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FDA Guidances

FDA Guidances

All Information was adapted from the Food and Drug Administration website as a service to our readers. The most current versions can be found on the FDA Website.

Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry

 

Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009

Guidance for Industry

CLICK HERE FOR FULL ARTICLE

 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry DRAFT GUIDANCE

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Sau L. Lee 240-506-9136.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2015 Pharmaceutical Quality/CMC

page1image8984 page1image9144

Advancement of Emerging

Technology Applications to

Modernize the Pharmaceutical

Manufacturing Base

Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

page2image5960

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2015 Pharmaceutical Quality/CMC

I. II. III.

A. B.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 DISCUSSION .................................................................................................................... 3 Scope ............................................................................................................................................... 3 Process............................................................................................................................................. 4

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Advancement of Emerging Technology Applications to Modernize

  2. 2 the Pharmaceutical Manufacturing Base

34 Guidance for Industry1

5 6 7 8 9

10 11

12
13
14
15
I. INTRODUCTION 16

  1. 17  This guidance provides recommendations to pharmaceutical companies interested in participating

  2. 18  in a program involving the submission of chemistry, manufacturing, and controls (CMC)

  3. 19  information containing emerging manufacturing2 technology to FDA. The program is open to

  4. 20  companies that intend the technology to be included as part of an investigational new drug

  5. 21  application (IND) or original or supplemental new drug application (NDA), abbreviated new

  6. 22  drug application (ANDA), or biologic license application (BLA) reviewed by the Center for

  7. 23  Drug Evaluation and Research (CDER), and where that technology meets other criteria described

  8. 24  in this guidance.

25

  1. 26  Issues in pharmaceutical manufacturing have the potential to significantly impact patient care in

  2. 27  that failures in quality may result in product recalls and harm to patients. Additionally, failures

  3. 28  in product or facility quality are a major factor leading to disruptions in manufacturing.

  4. 29  Modernizing manufacturing technology may lead to a more robust manufacturing process with

  5. 30  fewer interruptions in production, fewer product failures (before or after distribution), and

  6. 31  greater assurance that the drug products manufactured in any given period of time will provide

  7. 32  the expected clinical performance. For example, contemporary aseptic manufacturing facilities

  8. 33  that are highly automated and use isolators and other modern separation technologies have the

  9. 34  potential to decrease the risk of contamination from the processing line. Encouraging the

  10. 35  development of emerging manufacturing technology may lead to improved manufacturing, and

  11. 36  therefore improved product quality and availability throughout a product’s lifecycle.

37

  1. 38  In this program, pharmaceutical companies can submit pre-submission questions and proposals

  2. 39  about the use of specific emerging technology to a group within CDER (Emerging Technology

  3. 40  Team – ETT). The ETT will work in partnership with relevant pharmaceutical quality offices

  4. 41  and assume a leadership or co-leadership role for the cross-functional quality assessment team

    1 This guidance has been prepared by representatives from the Office of Pharmaceutical Quality and the Office of Compliance in the Center for Drug Evaluation and Research at the Food and Drug Administration.
    2 For the purpose of this guidance, the definition of manufacturing also includes testing, packaging and labeling operations, and quality control.

page4image26760

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

page4image40176
page4image41592

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 42  (including review and on-site Agency evaluation) for submissions involving emerging

  2. 43  technology. The ETT will serve as the primary point of contact for companies that are interested

  3. 44  in implementing emerging manufacturing technology in the manufacture of their drug products

  4. 45  and for the relevant quality assessment team to:

46
47 (a) 48
49
50 (b) 51
52
53
54 (c) 55
56
57
58 (d) 59
60

  1. 61  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 62  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 63  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 64  the word should in Agency guidances means that something is suggested or recommended, but

  5. 65  not required.

66
67
68
II. BACKGROUND 69

  1. 70  CDER is committed to supporting and enabling the modernization of pharmaceutical

  2. 71  manufacturing as part of the Agency’s mission to protect and promote the public health. These

  3. 72  efforts also may be one long-term solution to avoid drug shortages, as noted in FDA’s drug

  4. 73  shortage strategic plan.3 As part of its commitment to modernizing pharmaceutical

  5. 74  manufacturing, in 2002, FDA launched an initiative entitled “Pharmaceutical cGMPs for the 21st

  6. 75  Century: A Risk-Based Approach,” to encourage the implementation of a modern, risk-based

  7. 76  pharmaceutical quality assessment system.4 The initiative was published with several goals,

  8. 77  including encouraging the early adoption of new technological advances by the pharmaceutical

  9. 78  industry and ensuring that regulatory review, compliance, and inspection policies are based on

  10. 79  state-of-the-art pharmaceutical science. In 2004, this was further described in an FDA guidance

  11. 80  for industry entitled PAT—A Framework for Innovative Pharmaceutical Development,

  12. 81 Manufacturing, and Quality Assurance.5 This guidance describes the concept that quality cannot

    3 See http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf.
    4 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm137175.htm#_Toc84065754.

    5 See http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070305.pdf. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA

Answer sponsor/applicant questions about the information FDA expects to see in their submission;

Identify and help facilitate regulatory review of a new manufacturing technology in accordance with existing legal and regulatory standards, guidance, and Agency policy related to quality assessment;

Serve as the lead or co-lead on the quality assessment team, in partnership with relevant CDER pharmaceutical quality offices, to review and make the final quality recommendation regarding the potential approval of submissions in the program; and

Identify and capture resolution to policy issues that may inform FDA approaches and recommendations regarding future submissions that involve the same technology.

page5image28352 page5image28512 page5image28672 page5image28832 page5image28992

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 82  be tested into products; in other words, it should be built-in or should be present by design.

  2. 83  Quality is built into pharmaceutical products through a comprehensive understanding of the

  3. 84  intended use of the product, the characteristics of the product, and the design of the product and

  4. 85  manufacturing process using principles of engineering, material science, and quality assurance to

  5. 86  ensure acceptable and reproducible product quality and performance throughout a product’s

  6. 87  lifecycle.

88

  1. 89  While the implementation of emerging technology is critical to modernizing pharmaceutical

  2. 90  manufacturing and improving quality, FDA also recognizes that innovative approaches to

  3. 91  manufacturing may represent challenges to industry and the Agency. By the very nature of an

  4. 92  approach being innovative, a limited knowledge and experiential base about the technology may

  5. 93  exist. Pharmaceutical companies may have concerns that using such technologies could result in

  6. 94  delays while FDA reviewers familiarize themselves with the new technologies and determine

  7. 95  how they fit within existing regulatory approaches. Through the ETT, FDA intends to encourage

  8. 96  the adoption of innovative approaches to pharmaceutical manufacturing by leveraging existing

  9. 97  resources within the Agency to facilitate the regulatory review of submissions to the Agency

  10. 98  involving manufacturing technologies likely to improve product safety, identity, strength,

  11. 99  quality, and purity.

100
101
102
III. DISCUSSION 103

  1. 104  As part of this program, FDA intends to provide for early engagement and additional meeting

  2. 105  opportunities for the participants and FDA to discuss manufacturing design and development

  3. 106  issues as well as recommendations for submission content related to the emerging technology.

  4. 107  FDA intends to work with each participant on an individual basis, and expects that the process

  5. 108  will include appropriate coordination with the quality assessment team (FDA staff involved in

  6. 109  the review of the CMC sections of the application and evaluation of the manufacturing facilities).

  7. 110  Based on experience gained during the program, FDA intends to develop guidance and

  8. 111  standards, as necessary, on emerging technologies and approaches to enable the modernization of

  9. 112  the pharmaceutical manufacturing base.

113
114
A. Scope 115

  1. 116  Acceptance of a request to participate in this CDER program will depend on the applicant’s

  2. 117  proposed plan for submission of an IND or original or supplemental ANDA, BLA, or NDA,

  3. 118  based on the criteria described below. The planned submission should include one or more

  4. 119  elements subject to quality assessment for which the Agency has limited review or inspection

  5. 120  experience, where the technology has the potential to modernize the pharmaceutical

  6. 121  manufacturing body of knowledge to support more robust, predictable, or cost-effective

  7. 122  processes. Examples of such elements include an innovative or novel: (1) product manufacturing

  8. 123  technology, such as the dosage form; (2) manufacturing process (e.g., design, scale-up, and/or

  9. 124  commercial scale); and/or (3) testing technology. Every effort will be made to ensure that many

  10. 125  companies have the opportunity to participate and that a wide variety of novel manufacturing

    Drugs guidance Web page at

    http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

page6image30712 page6image30872

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 126  technologies are included in this program. This program only affects the quality section of the

  2. 127  submission (CMC and facility-related information). Existing requirements related to the review

  3. 128  and approval of a submission will not be waived, suspended, or modified for purposes of this

  4. 129  program. Applicants must make the submission in accordance with 21 CFR parts 312, 314, 601,

  5. 130  and other applicable standards.

131
132
B. Process 133

  1. 134  Interested parties planning to submit an IND or original or supplemental BLA or NDA as part of

  2. 135  this CDER program should submit a written request for a Type C meeting as described in the

  3. 136  guidance on Formal Meetings Between the FDA and Sponsors or Applicant.6 The request

  4. 137  should specify the meeting request as a “Type C meeting – request to participate in the ETT

  5. 138  program.” Interested parties planning to submit an ANDA should submit a pre-ANDA meeting

  6. 139  request and specify the meeting request as a “Pre-ANDA meeting – request to participate in the

  7. 140  ETT program.” Either type of request should be submitted at least three months prior to the

  8. 141  planned application (IND, ANDA, BLA, NDA) submission date. The meeting request and

  9. 142  related questions should be submitted electronically to This e-mail address is being protected from spambots. You need JavaScript enabled to view it . In addition to

  10. 143  the items outlined in the referenced guidance, the request should also include the following

  11. 144  items:

145
146 (1) 147
148 (2) 149
150
151 (3) 152
153
154

  1. 155  (4) A summary of the development plan and any perceived roadblocks to implementation

  2. 156  (e.g., technical or regulatory); and

157
158 (5) A timeline for a submission (IND, ANDA, BLA, NDA, original or supplemental). 159

  1. 160  The request document should generally not exceed five pages of narrative, including up to five

  2. 161  figures or tables. Based on the availability of Agency resources, we expect to limit acceptance

  3. 162  into the program to technologies that are likely to modernize pharmaceutical manufacturing in

  4. 163  order to improve product safety, identity, strength, quality, or purity, and with which the Agency

  5. 164  has limited prior experience and knowledge. FDA expects to notify companies of its decision

  6. 165  regarding acceptance into the program in writing within 60 days of receipt of the request.

  7. 166  Although incomplete and/or unclear requests will generally be denied, FDA may contact the

  8. 167  applicant to request additional information. Once accepted into the program, the participant can

    6 See http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf. 4

page7image25616

A brief description of the proposed testing, process, and/or proposed technology;

A brief explanation why the proposed testing, process, and/or technology are substantially novel and unique and should be considered under this program;

A description of how the proposed testing and/or technology could modernize pharmaceutical manufacturing and thus improve product safety, identity, strength, quality, or purity;

page7image29552 page7image29712

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 168  engage with the ETT and CMC review team in accordance with existing meeting procedures and

  2. 169  guidance(s)7 based on the availability of Agency resources.

page8image2768

7 See the guidances on Formal Meetings Between the FDA and Sponsors or Applicants (see information on “Type C” meetings) and Controlled Correspondence Related to Generic Drug Development.

5

 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry DRAFT GUIDANCE

page1image392

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Sau L. Lee 240-506-9136.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2015 Pharmaceutical Quality/CMC

page1image8984 page1image9144

Advancement of Emerging

Technology Applications to

Modernize the Pharmaceutical

Manufacturing Base

Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

page2image5960

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2015 Pharmaceutical Quality/CMC

I. II. III.

A. B.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 DISCUSSION .................................................................................................................... 3 Scope ............................................................................................................................................... 3 Process............................................................................................................................................. 4

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Advancement of Emerging Technology Applications to Modernize

  2. 2 the Pharmaceutical Manufacturing Base

34 Guidance for Industry1

5 6 7 8 9

10 11

12
13
14
15
I. INTRODUCTION 16

  1. 17  This guidance provides recommendations to pharmaceutical companies interested in participating

  2. 18  in a program involving the submission of chemistry, manufacturing, and controls (CMC)

  3. 19  information containing emerging manufacturing2 technology to FDA. The program is open to

  4. 20  companies that intend the technology to be included as part of an investigational new drug

  5. 21  application (IND) or original or supplemental new drug application (NDA), abbreviated new

  6. 22  drug application (ANDA), or biologic license application (BLA) reviewed by the Center for

  7. 23  Drug Evaluation and Research (CDER), and where that technology meets other criteria described

  8. 24  in this guidance.

