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TDR/ PRD/ SOP/ 01.1
STANDARD OPERATING PROCEDURESFOR CLI NI CAL INVESTIGATORS
SOP Authors: Juntra Karbwang and Claire Pattou
Final SOP status
Revised and approved by the Product Research and DevelopmentR&D Committee
UNDP/ World Bank/ WHOSpecial Programme for Research andTraining in Tropical Diseases (TDR)
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TABLE OF CONTENTS
Policy/ Scope/ Aims/ Applicable to . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
I nvestigator Standard Operating Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Prior to Initiation of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
During the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Investigators file, including storage and retention . . . . . . . . . . . . . . . . . . . . . . 213
Screening and recruitment of study subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Obtaining informed consent from trial subjects . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Protocol compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Providing medical care for trial subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Randomization procedures and unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Safety reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Completion and validation of the case report form . . . . . . . . . . . . . . . . . . . . . . 220
Source data and documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Product storage and accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Premature termination or suspension of a trial . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Progress and final reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Annexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
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ESTIGATORSSECTION2
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ESTIGATORSSECTION2Clinical Development
Standard Operating Procedures ( SOPs)
SOPs Tit le: Investigators Responsibilities
SOPs No.: CT 05
SOPs Author(s) : Junt ra Karbwang & Clai re Pat tou
SOPs Approbat ion: PRD R&D Commit tee
SOPs Status: Final Revision due date: March 2004
Status Date: 10 Apri l 2002
I mplementation Date: _____________
Document received by: _____________ _____________ _____________Date Signature
Agreement to comply wit h these SOPs: _____________ _____________
Date Signature
Policy: All clinical studies supported by TDR will be carried out according to
I nternati onal Conference on Harmonisat ion ( ICH)/ WHO good cli nical prac-
tice (GCP) standards, regulatory authorities requirements and TDR stan-
dard operating procedures (SOPs).All TDR investigators have an obligation to follow and adhere to the estab-
lished TDR clinical study SOPs.
Note: When a t rial is sponsored by another agency/ pharmaceuti cal company, t he
investigator may also be requested to follow their procedures in order to
comply with company obligations. Agreement between all parties will be
discussed before initiating the trial.
Scope: Phase I, II and III clinical trials conducted by the TDR unit on Product
Research and Development (TDR/ PRD).
Aims: To define investigators responsibilities and to provide instruction when
performing clinical study(ies) supported by TDR according to GCP (ICH)
standards and under applicable regulatory requirements.
Applicable to: TDR invest igat ors and, where relevant, UNAIDS invest igat ors.
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ESTIGATORSSECTION2 GLOSSARY*
Adverse drug reacti on (ADR)
In the pre-approval clinical experience with a new medicinal product or a productsnew usage, particularly as the therapeutic dose(s) may not be established: all
noxious and unintended responses to a medicinal product related to any dose
should be considered adverse drug reactions (the phrase responses to a medicinal
product means that a causal relationship between a medicinal product and an
adverse event is at least a reasonable possibility, i.e. the relationship cannot be
ruled out).
Regarding marketed medicinal products: a response to a drug which is noxious
and unintended and which occurs at doses normally used in human subjects for
prophylaxis, diagnosis, or therapy of diseases or for modification of physiological
function.
Adverse event ( AE)
Any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product which does not necessarily have a causal
relationship with this treatment. An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal (investiga-
tion) product, whether or not related to the medicinal (investigation) product.
Applicable regulatory requirement( s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investiga-
tion products.
Approval ( in relat ion to insti tutional review boards)
The affirmative decision of the institutional review board (IRB) that the clinical
trial has been reviewed and may be conducted at the institution site within the
constraints set forth by the IRB, the institution, good clinical practice (GCP), and
the applicable regulatory requirements.
Audit
A systematic and independent examinat ion of t rial- related act ivi t ies and documents
to determine whether the evaluated trial-related activities were conducted, and the
data were recorded, analysed and accurately reported, according to the protocol,
sponsors standard operating procedures (SOPs), good clinical practice (GCP), and
the applicable regulatory requirement(s).
* Unless otherwise stated, t hese defi ni t ions are derived f rom the I nternational Conferenceon Harmonisation of Technical Requirements for Registration of Pharmaceuticals for HumanUse. I CH Harmonised Tripart ite Guidelines.
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ESTIGATORSSECTION2Blinding
A procedure in which one or more part ies to t he tr ial are kept unaware of the treat-
ment assignment (s). Single-bli nding usuall y refers to t he subject( s) being unaware,
and double-blinding usually refers to the subject(s), investigator(s), monitor, and,
in some cases, data analyst(s), being unaware of the treatment assignment(s).
