NOTES to Sponsor-Investigators

Confidential

IND Application - [Date] page iv

[Sponsor-Investigator Name]

Investigational New Drug Application

21

Confidential

IND Application - [Date]

[Sponsor-Investigator Name]

SECTION 1. FORM FDA 1571 & FORM FDA 3674

-  Insert the completed Form 1571 and Form 3674 as Section 1 after this page

SECTION 2. TABLE OF CONTENTS

Section Page

SECTION 1. FORM FDA 1571 & FORM FDA 3674 2

SECTION 2. TABLE OF CONTENTS 3

SECTION 3. INTRODUCTORY STATEMENT AND GENERAL INVESTIGATIONAL PLAN 4

3.1 Introductory Statement 4

3.2 General Investigational Plan 4

SECTION 4. INVESTIGATOR’S BROCHURE (IB) 6

SECTION 5. PROTOCOL 8

5.1 Study Protocol 9

5.1.1 Consent Form 11

5.2. Investigator and Facilities Information 12

5.2.1 Principal Investigator 12

5.2.2 Form FDA 1572 13

5.2.3 Principal Investigator Curriculum Vitae 14

5.2.4 Co-Investigator Credentials 15

5.3 Colorado Multiple Institutional Review Board (COMIRB) Information 16

SECTION 6. CHEMISTRY, MANUFACTURING, AND CONTROL DATA 17

6.1 Letter of Authorization to Cross-Reference 18

6.2 Response to Gene Therapy Letter 18

6.3 Product Substance/Components 18

6.4 Final Product 18

6.5. Placebo Product 18

6.6. Labeling 18

6.7 Environmental Exemption Claim 19

SECTION 7. PHARMACOLOGY AND TOXICOLOGY DATA 20

7.1 Pharmacology 20

7.2 Safety Pharmacology 20

7.3 Pharmacokinetics 20

7.4 Pharmacology Summary 20

7.5 Pharmacology Conclusions 21

SECTION 8. PREVIOUS HUMAN EXPERIENCE 22

8.1 Marketed Experience 22

8.2 Clinical Research Experience 22

8.3 Off-Label Experience 22

SECTION 9. ADDITIONAL INFORMATION 23

9.1 Letter of Authorization to Cross-Reference 23

9.2 Additional information 24

SECTION 3. INTRODUCTORY STATEMENT AND GENERAL INVESTIGATIONAL PLAN

Instructions and Guidance:

-  The information in this section should place the developmental plan for the investigational agent into perspective and allow FDA to anticipate your needs.

-  This section should average 2-3 pages.

-  Sponsor-Investigators may provide information regarding the introductory statement and investigational plan in the cover letter.

-  Remember to delete all instructions and guidance from the submitted application.

3.1 Introductory Statement

Provide a brief summary of the objectives of the research plan(s) submitted in this IND application. This should include a brief discussion of the disease state to be assessed.

[For studies referencing another IND and/or marketed products:]

Provide a brief statement that includes the name of the drug, and the name and address of the manufacturer. The statement should contain a reference to the package insert or Letter of Authorization to cross-reference another IND in order to address the requirements to identify the drug, its active ingredients, structural formula and formulation.

Include a brief summary of the route of administration and planned exposure (e.g., duration of study drug administration). If it applies, include a statement that the drug will be used in the same dose, duration, route of administration as described in the labeling.

Note: Append the package insert in section 4 (Investigator’s Brochure) if applicable. Append the Letter of Authorization to cross-reference in section 9 (Additional Information).

[For studies not using a cross-reference:]

Provide a brief introductory statement including the drug name, all active ingredients), pharmacological class, structural formula (if known), formulation and dose, route of administration, and planned exposure (e.g., duration of study drug administration).

Provide a high level summary of preclinical data to date including mechanism of action, efficacy and safety. Content should be a brief synopsis of section 7 (Pharmacology and Toxicology Data).

Provide a high level summary of prior human experience with the investigational drug. Content should be a brief synopsis of section 8 (Previous Human Experience). Include a statement about whether the drug has been withdrawn from investigation or marketing in any country for reason related to safety or efficacy. Cite the reason for the withdrawal.

3.2 General Investigational Plan

Discuss the rationale for the use of the drug and the specific study (ies).

Include the indication(s) to be studied, overall objectives, study design, estimated enrollment in the trial, treatment plan, and anticipated risks based on preclinical and clinical experiences with the drug.

Note: Indicate whether research plans are developed for the entire year.

SECTION 4. INVESTIGATOR’S BROCHURE (IB)

Instructions and Guidance:

-  Sponsor-Investigators are not required to submit an Investigator’s Brochure for a single center study. An Investigator’s Brochure is required for multi-center studies.