25

  1. 26  Issues in pharmaceutical manufacturing have the potential to significantly impact patient care in

  2. 27  that failures in quality may result in product recalls and harm to patients. Additionally, failures

  3. 28  in product or facility quality are a major factor leading to disruptions in manufacturing.

  4. 29  Modernizing manufacturing technology may lead to a more robust manufacturing process with

  5. 30  fewer interruptions in production, fewer product failures (before or after distribution), and

  6. 31  greater assurance that the drug products manufactured in any given period of time will provide

  7. 32  the expected clinical performance. For example, contemporary aseptic manufacturing facilities

  8. 33  that are highly automated and use isolators and other modern separation technologies have the

  9. 34  potential to decrease the risk of contamination from the processing line. Encouraging the

  10. 35  development of emerging manufacturing technology may lead to improved manufacturing, and

  11. 36  therefore improved product quality and availability throughout a product’s lifecycle.

37

  1. 38  In this program, pharmaceutical companies can submit pre-submission questions and proposals

  2. 39  about the use of specific emerging technology to a group within CDER (Emerging Technology

  3. 40  Team – ETT). The ETT will work in partnership with relevant pharmaceutical quality offices

  4. 41  and assume a leadership or co-leadership role for the cross-functional quality assessment team

    1 This guidance has been prepared by representatives from the Office of Pharmaceutical Quality and the Office of Compliance in the Center for Drug Evaluation and Research at the Food and Drug Administration.
    2 For the purpose of this guidance, the definition of manufacturing also includes testing, packaging and labeling operations, and quality control.

page4image26760

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

page4image40176
page4image41592

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 42  (including review and on-site Agency evaluation) for submissions involving emerging

  2. 43  technology. The ETT will serve as the primary point of contact for companies that are interested

  3. 44  in implementing emerging manufacturing technology in the manufacture of their drug products

  4. 45  and for the relevant quality assessment team to:

46
47 (a) 48
49
50 (b) 51
52
53
54 (c) 55
56
57
58 (d) 59
60

  1. 61  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 62  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 63  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 64  the word should in Agency guidances means that something is suggested or recommended, but

  5. 65  not required.

66
67
68
II. BACKGROUND 69

  1. 70  CDER is committed to supporting and enabling the modernization of pharmaceutical

  2. 71  manufacturing as part of the Agency’s mission to protect and promote the public health. These

  3. 72  efforts also may be one long-term solution to avoid drug shortages, as noted in FDA’s drug

  4. 73  shortage strategic plan.3 As part of its commitment to modernizing pharmaceutical

  5. 74  manufacturing, in 2002, FDA launched an initiative entitled “Pharmaceutical cGMPs for the 21st

  6. 75  Century: A Risk-Based Approach,” to encourage the implementation of a modern, risk-based

  7. 76  pharmaceutical quality assessment system.4 The initiative was published with several goals,

  8. 77  including encouraging the early adoption of new technological advances by the pharmaceutical

  9. 78  industry and ensuring that regulatory review, compliance, and inspection policies are based on

  10. 79  state-of-the-art pharmaceutical science. In 2004, this was further described in an FDA guidance

  11. 80  for industry entitled PAT—A Framework for Innovative Pharmaceutical Development,

  12. 81 Manufacturing, and Quality Assurance.5 This guidance describes the concept that quality cannot

    3 See http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf.
    4 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm137175.htm#_Toc84065754.

    5 See http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070305.pdf. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA

Answer sponsor/applicant questions about the information FDA expects to see in their submission;

Identify and help facilitate regulatory review of a new manufacturing technology in accordance with existing legal and regulatory standards, guidance, and Agency policy related to quality assessment;

Serve as the lead or co-lead on the quality assessment team, in partnership with relevant CDER pharmaceutical quality offices, to review and make the final quality recommendation regarding the potential approval of submissions in the program; and

Identify and capture resolution to policy issues that may inform FDA approaches and recommendations regarding future submissions that involve the same technology.

page5image28352 page5image28512 page5image28672 page5image28832 page5image28992

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 82  be tested into products; in other words, it should be built-in or should be present by design.

  2. 83  Quality is built into pharmaceutical products through a comprehensive understanding of the

  3. 84  intended use of the product, the characteristics of the product, and the design of the product and

  4. 85  manufacturing process using principles of engineering, material science, and quality assurance to

  5. 86  ensure acceptable and reproducible product quality and performance throughout a product’s

  6. 87  lifecycle.

88

  1. 89  While the implementation of emerging technology is critical to modernizing pharmaceutical

  2. 90  manufacturing and improving quality, FDA also recognizes that innovative approaches to

  3. 91  manufacturing may represent challenges to industry and the Agency. By the very nature of an

  4. 92  approach being innovative, a limited knowledge and experiential base about the technology may

  5. 93  exist. Pharmaceutical companies may have concerns that using such technologies could result in

  6. 94  delays while FDA reviewers familiarize themselves with the new technologies and determine

  7. 95  how they fit within existing regulatory approaches. Through the ETT, FDA intends to encourage

  8. 96  the adoption of innovative approaches to pharmaceutical manufacturing by leveraging existing

  9. 97  resources within the Agency to facilitate the regulatory review of submissions to the Agency

  10. 98  involving manufacturing technologies likely to improve product safety, identity, strength,

  11. 99  quality, and purity.

100
101
102
III. DISCUSSION 103

  1. 104  As part of this program, FDA intends to provide for early engagement and additional meeting

  2. 105  opportunities for the participants and FDA to discuss manufacturing design and development

  3. 106  issues as well as recommendations for submission content related to the emerging technology.

  4. 107  FDA intends to work with each participant on an individual basis, and expects that the process

  5. 108  will include appropriate coordination with the quality assessment team (FDA staff involved in

  6. 109  the review of the CMC sections of the application and evaluation of the manufacturing facilities).

  7. 110  Based on experience gained during the program, FDA intends to develop guidance and

  8. 111  standards, as necessary, on emerging technologies and approaches to enable the modernization of

  9. 112  the pharmaceutical manufacturing base.

113
114
A. Scope 115

  1. 116  Acceptance of a request to participate in this CDER program will depend on the applicant’s

  2. 117  proposed plan for submission of an IND or original or supplemental ANDA, BLA, or NDA,

  3. 118  based on the criteria described below. The planned submission should include one or more

  4. 119  elements subject to quality assessment for which the Agency has limited review or inspection

  5. 120  experience, where the technology has the potential to modernize the pharmaceutical

  6. 121  manufacturing body of knowledge to support more robust, predictable, or cost-effective

  7. 122  processes. Examples of such elements include an innovative or novel: (1) product manufacturing

  8. 123  technology, such as the dosage form; (2) manufacturing process (e.g., design, scale-up, and/or

  9. 124  commercial scale); and/or (3) testing technology. Every effort will be made to ensure that many

  10. 125  companies have the opportunity to participate and that a wide variety of novel manufacturing

    Drugs guidance Web page at

    http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

page6image30712 page6image30872

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 126  technologies are included in this program. This program only affects the quality section of the

  2. 127  submission (CMC and facility-related information). Existing requirements related to the review

  3. 128  and approval of a submission will not be waived, suspended, or modified for purposes of this

  4. 129  program. Applicants must make the submission in accordance with 21 CFR parts 312, 314, 601,

  5. 130  and other applicable standards.

131
132
B. Process 133

  1. 134  Interested parties planning to submit an IND or original or supplemental BLA or NDA as part of

  2. 135  this CDER program should submit a written request for a Type C meeting as described in the

  3. 136  guidance on Formal Meetings Between the FDA and Sponsors or Applicant.6 The request

  4. 137  should specify the meeting request as a “Type C meeting – request to participate in the ETT

  5. 138  program.” Interested parties planning to submit an ANDA should submit a pre-ANDA meeting

  6. 139  request and specify the meeting request as a “Pre-ANDA meeting – request to participate in the

  7. 140  ETT program.” Either type of request should be submitted at least three months prior to the

  8. 141  planned application (IND, ANDA, BLA, NDA) submission date. The meeting request and

  9. 142  related questions should be submitted electronically to This e-mail address is being protected from spambots. You need JavaScript enabled to view it . In addition to

  10. 143  the items outlined in the referenced guidance, the request should also include the following

  11. 144  items:

145
146 (1) 147
148 (2) 149
150
151 (3) 152
153
154

  1. 155  (4) A summary of the development plan and any perceived roadblocks to implementation

  2. 156  (e.g., technical or regulatory); and

157
158 (5) A timeline for a submission (IND, ANDA, BLA, NDA, original or supplemental). 159

  1. 160  The request document should generally not exceed five pages of narrative, including up to five

  2. 161  figures or tables. Based on the availability of Agency resources, we expect to limit acceptance

  3. 162  into the program to technologies that are likely to modernize pharmaceutical manufacturing in

  4. 163  order to improve product safety, identity, strength, quality, or purity, and with which the Agency

  5. 164  has limited prior experience and knowledge. FDA expects to notify companies of its decision

  6. 165  regarding acceptance into the program in writing within 60 days of receipt of the request.

  7. 166  Although incomplete and/or unclear requests will generally be denied, FDA may contact the

  8. 167  applicant to request additional information. Once accepted into the program, the participant can

    6 See http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf. 4

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A brief description of the proposed testing, process, and/or proposed technology;

A brief explanation why the proposed testing, process, and/or technology are substantially novel and unique and should be considered under this program;

A description of how the proposed testing and/or technology could modernize pharmaceutical manufacturing and thus improve product safety, identity, strength, quality, or purity;

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Draft — Not for Implementation

  1. 168  engage with the ETT and CMC review team in accordance with existing meeting procedures and

  2. 169  guidance(s)7 based on the availability of Agency resources.

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7 See the guidances on Formal Meetings Between the FDA and Sponsors or Applicants (see information on “Type C” meetings) and Controlled Correspondence Related to Generic Drug Development.

5

 

Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND


NOTE: A stay is in effect for parts of subsection VI.D of this guidance. Additional information about this stay can be found in the Notice of Stay that published in the Federal Register of October 30, 2015 (80 FR 66907).

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Guidance for Clinical Investigators, Sponsors, and IRBs

Investigational New Drug Applications (INDs) Determining Whether Human Research Studies Can Be Conducted Without an IND

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Food Safety and Applied Nutrition (CFSAN)

September 2013 Clinical/Medical

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Guidance for Clinical Investigators, Sponsors, and IRBs

Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND

Additional copies are available from:

Office of Communications,
Division of Drug Information, WO 51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Rockville, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or
Office of Communication, Outreach and
Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
Phone: 800-835-4709 or 301-827-1800
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or
Outreach and Information Center
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5100 Paint Branch Parkway
College Park, MD 20740
Phone: 888-723-3366
http://www.fda.gov/Food/GuidanceRegulation/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Food Safety and Applied Nutrition (CFSAN)

September 2013 Clinical/Medical

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I. II. III.

A.

B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 RESEARCH STUDIES THAT REQUIRE AN IND ..................................................... 2 What Is a Drug? ........................................................................................................................... 3 What Is a Clinical Investigation?................................................................................................ 4

V.

A. B.

Certain Research Involving Marketed Drug Products ............................................................. 4

Bioavailability or Bioequivalence Studies in Humans............................................................... 8

Contains Nonbinding Recommendations

CLINICAL INVESTIGATIONS THAT ARE EXEMPT FROM THE IND

IV.
REQUIREMENTS BY REGULATION..................................................................................... 4

HUMAN RESEARCH STUDIES INVOLVING RADIOACTIVE OR COLD ISOTOPES..................................................................................................................................... 8

  1. Radioactive Isotopes .................................................................................................................... 8

  2. Cold Isotopes ................................................................................................................................ 9

VI. SPECIFIC ISSUES CONCERNING THE APPLICATION OF THE IND REGULATIONS ........................................................................................................................... 9

  1. Endogenous Compounds ........................................................................................................... 10

  2. Live Organisms .......................................................................................................................... 10

  3. Cosmetics .................................................................................................................................... 10

  4. Foods.......................................................................................................................................... 11

  5. Research With Noncommercial Intent ..................................................................................... 15

  1. FREQUENTLY ASKED QUESTIONS........................................................................ 15

  2. PROCESS FOR ADDRESSING INQUIRIES CONCERNING THE

APPLICATION OF THE IND REQUIREMENTS ................................................................ 18

APPENDIX.................................................................................................................................. 20

Part of this subsection is stayed.

i

Contains Nonbinding Recommendations

Guidance for Clinical Investigators, Sponsors, and IRBs1

Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

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I. INTRODUCTION

This guidance is intended to assist clinical investigators, sponsors, sponsor-investigators,2 and institutional review boards (IRBs) in determining whether research studies involving human subjects must be conducted under an investigational new drug application (IND), as described in title 21 of the Code of Federal Regulations, part 312 (21 CFR part 312) (the IND regulations). This guidance describes when an IND is required, specific situations in which an IND is not required, and a range of issues that, in FDA’s experience, have been the source of confusion or misperceptions about the application of the IND regulations.3 This guidance addresses only whether an IND is needed. If your study also involves the use of a device, you should determine whether such use is subject to 21 CFR part 812 (the IDE regulations).