Case report form ( CRF)
A printed, optical, or electronic document designed to record all of the protocol-
required information to be reported to the sponsor on each trial subject.
Clinical trial/ study
Any investigation in human subjects intended to discover or verify the clinical,
pharmacological and/ or other pharmacodynamic effects of an i nvest igat ion
product( s), and/ or to ident if y any adverse reacti ons to an investigation product(s),
and/ or to study the absorpt ion, di st ribut ion, metabolism, and excreti on of an inves-t igation product( s) wit h t he object of ascertaining i t s safety and/ or effi cacy. The
terms clinical trial and clinical study are synonymous.
Clinical trial/ study report
A writ ten descript ion of a tri al/ study of any therapeuti c, prophylacti c, or diagnost ic
agent conducted in human subjects, in which the clinical and statistical descrip-
tion, presentations, and analyses are fully integrated into a single report (see ICH
Guideline for structure and content of clinical study reports).
Compliance ( in relat ion to trials)Adherence to all the trial-related requirements, GCP requirements, and the applic-
able regulatory requirements.
Confidentiality
Prevention of disclosure, to unauthorized individuals, of a sponsors proprietary
information or of a subjects identity.
Contract
A written, dated, and signed agreement between two or more involved parties that
sets out any arrangements on delegation and distribution of tasks and obligations
and, if appropriate, financial matters. The protocol may serve as the basis of a con-
tract.
Direct access
Permission to examine, analyse, verify, and reproduce any records and reports that
are important to evaluation of a clinical trial. Any party (e.g. domestic and foreign
regulatory authorities, sponsors, monitors and auditors) with direct access should
take all reasonable precautions within the constraints of the applicable regulatory
requirement(s) to maintain the confidentiality of subjects identities and the
sponsors proprietary information.
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ESTIGATORSSECTION2 Documentation
All records, in any form (including, but not limited to, written, electronic, mag-
netic, and optical records; scans; X-rays; electrocardiograms) that describe or record
the methods, conduct and/ or result s of a t rial, t he factors aff ect ing a tri al, and the
actions taken.
Essential documents
Documents which individually and collectively permit evaluation of the conduct of
a study and the quality of the data produced.
Good clinical practice ( GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording,
analyses, and reporting of clinical trials that provides assurance that the data and
reported results are credible and accurate, and that the rights, integrity, and con-
fidentiality of trial subjects are protected.
Impartial witness
A person, who is independent of the trial, who cannot be unfairly influenced by
people involved in the trial, who attends the informed consent process if the sub-
ject or the subjects legally acceptable representative cannot read, and who reads
the informed consent form and any other written information supplied to the sub-
ject.
I ndependent ethics committ ee ( I EC)
An independent body (a review board or a committee, institutional, regional,
national, or supranational) , const i t uted of medical/ scienti fi c professionals and non-
medical/ non-scient if ic members, whose responsibil it y is to ensure protect ion of the
rights, safety and well-being of human subjects involved in a trial and to provide
public assurance of that protection, by, among other things, reviewing and
approving/ providing favourable opinion on the t rial protocol, suit abil it y of t he
investigator(s), facilities, and the methods and materials to be used in obtaining
and documenting informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements
pertaining to Independent Ethics Committee may differ among countries, but
should allow the Independent Ethics Committee to act in agreement with GCP.
I nformed consent
A process by which a subject voluntarily confirms his or her willingness to partici-
pate in a particular trial, after having been informed of all aspects of the trial that
are relevant to the subjects decision to participate. Informed consent is docu-
mented by means of a written, signed and dated informed consent form.
Inspection
The act by a regulatory authori t y(i es) of conducti ng an offi cial review of documents,
facil it ies, records, and any other resources that are deemed by the authori t y(i es) to
be related to the clinical trial and that may be located at the site of the trial, at
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ESTIGATORSSECTION2t he sponsors and/ or cont ract research organization s (CROs) facil i t ies, or at other
establishments deemed appropriate by the regulatory authority(ies).
Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical
trials are conducted.
I nsti tut ional review board ( I RB)
An independent body constituted of medical, scientific, and non-scientific mem-
bers, whose responsibility is to ensure the protection of the rights, safety and well-
being of human subjects involved in a trial by, among other things, reviewing,
approving, and providing continuing review of the trial protocol and amendments
and of the methods and materials to be used in obtaining and documenting
informed consent of the trial subjects.
I nterim clinical trial/ study reportA report of intermediate results and their evaluation based on analyses performed
during the course of a trial.
I nvestigati on product
A pharmaceutical form of an active ingredient or placebo being tested or used as a
reference in a clinical trial, including a product with a marketing authorizations
when used or assembled (formulated or packaged) in a way different from the
approved form, or when used for an unapproved indication, or when used to gain
further information about an approved use.
