology
data and concludes that human testing is safe must be provided. This individual
must also sign the summary to attest to its accuracy. This information may also
be provided in the Toxicology-Full Data Tabulation section.
5) A summary of the location of the animal studies as well as the primary records for
potential inspections must be stated. This information can also be provided in the
Toxicology-Full Data Tabulation section.
6) A statement that confirms that each of the studies cited were carried out in
compliance with the Good Laboratory Practice regulations (GLP's) per 21CFR58
must be included here. If there were any instances of noncompliance the sponsorinvestigator must provide a brief justification for the noncompliance which includes
a statement regarding how these breaches in GLP compliance may affect the
results of these studies. This information can also be provided in the ToxicologyFull Data Tabulation section.
NOTE: The information described in paragraphs "4", "5", and "6" may be supplied
as part of the integrated summary or as part of the full data tabulations described
below.
8.3
Toxicology -Full Data Tabulation
[INSTRUCTIONS: The sponsor-investigator should submit, for each animal toxicology
study that is intended to support the safety of the proposed clinical investigation, a full
tabulation of data suitable for detailed review. This should consist of line listings of the
individual data points. To allow interpretation of the line listings, accompanying the line
listings should be either: 1) a brief (usually a few pages) description (i.e., a technical
report or abstract including a methods description section) of the study or 2) a copy of
the study protocol and amendments.]
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8.3.1
Study Reports
[INSTRUCTIONS: A summary of toxicity studies performed is required here and
can be presented in tabular form. The following information should be reported for
each study:
Study Type (i.e. pharmacokinetics, hematologic toxicity/escalating doses, etc.)
For Somatic Cell therapy studies1 In vivo biological/pharmacological activity: The
transduction procedure, dose of expanded or genetically modified cells, and route
of administration planned for the clinical trial should be evaluated preclinically.
Pharmacologic studies in animals may provide useful information regarding the in
vivo function, survival time and appropriate trafficking of the modified cells.
Animal Model
For Somatic Cell therapy studies1: Preclinical pharmacologic and safety testing
of these agents should employ the most appropriate, pharmacologically relevant
animal model available. A relevant animal species would be one in which the
biological response to the therapy would be expected to mimic the human
response.
Drug dose tested
Self-explanatory
Parameters Monitored
For Somatic Cell Therapy Toxicology studies1:
o
Data on distribution, trafficking, and persistence of these cells in vivo
should be evaluated in animals for safety implications as well as for
pharmacologic information.
o
At a minimum, treated animals should be monitored for general health
status, serum biochemistry, and hematologic profiles.
o
Target tissues should be examined microscopically for histopathological
changes.
Time Points Assayed
Self-explanatory
Results
Self-explanatory
Conclusions
Self-explanatory
NOTE: A reference section should also be included here.]
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Section 9: Previous human experience
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(9) – Previous human experience with the
investigational drug. A summary of previous human experience known to the applicant, if any, with
the investigational drug. The information is required to include the following:
(i) If the investigational drug has been investigated or marketed previously, either in the United
States or other countries, detailed information about such experience that is relevant to the safety
of the proposed investigation or to the investigation's rationale. If the drug has been the subject of
controlled trials, detailed information on such trials that is relevant to an assessment of the drug's
effectiveness for the proposed investigational use(s) should also be provided. Any published
material that is relevant to the safety of the proposed investigation or to an assessment of
the drug's effectiveness for its proposed investigational use should be provided in full.
Published material that is less directly relevant may be supplied by a bibliography.
(ii) If the drug is a combination of drugs previously investigated or marketed, the information
required under paragraph (a)(9)(i) of this section should be provided for each active drug
component. However, if any component in such combination is subject to an approved marketing
application or is otherwise lawfully marketed in the United States, the sponsor is not required to
submit published material concerning that active drug component unless such material relates
directly to the proposed investigational use (including publications relevant to componentcomponent interaction).
(iii) If the drug has been marketed outside the United States, a list of the countries in which the
drug has been marketed and a list of the countries in which the drug has been withdrawn from
marketing for reasons potentially related to safety or effectiveness.
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9. Previous human experience
[INSTRUCTIONS: Provide the information requested per the above regulatory requirements. Insert
subheadings as needed for the information provided. For each study cited, the information presented
should include any of the following which are applicable:






Number of patients treated and/or evaluated
Drug Dosing, Scheduling Plan and Number of Patients Assigned to a Dose Level
Safety and Toxicity Results
Efficacy Evaluated through Surrogate Endpoints
Clinical Efficacy
Pertinent Observations
If there is no previous human experience data, insert text stating that there is no previous human
experience here.]