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should

1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Food Safety and Applied Nutrition (CFSAN) at the Food and Drug Administration (FDA or the Agency).
2 The definitions in the IND regulations describe specific roles for the individual or individuals who conduct a clinical investigation (the investigators) and the individual or entity who has primary responsibility for and initiates the clinical investigation (the sponsor) (§ 312.3(b)). In the most common scenario, a commercial sponsor has primary responsibility for and initiates the clinical investigation, and multiple investigators are responsible for the actual conduct of the investigation at their respective study sites. The term sponsor-investigator typically refers to an individual at an academic institution who takes responsibility for, initiates, and conducts a clinical investigation at a single site (sometimes referred to as an investigator-initiated study) and therefore meets the definition of both a sponsor and an investigator for purposes of the IND regulations.
3 This guidance does not address expanded access to investigational drugs for treatment use under subpart I of 21 CFR part 312.

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be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

FDA has two primary objectives in reviewing an IND: (1) to assure the safety and rights of subjects in all phases of an investigation and (2) in phases 2 and 3, to help assure that the quality of the scientific evaluation of the drug is adequate to permit an evaluation of the drug’s effectiveness and safety (21 CFR 312.22).

FDA receives frequent inquiries from the academic community (e.g., clinical investigators, IRBs) and the pharmaceutical industry about whether an IND should be submitted for various types of clinical research. Inquiries have related to a range of issues concerning application of the IND requirements in part 312, including, for example:

  • Clinical investigations using marketed drugs

  • Bioequivalence/bioavailability studies

  • Studies using radiolabeled or cold isotopes

  • Studies using dietary supplements or foods

  • Studies using endogenous compounds

  • Pathogenesis studies using modified organisms

  • Studies using wild-type organisms in challenge models

  • Studies that do not have a commercial purpose

    Because of the large number of inquiries and wide range of issues, FDA determined that it would be helpful to provide to potential sponsors, clinical investigators, and sponsor-investigators an overview of the IND requirements and related issues.

    With certain exceptions, clinical investigations in which a drug is administered to human subjects must be conducted under an IND as required in part 312. Sections III, IV, and V of this guidance elaborate on the criteria for when a study must be conducted under an IND; the types of studies that involve drugs, but that are exempt from the IND requirements; studies involving radioactive drugs that are generally recognized as safe and effective (and to which IND requirements therefore do not apply); and FDA’s use of enforcement discretion with respect to certain studies using cold isotopes conducted without an IND. Section VI discusses specific issues that frequently arise concerning application of the IND regulations; section VII contains frequently asked questions; and section VIII describes the process for seeking advice from FDA concerning the application of the IND regulations to a planned clinical investigation.

III. RESEARCH STUDIES THAT REQUIRE AN IND

In general, the IND regulations in part 312 require that human research studies be conducted under an IND if all of the following conditions exist:

2

Contains Nonbinding Recommendations

  • The research involves a drug as that term is defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 321(g)(1)).

  • The research is a clinical investigation as defined in the IND regulations (21 CFR 312.3).

  • The clinical investigation is not otherwise exempt from the IND requirements in part 312

    (see section IV of this guidance).

A. What Is a Drug?

The definition of the term drug in section 201(g)(1) of the FD&C Act includes, among other things, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease . . .” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” Biological products subject to licensure under section 351 of the Public Health Service Act (42 U.S.C. 262) may also be considered drugs within the meaning of the FD&C Act. A biological product is:

. . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

(42 U.S.C. 262(i))

Biological products include, among other products, bacterial vaccines, allergenic extracts, gene therapy products, growth factors, cytokines, and monoclonal antibodies.

It is important to note that the drug definition is not limited to compounds intended for a therapeutic purpose.4 The definition also includes compounds intended to affect the structure or function of the body, without regard to whether the compound is intended to influence a disease process. For example, the definition includes compounds administered to healthy individuals to prevent pregnancy or treat male pattern baldness. The definition also includes compounds used for research purposes in healthy subjects to blunt or provoke a physiologic response or study the mechanism of action or metabolism of a drug (see section VI.A). Note, however, that (1) a dietary supplement intended only to affect the structure or function of the body and not intended for a therapeutic purpose is not a drug5 (see section VI.D.1) and (2) a food used as such (i.e., primarily for its taste, aroma, or nutritive value) and not for a therapeutic purpose or to affect the structure or function of the body, other than by providing nutrition, is not a drug (see section VI.D.2).6

4 In this guidance, the term therapeutic purpose is intended to encompass diagnosis, cure, mitigation, treatment, and prevention of disease.
5 See 21 CFR 101.93(f) and (g); 65 FR 1000 (Jan. 6, 2000).
6 See 21 U.S.C. 321(f) and (g)(1); Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983)).

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B. What Is a Clinical Investigation?

The IND regulations in § 312.3(b) define clinical investigation7 as:

. . . [an] experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of [the IND regulations], an experiment is any use of a drug [whether approved or unapproved] except for the use of a marketed drug in the course of medical practice.

For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND.8 In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient.

IV. CLINICAL INVESTIGATIONS THAT ARE EXEMPT FROM THE IND REQUIREMENTS BY REGULATION

FDA regulations describe two categories of clinical investigations that are exempt from the IND requirements in part 312, provided the criteria for exemption are met (see 21 CFR 312.2(b) and 320.31(b)). The two categories of clinical investigations and the applicable criteria are described in the following subsections. Ordinarily, clinical investigations of drugs that do not meet these criteria must be conducted under an IND as required in part 312.

A. Certain Research Involving Marketed Drug Products

Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 312.2(b) are met:

  • The drug product is lawfully marketed in the United States.

  • The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.

  • In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.

  • The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).

    7 Additional information on clinical investigations is available on FDA's Web site at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm. 8 See section IV.A of this guidance.

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  • The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).

  • The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).

    The potential sponsor or sponsor-investigator of a planned clinical investigation using a marketed drug is responsible for determining whether the investigation meets the criteria for an exemption.9 If there is uncertainty about whether the exemption criteria are met, the potential sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND regulations (§ 312.2(e)).

    Three of the criteria for exemption listed previously merit further discussion.

What is meant by a drug product that is lawfully marketed in the United States?

The preamble to the final rule incorporating the IND exemption criteria into the IND regulations makes clear that the exemption provision was not intended to require use of only the marketed version of the drug product for a clinical investigation to be exempt from the IND requirements. The intent was to provide some latitude to modify the marketed version of the drug product for use in a clinical investigation. In responding to comments asking FDA to clarify to what extent a sponsor could change the marketed drug product or conditions of use and still be exempt from the IND regulations, FDA stated that:

The exemption was not intended to require an investigator to use the drug in exactly the same dosage form, dosage levels, and patient populations described in the marketed labeling for the product, but rather to permit changes to the lawfully marketed drug product that do not increase the risks . . . over the risk presented by use of the product in conformance with its marketed labeling.10

Therefore, sponsors or sponsor-investigators can make low-risk modifications to the lawfully marketed dosage form to, for example, blind a study.

In making modifications to the marketed dosage form, sponsors and sponsor-investigators should consider the potential risk implications of the modifications based on the type and complexity of the dosage form. For example, minor variations to solid oral dosage forms,

9 The preamble to the rule finalizing the IND regulations provides:

FDA recognizes that a considerable amount of professional judgment must be exercised in determining whether the conditions of an investigation “significantly increase” the risk associated with use of the drug. Because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of medicine, the individual investigator should usually be able to determine the applicability of the exemption.

(See the final rule on New Drug, Antibiotic, and Biologic Drug Product Regulations that published in the Federal Register of March 19, 1987 (52 FR 8798 at 8802)).
10 Final rule, “New Drug, Antibiotic, and Biologic Drug Product Regulations” (52 FR 8798 at 8801, March 19, 1987).

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Contains Nonbinding Recommendations

such as changing the color, scoring, or capsule size of the marketed dosage form for blinding purposes, would generally be low risk, provided the changes did not involve major manufacturing or formulation changes. Similarly, using capsules to over-encapsulate the marketed dosage form would generally be low risk, provided the capsule met appropriate standards. Changes to more complex oral dosage forms and injectable and other non-oral dosage forms might carry greater risk. Products that are very sensitive to conditions in their environment (e.g., protein products) also carry greater risk because changes to the formulation, dosage form, manufacturing, or primary packaging might change the pharmacokinetics, immunogenicity, or other characteristics of such products.

Given the range of possible modifications to a marketed dosage form, FDA cannot provide comprehensive guidance on the degree of risk presented by all such modifications. If sponsors or sponsor-investigators have concerns about whether changes to a lawfully marketed dosage form increase risk to an extent that an IND would be required, they should consult FDA (see section VIII). If a sponsor or sponsor-investigator consults FDA, they should provide FDA with a listing of chemistry, manufacturing, and controls (CMC) variations from the marketed version of the drug product, if CMC information for the marketed product is available to them, and any other pertinent information that would assist FDA in responding to an inquiry.

Is the risk associated with the product significantly increased (or the acceptability of the risk significantly decreased)?

Historically, assessing whether a particular use of a drug in a clinical investigation significantly increases the risk or decreases the acceptability of the risk, compared to its approved use or uses, has been the most difficult issue in determining whether an IND is needed for a clinical investigation of a marketed drug (21 CFR 312.2(b)(1)(iii)). This provision has been particularly difficult in the oncology setting where many of the therapies have significant toxicity; for that reason, FDA has issued guidance to help clinical investigators studying cancer treatments determine whether the risk associated with the use of the drug in a planned clinical investigation is significantly increased or the acceptability of the risk is significantly decreased.11 FDA’s cancer treatment guidance is also a useful reference for clinical studies of marketed drugs in other therapeutic areas, particularly for studies in other serious and life-threatening conditions, as the risk-benefit scenarios are at least somewhat relevant to non-oncologic settings. Investigators should carefully consider the risk implications of any conditions of use in the study that deviate from the conditions of use described in the drug’s labeling, with particular attention to the following:

11 See the guidance for industry IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer (the cancer treatment guidance). We update guidances periodically. To make sure you have the most recent version of a guidance, check the Drugs guidance page at http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the Biologics guidance page at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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  • - Route of Administration: A change in the route of administration can introduce a significant new risk. For example, there could be a significant increase in risk if a marketed drug for oral administration is converted to a dosage form that is to be administered by injection or intravenous, intrathecal, or inhalation route. These other routes of administration introduce concerns with increased local concentrations, sterility, pyrogenicity, hypersensitivity (e.g., airway reactivity), variations in metabolism, and other issues not present with oral administration that can significantly increase the risk, or decrease the acceptability of the risk, associated with use of the drug.

  • - Dose: Increases in dose, frequency, or duration of administration, compared to labeled dosing regimens, can significantly increase the risk in a study using a marketed drug. It is also possible that a decrease in dose could significantly increase risk. For example, administering a sub-therapeutic dose of an antiviral drug to study subjects could induce resistance in the subjects, thus rendering a subsequent therapeutic dose of the drug ineffective in treating the virus. The significance of changes in dose (in particular, increases in dose) can vary across therapeutic areas. For example, the cancer treatment guidance provides some latitude for conducting studies of high-dose cancer treatments without an IND because oncologists are generally familiar with the implications of high-dose regimens. In other clinical settings, use of higher doses than are recommended in labeling may be much more likely to significantly increase the risk or decrease the acceptability of the risk.