Investigator
A person responsible for the conduct of a clinical trial at a trial site. If a trial is
conducted by a team of individuals at a trial site, the investigator is the respon-
sible leader of the team and may be called the principal investigator. See also sub-
investigator.
I nvestigator/ insti tution
An expression meaning the invest igator and/ or inst it ut ion, where required by the
applicable regulatory requirements.
I nvestigators brochure ( I B)
A compilation of the clinical and non-clinical data on the investigation product(s)
which is relevant to the study of the investigation product(s) in human subjects.
Legally acceptable representat ive
An individual or juridical or other body authorized under applicable law to consent,
on behalf of a prospecti ve subject , t o t he subject s part icipation in t he cli nical t rial.
Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is con-
ducted, recorded, and reported in accordance with the protocol, standard operating
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ESTIGATORSSECTION2 procedures (SOPs), good clinical practice (GCP), and applicable regulatory require-
ment(s).
Monitoring report
A writ ten report from the monit or t o t he sponsor after each sit e visit and/ or other
trial-related communication according to the sponsors SOPs.
Multicentre trial
A clinical trial conducted according to a single protocol but at more than one site,
and therefore carried out by more than one investigator.
Open trial
The opposite of a double-blind study, in that everyone knows what medication each
patient is receiving. This may occur in a study involving either one or more than
one treatment. (Definition from: Winslade J., Hutchinson D.R., 1992. Dictionary of
clinical research. Surrey, UK: Brookwood Medical Publications Ltd.)
Opinion ( in relat ion to an independent ethics commit tee)
The judgement and/ or advice provided by an independent et hics commit tee (I EC).
Protocol
A document that describes the objective(s), design, methodology, statistical con-
siderations, and organization of a trial. The protocol usually also gives the back-
ground and rationale for the trial, but these could be provided in other protocol ref-
erenced documents. Throughout the I CH GCP Guideli ne, the term protocol refers to
protocol and protocol amendments.
Protocol amendment
A written description of a change(s) to, or formal clarification of a protocol.
Protocol deviat ion/ violation
Noncompliance with protocol requirements. This may include noncompliance with
the following protocol provisions: inclusion and exclusion criteria, randomization
procedures, bli nding procedures, informed consent procedure, assignment of subject
identification numbers, dosing and assessment schedules, reporting and procedures
for adverse events, concomitant medications. (Definition from the authors)
Quali ty assurance ( QA)
All those planned and systematic actions that are established to ensure that the
trial is performed and the data are generated, documented (recorded), and reported
in compliance with good clinical practice (GCP) and applicable regulatory require-
ment(s).
Quali ty control ( QC)
The operational techniques and activities undertaken within the quality assurance
system to verify that the requirements for quality of the trial-related activities have
been fulfilled.
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ESTIGATORSSECTION2Randomization
The process of assigning trial subjects to treatment or control groups using an ele-
ment of chance to determine the assignments, in order to reduce bias.
Regulatory authoritiesBodies having t he power to regulat e. I n t he ICH GCP Guideli ne the expression regu-
latory authorities includes the authorities that review submitted clinical data and
those that conduct inspections. These bodies are sometimes referred to as compe-
tent authorities.
Serious adverse event ( SAE) or serious adverse drug reaction ( serious ADR)
Any untoward medical occurrence that, at any dose, has one or more of the fol-
lowing attributes:
Results in death.
Is l if e-threatening. Requires inpatient hospit alizat ion or prolongat ion of existi ng hospit alizat ion.
Result s in persistent or signif icant disabil it y/ incapacit y.
Is a congenit al anomaly/ birth defect .
Result s in an important medical event that may not be immediately li fe-t hreat -
ening or does not directly result in death or hospitalization, but which may jeop-
ardize the patient or may require intervention to prevent the other outcomes
listed above.
Source data
All information, in original records and certified copies of original records, of clini-cal findings, observations, or other activities in a clinical trial necessary for the
reconstruction and evaluation of the trial. Source data are contained in source
documents (original records or certified copies).
Source documents
Original documents, data, and records (e.g. hospital records, clinical and office
charts, laboratory notes, memoranda, subjects diaries or evaluation checklists,
pharmacy dispensing records, recorded data from automated instruments, copies or
t ranscript ions cert if ied aft er veri fi cat ion as being accurate copies, microfi ches, pho-
tographic negatives, microfilm or magnetic media, X-rays, subject files, and recordskept at the pharmacy, at the laboratories, and at medico-technical departments
involved in the clinical trial).
Sponsor
An individual, company, institution, or organization which takes responsibility for
the ini t iati on, management, and/ or fi nancing of a cli nical t rial.
