GUIDANCE DOCUMENT

This content was archived on June 24, 2013.

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact : BGTD RAD Enquiries

This document is also available in PDF format
GUIDANCE DOCUMENT (PDF Version, 57 kb)
Date: 2006-02-24

TABLE OF CONTENTS

• 1. INTRODUCTION
  • 1.1 Objective
  • 1.2 Policy Statements
  • 1.3 Scope and Application
  • 1.4 Definitions
  • 1.5 Abbreviations
  • 1.6 Background
• 2. ASSESSING WHETHER A STUDY FALLS WITHIN THE SCOPE OF THE PER BASIC RESEARCH COMPLIANCE POLICY
  • 2.1 Criteria for Basic Research
  • 2.2 Supporting Scientific Data
    • 2.2.1 Clinical Data
    • 2.2.2 Quality (Chemistry and Manufacturing) Data
  • 2.3 Amendments to Previously Approved PERs Research Studies
  • 2.4 Records
  • 2.5 Adverse Drug Reaction Monitoring and Reporting
• 3. ADDITIONAL INFORMATION

---

Biologics and Genetic Therapies Directorate
2nd Floor, Health Protection Building
Address Locator: 0702E
Ottawa, Ontario
K1A 0K9

February 24, 2006

We are pleased to inform you that the guidance document, Factors Considered in the Assessment of the Risks involved in the Use of Positron Emitting Radiopharmaceuticals in Basic Research involving Humans, is now available on Health Canada's website on the following page:

http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/
guides/radiopharm/index-eng.php

This document accompanies the Health Products and Food Branch Inspectorate's compliance policy, Use of Positron Emitting Radiopharmaceuticals in Basic Research, which has been posted here:

http://www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/
drugs-drogues/docs/index-eng.php

These documents will come into effect on February 24, 2006 and will remain in effect until the proposed regulatory amendment regarding the use of positron emitting radiopharmaceuticals in basic research is completed.

Inquiries about the guidance document can be addressed to:

Regulatory Affairs Division
Biologics and Genetic Therapies Directorate
Phone: (613) 957-1722
Fax: (613) 946-9520
E-mail: BGTD_D_Enquiries@hc-sc.gc.ca

Original signed by:

Dr. Pierre J. Charest
Director General

FACTORS CONSIDERED IN THE ASSESSMENT OF RISKS INVOLVED IN THE USE OF POSITRON EMITTING RADIOPHARMACEUTICALS IN BASIC RESEARCH INVOLVING HUMANS

Published by authority of the Minister of Health

• Date Adopted: February 24, 2006
• Effective Date: February 24, 2006

Health Products and Food Branch Guidance Document

© Minister of Public Works and Government Services Canada 2005

Available in Canada through

Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9
Tel: (613) 954-5995
Fax: (613) 941-5366

Également disponible en français sous le titre :

Catalogue No. E
ISBN

FOREWORD

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

1. INTRODUCTION

1.1 Objective

To provide guidance and clarification on Health Canada's compliance policy with respect to the use of positron emitting radiopharmaceuticals (PERs) in basic research¹ involving humans, in light of a proposal to amend Part C, Division 5 of the Food and Drug Regulations as it applies to PERs.

1.2 Policy Statements

1.2.1 Basic research studies using PERs with an established safety profile in humans that fall within the scope of this guidance document are not considered to be a compliance and enforcement priority.

1.2.2 The information contained within this guidance document may form the basis for proposed amendments to Part C, Division 3 of the Food and Drug Regulations. Pending the regulatory amendment, the Compliance Policy, Use of Positron Emitting Radiopharmaceuticals in Basic Research, applies to all PERs used in humans for basic research.

1.2.3 Research studies which do not fall within the scope of this document will be a priority for enforcement of Part C, Division 5 of the Food and Drug Regulations.

1.3 Scope and Application

1.3.1 This guidance document applies to PERs used in basic research as defined herein.

1.3.2 This guidance document does not apply to PERs which have not previously been used in humans.

1.3.3 This guidance document does not apply to PERs manufactured from a Schedule D bulk process intermediate (i.e., a biologic PER).

