Clinical Study Protocol Appendix D <<1>>
Drug Substance
<<2>>
Study Code
<<3>>
Appendix Edition Number <<4>>
Appendix Date
<<Day Month Year>>
Appendix D
Pharmacogenetics Research
NOTE: The authoring instruction box should be deleted from the document before it
is finalised
To the Author:
• The standard text (mandatory) provided in the template is to be used unless stated
otherwise.
• The dates of the different appendices do not need to be the same as long as they are
dated before the final Clinical Study Protocol or at the same day as the final Clinical
Study Protocol.
• Where Pharmacogenetic (PGx) analysis is a co-primary objective within a clinical study,
or where genetic sample collection is a mandatory part of the study, the information
relating to PGx research should be captured in the main Clinical Study Protocol
template.
• Where PGx is a secondary or an exploratory objective for the study the information
may be captured within the main Clinical Study Protocol or it may be used as an
appendix.
• Where the study will be recruiting in territories that are known to have specific issues
regarding local regulations for genetics research or large multicentre studies a PGx
appendix should be used, where possible.
• The main Clinical Study Protocol template contains information relating to the collection
of Pharmacogenetics (PGx) samples. If a study is planning to use a PGx appendix
ensure that duplicate text in the main Clinical Study Protocol is removed and that
reference is, instead, made to the PGx appendix.
Clinical Study Protocol (CSP) Appendix D Pharmacogenetics Research 20101020
Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
Clinical Study Protocol (CSP) Appendix D Pharmacogenetics Research 20101020
22
Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
TABLE OF CONTENTS
PAGE
TITLE PAGE ................................................................................................. 1
TABLE OF CONTENTS .................................................................................... 3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................... 4
1.
BACKGROUND AND RATIONALE ....................................................... 5
2.
GENETIC RESEARCH OBJECTIVES ..................................................... 5
3.
GENETIC RESEARCH PLAN AND PROCEDURES .................................... 6
3.1
3.1.1
3.1.2
3.1.3
3.1.4
Selection of genetic research population ............................................ 6
Study selection record ..................................................................... 6
Inclusion criteria ............................................................................. 6
Exclusion criteria ............................................................................ 6
Discontinuation of subjects from this genetic research......................... 6
3.2
Collection of samples for genetic research ......................................... 7
3.3
Coding and storage of DNA samples .................................................. 7
4.
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 8
4.1
Informed consent ........................................................................... 8
4.2
Subject data protection ................................................................... 9
5.
DATA MANAGEMENT ....................................................................... 9
6.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ........ 10
7.
LIST OF REFERENCES ................................................................... 10
Clinical Study Protocol (CSP) Appendix D Pharmacogenetics Research 20101020
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or
Explanation
special term
CSR
Clinical Study Report
DNA
Deoxyribonucleic acid
LIMS
Laboratory information management system
PGx
Pharmacogenetics
Clinical Study Protocol (CSP) Appendix D Pharmacogenetics Research 20101020
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
1.
BACKGROUND AND RATIONALE
To the Author:
Briefly justify the reasons for the inclusion of the genetic component of the study explaining
the strategy and hypothesis on which this is based and how it fits into the clinical
development plan.
<<Insert Sponsor’s Name>> intends to perform genetic research in the <<drug name>>
clinical development programme to explore how genetic variations may affect the clinical
parameters associated with <<drug name and/or agents used in combination or as
comparators>>. Collection of DNA samples from populations with well described clinical
characteristics may lead to improvements in the design and interpretation of clinical trials
and, possibly, to genetically guided treatment strategies.
<<Future research may suggest other genes or gene categories as candidates for
influencing not only response to <<drug name and/or agents used in combination or as
comparators >> but also susceptibility to << (use MedDRA terminology when possible:
the ‘response’/disease>> for which <<drug name>> may be evaluated.
Thus, this
genetic research may involve study of additional un-named genes or gene categories, but
only as related to <<disease susceptibility and drug action.>>
OR
<<It is emphasised that the Sponsor will only look for markers within genes relevant to
the mode of action of, and response to << drug name and/or agents used in combination
or as comparators >>, and <<disease/response>> under study within the current
Clinical Study Protocol. No other research will be performed on the samples.>>
2.