Standard operat ing procedures ( SOPs)
Detailed written instructions to achieve uniformity of the performance of a specific
function.
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ESTIGATORSSECTION2 Study sit e/ trial sit e
The location(s) where trial-related activities are actually conducted.
Sub-investigator
Any individual member of the clinical trial team designated and supervised by the
invest igator at a t rial sit e to perform crit ical t rial- related procedures and/ or make
important trial-related decisions (e.g. associates, resident physicians, research fel-
lows). See also investigator.
Subject/ trial subject
An individual who participates in a clinical trial, either as a recipient of the inves-
tigation product(s) or as a control.
Subject identification code
A unique identifier assigned by the investigator to each trial subject to protect the
subjects identity and used in lieu of the subjects name when the investigator
reports adverse events and/ or ot her t rial- related data.
Unexpected adverse drug reaction
An adverse reaction, the nature or severity of which is not consistent with the
applicable product information (e.g. investigators brochure for an unapproved
invest igat ion product, or package insert/ summary of product characteristi cs for an
approved product) (see the ICH Guideline for clinical safety data management: defi-
ni t ions and standards for expedited reporti ng (E2A)) .
Well- being (of the t rial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
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ESTIGATORSSECTION2INVESTIGATOR STANDARD OPERATI NG
PROCEDURES
Objectives:
To provide the invest igator wit h general i nst ruct ions to ensure that he/ she
understands and accepts the obligations incurred in undertaking the study.
To ensure that t he study is planned, set up, conducted, documented and
reported according to the protocol, related standard operating procedures
(SOPs), International Conference on Harmonisation (ICH) good clinical prac-
tice (GCP), and applicable regulatory requirements.
To ensure that t he right s, safety, and welfare of study subjects are properly
protected.
To ensure that data are generated, collected and documented wit h accuracy,
consistency and integrity.
To ensure that the invest igator i s acquaint ed wit h t he study procedures, veri-
fication procedures, audits and inspection procedures.
The principal i nvest igator i s the one who wil l sign t his document. He/ she is respon-
sible for sharing t he information contained in t his document wit h all of his/ her
team.
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ESTIGATORSSECTION2 PRI OR TO I NI TI ATI ON OF THE STUDY
The investigator should:
Be interested in the scientific aspects of the study and ensure that the study
is responsive to the needs of public health within the country or the popula-
tion in which it will be conducted.
Ensure the confidentiality of the product, the protocol and trial procedures
by giving a confidentiality agreement in writing to the Product Research and
Development uni t at TDR ( TDR/ PRD) and/ or the other sponsoring agencies.
Have sufficient time free from other obligations to prepare and conduct the
trial. Clinical trials are time consuming and the investigator should ensure thatsufficient time can be dedicated to the study, including time for informing and
supervising study staff.
Review the investi gators brochure ( IB) and any up to date information on
the investigation product. The investigator must be familiar with the product,
including preclinical toxicology, pharmacology, pharmacokinetics and up-to-date
clinical data.
Review, and discuss in det ail, the I CH GCP guideli ne, investigators SOPs and
protocol with the clinical monitor. The investigator should clearly define:
Factors that may alt er t he feasibili t y and acceptabili t y of the t rial.
An adequate recruit ment rate for the tri al by providing ret rospecti ve data on
numbers of patients who would have satisfied the proposed entrance criteria
during preceding time periods.
Ensure that the procedures stated in the study protocol are applicable in
his/ her centre and fully understood. The investi gator should ask the clinical
monitor to clarify any points of possible misunderstanding.
Ensure that there are sufficient medical, paramedical and clerical staff to sup-
port the study and deal with foreseeable emergencies.
Provide a li st of study personnel and funct ions in t he study to the clinical mon-
i tor/ product manager (see annex 2, authorized signatory form).
Provide his/ her curriculum vit ae and the curricula vit ae of t he sub-invest igators
and the head of the laboratory
Ensure that all persons assisting with the trial are adequately informed about
the protocol, the investigation product( s) , and their t rial- related duties and
functions.
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ESTIGATORSSECTION2Ensure that the physical location and facilities are sufficient to allow the study
to be undertaken efficiently. Ensure:
Confident ialit y and safety condit ions for trial subjects.
Adequate equipment/ facil it ies for subject follow-up, examinat ion and care.
Adequate facil it ies for product storage.
Adequate facil i t ies for laboratory assay. The laboratory assay should be validated
according to good clinical pract ice laboratory for cli nical t rials (Annex A).
Adequate facili t ies for retenti on of t rial documents, ensuring confident ialit y of
all i nformation about t rial subjects and in format ion supplied by TDR and/ or other
sponsoring agencies.