  • - Patient Population: The acceptability of known and unknown risks can vary across different treatment populations (see § 312.2(b)(1)(iii)). The population chosen for study could be at increased risk compared to the approved use population for a variety of reasons, such as increased age, different disease or stage of disease, concomitant illness, decreased renal or hepatic function, or concomitant therapy. For example, a drug with significant toxicity can be approved for use in a population with a life- threatening or severely debilitating disease because the risk of toxicity is acceptable in that population. Use of that drug in a clinical investigation in a population that is not so ill (e.g., to evaluate the drug for prevention of disease or symptomatic relief), however, would present a different risk-benefit situation in which the known risks might not be acceptable. When use of the drug in a specific patient population decreases the acceptability of the known risks, the study would have to be conducted under an IND as required under 21 CFR part 312.

Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study in support of a new indication, (2) use it to support any other significant change in the labeling of the drug, or (3) use it to support a significant change in the advertising (for prescription drugs only) for the drug?

Generally, it seems reasonable to infer that any well-controlled trial of a marketed drug (e.g., a study of a new indication) sponsored by the manufacturer of the drug would be intended to be used to influence labeling or promotion in some significant way and would have to be conducted under an IND. On the other hand, similar studies of marketed drugs conducted by an entity that

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7

V.

Contains Nonbinding Recommendations

does not have an independent ability to change a drug’s labeling – e.g., a study conducted by a sponsor-investigator in an academic setting or Government agency sponsor – would not generally be intended to be submitted to FDA to support a new indication or to otherwise influence the drug’s labeling or promotion. However, data from such studies may subsequently be submitted to FDA for that purpose and, therefore, FDA has an interest in helping to ensure that these studies are designed to yield data adequate to support a labeling change. A sponsor who would like to obtain FDA advice on study design can submit an IND for FDA review.

B. Bioavailability or Bioequivalence Studies in Humans

FDA regulations describe criteria under which bioavailability or bioequivalence (BA/BE) studies using unapproved versions of approved drug products can be conducted without submission of an IND (21 CFR 320.31(b) and (d)). Although these regulations are intended to facilitate development of generic drugs, a planned BA/BE study need not be intended for that purpose to be exempt from the IND regulations. A BA/BE study in humans does not require an IND if all of the following conditions are met:

• • • •

The drug product does not contain a new chemical entity (21 CFR 314.108), is not radioactively labeled, and is not cytotoxic.

The dose (single dose or total daily dose) does not exceed the dose specified in the labeling of the approved version of the drug product.

The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).

The sponsor meets the requirements for retention of test article samples (21 CFR 320.31(d)(1)) and safety reporting (21 CFR 320.31(d)(3)).

HUMAN RESEARCH STUDIES INVOLVING RADIOACTIVE OR COLD ISOTOPES

A. Radioactive Isotopes

FDA regulations (21 CFR 361.1) describe conditions under which radioactive drugs (drugs containing unstable isotopes) can be used for certain research without an IND because they are generally recognized as safe and effective for those uses. These regulations apply to radioactive versions of both approved and unapproved drugs.12

Under 21 CFR part 361, human research using a radioactive drug or biological product may be conducted without an IND if (1) it involves basic research not intended for immediate therapeutic, diagnostic, or similar purposes, or otherwise to determine the safety and efficacy of

12 For information on determining whether human research with a radioactive drug can be conducted under a Radioactive Drug Research Committee (RDRC), see FDA’s guidance for industry and researchers The Radioactive Drug Research Committee: Human Research Without an Investigational New Drug Application (the RDRC guidance).

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VI.

Contains Nonbinding Recommendations

the product, (2) the use in humans is approved by a Radioactive Drug Research Committee (RDRC) that is composed and approved by FDA, (3) the dose to be administered is known not to cause any clinically detectable pharmacological effect in humans, and (4) the total amount of radiation to be administered as part of the study is the smallest radiation dose practical to perform the study without jeopardizing the benefits of the study and is within specified limits.

B. Cold Isotopes

Cold isotopes (isotopes that lack radioactivity) have been increasingly used for the same research purposes as radioactive isotopes—to obtain basic information about drug metabolism or about human physiology, pathophysiology, or biochemistry. When used for these basic research purposes, cold (or stable) isotopes ordinarily present fewer safety concerns than radioactive isotopes. Unlike radioactive isotopes, however, there is no specific regulation analogous to 21 CFR 361.1 that addresses cold isotopes of approved drugs and unapproved drugs when used for these basic research purposes. However, FDA believes there is no need to have more stringent requirements for studies that use cold isotopes than for those that use radioactive isotopes, and historically, FDA has not objected to studies using cold isotopes being conducted without an IND. In exercising its enforcement discretion, FDA does not intend to object to clinical investigations using cold isotopes of unapproved drugs being conducted without an IND, provided the following conditions are met (the conditions are based on the criteria for studies using radiolabeled drugs (see 21 CFR 361.1)):13

• •

• •

The research is intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a drug labeled with a cold isotope or regarding human physiology, pathophysiology, or biochemistry.

The research is not intended for immediate therapeutic, diagnostic, or preventive benefit to the study subject.

The dose to be administered is known not to cause any clinically detectable pharmacologic effect in humans based on clinical data from published literature or other valid human studies.

The quality of the cold isotope meets relevant quality standards.

The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and the requirements for informed consent (21 CFR part 50).

SPECIFIC ISSUES CONCERNING THE APPLICATION OF THE IND REGULATIONS

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13 Note that studies using cold isotopes of approved drugs frequently meet the criteria for exemption from the IND requirements in part 312 for studies of marketed drugs (see section IV.A) because the studies involve low doses and present low risk. In such cases, enforcement discretion would not be needed for these studies to be conducted without an IND.

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Contains Nonbinding Recommendations

This section addresses specific issues that frequently arise in discussions with outside parties concerning the application of the IND requirements in 21 CFR part 312.

A. Endogenous Compounds

FDA has received numerous questions concerning the application of the IND requirements to studies in which endogenous compounds are administered to human subjects. A common question is whether provocation or challenge studies in which an endogenous compound (e.g., bradykinin, histamine, angiotensin) is administered to subjects to evoke a physiologic response, characterize a disease, or establish the mechanism of action are subject to IND requirements. In these cases, the endogenous compound is plainly not being used for a therapeutic purpose. There is, however, intent to affect the structure or function of the body, so the compound would be considered a drug under these circumstances. Therefore, these types of studies are clinical investigations and require an IND under part 312, unless the study meets the criteria for an exemption in § 312.2(b) or § 320.31(b) (see section IV) or the criteria in § 361.1, or the compound is labeled with a cold isotope and used in the manner described in section V, is a dietary supplement (see section VI.D.1), or is an article used for food or drink (i.e., primarily for taste, aroma, or nutritive value, rather than for some other effect on the structure or function of the body) in the study (see section VI.D.2).

B. Live Organisms

An IND is required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi, whether modified or wild-type) is administered to subjects to study the pathogenesis of disease or the host response to the organism (see part 312). Although the challenge organism is not intended to have a therapeutic purpose, there is intent to affect the structure or function of the body. Thus, the organism is both a biological product (see 21 CFR 600.3(h)(1)) and a drug, and an IND is required for the clinical investigation, unless the criteria for exemption in 21 CFR 312.2 are met or the product meets the definition of a dietary supplement14 or is an article used for food or drink (i.e., primarily for taste, aroma, or nutritive value, rather than for some other effect on the structure or function of the body) in the study. Similarly, an IND is required for a clinical investigation designed to evaluate whether colonization with a strain of bacteria can treat or prevent disease in patients with a chronic immune disorder.

C. Cosmetics

14 Section 201(ff) of the FD&C Act does not specifically mention live organisms in the definition of a dietary supplement (21 U.S.C. 321(ff)), but does include more general language that results in some products containing live organisms falling within the dietary supplement definition, depending on the specific facts related to the product. The relevant language is found in section 201(ff)(1), which lists the substances that may be used as “dietary ingredients” in dietary supplements. Section 201(ff)(1)(E) provides that “dietary substance[s] for use by man to supplement the diet by increasing the total dietary intake” are dietary ingredients; section 201(ff)(1)(F) further defines dietary ingredient to include “a concentrate, metabolite, constituent, extract, or combination” of any other dietary ingredient. Taken together, these two provisions indicate that a live organism that is a constituent of an article that is commonly used as human food or drink (e.g., a probiotic in yogurt) may be used as a dietary ingredient in a dietary supplement.

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Section 201(i) of the FD&C Act (21 U.S.C. 321(i)) defines a cosmetic as “(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.” With the exception of color additives and a few prohibited ingredients, a cosmetic manufacturer may use almost any raw material as a cosmetic ingredient and market the product without an approval from FDA.

As a general matter, studies of ingredients or products marketed as cosmetics require an IND if the ingredient is being studied for use to affect the structure or function of the body or to prevent, treat, mitigate, cure, or diagnose a disease (see 21 U.S.C. 321(g)(1); 21 CFR 312.2). This is true even if the study is intended to support a cosmetic claim about the ingredient or product’s ability to cleanse, beautify, promote attractiveness, or alter the appearance, rather than a structure/function claim. For example, a study of the effect of a cosmetic product containing human or animal biological material (such as placenta) on skin repair mechanisms would require an IND, even if the study is intended only to support a claim of younger looking skin.

D. Foods

Those who are evaluating published clinical literature or sponsoring new clinical studies while conducting safety assessments for dietary ingredients, food additives (including food contact substances), and GRAS substances, as well as those who conduct or sponsor research intended to support labeling claims for conventional foods or dietary supplements, should be aware of two provisions of the FD&C Act that, depending on the circumstances, may restrict the marketing of products containing substances that have been the subject of “substantial clinical investigations” whose existence has been made public. Section 301(ll) of the FD&C Act (21 U.S.C. 331(ll)) prohibits the marketing of any food to which has been added a drug or biologic for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, unless the drug or biologic was marketed in food before any substantial clinical investigations involving the drug or biologic were instituted or one of the other exceptions in section 301(ll) applies. Section 201(ff)(3)(B)(ii) of the FD&C Act (21 U.S.C. 321(ff)(3)(B)(ii)) excludes from the dietary supplement definition any article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, unless the article was marketed as a dietary supplement or as a conventional food before the IND became effective.15 FDA interprets “authorized for investigation” to mean that the article is the subject of an IND that has gone into effect (see 21 CFR 312.40). Marketing the substance of interest “as a dietary supplement or as a food” (under section 201(ff)) or “in food” (under section 301(ll)) before seeking an IND or beginning any clinical investigations preserves the option to continue to market the substance in those forms after substantial clinical investigations have been instituted and their existence has been made public.

15 FDA can create an exception to the exclusion by regulation, but only if the Agency finds that the use of the article in dietary supplements would be lawful. To date, no such regulations have been issued. The appropriate mechanism to request such a regulation is to file a citizen petition under 21 CFR 10.30.

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1. Dietary Supplements

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary supplement is defined, in part, as a product taken by mouth that is intended to supplement the diet and that contains one or more dietary ingredients.16 The dietary ingredients in these products can include vitamins, minerals, herbs and other botanicals, amino acids, other dietary substances intended to supplement the diet, and concentrates, metabolites, constituents, extracts, or combinations of the preceding types of ingredients. Dietary supplements can be found in many forms such as tablets, capsules, softgels, liquids, or powders.

Under DSHEA, a dietary supplement is not considered a drug and is not subject to the premarket approval requirements for drugs if the intended use for which it is marketed is only to affect the structure or any function of the body (i.e., not intended to be used for a therapeutic purpose). Similarly, whether an IND is needed for a clinical investigation evaluating a dietary supplement is determined by the intent of the clinical investigation. If the clinical investigation is intended only to evaluate the dietary supplement’s effect on the structure or function of the body, an IND is not required.

However, if the clinical investigation is intended to evaluate the dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent a disease,17 an IND is required under part 312. For example, a clinical investigation designed to study the relationship between a dietary supplement’s effect on normal structure or function in humans (e.g., guarana and maximal oxygen uptake) or to characterize the mechanism by which a dietary supplement acts to maintain such structure or function (e.g., fiber and bowel regularity) would not need to be conducted under an IND. However, a clinical investigation designed to evaluate a dietary supplement’s ability to prevent osteoporosis or to treat chronic diarrhea or constipation would need to be conducted under an IND.

2. Conventional Food

Section 201(f) of the FD&C Act (21 U.S.C. 321(f)) defines a food as “(1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.” For studies intended to evaluate the effects of a food, the analysis for whether an IND is needed turns on the intent of the clinical investigation.