GENETIC RESEARCH OBJECTIVES
To the Author:
• Use the default paragraph below.
• Where the study team has agreed that an objective with a “narrow” scope of research is
appropriate, the above paragraph should be edited to provide the specific details– eg,
research only on drug response, or only on named genes etc.
• Consult the local or therapeutic area pharmacogenetics advisor/ project for advice.
The objective of this research is to collect and store DNA for future exploratory research
into genes/genetic variation that may influence response (ie, distribution, safety,
tolerability and efficacy) and/or <<susceptibility to disease>> << (use MedDRA
terminology when possible: the ‘response’/disease>> to XXXX <<and/or agents used in
combination and/or as comparators>>.
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
3.
GENETIC RESEARCH PLAN AND PROCEDURES
3.1
Selection of genetic research population
3.1.1
Study selection record
<<All or other criteria>> subjects will be asked to participate in this genetic research.
Participation is voluntary and if a subject declines to participate there will be no penalty or
loss of benefit. The subject will not be excluded from any aspect of the main study.
3.1.2
Inclusion criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria
described in the main body of the Clinical Study Protocol and:
• Provide informed consent for the genetic sampling and analyses.
3.1.3
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in
the main study or any of the following:
To the Author:
The PGx exclusion criteria below apply to blood and saliva samples.
If a buccal swab is
being taken for DNA extraction and analysis the two exclusion criteria listed below should be
deleted.
• <<Previous allogeneic bone marrow transplant>>
• <<Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample
collection>>
3.1.4
Discontinuation of subjects from this genetic research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research:
Subjects may withdraw from this genetic
research at any time, independent of any decision concerning participation in other
aspects of the main study. Voluntary discontinuation will not prejudice further treatment.
Procedures for discontinuation are outlined in Section 7.5 of the main Clinical Study
Protocol.
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
3.2
Collection of samples for genetic research
To the Author:
• Describe when samples will be collected.
• A blood sample is the preferred sample type for the majority of genetic research
samples.
• Capture details of sampling, handling, storage and transport of the samples in the
Laboratory Manual. Samples may be collected at any time after randomisation,
however; ideally samples should be collected early in the study to avoid bias in the
sample collection (ie, failure to collect samples from patients who have suffered an AE
etc).
The blood <<or other appropriate sample type eg, saliva or buccal swab>> sample for
genetic
research
will
be
obtained
from
the
subjects
at
Visit
<<
X
at
or
after>>randomisation. Although genotype is a stable parameter, early sample collection
is preferred to avoid introducing bias through excluding patients who may withdraw due to
an adverse event (AE), such patients would be important to include in any genetic
analysis. If for any reason the sample is not drawn at Visit <<X>>, it may be taken at
any visit until the last study visit. Only one sample should be collected per subject for
genetics during the study.
Samples will be collected, labelled, stored and shipped as
detailed in the Laboratory Manual.
For blood volume, see Section 7.1 of the Clinical Study Protocol.
3.3
Coding and storage of DNA samples
To the Author:
The recommended default storage time is 25 years; this may vary in different territories. In
some circumstances, there may be a rationale for the storage of DNA samples until they are
depleted.
When defining the storage time local laws and regulations for the storage of
genetic samples must be considered.
The processes adopted for the coding and storage of samples for genetic analysis are
important to maintain subject confidentiality. Samples will be stored for a maximum of
<<XX years>>, from the date of last subject last visit, after which they will be destroyed.
DNA is a finite resource that is used up during analyses. Samples will be stored and used
until no further analyses are possible or the maximum storage time has been reached.
For all samples irrespective of the type of coding used the DNA will be extracted from the
blood <<or other appropriate sample type eg, saliva or buccal swab>> sample. The DNA
sample will be assigned a unique number replacing the information on the sample tube.
Thereafter, the DNA sample will be identifiable by the unique DNA number only. The DNA
number is used to identify the sample and corresponding data at the Sponsor’s genetics
laboratories, or at the designated contract laboratory. No personal details identifying the
individual will be available to any person (Sponsor’s employee or contract laboratory staff
working with the DNA.)