Discuss the case report form ( CRF) , serious adverse event ( SAE) reporting form
and source documents in detail with the clinical monitor (see annexes 3 and 4
for sample forms). Clearly define: Who will be responsible for CRF complet ion.
Source documents/ source data and access to source data.
Arrange for archiving of trial documents according to GCP and regulatory
requirements. It is important to check the duration of retention of patient records
with the institutions archive. In case the institutions archive does not ensure
retention of documents for t he period of t ime requested by TDR and/ or other spon-
sors, the investigator must arrange for the retention of the subjects source docu-
ments/ records for the period requested by TDR and/ or ot her sponsors and regula-
tory requirements.
Finalize the informed consent forms (see annex 5 for sample form) and associ-
ated tri al subject information materials ( advertisements) ; and establish pro-
cedures regarding application for local clearance ( e.g. dean of the instit ution)
and independent ethical commit tee ( IEC) / instit utional review board ( I RB)
approval.
Clearly define how subjects will be approached and informed, who wi ll i nform
them, and what material will be used. The informed consent form and all infor-
mation (leaflet written in simple language, video) should be developed collabo-rati vely wit h head members of t he study population/ communit y to ensure the
methods are appropriate.
I n case of the need for screening tests, i ncluding biological specimen collect ion,
before entering a t rial, two types of consent form can be developed: one for bio-
logical specimen collection and analysis, and one for participation in the study
after obtaining satisfactory laboratory results and respecting inclusion criteria.
As a rule, t he advert isement must not make reference to TDR or t he compound,
or make any claims.
I nformed consent forms and adverti sements must be submit ted to TDR for review
and must be included in documentat ion submit ted to t he IEC/ I RB.
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ESTIGATORSSECTION2 Ensure that the local ethics committ ee fulf ils the I CH GCP requirements:
ICH GCP composition and operations of the I ndependent Ethics
Committ ee ( I EC) and Insti tutional Review Board ( I RB)
The IEC/ I RB should determine t he authorit y under which i t is established, and
the composition (names and qualifications) of its members, which should con-
sist of:
A reasonable number of members who collect ively have the qualif icati ons
and experience to review and evaluate the science, medical aspects and
ethics of the proposed trial.
At least f ive members.
At least one member whose primary interest is in a non-scienti fi c area.
At least one member who is independent of the t rial sit e.The IEC/ I RB may invi te non-members with expert ise in special areas to give
assistance.
The investigator may provide information on any aspect of the trial, but may
not part icipate in the I EC/ I RB deli berations, vote, or provide opinion.
Only members who participate in review and discussion of the protocol, and
who are independent of the investigator and the sponsor, can vote or provide
opinion.
The IEC/ I RB should perform ini t ial and cont inual reviews of t he tr ials accord-
ing to the written operating procedures, and maintain records of activities andminutes of meetings.
The I EC/ I RB should noti fy promptly, and in writ ing, all t rial- related decisions
and opinions, specifying the reasons for each.
See ICH Guidelines
Guideline for GCP Part. 3.2
(See also: Operational guidelines for ethics committees that review biomedical
research. Geneva, World Healt h Organizati on, 2000, TDR/ PRD/ ETHICS/ 2000.1)
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ESTIGATORSSECTION2Prepare the required documents to be submit ted t o the IEC/ IRB:
Documents usually required by ethics committees
I nvest igator brochure and up to date safety informat ion.
Trial protocol (f inal version and amendments).
Consent form(s) and subject information sheets.
Subject recruit ment procedures (e.g. advert isement) .
I nformation on payment and compensat ion avail able to subjects.
Current curriculum vit ae for each invest igator.
Any other document requested by t he IEC/ I RB.
See ICH Guidelines
Guideline for GCP Part. 3.1.2
Obtain the approval document from the ethics committee, which must identify
the documents reviewed and state that the study is acceptable and can be
initiated.
Send the approval document of the ethics committee, with a list of committee
members, to TDR/ PRD as a supporting document for approval of the WHO
Secretariat Commit tee on Research Involving Human Subjects (SCRI HS) .
Prepare the application for health authority clearance in collaboration with
TDR and other sponsoring agencies.
Prepare the appli cation for product exportat ion/ importation in collaboration
with TDR and other sponsoring agencies.
I f t he IEC/ IRB and others approve the tri al, sign the f inal copy of the protocol
and confirm in wri ti ng that he/ she has read and understood, and wil l adhere
to, the protocol, study procedures and ICH good cli nical practice, will collabo-rate wi th the moni tor, and accords wit h TDR and/ or other sponsoring agencies
on publication policy.
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ESTIGATORSSECTION2 Submit requested documents to the clinical monitors, including:
Signed agreement t o comply wit h these SOPs (page 1; see also annex 6).