-  A cross-reference letter or package insert may be submitted in lieu of required information for the Investigator’s Brochure.

-  The package insert may be found in the Physician’s Desk Reference, the FDA website, or the United States Pharmacopoeia – National Formulary.

-  Remember to delete all instructions and guidance from the submitted application.

[For studies limited to UCD:]

Include a statement that the IND meets the requirements for a Sponsor-Investigator single center study, and that under the provisions of 21 CFR 312.55, an Investigator’s Brochure is not required.

[For studies referencing another IND and/or marketed products:]

Provide a brief statement that references the package insert or Letter of Authorization to cross-reference another IND in order to address the requirements of an Investigator’s Brochure.

Notes: Append a copy of the package insert behind this page. Append the Letter of Authorization to cross-reference in section 9 (Additional Information).

[For multi-center studies not using a cross-reference:]

Provide an Investigator’s Brochure. The outline below embodies the elements of an Investigator’s Brochure according to Good Clinical Practice. For detailed guidance related to content of the sub-sections, refer to the ICH Guidance for Good Clinical Practice. (See http://www.ich.org - Efficacy Guidelines – E6.)

4.1 Title Page

4.2 Table of Contents

4.3 Summary

4.4 Introduction

4.5 Physical, Chemical, and Pharmaceutical Properties and Formulation

4.6 Nonclinical Studies

4.6.1  Non-Clinical Pharmacology

4.6.2  Pharmacokinetics and Product Metabolism in Animals

4.6.3  Toxicology

4.7 Effects in Humans

4.7.1  Pharmacokinetics and Product Metabolism in Humans

4.7.2  Safety and efficacy

4.7.3  Marketing Experience

4.8 Summary of Data and Guidance for the Investigator

4.9 References

SECTION 5. PROTOCOL

Instructions and Guidance:

-  A separate title page should be included for each section.

-  The study protocol should use the standard UCD protocol format.

-  Remember to delete all instructions and guidance from the submitted application.

Section Page

5.1  Study Protocol

5.1.1 Consent Form

5.2  Investigator and Facilities Information

5.2.1  Principal Investigator

5.2.2  Form FDA 1572

5.2.3  Principal Investigator Curriculum Vitae

5.2.4  Co-investigator Credentials

5.3  Institutional Review Board Information

Instructions and Guidance:

-  List all protocols by title on this face sheet in the order they are attached.

-  Include copies of all protocols to be conducted under this IND application.

-  Remember to delete all instructions and guidance from the submitted application.

5.1 Study Protocol

Insert Protocol(s) on next page.

Instructions and Guidance:

-  Insert the study protocol(s) at this point.

-  Phase 1 studies should provide an outline of the investigation including a statement of the objectives and purpose of the investigation, an estimate of subjects to be studied, a description of safety exclusions, a description of dosing plan (duration, dose, method used to determine dose), measures to ensure and evaluate subject safety (e.g., performance of blood chemistries, and toxicity-based stopping or dose adjustment rules).

-  Phase 2 and 3 protocols should include alternative plans to address anticipated deviations (i.e. early crossover of non-responders to alternative therapy).

-  Remember to delete all instructions and guidance from the submitted application.

Instructions and Guidance:

-  List protocol title(s) for which consent forms are attached. List in the order they are attached.

-  Include copies of all consent forms for protocols noted in the protocol section.

-  For gene therapy studies, the gene therapy component of the treatment and any associated risks to the subject should be clearly identified in the consent form.

-  Remember to delete all instructions and guidance from the submitted application.

5.1.1 Consent Form

Insert Protocol Consent Form(s) on next page.

Instructions and Guidance:

-  Remember to delete all instructions and guidance from the submitted application.

5.2. Investigator and Facilities Information

5.2.1 Principal Investigator

The principal investigator for the protocol entitled “insert protocol name” is [name of PI].

His/Her office is located at:

University of Colorado Denver Anschutz Medical Campus

Department of supply correct department name

Street Address, Building and room #

Aurora, CO 80045

Instructions and Guidance:

-  The current version of this form may be downloaded from the FDA web site at:

http://www.fda.gov/opacom/morechoices/fdaforms/cder.html

-  The names of each co-investigator, research fellow, resident, or other clinical staff working under the supervision of the Sponsor-Investigator should be included in Item 6 of the Form 1572.

-  The Sponsor-Investigator signs the Form 1572.

-  Remember to delete all instructions and guidance from the submitted application.

5.2.2 Form FDA 1572

Insert Form 1572 on next page.