As is the case for a dietary supplement, a food is considered to be a drug if it is “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,”18 except that a food may bear an authorized health claim about reducing the risk of a disease without becoming a drug (see section VI.D.3). Therefore, a clinical investigation intended to evaluate the effect of a food

16 See section 201(ff) of the FD&C Act (21 U.S.C. 321(ff)).
17 For purposes of the dietary supplement labeling requirements, a “‘disease’ is damage to an organ, part, structure, or system of the body such that it does not function properly (e.g., cardiovascular disease), or a state of health leading to such dysfunctioning (e.g., hypertension); except that diseases resulting from essential nutrient deficiencies (e.g., scurvy, pellagra) are not included in this definition” (21 CFR 101.93(g)(1)).
18 21 U.S.C. 321(g)(1)(B).

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on a disease would require an IND under part 312. For example, a clinical investigation intended to evaluate the effect of a food on the signs and symptoms of Crohn’s disease would require an IND.

The following paragraph in brackets [ ] is STAYED.

[The FD&C Act also defines drug to include “articles (other than food) intended to affect the

structure or any function of the body.”19 This provision contains a parenthetical exception for

foods that affect the structure and function of the body by virtue of providing nutrition to sustain

life and health. Consistent with case law interpreting the “other than food” exception as applying

to articles consumed primarily for taste, aroma, or nutritive value, FDA regulates conventional

foods (including infant formula) that are intended to affect the structure or function of the body

as foods, not drugs, as long as the intended structure or function effect derives from the product’s

character as a food — its taste, aroma, or nutritive value.20 However, if an edible product that

might otherwise be a conventional food is intended for a use other than providing taste, aroma, or

nutritive value, such as blocking the absorption of carbohydrates in the gut, the product becomes

a drug because the primary purpose of consuming it has changed. In other words, the product is

no longer being consumed as a food — primarily for taste, aroma, or nutritive value — but used

as a drug for some other physiological effect. Accordingly, a clinical investigation intended only

to evaluate the nutritional effects of a food (including medical foods21) would not require an

IND, but an investigation intended to evaluate other effects of a food on the structure or function

of the body would. For example, a study of the effect of iron on hemoglobin levels in which

subjects were fed beef or lamb as a source of iron would not require an IND, but a study of the

effect of soy isoflavones on bone metabolism would. Similarly, a study of the ability of an infant

formula to support growth of infants or of other nutritional properties of the formula would not

require an IND. However, a study of other effects of the formula on the structure or function of

the body (e.g., an investigation of the effects of docosahexaenoic acid in infant formula on visual

acuity of infants) would require an IND.]

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A clinical study intended to evaluate the safety of a food ingredient generally does not require an IND, even if the ingredient is known to have an effect on the structure and function of the body that is in addition to its taste, aroma, or nutritional effect. For example, a study of the safety of a flavor ingredient that has been found to bind to a receptor outside of the target location in the mouth would not require an IND if the intent of the study was to evaluate the safety of the ingredient when ingested as food.

Similarly, a clinical study may be performed to evaluate the tolerability of a food in a specific susceptible population, including individuals with a disease. In such an evaluation, biological parameters

affected by the disease may need to be assessed in order to establish tolerance. For example, the

19 21 U.S.C. 321(g)(1)(C).
20 See Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983).
21 A medical food is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” 21 U.S.C. 360ee(b)(3).

The following sentence in brackets [ ] is STAYED. [In

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contrast, if the intent of the study was to evaluate the beneficial effects (beyond nutritional

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effects) of binding the newly found receptor, the study would require an IND.]

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administration of high intensity sweeteners to diabetic patients to establish no adverse effect on HbA1c levels or the administration of a novel food protein ingredient to a potentially allergic population to establish lack of allergic reactivity in this population would not require an IND. However, if the intent of the study was to demonstrate an effect of the food in decreasing HbA1c levels in diabetic patients or an effect of the food to desensitize or raise threshold levels of allergic reactivity in sensitive individuals, the study would require an IND.

Consistent with the considerations for conventional foods described in the previous paragraph, an investigation intended to evaluate the effects of a medical food on a disease would require an IND. However, if the medical food is simply being fed to subjects for nutritional purposes during a study examining the effects of another intervention, the use of the medical food in the study would not trigger the need for an IND, although the study might require an IND or investigational device exemption (IDE) for the intervention being studied.

3. Studies Intended to Support a Health Claim

NOTE: The stay does not apply to clinical investigations intended to evaluate whether a food substance may reduce the risk of a disease in individuals less than 12 months of age, those with altered immune systems, and those with serious or life-threatening medical conditions. This subsection is in effect for such clinical investigations.

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The following paragraph in brackets [ ] is STAYED, except as noted above.

[Section 201(g) of the FD&C Act provides that a health claim in the label or labeling of a food

(conventional food or dietary supplement) characterizing the relationship between a substance

(food or food component) and a disease or health-related condition does not cause the food to be a drug on the basis of that claim, provided the claim is authorized under and made in accordance

with the requirements of section 403(r)(1)(B) and (r)(3) of the FD&C Act22 (for conventional

foods) or under section 403(r)(1)(B) and (r)(5)(D) (for dietary supplements). Notwithstanding

this provision, however, a clinical study designed to evaluate the relationship between a food

substance and a disease and intended to provide support for such a claim is required to be

conducted under an IND (21 CFR part 312), unless the substance-disease relationship being

studied is already the subject of an authorized health claim. Section 201(g) provides, in effect,

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an exemption from the normal operation of the drug definition — it permits the use of health

claims that would, without the exemption, cause a conventional food or dietary supplement to be

a drug. However, the exemption does not apply until the health claim has been authorized by

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FDA. Therefore, a study conducted to support a new or expanded health claim would require an

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IND. For example, a study designed to evaluate whether vitamin D may reduce the risk of one

or more site-specific cancers would require an IND, as there is currently no authorized health

claim for this substance-disease relationship. Similarly, a study conducted to support a petition

to amend the health claim for soluble fiber from certain foods and reduced risk of coronary heart

disease (21 CFR 101.81) to include a new type of fiber would require an IND.]

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E. Research With Noncommercial Intent

Some believe that the IND regulations do not apply to clinical investigations that are not intended to investigate a drug’s potential for commercial sale. Whether the IND regulations apply to a planned clinical investigation does not depend on whether the intent of the clinical investigation is commercial or noncommercial. Therefore, these types of studies would require an IND under part 312, unless they meet the criteria for an exemption in §§ 312.2(b) or 320.31(b) (see section IV) or the criteria in § 361.1, or the compound used is labeled with a cold isotope and used in the manner described in section V.

VII. FREQUENTLY ASKED QUESTIONS

1. Do I need an IND if I use a lawfully marketed drug for an unlabeled indication?

If you are a health care provider and you prescribe a marketed drug to treat a patient for an unlabeled indication (also referred to as off-label use), an IND is not required because this use is considered to be within the scope of medical practice and not a clinical investigation. However, if you use the marketed drug for the same purpose in a clinical investigation intended to evaluate the drug’s ability to treat a disease or condition, an IND is required under part 312 unless the clinical investigation meets the criteria for an exemption for studies of lawfully marketed drugs (see 21 CFR 312.2(b) and section IV.A of this guidance).

2. If a drug marketed for use in adults is studied in an investigator-initiated, single-center study involving children, is an IND needed?

An IND is required under part 312 unless the clinical investigation meets the criteria for an exemption in § 312.2(b) (see section IV.A). The criterion of most importance for the exemption in this situation is whether the change in study population from adult to pediatric, or any other condition of use in the study, would significantly increase the risks (or decrease the acceptability of the risks) associated with the use of the drug (21 CFR 312.2(b)(1)(iii)). Whether risk would be significantly increased would depend on a variety of factors, including, for example, the age of the pediatric population being studied, the extent of prior pediatric experience with the drug in clinical studies or clinical practice, the amount of information available to support dosing in the study population, and the overall toxicity profile of the drug.

3. There are drugs on the market that have not been approved by FDA. Do clinical investigations using those drugs need an IND?

There are certain currently marketed drug ingredients that were first marketed before Congress passed the FD&C Act of 1938 (requiring demonstration of safety before marketing) or before it passed the 1962 amendments to the FD&C Act (requiring demonstration of effectiveness and safety before marketing). Sponsors of clinical investigations that use products with these

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ingredients should consult with FDA to determine whether the ingredient is lawfully marketed.23 If the ingredient is not lawfully marketed, an IND is required under part 312.

4. Can I do research on radiolabeled endogenous peptides, such as neuropeptides, without an IND?

If the research is intended to obtain basic information about the metabolism of the peptide or its role in physiology, pathophysiology, and biochemistry, and the criteria in 21 CFR 361.1 are met (i.e., among other things, the dose of endogenous peptide to be administered is known not to cause a clinically detectable pharmacologic effect in humans), an IND is not required (see the RDRC guidance). However, if the study hypothesis concerns the diagnosis, cure, mitigation, treatment, or prevention of a disease in patients, or the criteria in § 361.1 are otherwise not met, an IND is required under part 312.

5. Do clinical investigations of positron emission tomography (PET) drugs need INDs?

An IND generally would be required for a PET drug investigation, unless the investigation meets the criteria in 21 CFR 361.1. To meet these criteria, the research must be intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry, but not intended for immediate therapeutic, diagnostic, or similar purposes or to determine the safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial) (21 CFR 361.1(a)).

6. If a complementary or an alternative medicine that was derived from organic materials from a botanical source (e.g., broccoli, sprouts) is administered to subjects to study cancer prevention, is an IND required?

A clinical investigation of a complementary or an alternative medicine derived from organic materials that is intended to evaluate the medicine’s ability to diagnose, cure, mitigate, treat, or prevent disease requires an IND under part 312.24

7. Is an IND required if a product containing attenuated microorganisms is evaluated for amelioration of symptoms of a disease or prevention of the disease?

Even when a microorganism is attenuated with the intention to increase safety of a product, a clinical investigation that evaluates the potential for that microorganism to relieve symptoms of a disease or prevent the disease requires an IND under part 312, unless the study meets the criteria for an exemption under 21 CFR 312.2(b).

23 Ordinarily, such inquiries would be directed to CDER, Office of Compliance, Office of Unapproved Drugs & Labeling Compliance.
24 See the guidance for industry on Botanical Drug Products.

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8. If a product containing substances generally recognized as safe (GRAS) for use in food is administered to subjects in a study intended to evaluate the effect of the substance on the pathogenesis of a human disease, is an IND required?

Substances designated as GRAS for use in food are generally not approved as drug products. A clinical investigation of a GRAS substance that is intended to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease requires an IND under part 312, unless the substance to be studied is also a lawfully marketed drug and the clinical investigation meets the criteria for exemption under 21 CFR 312.2(b).

9. For purposes of the exemption from the IND requirements for studies using radioisotopes and FDA’s exercise of enforcement discretion for studies using cold isotopes, what support is needed to determine that the labeled drug does not have a clinically detectable pharmacological effect?

There is no requirement for a formal dose-response study to define the lower threshold for a clinically detectable pharmacological effect, and, in some cases, a study may not be needed. For example, if the labeled drug is an endogenous compound and the circulating blood levels or excretion rates of the endogenously produced substance are well known, there could be a basis to conclude that some small fraction of these levels or rates of administration (e.g., administration over a given interval of a very low percentage of the amount of a substance that is produced endogenously during the same interval) represents an amount without detectable pharmacological effect. Similarly, if large amounts of a substance such as an amino acid or a sugar are regularly consumed as foodstuffs, it may be possible to conclude that consumption of a small amount of these substances (e.g., a small percentage of the amount usually consumed during a meal), at least by the oral route, would be without detectable pharmacological activity (also see footnote 11).

10. Do I need an IND if my study uses a home-made version of a lawfully marketed drug?

Some investigators, or research pharmacies affiliated with the institution in which an investigator is conducting a study, compound their own versions of lawfully marketed drug products for use in clinical studies. For example, FDA is aware of instances in which the methacholine used in respiratory studies for challenge purposes has been prepared locally from raw materials obtained from a chemical supply company. Studies that use a drug product that is prepared from raw materials in place of the approved, finished product marketed by the manufacturer must be conducted under an IND (21 CFR part 312). These studies cannot meet the criteria for an exemption from the IND requirements for marketed drugs (§ 312.2(b)) because the drug product manufactured by the investigator or research pharmacy is not considered to be the lawfully marketed drug.

11. Do I need an IND if my study enrolls only a small number of subjects?

The number of subjects enrolled has no bearing on whether the study is subject to the IND regulations. The definition of clinical investigation specifically includes studies with as few as one subject (see section III.B).

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12. Do I need an IND if my study enrolls only healthy volunteers?