Approved protocol, signed and dated.
Approved informed consent form (see annex 5) and other subject information,
and the advertisement (local language and English translation).
I nvest igators and co-invest igators curricula vit ae.
Authorized signatory form (see annex 2).
Product exportati on/ importati on authorizat ion.
Laboratory cert if icat ion/ li st of normal laboratory ranges, dated and signed by
investigator.
Technical services agreement (TSA), signed and dated.
Signed agreement t hat the product wil l not be used before the t rial ini t iati on
monit oring visit has been made and authori zat ion obtained from the TDR clinicalcoordinator ( if applicable).
Signed FDA 1572 form (i f applicable, e.g. study under invest igat ion new drug
[ I ND] ) ( see annex 8).
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ESTIGATORSSECTION2DURING THE STUDY
The t rial can be in it iated (begin screening and/ or enroll ing t rial subjects) only aft er
the clinical monitor has satisfactorily conducted a trial initiation monitoring visit
and the TDR clinical coordinator has given written authorization.
Investigators file, including storage and retention
On initiation of the study, the investigator must prepare a file containing docu-
ments related to the t rial ( see invest igators fi le form, annex 1). During the study,
the investigator is responsible for updating the file and regularly adding trial-
related documents.
The investigator should keep the file in a locked cabinet, in a secure area acces-sible only to the investigator and authorized study staff. The investigator file and
associated source documents should be retained for the time agreed with TDR
and/ or other sponsors. Patient i dent if icati on codes should be kept for at least
15 years after completion of the trial. Written approval from all sponsors must
be obtained prior to destroying records.
Screening and recruitment of study subjects
I t is important that t he invest igator resolves all quest ions from his/ her staff con-
cerning t he interpretat ion of inclusion/ exclusion crit eria.
The investigator should be able to dedicate time to the recruitment of suitable trial
subjects the consultation time for recruitment of each subject is likely to be
longer than the time required for normal consultation.
The investigator must ensure the unbiased selection of an adequate number of suit-
able study subjects as defined by the protocol.
The investigator must allow study subjects who meet the inclusion criteria the
opportunity to decide for themselves whether or not to be entered into the study.
The investigator must document the identification of subjects who enter trial
screening by completing a subject screening/ enrolment log (see annexes 9
and 10).
Obtaining informed consent from trial subjects
The concept of obtaining informed consent is considered to be the heart of GCP.
Informed consent is the process by which a study subject voluntarily confirms
his/ her wil li ngness to part icipate in t he t rial. Only study subjects who have ful ly
understood all aspects of their participation in the trial can make proper judge-
ments and give their consent to participate in the trial.
Information on disease prevention and transmission must be provided to the study
subjects for the whole of the trial period.
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ESTIGATORSSECTION2 Before any subject enters a trial, and before any study-related procedures begin,
writ t en in formed consent must be obtained from the subject and/ or his/ her legall y
acceptable representative. In the case of a screening test that requires the collec-
tion of biological specimens prior to entering a trial, two types of consent form can
be obtained; one for biological specimen collection and analysis, and the other forparticipation in the study having obtained satisfactory laboratory results respecting
the inclusion criteria. Study subjects found ineligible at screening (for medical rea-
sons) should receive, if appropriate, supportive counselling, any necessary available
treatment, and referral for continued counselling.
The investigator can delegate the consent process to an appropriately qualified
person; however, the investigator should see the subject afterwards to ensure that
the consent has been properly obtained. Verbal and written information given to
the tri al subject should be in simple t erms and in his/ her fi rst l anguage. Medical
terms should be avoided.
The investi gator/ designat ed person should perform informed consent proceduresfully with each subject during recruitment:
The informed consent form (see annex 5 for a sample form) should be personall y
dated and signed by the t rial subject and/ or his/ her legall y acceptable repre-
sentati ve as well as the invest igator/ designated person responsible for t he
informed consent procedures.
I f t he study subject and/ or legally acceptable representat ive is (are) unable
to read, an impartial witness for the investigator should be present during the
enti re informed consent discussion. Aft er oral approval by t he study subject and/
or legally acceptable representative, the witness must sign and personally date
the informed consent form and attest that the information was accurately
explained and apparently understood, and that informed consent was given freely
by t he subject and/ or legally acceptable representati ve. The subject and/ or
legally acceptable representative should personally sign and date the form if
capable of doing so.
The study subject and/ or legall y acceptable representat ive should be given a
copy of the signed and dated informed consent form and any other written infor-
mation.
The original signed and dated informed consent form should be kept in the
investigators file (see annex 1) with the study subjects data.Trial subjects and/ or their legall y acceptable representati ves should be kept
informed throughout the trial of any new findings or information about the
tested product which might be of consequence to their participation in the trial.