1.4 Definitions

1.4.1 Basic research study is an investigation in humans, involving a drug with a predefined safety profile, intended to obtain data on pharmacokinetics or metabolism of the drug or to obtain basic data related to normal human biochemistry or physiology, changes caused by aging, disease or treatment interventions and not primarily intended to:

1. discover, verify, or identify the pharmacodynamic effects of the drug;
2. identify any adverse events in respect of the drug;
3. fulfill any immediate therapeutic or diagnostic purpose, or,
4. assess the safety or efficacy of the drug.

1.4.2 Positron Emitting Radiopharmaceutical (PER) is a drug that is chemically labelled with positron emitting radionuclides or containing positron emitting radionuclides that exhibit spontaneous transformation of unstable nuclei through positron decay.

1.4.3 Research Ethics Board (REB) is a body which is not affiliated with the researcher, and:

1. the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and
2. that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration and Refugee Protection Act, that is composed of both men and women and that includes at least:
   1. two members whose primary experience and expertise are in a scientific discipline, who have broad experience in the methods and areas of research to be approved and one of whom is from a medical discipline,
   2. one member knowledgeable in ethics,
   3. one member knowledgeable in Canadian laws relevant to the research to be approved,
   4. one member whose primary experience and expertise are in a non-scientific discipline, and
   5. one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the applicant or the site where the study is to be conducted.

1.5 Abbreviations

ADR

Adverse Drug Reaction

CTA

Clinical Trial Application

[¹⁸ F]FDG

[¹⁸ F]-fluorodeoxyglucose

MBq

Megabecquerel

mCi

millicurie

mGy

milligray

mSv

millisievert

PER

Positron Emitting Radiopharmaceutical

PET

Positron Emission Tomography

REB

Research Ethics Board

rem

radiation equivalent man

1.6 Background

PERs are used as tracers in human imaging research studies with Positron Emission Tomography (PET). Typically, a non-pharmacological dose of a PER is administered to human subjects in order to study normal body functions or disease. Most positron emitting radionuclides used in the production of PERs have a very short physical half-life (minutes to hours), and hence the final product has a short shelf-life (a few hours). As a result, most PERs are generally manufactured on-site and must be administered to a subject shortly thereafter.

[¹⁸ F]-Fluorodeoxyglucose ([¹⁸F]FDG), the most commonly used PER, has a long history of safe use in basic research². The use of non-pharmacological doses, established maximum radiation dose limits, proper control of production methodology, equipment, and facilities and adequate quality control of the product have all contributed to the safety of these radiopharmaceuticals.

The application of CTA requirements to PERs research studies is thought to place an undue regulatory burden on the researchers in this field and impede basic research involving PERs in Canada. Health Canada recognizes that, although most PERs used in basic research have not been conducted pursuant to an application filed and reviewed in accordance with the CTA requirements, there is an established history of safe use of some drugs in this class for this purpose. The proposed regulatory amendments will take into account the size and nature of the affected basic research community, the established safety profiles of some commonly used PERs, the models of review used by other competent regulators and, most importantly, assessment and management of the risk to which human research subjects are exposed.

2. ASSESSING WHETHER A STUDY FALLS WITHIN THE SCOPE OF THE PER BASIC RESEARCH COMPLIANCE POLICY

2.1 Criteria for Basic Research

The following is used in determining if a study is considered basic research:

2.1.1 Pharmacological dose. The amount of active ingredients or combination of active ingredients within the PER(s) is known not to cause any clinically detectable pharmacological effect in humans.

2.1.2 Radiation dose. The total radiation dose incurred by a subject, including from multiple administrations of PERs, significant contaminants or impurities, and use of other procedures for the purposes of the study is within the limits herein. Dose calculation takes into account radiation doses from other research studies the subject participated in within the year and the possibility of follow-up studies.

Whole body:Single dose: 20 mSv (2 rem)
Annual and total dose commitment: 20 mSv (2 rem)

2.1.3 Qualifications of investigators. Each investigator is qualified by training and experience to conduct the proposed research study, and a minimum of one investigator involved in the study is a licensed physician, responsible for the medical safety of the subjects.