The clinical condition of study subjects (e.g., the presence or absence of disease) has no bearing on whether the study is subject to the IND requirements in part 312. The definition of clinical investigation refers only to subjects involved in an experiment. It makes no distinction between healthy subjects or those with a disease (see section III.B).

VIII. PROCESS FOR ADDRESSING INQUIRIES CONCERNING THE APPLICATION OF THE IND REQUIREMENTS

The sponsor (or sponsor-investigator of an individual investigator-initiated study) should, in most cases, be able to determine whether the IND regulations apply to a planned clinical investigation as required under 21 CFR 312.2(a). If a sponsor is uncertain, however, we recommend that the sponsor contact the appropriate review division (i.e., for the therapeutic area being studied) in the appropriate FDA center for advice about whether the IND regulations apply (21 CFR 312.2(e)). For products regulated by CDER, an inquiry concerning the application of the IND regulations should be directed to the Chief, Project Management Staff, in the appropriate CDER review division. For products regulated by CBER, the inquiry should be directed to the applications division of the appropriate review Office.

  • Organizational charts listing the CDER review divisions and their telephone numbers are available on the Internet at http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135674.htm.

  • Organizational charts listing the CBER review divisions and their telephone numbers are available on the Internet at http://www.fda.gov/AboutFDA/CentersOffices/ OrganizationCharts/ucm135943.htm.

  • If the relevant review division is not known, we recommend the sponsor contact CDER’s Division of Drug Information ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ) or CBER’s Division of Manufacturer’s Assistance and Training ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ), Office of Communication, Outreach and Development (both addresses and telephone numbers are provided on the second title page of this guidance).

    FDA will categorize inquiries concerning the application of the IND regulations as either informal or formal based on the following factors:

  • The medium in which the inquiry is received

  • The relative complexity of the inquiry

  • The type of response requested by the inquirer or given by FDA

    Informal inquiries have the following features:

They can be communicated either orally or in writing (written communication includes email, fax, or other written correspondence).

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  • They pose only relatively uncomplicated questions about a planned clinical investigation that FDA can answer based on somewhat limited information.

  • The inquirer is not seeking a formal written response.

    In response to an inquiry intended to be informal, FDA can (1) provide an informal (qualified, nonbinding) response, either orally or in writing, concerning the applicability of the IND regulations based on its understanding of the planned clinical investigation; (2) ask for additional information before providing an informal response; or (3) determine that the inquiry poses a complex question that should be submitted as a formal inquiry. FDA will not retain and track informal responses to inquiries concerning the applicability of the IND regulations to planned clinical investigations.

    Formal inquiries have all of the following features:

  • They are in writing (can be paper or electronic).

  • They pose a question of any level of complexity.

  • The inquirer is seeking a formal written response or FDA determines that a formal written response should be given (i.e., that the inquiry cannot be answered informally).

  • The documentation contains enough detail to permit FDA to provide a formal response concerning the applicability of the IND regulations to a planned clinical investigation (e.g., a study protocol, information about the drug product).

    In response to a formal inquiry, FDA may provide a formal written response concerning the application of the IND requirements to a planned clinical investigation or may determine that it has insufficient information to provide a formal response and seek additional information before providing a response. The scope of any formal response would be limited to the conduct of a clinical investigation consistent with the investigation described in documentation provided to FDA. If there are significant changes to the protocol or other aspects of the planned investigation after FDA has provided a response, that response may no longer be valid. FDA will archive formal inquiries and FDA responses to those inquiries.

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APPENDIX

Other Guidances that May Be Relevant to Questions Concerning the Application of the IND Requirements

FDA has issued guidances in related areas. Interested persons may wish to refer to the following documents, available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm:

  • Guidance for industry on Botanical Drug Products, which includes guidance on submitting INDs for botanical drug products, including those botanical products currently lawfully marketed as foods (including conventional foods and dietary supplements) in the United States.

  • Guidance for industry, investigators, and reviewers on Exploratory IND Studies, which is intended to clarify what preclinical and clinical approaches, as well as chemistry, manufacturing, and controls information, should be considered when planning exploratory studies in humans, including studies of closely related drugs or therapeutic biological products, under an IND.

  • Guidance for industry on CGMP for Phase 1 Investigational Drugs.

  • Guidance for industry and researchers on The Radioactive Drug Research Committee: Human Research Without an Investigational New Drug Application, which is intended to clarify whether research using a radioactive drug must be conducted under an IND (21 CFR part 312), may be exempt from IND requirements (21 CFR 312.2(b)), or if certain conditions are met, can be conducted under the supervision and approval of an FDA- approved Radioactive Drug Research Committee (21 CFR 361.1) without an IND. In addition, FDA has established a Web site at http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Oncology/default.htm for easy access to information by IRBs, clinical investigators, sponsors, and others.

  • Guidance for industry and FDA staff on FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions, which is intended to clarify for sponsors how they can demonstrate compliance with the requirements of 21 CFR 312.120, as well as provide recommendations for the submission of information, whether in an IND or application for marketing approval for a drug or biological drug product, to demonstrate that a non-IND foreign clinical study was conducted in accordance with GCP.

  • Guidance on Emergency Use Authorization of Medical Products, which is intended to inform industry, government agencies, and FDA staff of the Agency’s general recommendations and procedures for issuance of Emergency Use Authorizations (EUAs).

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Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants Guidance for Industry

page1image392

Formal Meetings Between the

FDA and Biosimilar

Biological Product Sponsors

or Applicants Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2015 Procedural

OMB Control No. 0910-0802
Expiration Date 9/30/2018
See additional PRA statement in section XV of this guidance.

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Formal Meetings Between the

FDA and Biosimilar

Biological Product Sponsors

or Applicants Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Tel: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

or

Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Tel: 800-835-4709 or 240-402-8010; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2015 Procedural

I. II. III. IV.

V. A.

B. C. D. E.

VI. VII. A.

B. VIII.

IX. X.

A. B. C.

XI.

XII. XIII. XIV . XV.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

MEETING TYPES ........................................................................................................... 3

PARTICIPATION IN THE FDA’S BIOSIMILAR BIOLOGICAL PRODUCT DEVELOPMENT PROGRAM ....................................................................................... 5

MEETING PROCEDURES............................................................................................. 6

Biosimilar Initial Advisory Meeting ............................................................................................. 6

BPD Type 1 Meeting ...................................................................................................................... 6

BPD Type 2 Meeting ...................................................................................................................... 6

BPD Type 3 Meeting ...................................................................................................................... 6

BPD Type 4 Meeting ...................................................................................................................... 7

MEETING REQUESTS BY SPONSORS OR APPLICANTS..................................... 7

ASSESSING MEETING REQUESTS............................................................................ 9

Meeting Denied .............................................................................................................................. 9

Meeting Granted .......................................................................................................................... 10

RESCHEDULING MEETINGS ................................................................................... 10

CANCELLING MEETINGS......................................................................................... 11

MEETING PACKAGE CONTENT AND SUBMISSION.......................................... 12

Timing of Submission .................................................................................................................. 12

Where and How Many Copies of Meeting Packages to Send .................................................. 12

Meeting Package Content............................................................................................................ 13

PREMEETINGS AND COMMUNICATIONS WITH SPONSORS OR APPLICANTS ................................................................................................................. 14

PROCEDURES FOR THE CONDUCT OF MEETINGS.......................................... 15 DOCUMENTATION OF MEETINGS......................................................................... 15 RESOLUTION OF DISPUTE ABOUT MEETING MINUTES................................ 15 PAPERWORK REDUCTION ACT OF 1995.............................................................. 16

Contains Nonbinding Recommendations

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants Guidance for Industry1

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance provides recommendations to industry on formal meetings between the Food and Drug Administration (FDA) and biosimilar biological product sponsors or applicants. The Biosimilar User Fee Act of 2012 (BsUFA), enacted as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to authorize a new user fee program for biosimilar biological products.2,3 The FDA has committed to meeting certain performance goals set forth in a letter from the Secretary of Health and Human Services to the Chairman of the Committee on Health, Education, Labor, and Pensions of the Senate and the Chairman of the Committee on Energy and Commerce of the House of Representatives.4 The performance goals include meeting management goals for formal meetings that occur between the FDA and sponsors or applicants during the development phase of a biosimilar biological product. The FDA encourages sponsors and applicants to use

1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.

2 For the statutory definition of biosimilar and biological product and definitions of selected terms used in this guidance, see the Glossary of the guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. (We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.) For the statutory definition of biosimilar biological product application, see section 744G(4) of the FD&C Act.

3 Sections 401-408 of FDASIA, adding sections 744G, 744H, and 744I to the FD&C Act.

4 The BsUFA goals letter, which is titled “Biosimilar Biological Product Authorization Performance Goals and Procedures Fiscal Years 2013 Through 2017,” is available on the FDA’s Web site at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv alApplications/TherapeuticBiologicApplications/Biosimilars/UCM281991.pdf.

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the meetings described in this guidance to optimize product development and facilitate submission of marketing applications.

For the purposes of this guidance, formal meeting includes any meeting that is requested by a sponsor or applicant following the request procedures provided in this guidance and includes meetings conducted in any format (i.e., face-to-face meeting, teleconference, or videoconference).

This guidance reflects a unified approach to all formal meetings between sponsors or applicants and the FDA for biosimilar biological products. This guidance is intended to assist sponsors or applicants in generating and submitting a meeting request and the associated meeting package to the FDA for biosimilar biological products intended to be submitted under 351(k) of the Public Health Service Act (PHS Act). This guidance does not apply to meetings associated with new drug applications or abbreviated new drug applications under section 505 of the FD&C Act or to biologics license applications (BLAs) under section 351(a) of the PHS Act.5

This guidance discusses the principles of good meeting management practices (GMMPs) and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

Each year, FDA review staff participate in many meetings with biosimilar biological product sponsors or applicants who seek advice relating to the development and review of biosimilar biological products. Because these meetings often represent critical points in the regulatory and development process, it is important that there are efficient, consistent procedures for the timely and effective conduct of such meetings. The GMMPs in this guidance are intended to provide consistent procedures that will promote well-managed meetings, and ensure that such meetings are scheduled within a reasonable time, conducted efficiently, and documented appropriately.

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5 For information on meetings for new drug applications and 351(a) BLAs, see the guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants.

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III. MEETING TYPES6

There are five types of formal meetings that can occur between sponsors or applicants and FDA staff to discuss development of a biosimilar biological product:

1. Biosimilar Initial Advisory meeting: A Biosimilar Initial Advisory meeting is an initial assessment limited to a general discussion regarding whether licensure under section 351(k) of the PHS Act may be feasible for a particular product, and, if so, general advice on the expected content of the development program. This meeting type does not include any meeting that involves substantive review of summary data or full study reports. However, preliminary comparative analytical similarity data from at least one lot of the proposed biosimilar biological product compared to the U.S.-licensed reference product should be provided in the meeting package. The analytical similarity data should be sufficient to enable the FDA to make a preliminary determination as to whether licensure under section 351(k) of the PHS Act may be feasible for a particular product, and to provide meaningful advice. A general overview of the development program, including synopses of results and findings from all completed studies and information about planned studies, also should be provided.

Extensive analytical, nonclinical, and/or clinical data are not expected to be provided based on the expected stage of development of the proposed biosimilar biological product. If the sponsor or applicant is seeking targeted advice on the adequacy of any comparative data or extensive advice for any aspect of an ongoing biosimilar development program, a different meeting type should be requested.

2. BPD Type 1 meeting: A Biosimilar Biological Product Development (BPD) Type 1 meeting is a meeting that is necessary for an otherwise stalled BPD program to proceed. Examples of a BPD Type 1 meeting include:

  • Meetings to discuss clinical holds: (1) in which the sponsor or applicant seeks input on how to address the hold issues; or (2) in which a response to hold issues has been submitted, and reviewed by the FDA, but the FDA and the sponsor or applicant agree that the development is stalled and a new path forward should be discussed

  • Special protocol assessment meetings that are requested after receipt of an FDA letter in response to protocols submitted under the special protocol assessment procedures as described in section VI of the BsUFA goals letter

  • Meetings to discuss an important safety issue, when such an issue is identified and the FDA and the sponsor or applicant agree that the issue should be discussed

    6 The meeting types and goal dates for BPD meetings were developed by the FDA in consultation with public and industry stakeholders as directed by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). For more information about BsUFA and the fee criteria for BPD meetings, refer to the BsUFA Web page at http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/default.htm.