They should receive updates of the signed and dated consent form as well as
copies of any amendments to the written information. Updates of the original
signed and dated consent form should be kept in the investigators file.
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ESTIGATORSSECTION2
I NFORMED CONSENT PROCEDURES
Give informat ion regarding the t rial to the subject / pat ient, making sure
he/ she understands that the study involves research.
Give the purpose of t he study, t rial t reatment and the probabil it y for randomassignment to each treatment.
Explain in simple language the procedures to be fol lowed, including invasive
procedures.
Explain the responsibili t ies of the subject / pat ient .
List t he expected risks or inconvenience to the subject / pat ient.
List t he expected benefi t s, making it clear if t here is no int ended cli nical
benefit to the subject.
List t he alternat ive t reatment t hat may be avail able to the subject .
List t he t reatment avail able in t he event of study-related injury.
Discuss the anti cipated prorated payment , i f any, t o the subject for part ici-pating in the trial.
Discuss the anti cipated expenses, i f any, t o the subject for part icipati ng in
the trial.
Let t he pat ient know that the t rial is voluntary and that he/ she may refuse
to part icipate or can wit hdraw from the trial at any t ime, wi thout penalt y or
loss of benefi ts to which he/ she is otherwise enti t led.
Let the subject / pat ient know that the monitor, the audit or, t he I EC/ I RB and
the regulatory authorit y wil l be granted direct access to his/ her original
medical records for verif icati on of cli nical t rial procedures and/ or data,
without violating the confidentiality of the subject, to the extent permitted
by the applicable laws and regulations, and that, by signing a written
informed consent form, the subject or t he subjects legall y acceptable repre-
sentative is authorizing such access.
Assure the subject / pat ient that records identi fying him/ her wil l be kept con-
fi dent ial and, to t he extent permit ted by the applicable laws and/ or regula-
t ions, wi ll not be made publicly avail able; and that, if t he result s of the trial
are published, the subjects identity will remain confidential.
Assure that the subject or t he subject s legally acceptable representat ive wil l
be informed in a timely manner if information becomes available that may
be relevant to t he subject s will ingness to conti nue part icipation in t he trial.
Provide the name(s) of the person(s) to contact for furt her informat ion
regarding the trial and the rights of trial subjects, and in the event of trial-
related injury.
Explain to t he subject / pat ient the foreseeable circumstances and/ or reasons
under which hi s/ her participat ion i n t he trial may be terminated.
Provide the expected durat ion of the subject s part icipation in t he t rial.
Provide the approximate number of study subjects involved in the t rial.
See ICH Guidelines
Guideline for GCP Part. 4.8.10
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ESTIGATORSSECTION2 Protocol compliance
Once the study has started, the investigator must adhere to the protocol and ensure
that it is strictly followed. Deviations to protocol procedure(s) should not be made
without the agreement of TDR and/ or ot her sponsoring agencies, except when
necessary to avoid immediate danger to a trial subject. Whenever the investigatorfeels that changes are required, these can be suggested to, and discussed with, the
clinical monit or/ clinical coordinator. I f changes are agreed by the product manager,
clinical coordinator and sponsor, then the change(s) can be made in the form of a
protocol amendment, signed by the investigator and sponsor, and appended to the
original protocol.
The amendment should be described in an appropriate format, as follows:
PROTOCOL AMENDMENT FORMAT
Protocol number and date.
Protocol t i t le.
Date of approval of the amendment .
Protocol amendment number.
Text to be amended, wi th reference to t he page, paragraph and line of t he
protocol.
New text of t he amendment.
Signatures of the invest igator, product manager and/ or sponsor.
Amendments that are li kely t o aff ect the safet y of a subject/ pat ient or the conduct
of a trial must be submitted in writing to the ethics committee. The changes cannot
be implemented unti l t he IEC/ I RB has approved t he amendment to t he protocol.
However, implementation of the change(s) may take place prior t o IEC/ I RB approval
to avoid immediate danger(s) t o a subject / pat ient. I n t his sit uat ion, t he invest i-
gator must immediately notify the ethics committee of the reasons for the changes
and submit the proposed protocol amendment(s) t o TDR and/ or ot her sponsors for
agreement and t o the IEC/ I RB for approval. A copy of t he IEC/ I RB approval should
be kept on the invest igators fi le and a furt her copy given t o TDR and/ or other
sponsors.
In the case of minor modifications that do not have impact on the safety or burden
requested of the subject / pat ient for parti cipat ion in the t rial, or t hat only impact
on administrative activities, the modification might be considered a simple notifi-
cation, which does not require formal approval.