2.1.4 Human research subjects. Each investigator selected the appropriate subjects and obtain their informed consent. Research subjects are at least 18 years of age and legally competent. Each female research subject is, on the basis of a pregnancy test, confirmed as not pregnant. Female subjects is not be lactating.

2.1.5 Quality of PER(s). The PER(s) used in the research study are fully characterized and meet the required chemical, pharmaceutical, radiochemical, and radionuclidic standards of identity, strength, quality, purity and impurities. The quality of the PERs is reproducible so as to give significance to the research study.

2.1.6 Approval by a Research Ethics Board (REB). The study protocol should be reviewed and approved by a REB.

2.2 Supporting Scientific Data

The information detailed in the following section may be considered by the Department in relation to PER basic research studies to assist it in determining whether or not that research falls within the scope of the Compliance Policy.

2.2.1 Clinical Data

1. Information/evidence from valid human studies or published literature to demonstrate that the PER and/or carrier molecule (ligand) has no pharmacological effect in humans in the proposed mass dose range.
2. Information/evidence from valid human or animal studies or published literature to demonstrate the safety of the radioactive dose proposed.
   
   Radiation absorbed dose estimates (radiation dosimetry) per unit of administered activity (mGy/MBq or rad/mCi) was determined for the whole body and organs and tissues. The Effective Dose and/or Effective Dose Equivalent estimates per unit of administered activity (mSv/MBq or rem/mCi) was determined. The radiation absorbed dose calculation was based on valid biodistribution studies either in animals or in humans, and calculated by internal radiation dosimetry methodology³. Radiation absorbed dose estimates was determined for all significant radionuclidic and radiochemical impurities that might be present in the final dose form.
3. Concurrent drugs other than PERs to be given as part of the research study have received market authorization in Canada.
   
   A research study in which the concurrent drug has not received marketing authorization from Health Canada shall be submitted as a CTA.
4. A plan detailing the subject monitoring procedures and documentation of adverse drug reactions (ADRs).
   
   Note that suspected serious ADRs attributable to the use of PERs are to be reported to Health Canada.

2.2.2 Quality (Chemistry and Manufacturing) Data

1. A list of all non-active (other than the ligand/precursor) ingredients.
2. Information on the radioisotope, ligand/precursor, and other accessories used in the manufacturing.
3. The specifications and batch analysis data, including sterility and pyrogen testing, pH, purity, stability, etc.
4. Quality control test parameters as to what tests are performed prospectively and/or retrospectively.
5. The contents and/or composition of the final product; and a list of residual solvents, catalysts, and the vehicle used and the amount of each present in the final product (PER).
6. Certificates of Analysis for at least three production runs for the PER, in support of the product quality validation, particularly for stability, sterility and apyrogenicity of the final drug product.

2.3 Amendments to Previously Approved PERs Research Studies

If a change is made to the study protocol that puts it in conflict with the aforementioned scope or criteria, the amended study may then become an enforcement priority.

2.4 Records

All information related to the research study is recorded, handled and stored in a way that allows its complete and accurate reporting as well as its interpretation and verification.

2.5 Adverse Drug Reaction Monitoring and Reporting

The investigator implemented appropriate adverse drug reaction (ADR) monitoring and recording procedures.

3. ADDITIONAL INFORMATION

If you have any questions regarding this guidance, please contact:

Regulatory Affairs Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
1st Floor, Health Protection Building, A.L. 0701A
Tunney's Pasture, Ottawa, Ontario K1A 0K9
Telephone: 613-957-1722
Fax : 613-946-9520
Email: BGTD_D_Enquiries@hc-sc.gc.ca

Footnotes

• ¹ See definition
• ² Silberstein E.B. 1998 Prevalence of adverse reaction to positron emitting radiopharmaceuticals in nuclear medicine. Pharmacopeia Committee of the Society of Nuclear Medicine. J. Nucl. Med. 39 2190-2192.
• ³ The absorbed fraction method of radiation absorbed dose calculation is described in two systems, the Medical Internal Radiation Dose Committee (MIRD) of the Society of Nuclear Medicine, and the International Commission on Radiological Protection (ICRP).