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IND Application - [Date][Sponsor-Investigator Name]

Investigational New Drug Application

Regulatory Sponsor: Provide name of Sponsor-Investigator, department name, address, and phone number during working hours

Funding Sponsor: Provide name of primary funding institution, address, and phone number during working hours

Study Product: Provide study drug name - generic, followed by trade name(s), if applicable

Protocol Number: Provide COMIRB protocol number if availableDate: Provide date submitted to FDA

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SECTION 1. FORM FDA 1571 & FORM FDA 3674

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

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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.......................................................................................................................43.2 GENERAL INVESTIGATIONAL PLAN................................................................................................................4

SECTION 4. INVESTIGATOR’S BROCHURE (IB)....................................................................................6

SECTION 5. PROTOCOL..................................................................................................................... 8

5.1 STUDY PROTOCOL.....................................................................................................................................95.1.1 Consent Form.......................................................................................................................11

5.2. INVESTIGATOR AND FACILITIES INFORMATION..............................................................................................125.2.1 Principal Investigator..................................................................................................................125.2.2 Form FDA 1572............................................................................................................................135.2.3 Principal Investigator Curriculum Vitae.......................................................................................145.2.4 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........................................................................................186.2 RESPONSE TO GENE THERAPY LETTER.........................................................................................................186.3 PRODUCT SUBSTANCE/COMPONENTS.........................................................................................................186.4 FINAL PRODUCT.....................................................................................................................................186.5. PLACEBO PRODUCT................................................................................................................................186.6. LABELING.............................................................................................................................................186.7 ENVIRONMENTAL EXEMPTION CLAIM.........................................................................................................19

SECTION 7. PHARMACOLOGY AND TOXICOLOGY DATA...................................................................20

7.1 PHARMACOLOGY....................................................................................................................................207.2 SAFETY PHARMACOLOGY..........................................................................................................................207.3 PHARMACOKINETICS................................................................................................................................207.4 PHARMACOLOGY SUMMARY.....................................................................................................................207.5 PHARMACOLOGY CONCLUSIONS................................................................................................................21

SECTION 8. PREVIOUS HUMAN EXPERIENCE....................................................................................22

8.1 MARKETED EXPERIENCE...........................................................................................................................228.2 CLINICAL RESEARCH EXPERIENCE................................................................................................................228.3 OFF-LABEL EXPERIENCE...........................................................................................................................22

SECTION 9. ADDITIONAL INFORMATION.........................................................................................23

9.1 LETTER OF AUTHORIZATION TO CROSS-REFERENCE........................................................................................239.2 Additional information.......................................................................................................................24

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SECTION 3. INTRODUCTORY STATEMENT AND GENERAL INVESTIGATIONAL PLANInstructions 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 StatementProvide 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 PlanDiscuss 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.

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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

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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

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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 Protocol5.1.1 Consent Form

5.2 Investigator and Facilities Information5.2.1 Principal Investigator5.2.2 Form FDA 15725.2.3 Principal Investigator Curriculum Vitae5.2.4 Co-investigator Credentials

5.3 Institutional Review Board Information

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Newman, Heike, 12/11/13,

Required for PET IND studies

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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.

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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.

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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.

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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 CampusDepartment of supply correct department nameStreet Address, Building and room #Aurora, CO 80045

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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 1572Insert Form 1572 on next page.

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

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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.

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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.

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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 Board13007 E. 17th PlaceAurora, CO 80045

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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

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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.

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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.

Phase 1: FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products. (See http://www.fda.gov/cder/guidance/phase1.pdf.)

Phase 2 and 3: FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information. (See http://www.fda.gov/cder/guidance/3619fnl.pdf.)

Gene Therapy: Draft Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). (See http://www.fda.gov/cber/gdlns/gtindcmc.htm.)

6.7 Environmental Exemption Claim

Most drugs qualify for a categorical exclusion from an environmental assessment. The categorical exclusion claim is a statement that the investigational product meets the exclusion categories as not having a significant effect on the quality of the human environment. The exclusion claim should include statements that: the action qualifies for a categorical exclusion, with a citation to the regulations for the specific categorical exemption claimed, and that to the applicant’s knowledge, no circumstances exist that would warrant an environmental assessment.