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
<<Choose one of the following procedures of the coding procedure to be used: Option 1 is
the preferred choice
Where samples and data will be “single coded” (Option 1):
The samples and data for genetic analysis in this study will be single coded.
The link
between the subject enrolment/randomisation code and the DNA number will be
maintained and stored in a secure environment, with restricted access WITHIN the Clinical
Genotyping Group Laboratory Information Management System (LIMS) at <<insert
Sponsor’s Name>>.
The link will be used to identify the relevant DNA samples for
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit
and to trace samples for destruction in the case of withdrawal of consent.>>
<<Where samples and data will be “double coded” (Option 2):
The samples and data for genetic analysis in this study will be double coded.
The link
between the subject enrolment/randomisation code and the DNA number will be
maintained and stored in a secure environment OUTSIDE of the Clinical Genotyping Group
LIMS database at <<insert the Sponsor’s Name>>. The link file will be used to identify
the relevant DNA samples for analysis, facilitate correlation of genotypic results with
clinical data, allow regulatory audit and to trace samples for destruction in the case of
withdrawal of consent.>>
4.
ETHICAL AND REGULATORY REQUIREMENTS
The principles for ethical and regulatory requirements for the study, including this genetics
research component, are outlined in Section 8 of the main Clinical Study Protocol.
4.1
Informed consent
To the Author:
• Describe when and how the informed consent will be obtained.
• Include the following standard text where the informed consent for genetic analyses is
separate to the consent for the main study.
The genetic component of this study is optional and the subject may participate in other
components of the main study without participating in the genetic component.
To
participate in the genetic component of the study the subject must sign and date both the
consent form for the main study and the genetic component of the study. Copies of both
signed and dated consent forms must be given to the subject and the original filed at the
study centre.
The principal investigator(s) is responsible for ensuring that consent is
given freely and that the subject understands that they may freely discontinue from the
genetic aspect of the study at any time.
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
4.2
Subject data protection
To the Author:
Delete duplicate text in the main CLINICAL STUDY PROTOCOL.
The Sponsor will not provide individual genotype results to subjects, any insurance
company, any employer, their family members, general physician or any other third party,
unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being
linked to the identity of the subject.
In exceptional circumstances, however, certain
individuals might see both the genetic data and the personal identifiers of a subject. For
example, in the case of a medical emergency, the Sponsor’s Physician or an investigator
might know a subject’s identity and also have access to his or her genetic data.
Also
Regulatory authorities may require access to the relevant files, though the subject’s
medical information and the genetic files would remain physically separate.
5.
DATA MANAGEMENT
To the Author:
• Delete this duplicate text from the CLINICAL STUDY PROTOCOL and reference the PGx
Appendix.
• Indicate whether data will be reported in the CSR for the main study or will be reported
separately.
• Where genetic data will be merged with the clinical database use the standard text given
in option 1 below.
• Where genetic data will not be merged with the clinical database use standard text given
in option 2 below.
Any genotype data generated in this study will be stored in the Sponsor’s genotyping LIMS
database, or other appropriate secure system within the Sponsor and/or third party
contracted to work with the Sponsor to analyze the samples.
The results from this genetic research may be reported in the CSR for the main study, or
in a separate report as appropriate.
<<Choose one of the following procedures, Option 1:
Genotype data will be transferred to the clinical database, and merged with the clinical
data from the main study, prior to the statistical analysis and reporting of the study. >>
<<or Option 2:
Some or all of the clinical datasets from the main study may be merged with the genetic
data in a suitable secure environment separate from the clinical database.>>
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Clinical Study Protocol Appendix D <<1>>
Drug Substance <<2>>
Study Code <<3>>
Appendix Edition Number<<4>>
Appendix Date <<Day Month Year>>
6.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
The number of subjects that will agree to participate in the genetic research is unknown.
It is therefore not possible to establish whether sufficient data will be collected to allow a
formal statistical evaluation or whether only descriptive statistics will be generated.
A
statistical analysis plan will be prepared where appropriate.
7.
LIST OF REFERENCES
<<>>
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