Instructions and Guidance:

-  The Principal Investigator should sign and date the CV in the upper right corner.

-  Remember to delete all instructions and guidance from the submitted application.

5.2.3 Principal Investigator Curriculum Vitae

Insert CV on next page.

Instructions and Guidance:

-  Each co-investigator should sign and date the respective biosketch or CV in the upper right corner.

-  Remember to delete all instructions and guidance from the submitted application.

5.2.4 Co-Investigator Credentials

Insert co-investigator credentials (i.e., biosketch or CV) on the next page.

Instructions and Guidance:

-  Indicate if COMIRB approval is pending.

-  For multi-center studies (more than one IRB of record), indicate the IRB approval status for each research institution and provide the name and address of the corresponding IRB.

-  Remember to delete all instructions and guidance from the submitted application.

5.3 Colorado Multiple Institutional Review Board (COMIRB) Information

The protocol entitled “[insert protocol name]” select the appropriate text

has not been submitted to the local Institutional Review Board. The Certificate of Approval will be forwarded to FDA upon receipt.

Or

has been submitted to the local Institutional Review Board. IRB approval is pending. The Certificate of Approval will be forwarded to FDA upon receipt.

The protocol [select best response: will be or was] reviewed by:

Colorado Multiple Institutional Review Board

13007 E. 17th Place

Aurora, CO 80045

SECTION 6. CHEMISTRY, MANUFACTURING, AND CONTROL DATA

Instructions and Guidance:

-  The information in this section should assure the proper identification, quality, purity, and strength of the investigational drug and provide information to evaluate drug safety.

-  A cross-reference letter or package insert may be submitted in lieu of required information on chemistry, manufacturing, and control data.

-  The package insert may be found in the Physician’s Desk Reference, the FDA website, or the United States Pharmacopoeia – National Formulary.

-  If the proposed dose, route, frequency of dosing and duration of therapy do not exceed the approved labeled dosing regimen, the investigator-sponsor may provide the product’s labeling information and state in the non-clinical section of the application that they believe their IND application may rely on the previous FDA’s acceptance of the CMC and/or Pharmacology and Toxicology information related to the approved marketed drug intended for this investigation.

-  Remember to delete all instructions and guidance from the submitted application.

-  Delete any sub-section if not applicable.

Section Page

6.1  Letter of Authorization to Cross-Reference (if applicable)

6.2  Response to Gene Therapy Letter (if applicable)

6.3  Product Substance/Components (if applicable)

6.4  Final Product (if applicable)

6.5  Placebo Product (if applicable)

6.6  Labeling (if applicable)

6.7  Environmental Exemption Claim

Instructions and Guidance:

6.1 Letter of Authorization to Cross-Reference

[For studies referencing another IND and/or marketed products:]

Provide a brief statement that includes a reference to the package insert or Letter of Authorization to cross-reference another IND in order to address the requirements for chemistry, manufacturing, and control information.

If the proposed dose, route, frequency of dosing and duration of therapy do not exceed the approved labeled dosing regimen, the investigator-sponsor may provide the product’s labeling information and state in the non-clinical section of the application that they believe their IND application may rely on the previous FDA’s acceptance of the CMC and/or Pharmacology and Toxicology information related to the approved marketed drug intended for this investigation.

Note: Append the package insert in section 4 (Investigator’s Brochure). Append the Letter of Authorization to cross-reference in section 9 (Additional Information).

6.2 Response to Gene Therapy Letter

[For gene therapy studies]

Information requested in the FDA’s March 6, 2000, Gene Therapy Letter should be provided as part of the IND application. (See http://www.fda.gov/cber/ltr/gt030600.htm.)

Note: Responses to items 1-5 of the letter may be cross-referenced, if applicable. Responses to item 6 of the letter may be addressed by the UCD Institutional Data and Safety Monitoring Plan included in section 9 of this IND application. Responses to item 7 of the letter may be included in the cover letter that accompanies this IND application.

6.3 Product Substance/Components

[For studies not using a cross-reference]

6.4 Final Product

[For studies not using a cross-reference]

6.5. Placebo Product

[For studies not using a cross-reference]

6.6. Labeling

[For studies not using a cross-reference]

Describe the composition, manufacture, and control of the bulk substance and final product. Pertinent information includes the name and address of the manufacturer, methods of manufacture, container/closure system(s), analytical methods, and stability testing. Additional information may include descriptions of any placebo used in the clinical trial, and labeling to be provided to investigators.

The amount of supporting information varies with the investigational phase and product used in the clinical trial. For detailed information on the content of this section, refer to the appropriate FDA guidance document.