[Sample text:]In accordance with 21 CFR 25.30/25.31, [add Sponsor-Investigator name] requests a categorical exclusion from the requirement for an environmental assessment for the manufacture and formulation of [drug name] for use in human clinical trials. All waste from the investigational drug(s) will be properly controlled. The amount of waste expected to enter the environment may reasonably be expected to be nontoxic.

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http://www.fda.gov/cber/gdlns/gtindcmc.htm

http://www.fda.gov/cder/guidance/3619fnl.pdf

http://www.fda.gov/cder/guidance/phase1.pdf

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SECTION 7. PHARMACOLOGY AND TOXICOLOGY DATA

Instructions and Guidance:- A cross-reference letter or package insert may be submitted in lieu of required information on

pharmacology and toxicology 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.

[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 for available pharmacology and toxicology data.

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

[For gene therapy studies:]Add the following statement where appropriate: Animal safety information provided to [add Sponsor-Investigator name] has been submitted as described in 21 CFR 312.32-33.

[For studies not using a cross-reference:]Describe the pharmacological effects and mechanism of action in animals, pharmacokinetics (absorption, distribution, metabolism, excretion), and toxicological effects in animals and in vitro. The outline below embodies the elements of pharmacology/toxicology reviews. For detailed guidance related to content of the sections, refer to the FDA guidance for Pharmacology/Toxicology review Format. (See http://www.fda.gov/cder/guidance//4120fnl.pdf).

[For PET IND studies:]Make sure you include animal and/or clinical pharmacology toxicology information that supports safety of‐ study/trial, Summary of previous PET drug clinical experience and an estimate of radiation absorbed dose ‐to body and critical organs, with justification.

7.1 Pharmacology

7.2 Safety Pharmacology

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7.3 Pharmacokinetics

7.4 Pharmacology Summary

7.5 Pharmacology Conclusions

7.6 Toxicology

7.7 Genetic Toxicology

7.8 Carcinogenicity

7.9 Reproductive and Developmental Toxicology

7.10 Special Toxicity Studies

7.11 Toxicology Summary

7.12 Toxicology Conclusions

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SECTION 8. PREVIOUS HUMAN EXPERIENCE

Instructions and Guidance:- A cross-reference letter or package insert may be submitted in lieu of required information on

previous human experience.- 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.- Delete any sub-section if not applicable.

[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 for information regarding previous human experience.

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

[For studies not using a cross-reference:]Summarize any relevant clinical information available. The sub-sections below should be considered.

8.1 Marketed Experience

Provide marketed indications for the study drug either in the US or abroad . If the drug was withdrawn from the market for any reason related to safety or effectiveness, identify the country (ies) where the drug was withdrawn and the reasons for withdrawal.

8.2 Clinical Research Experience

Summarize results from any clinical trials using the investigational drug. Include published research and any available unpublished research that relates to the safety and efficacy of the investigational drug or the rationale of the proposed trial. Attach full reprints for highly relevant publications. Supply a bibliography for lesser relevant publications.

8.3 Off-Label Experience

If available, indicate any published literature on the safety of the drug used in clinical care settings to treat patients for indications that do not have FDA approval, published practice guidelines of the use of the drug for standard-of-care, and any associated safety information.

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SECTION 9. ADDITIONAL INFORMATION

Instructions and Guidance:- Supply additional information if it is applicable to the investigational drug and/or study.- Remember to delete all instructions and guidance from the submitted application.- Delete any sub-section if not applicable.

9.1 Letter of Authorization to Cross-Reference

Attach the letter behind this page.

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9.2 Additional information[Add any additional pertinent information not already included in other sections, such as labels and labeling to be provided to investigators, drug dependence and abuse potential, radioactive drugs, pediatric safety and efficacy studies, or other information that would aid in the evaluation of the safety or design of the clinical investigation.]

Attach any additional pertinent information not already included in other sections behind this page.

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