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Dispute resolution meetings as described in 21 CFR 10.75 and 312.48, and in section IV of the BsUFA goals letter, and the draft guidance for industry and review staff Formal Dispute Resolution: Appeals Above the Division Level7

3. BPD Type 2 meeting: A BPD Type 2 meeting is a meeting to discuss a specific issue (e.g., proposed study design or endpoints) or questions where the FDA will provide targeted advice regarding an ongoing BPD program. This meeting type can include substantive review of summary data, but does not include review of full study reports.

4. BPD Type 3 meeting: A BPD Type 3 meeting is an in-depth data review and advice meeting regarding an ongoing BPD program. This meeting type includes substantive review of full study reports or an extensive data package (e.g., detailed and robust analytical similarity data), FDA advice regarding the similarity between the proposed biosimilar biological product and the reference product based on a comprehensive data package, and FDA advice regarding the need for additional studies, including design and analysis, based on a comprehensive data package.

  • Examples of a BPD Type 3 meeting submission include:

    • Comprehensive analytical similarity data that permit the FDA to make a preliminary evaluation of analytical similarity during development. The level of analytical data provided should be similar to what the sponsor or applicant intends to submit in a 351(k) BLA (e.g., full study reports and/or datasets that support the full study reports).

    • Full study report(s) for a clinical study(ies).

  • Based on the data and/or datasets and results reported in the full study reports, the FDA encourages the sponsor or applicant to provide an update on the development plan of the proposed biosimilar biological product. Examples of topics the sponsor or applicant can address as part of a BPD Type 3 meeting in addition to the in-depth data submitted include the following:

    • Proposal for any planned additional studies

    • Proposal for extrapolation

      5. BPD Type 4 meeting: A BPD Type 4 meeting is a meeting to discuss the format and content of a biosimilar biological product application or supplement to be submitted under section 351(k) of the PHS Act. Although the proposed content of the application will be discussed, this meeting type does not include substantive review of summary data or full study reports.

      7 When final, this guidance will represent the FDA’s current thinking on this topic. 4

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Sponsors or applicants are not required to request meetings in sequential order (i.e., Biosimilar Initial Advisory meeting, BPD Type 2, BPD Type 3, then BPD Type 4). The meeting type requested depends on the stage of the development program and/or the advice being sought. Although the FDA would most likely grant one Biosimilar Initial Advisory meeting and BPD Type 4 meeting for a particular biosimilar biological product, sponsors or applicants can request, as appropriate, as many BPD Type 2 and Type 3 meetings as needed to support ongoing development of a biosimilar biological product.

IV. PARTICIPATION IN THE FDA’S BIOSIMILAR BIOLOGICAL PRODUCT DEVELOPMENT PROGRAM

As stipulated by statute, a sponsor or applicant must pay a biosimilar biological product development fee (BPD fee) to participate in the FDA’s BPD program to receive a BPD Type 1, 2, 3, or 4 meeting for a product.8 There is no fee for a Biosimilar Initial Advisory meeting. The BPD fee is an annual per-product fee, not a per-meeting or per-review activity fee. There are three types of BPD fees: the initial BPD fee, the annual BPD fee, and the reactivation fee. The initial BPD fee is due on the date a sponsor or applicant submits an investigational new drug application (IND) for an investigation that the FDA determines is intended to support a biosimilar biological product application for a product, or within 5 calendar days after the FDA grants the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for that product, whichever occurs first.9

After a sponsor or applicant has paid the initial BPD fee, beginning in the next fiscal year, an annual BPD fee will be assessed for the product until the sponsor or applicant submits a marketing application that is accepted for filing, or discontinues participation in the BPD program for that product.10 If a sponsor or applicant has discontinued participation in the BPD program for a product and wants to again engage with the FDA on development of the product as a biosimilar biological product, the sponsor must pay a reactivation fee to resume participation in the BPD program for that product.11 The reactivation fee is due on the date the sponsor submits an IND for an investigation that the FDA determines is intended to support a biosimilar biological product application for the product, or within 5 calendar days after the FDA grants the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for the product, whichever occurs first.12

Section 744H(a)(1)(E) of the FD&C Act establishes the consequences of failure to pay BPD fees. With respect to meetings, if the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, and the granting of the meeting request triggers an obligation to pay an initial BPD

8 See section 744H(a)(1)(E) of the FD&C Act. 9 See section 744H(a)(1)(A) of the FD&C Act. 10 See section 744H(a)(1)(B) of the FD&C Act. 11 See section 744H(a)(1)(D) of the FD&C Act. 12 Id.

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fee or a reactivation fee for the product, the meeting will be cancelled if the sponsor or applicant fails to pay the fee within 5 calendar days after the meeting is officially granted.13 Additionally, if a sponsor or applicant is in arrears with respect to an annual BPD fee for a product, the FDA will deny the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for that product, and cancel any scheduled BPD meetings for that product.14

V. MEETING PROCEDURES

Each meeting type is subject to different procedures, as described below.

A. Biosimilar Initial Advisory Meeting

Biosimilar Initial Advisory meetings should be scheduled to occur within 90 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 90 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

B. BPD Type 1 Meeting

If sponsors or applicants are considering submission of a request for a BPD Type 1 meeting, they should first contact the relevant division in either the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER) to discuss the suitability of the request. BPD Type 1 meetings should be scheduled to occur within 30 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 30 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

C. BPD Type 2 Meeting

BPD Type 2 meetings should be scheduled to occur within 75 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 75 days from the date of request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

D. BPD Type 3 Meeting

BPD Type 3 meetings should be scheduled to occur within 120 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 120 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

13 See section 744H(a)(1)(E) of the FD&C Act. 14 Id.

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E. BPD Type 4 Meeting

BPD Type 4 meetings should be scheduled to occur within 60 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 60 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

VI. MEETING REQUESTS BY SPONSORS OR APPLICANTS

To make the most efficient use of FDA resources, before seeking a meeting with CBER or CDER, sponsors or applicants should consider other sources of information applicable to their product development program, such as FDA and International Conference on Harmonisation guidances. Written correspondence to request such a meeting should be submitted to the sponsor’s or applicant’s application (e.g., IND, BLA) through the controlled document system.15

If there is no application, the request should be submitted to either the appropriate CDER division director with a copy sent to the division’s chief of project management staff or to the office director/division director of the appropriate product office within CBER. Before submitting any meeting request by fax or email when there is no application, the sponsor or applicant should contact the appropriate product office within CBER, or the appropriate division or the Biosimilars Program staff within CDER, Office of New Drugs, to determine to whom the request should be directed, how the request should be submitted, and the appropriate format for the request, and to arrange for confirmation of receipt of the request. This contact reduces the possibility that faxed or emailed requests will be overlooked because of the volume of faxes and emails received daily by FDA staff. Faxed or emailed requests should be sent during official business hours (8:00 a.m. to 4:30 p.m. EST/EDT) Monday through Friday (except Federal government holidays).

A meeting request for the development of a proposed biosimilar biological product with multiple indications that span multiple review divisions should be submitted to the division that has regulatory oversight of the reference product.

The meeting request, regardless of the submission method, should include adequate information for the FDA to assess the potential utility of the meeting and to identify FDA staff necessary to discuss proposed agenda items. The meeting request should include the following information:

  1. The product name.

  2. The application number (if applicable).

  3. The proposed proper name (or proper name if post-licensure).

15 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/de fault.htm#Addresses.

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  1. The structure (if applicable).

  2. The reference product name.

  3. The proposed indication(s) or context of product development.

  4. The meeting type being requested (i.e., Biosimilar Initial Advisory meeting, BPD Type 1, 2, 3, or 4 meeting). The rationale for requesting the meeting type should be included.

  5. A brief statement of the purpose of the meeting. This statement should include a brief background of the issues underlying the agenda. It also can include a brief summary of completed or planned studies or data that the sponsor or applicant intends to discuss at the meeting, the general nature of the critical questions to be asked, and where the meeting fits in overall development plans. Although the statement need not provide detailed documentation of trial designs or completed studies and clinical trials, it should provide enough information to facilitate understanding of the issues, such as a small table that summarizes major results.

  6. A list of the specific objectives/outcomes the requester expects from the meeting.

  7. A proposed agenda, including estimated times needed for discussion of each agenda item not to exceed the total allotted meeting time.

  8. A list of questions, grouped by discipline. Each question should be precise, and there should be a brief explanation of the context and purpose of the question.

  9. A list of all individuals with their titles and affiliations who will attend the requested meeting from the sponsor’s or applicant’s organization, including consultants and interpreters.

  10. A list of FDA staff, if known, or disciplines, asked to participate in the requested meeting. Note that requests for attendance by FDA staff who are not otherwise essential to the application’s review may affect the ability to hold the meeting within the specified time frame of the meeting type being requested. Therefore, when attendance by nonessential FDA staff is requested, the meeting request should state whether a later meeting date is acceptable to the requester to accommodate the nonessential FDA attendees.

  11. Suggested dates and times (e.g., morning or afternoon) for the meeting that are within or beyond the appropriate time frame of the meeting type being requested. Nonavailability dates and times also should be included.

  12. The proposed format of the meeting (i.e., face-to-face, teleconference, or videoconference).

The sponsor or applicant should define in its written meeting request the specific areas of input requested from CBER or CDER. A well-written meeting request that uses the above

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components as a guide can help the FDA understand and assess the utility and timing of the meeting related to product development or review. Although CBER or CDER will determine the final meeting type (i.e., Biosimilar Initial Advisory meeting, or BPD Type 1, 2, 3, or 4 meeting), the sponsor or applicant should provide its meeting type assessment as it relates to the product’s development. The list of sponsor or applicant attendees and the list of requested FDA attendees can be useful in providing or preparing for the input needed at the meeting. However, during the time between the request and the meeting, the projected attendees can change. If there are changes, an updated list of attendees with their titles and affiliations should be provided to the appropriate FDA contact at least 1 week before the meeting.

The objectives and agenda provide overall context for the meeting topics, but it is the list of questions that is most critical to understanding the kind of information or input needed by the sponsor or applicant and to focus the discussion, should the meeting be granted. Each question should be precise and include a brief explanation of the context and purpose of the question. The questions submitted within a single meeting request should be limited to those that can be reasonably answered within the allotted meeting time, taking into consideration the complexity of the questions submitted.

VII. ASSESSING MEETING REQUESTS

The meeting request should be accompanied by the meeting package (see section X., Meeting Package Content and Submission, for additional information regarding the content of the meeting package). This ensures that the FDA will have adequate information to assess the potential utility of the meeting and prepare for the meeting. If the meeting package is not submitted to the appropriate division with the meeting request, the meeting request will be considered incomplete and the FDA generally will deny the meeting. The CBER or CDER division director or designee who receives a meeting request will determine whether to hold the meeting and will respond to the sponsor or applicant by granting or denying the meeting within 14 calendar days of receipt of the request and meeting package for a BPD Type 1 meeting, and within 21 calendar days of receipt of the request and meeting package for a Biosimilar Initial Advisory meeting or a BPD Type 2, 3, or 4 meeting.

A. Meeting Denied

If a meeting request is denied, notification to the sponsor or applicant will include an explanation of the reason for the denial. Denials will be based on a substantive reason, not merely on the absence of a minor element of the meeting request or a minor element of the meeting package. For example, as noted in section IV., Participation in the FDA’s Biosimilar Biological Product Development Program, the FDA will deny a BPD Type 1, 2, 3, or 4 meeting if the sponsor or applicant is in arrears with respect to an annual BPD fee for that product.16 Additionally, a meeting can be denied because it is premature for the product development stage or is clearly unnecessary. However, if a sponsor or applicant is not in arrears with respect to an annual BPD

16 See section 744H(a)(1)(E) of the FD&C Act.

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fee for a product, requests for BPD Type 1, 2, 3, and 4 meetings for that product will be honored except in the most unusual circumstances.

Following denial of a meeting, a subsequent request to schedule the meeting will be considered as a new request (i.e., a request that merits a new set of time frames as described in section V., Meeting Procedures).

B. Meeting Granted

If a meeting request is granted, CBER or CDER will notify the sponsor or applicant in writing of the decision and schedule the meeting by determining the meeting type, date, time, length, place, format (i.e., a scheduled face-to-face meeting, teleconference, or videoconference), and expected FDA participants. All of the scheduling information will be forwarded to the sponsor or applicant as soon as possible following the granting notification, and within the specified BsUFA timelines.