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Section 10: Additional Information
[SECTION INTRODUCTION: The requirements for this section of the IND application are
provided below. NOTE: Some of the information included may not be applicable to all IND
applications.
General instructions and comments on the format and content of this section of the IND
application, along with a list of guidance documents and additional regulation references, are
provided. Within each subheading of this section are additional instructions, comments,
suggested text, web addresses for forms, web addresses for specific guidance documents,
and/or regulations.]
[REGULATORY REFERENCE: 21CFR312.23(a)(10) - Additional information. In certain IND
applications, as described below, information about special topics may be needed. Such information
should be submitted in this section as follows:]
(i)
Drug dependence and abuse potential. If the drug is a psychotropic substance or
otherwise has abuse potential, a section describing relevant clinical studies and
experience and studies in test animals.]
(ii)
Radioactive drugs. If the biologic is radioactive, sufficient data from animal or human
studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and
critical organs upon administration to a human subject. Phase 1 studies of radioactive
biologics must include studies which will obtain sufficient data for dosimetry calculations.]
(iii)
Pediatric studies. Plans for assessing pediatric safety and effectiveness]
(iv)
Other information. A brief statement of any other information that would aid evaluation of
the proposed clinical investigations with respect to their safety or their design and potential
as controlled clinical trials to support marketing of the drug.]
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10.
Additional information
[INSTRUCTIONS: Under each heading below are listed the regulatory requirements per the above
regulatory reference. Note: Each section should be addressed and, if not applicable, state “not
applicable” and provide an explanation as to why it does not apply here.]
10.1
Drug dependence and abuse potential
[INSTRUCTIONS: Drug dependence and abuse potential. If the investigational biological product
is a psychotropic substance or has other abuse potential, a section describing relevant clinical
studies and experience and studies in test animals should be included here. A link is provided
below for the FDA draft guidance on assessment of abuse potentials.]
[FDA DRAFT Guidance: Assessment of Abuse Potential of Drugs ]
10.2
Radioactive drugs
[INSTRUCTIONS: If this application involves an investigational therapeutic radioactive biological
product, please discuss the placement of information within the application with the Research
Navigators. For more information on radioactive drugs, please review information available at the
FDA‟s Medical Imaging and Drug Development website (provided below).]
[FDA Medical Imaging and Drug Development website]
10.3
Pediatric studies
[INSTRUCTIONS: Describe the plans for assessing pediatric safety and effectiveness here. If there
are no plans to assess pediatric safety or efficacy, explain why here. The FDA site on Pediatric Drug
Development has more information on pediatric safety and effectiveness assessment and their web
address is provided below.
[FDA Pediatric Drug Development website]
10.4
Other information
[INSTRUCTIONS: Provide any additional information here which, in your opinion, will add to the FDA
review of this IND application (e.g. pre-IND meeting information materials such as information
package, meeting minutes, etc.)]
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Section 11: Relevant Information
[SECTION INSTRUCTIONS: Per regulatory requirements, include in this section any relevant
information requested by the FDA that may be needed for the review of this IND application.]
[REGULATORY REFERENCE: 21CFR312.23(a)(10) - Relevant information. If requested by FDA,
any other relevant information needed for review of the application.]
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11.0
Relevant Information
[INSTRUCTIONS: Per the section instructions and regulatory reference, provide any relevant
information the FDA requested be submitted with the application. If the FDA did not make such a
request, then either remove this section or insert text stating the FDA did not request relevant
information be submitted with this application.]
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Section 12: Bibliography
[SECTION INSTRUCTIONS: Provide a list of references cited in the IND application here. Note: The
bibliographical information may instead be provided after each of the above IND application sections.
If the Sponsor-Investigator chooses to do this, delete this section here and from the table of contents.]
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12.
Bibliography
[INSTRUCTIONS: Insert bibliography/literature cited.]
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Section 13: Appendices
[SECTION INSTRUCTIONS: Provide a list of the appendices in order of appearance in the
sections of the IND application. Before each appendix, include a cover page describing the
document(s) that will be found in that appendix.]
[ADDITIONAL INSTRUCTIONS - Copies of selected papers referenced in the IND application:
While not required, it is strongly suggested that the Sponsor-Investigator provide copies of key papers
that are referenced in the body of the IND application. Providing copies of any key papers will make it
easier for the FDA reviewers to access the papers if they want more information. As with the other
Appendices, include a cover page with this appendix, listing in order of appearance the citations for
the papers being submitted with the IND application.]
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ICTR DDRS: IND Application Guidance & Template for Biological Products (Somatic Cell Therapy) Version 1.0
13. Appendices
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