The Center (i.e., CBER or CDER) may determine that a different meeting type is more appropriate and it may grant a meeting of a different type than requested (e.g., if a sponsor or applicant requests a Biosimilar Initial Advisory meeting for a product, but the Center determines that a BPD Type 3 meeting is more appropriate, the FDA may grant a BPD Type 3 meeting instead of a Biosimilar Initial Advisory meeting).

As described in section IV., Participation in the FDA’s Biosimilar Biological Product Development Program, if the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, the sponsor or applicant may be required to pay an initial BPD fee or a reactivation fee for the product within 5 calendar days.17

VIII. RESCHEDULING MEETINGS

Occasionally, circumstances arise that necessitate the rescheduling of a meeting either by the FDA or the sponsor or applicant. If a meeting needs to be rescheduled, it should be rescheduled as soon as possible after the original date. A new meeting request should not be submitted and new time frames should not be set for rescheduled meetings. Sponsors or applicants and the FDA should take reasonable steps together to avoid rescheduling meetings. For example, if an attendee becomes unavailable, a substitute can be identified, or comments on the topic that the attendee would have addressed can be forwarded to the sponsor or applicant following the meeting. It will be at the discretion of the appropriate division whether the meeting should be rescheduled depending on the specific circumstances.

The following situations are examples of when a meeting can be rescheduled. This list includes representative examples and is not intended to be an exhaustive list.

17 See section 744H(a)(1)(A) and (D) of the FD&C Act.
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 

The review team determines that additional information is needed from the sponsor or applicant for the FDA to address the sponsor’s or applicant’s questions or other important issues for discussion, and it is possible to identify the additional information needed and arrange for its submission in a timely manner.

Essential attendees are no longer available for the scheduled date and time because of an unexpected or unavoidable conflict or an emergency situation.

After the meeting package is submitted but before preliminary responses are sent by the FDA, the sponsor or applicant sends CBER or CDER additional questions or data that are intended for discussion at the meeting and require additional review time.

It is determined that attendance by additional FDA personnel not originally anticipated or requested are critical and their availability precludes holding the meeting on the original date.

CANCELLING MEETINGS

Contains Nonbinding Recommendations

When the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, the sponsor or applicant may be required to pay an initial BPD fee or a reactivation fee for the product within 5 calendar days.18 If the sponsor or applicant fails to pay the fee within the required time frame, the meeting will be cancelled.19 If the sponsor or applicant pays the initial BPD fee or reactivation fee after the meeting has been cancelled because of nonpayment, the time frame described in section V., Meeting Procedures, for the new meeting will be calculated from the date on which the FDA received the payment, rather than the date on which the sponsor or applicant originally submitted the meeting request.

Occasionally, other circumstances arise that necessitate the cancelling of a meeting. If a meeting is cancelled for reasons other than nonpayment of a required initial BPD fee or reactivation fee, the FDA will consider a subsequent request to schedule a meeting to be a new request (i.e., a request that merits a new set of time frames as described in sections V., Meeting Procedures, and VII., Assessing Meeting Requests). Both sponsors or applicants and the FDA should take reasonable steps to avoid cancelling meetings (unless the meeting is no longer necessary). Cancellation will be at the discretion of the appropriate division, and will depend on the specific circumstances.

The following situations are examples of when a meeting can be cancelled. This list includes representative examples and is not intended to be an exhaustive list.

If the FDA grants the sponsor’s or applicant’s meeting request, but the sponsor or applicant subsequently fails to pay a required initial BPD fee, annual BPD fee, or

18 See section 744H(a)(1)(A) and (D) of the FD&C Act. 19 See section 744H(a)(1(E) of the FD&C Act.

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X.

reactivation fee within the time frame required under section 744H(a)(1)(A), (B), or (D) of the FD&C Act, as applicable.

The sponsor or applicant determines that the written premeeting responses to its questions are sufficient for its needs and additional discussion is not necessary (see section XII., Procedures for the Conduct of Meetings). In this case, the sponsor or applicant should contact the CBER or CDER regulatory project manager to request cancellation of the meeting. The division will consider whether it agrees that the meeting should be cancelled. Some meetings can be valuable because of the discussion they generate and the opportunity for the division to ask about relevant matters, even if the premeeting communications seem sufficient to answer the sponsor’s or applicant’s questions. If the division agrees with the sponsor or applicant that the meeting can be cancelled, the division will document the reason for cancellation and the premeeting communication will represent the final responses and the official record of the meeting.

The FDA determines that the meeting package is grossly inadequate. Meetings are scheduled on the condition that appropriate information to support the discussion has been submitted. Adequate planning by the sponsor or applicant should avoid this problem.

MEETING PACKAGE CONTENT AND SUBMISSION

Contains Nonbinding Recommendations

Premeeting preparation is critical for achieving a productive discussion or exchange of information. Preparing the meeting package should help the sponsor or applicant focus on describing its principal areas of interest. The meeting package should provide information relevant to the discussion topics and enable the FDA to prepare adequately for the meeting.

A. Timing of Submission

As discussed in section VII., Assessing Meeting Requests, if the meeting package is not submitted with the meeting request to the appropriate division, the meeting request will be considered incomplete and the FDA generally will deny the meeting.

B. Where and How Many Copies of Meeting Packages to Send

An archival copy of the meeting package should be submitted to the relevant application (e.g., pre-IND, IND, or BLA); if there is no established application, the sponsor or applicant should contact the division for additional instructions. The FDA strongly encourages sponsors or applicants to submit the archival meeting package electronically according to the electronic submission formatting recommendations (see the draft guidance for industry Providing Regulatory Submissions in Electronic Format — General Considerations).20

20 When final, this guidance will represent the FDA’s current thinking on this topic. 12

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The number of copies of a meeting package will vary based on the meeting. The responsible point of contact in the division will advise on the number of copies needed for the meeting attendees. To facilitate the meeting process, the FDA strongly suggests that copies of meeting packages provided in electronic format also be provided in paper.

C. Meeting Package Content

The meeting package should provide information relevant to the product, development stage, and meeting type requested (see section III., Meeting Types), in addition to any supplementary information needed to develop responses to issues raised by the sponsor or applicant or division. The meeting package should contain sufficient detail to meet the intended meeting objectives. For example, inclusion of raw data in addition to the derived conclusions may be appropriate in some situations. Similarly, merely describing a result as significant does not provide the division with enough information to give good advice or identify important problems the sponsor or applicant may have missed. FDA guidances identify and address many issues related to biosimilar biological product development and should be considered in planning, developing, and providing information needed to support a meeting with the FDA.21 If a product development plan deviates from current guidances, or from current practices, the deviation should be recognized and explained. Known or expected difficult design and evidence issues should be raised for discussion (e.g., selection of study populations, doses, or endpoints different from those studied for the reference product’s licensure; extrapolation of indications).

To facilitate FDA review, the meeting package content should be organized according to the proposed agenda. The meeting package should be a sequentially paginated document (individual sections can be numbered separately, as long as there is an overall pagination covering the whole submission) with a table of contents, appropriate indices, appendices, cross references, and tabs differentiating sections. Meeting packages generally should include the following information:

  1. The product name and application number (if applicable).

  2. The proposed proper name (or proper name if post-licensure).

  3. The structure (if applicable).

  4. The reference product name.

  5. The proposed indication(s) or context of product development.

  6. The dosage form, route of administration, dosing regimen (frequency and duration), and presentation(s).

21 See the guidances for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.

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7.

8.

9. 10. 11.

12.

A list of all individuals, with their titles and affiliations, who will attend the requested meeting from the sponsor or applicant organization, including consultants and interpreters.

A background section that includes the following:

a. A brief history of the development program.

b. The status of product development (e.g., chemistry, manufacturing, and controls; nonclinical; and clinical, including any development outside the United States, as applicable).

A brief statement summarizing the purpose of the meeting. A proposed agenda.

A list of questions for discussion grouped by discipline and with a brief summary for each question to explain the need or context for the question.

Data to support discussion organized by discipline and question. The level of detail of the data should be appropriate to the meeting type requested and the product development stage.

PREMEETINGS AND COMMUNICATIONS WITH SPONSORS OR APPLICANTS

Contains Nonbinding Recommendations

CBER and CDER hold internal meetings, including meeting with the Biosimilar Review Committee (BRC),22 to discuss meeting packages and to gain internal alignment on the preliminary responses to a sponsor’s or applicant’s questions. Our goal is to communicate these preliminary responses to the sponsor or applicant no later than 2 days before the scheduled meeting date. Communications before the meeting between sponsors or applicants and the FDA, including preliminary responses, can serve as a foundation for discussion or as the final meeting responses. Nevertheless, preliminary responses should not be construed as final unless there is agreement between the sponsor or applicant and the FDA that additional discussion is not necessary for any question (i.e., when the meeting is canceled because the sponsor or applicant is satisfied with the FDA’s preliminary responses), or a particular question is considered resolved allowing extra time for discussion of the more complex questions during the meeting. Preliminary responses communicated by the FDA are not intended to generate the submission of a new meeting agenda or new questions. If, however, a sponsor or applicant provides new data or a revised or new proposal, the FDA may not be able to provide comments on the new data or it may necessitate the submission of a new meeting request by the sponsor or applicant.

22 For more information about the BRC, refer to the Web page on implementation of the BPCI Act at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm.

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XII. PROCEDURES FOR THE CONDUCT OF MEETINGS

Meetings will be chaired by an FDA staff member and will begin with introductions and a statement of the agenda. Presentations by sponsors or applicants generally are not needed because the information necessary for review and discussion should be part of the meeting package. If a sponsor or applicant plans to make a presentation, the presentation should be discussed ahead of time with the CBER or CDER point of contact to determine if a presentation is warranted and ensure that CBER or CDER has the presentation materials ahead of the meeting if possible. All presentations should be kept brief to maximize the time available for discussion.

The length of the meeting will not be increased to accommodate a presentation. If a presentation contains more than a small amount of content distinct from clarifications or explanations of previous data and that were not included in the original meeting package submitted to CBER or CDER for review, FDA staff may not be able to provide comments on the new data.

Before the end of the meeting, FDA attendees and the sponsor or applicant attendees should summarize the important discussion points, agreements, clarifications, and action items. Generally, the sponsor or applicant will be asked to present the summary to ensure that there is mutual understanding of meeting outcomes and action items. FDA staff can add or further clarify any important points not covered in the summary and these items can be added to the meeting minutes. The summary can be done at the end of the meeting or after the discussion of each question.

XIII. DOCUMENTATION OF MEETINGS

Documentation of meeting outcomes, agreements and disagreements, issues for further discussion, and action items is critical to ensuring that this information is preserved for meeting attendees and future reference. FDA minutes are the official record of the meeting. The FDA intends to issue the official, finalized minutes to the sponsor or applicant within 30 days of the meeting.

XIV. RESOLUTION OF DISPUTE ABOUT MEETING MINUTES

This section refers to disputes regarding the accuracy and sufficiency of the minutes. A sponsor or applicant who objects to the accuracy of the minutes or who needs additional clarification of the meeting minutes issued by the FDA should contact the assigned FDA point of contact. This process addresses issues with the meeting minutes only. If a sponsor or applicant needs to discuss additional issues that were not addressed at the meeting, it should submit a correspondence or a new meeting request.

If, after following up as described above, there are still significant differences in the sponsor’s or applicant’s and the FDA’s understanding of the content of the official meeting minutes, the sponsor or applicant should notify the FDA in writing with respect to specific disagreements. The sponsor or applicant should submit the correspondence to its application or, if there is no

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Contains Nonbinding Recommendations

application, forward a letter to the office director/division director of the responsible division, with a copy to the point of contact describing the concerns.

The sponsor’s or applicant’s concerns will be taken under consideration by the division and the office director if the office director was present at the meeting. If the minutes are deemed to accurately and sufficiently reflect the meeting discussion, the point of contact will convey this decision to the sponsor or applicant and the minutes will stand as the official documentation of the meeting. If after discussions with the sponsor or applicant the FDA deems it necessary to effect a change to the official minutes, the changes will be documented in an addendum to the official minutes. The addendum will also document any continued sponsor or applicant objections.

XV. PAPERWORK REDUCTION ACT OF 1995

This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

The time required to complete the information collection for a meeting request and information package is estimated to average 15 hours and 30 hours per response, respectively, including the time to review instructions, search existing data sources, and gather the data needed, and complete and review the information collection. Send comments regarding this burden estimate or suggestions for reducing this burden to:

Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Attention: Document Control Room, 5901-B Ammendale Road, Beltsville, MD 20705.

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An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control number for this information collection is 0910-0802 (expires 9/30/18).

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