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ESTIGATORSSECTION2Providing medical care for trial subjects
A qualified physician, who is an investigator or sub-investigator, must be respon-
sible for all trial-related medical decisions:
The invest igator should ensure that adequate medical care is provided to the t rial
subject for any adverse events, including clinically significant laboratory abnor-malities related to the trial.
The invest igator should inform the subject s primary physician about his/ her par-
ticipation in the trial if the subject has a primary physician and agrees that
he/ she be informed.
The investigator should make a reasonable effort to ascertain the reason(s) for
withdrawing prematurely from the trial, while fully respecting the subjects rights.
See ICH Guidelines
Guideline for GCP Part. 4.3
Randomization procedures and unblinding
The investigator must follow the randomization procedures, if any. In the case of
a randomized, controlled, double-blinded trial, the code is usually prepared in the
form of numbered envelopes, each containing the identification of the corre-
sponding treatment in order to enable the investigator to open the code when
needed, without identifying other patients treatment (follow SOP CT 06: Breaking
Code).
Ensure that the code is broken only i n accordance wit h t he protocol and mainl y
for medical reason(s).
Premature unblinding must be reported immediately to the clinical monit or and
should be documented in the investigators file. The reason for premature
unblinding of the investigation product should be given, e.g. due to a serious
adverse event.
At the end of t he t rial, t he invest igator must return all t he unbroken codes to
the clinical monitor to prove that the study was blinded throughout.
Safety reporting
Trial subjects should be instructed to report any adverse event (AE) that they expe-
rience to the investigator. Investigators should assess AEs at each visit. The AE
is considered to be serious when it is fatal, life threatening, causes permanent
disability, causes or prolongs hospitalization, or causes congenital anomaly (see
glossary).
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ESTIGATORSSECTION2 Terms for causality assessment
( Note: t hese categories and defini t ions are recommended by TDR; they may be modi-
fied according to the aims of the study and the nature of the trial product.)
Not relatedThe experience is clearly related to other factors such as the patients clinical
state, therapeutic intervention or concomitant therapy.
Unlikely
The experience was most probably produced by other factors such as the
patients clinical state, therapeutic intervention or concomitant therapy, and
does not follow a known response pattern to the trial product.
Possible
The experience:
follows a reasonable temporal sequence from the time of product adminis-
tration; and/ or
follows a known response pat tern to t he t rial product; but
could have been produced by other factors such as the patients cli nical
state, therapeutic intervention or concomitant therapy.
Probable
The experience:
follows a reasonable temporal sequence from the time of product adminis-
tration; and/ or
follows a known response pat tern to t he t rial product; and
could not have been produced by other factors such as the patients cli nical
state, therapeutic intervention or concomitant therapy.
Most probable
The experience:
follows a reasonable temporal sequence from the time of product adminis-
tration; and/ or
follows a known response pat tern to t he t rial product; and
could not have been produced by other factors such as the patients cli nical
state, therapeutic intervention or concomitant therapy; and
eit her occurs immediately following t rial product admini st rat ion, or improves
on stopping the product, or there is positive reaction at the application site.
Insufficient data to assess
There is not enough clini cal and/ or laboratory in format ion t o suggest the rela-
tionship between the experience and the trial product.
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ESTIGATORSSECTION2Follow up of adverse event
The investigator must ensure the safety of the trial subject. When a trial subject
experiences adverse event(s) (AEs), the following action should be taken:
The occurrence of t he AE(s) must be monit ored carefully.
The invest igator must provide the best possible care avail able and fol low up thetrial subjects adverse event until its complete disappearance. An adverse event
that is li kely t o be related to t he product and that persists at t he end of the trial,
or any serious adverse event (SAE) occurring after termination of the trial and
likely to be related to the product, should be followed up by the investigator
until its complete disappearance.
A thorough invest igation must be conducted to determine causalit y.
The adverse event must be recorded in detai l during the course of t he t rial, i rre-
spective of the possible causal relationship with the investigation product.
Adverse event reporting procedure
All adverse events occurring during the trial should be accurately reported in the
appropriate annex of the case report form.
REPORTI NG OF SERIOUS ADVERSE EVENTS
The investigator should report all serious adverse events (SAEs) immediat ely
(wit hin 24h) t o the TDR clinical monit or, t he TDR clinical coordinator and/ or
the TDR product manager, and, when appropriate, the other sponsors, even if
the adverse event is considered not to be related to the investigation product.
The investigator should also comply with the applicable regulatory require-
ment(s) related to the reporting of unexpected serious adverse drug reactions
to the regulatory authorit y(i es) and the IEC/ I RB.
The anonymity of the subjects shall be respected when forwarding all infor-
mation.See ICH Guideli nes
Guideline for GCP Part. 4.11
Noti fi cat ion should be made by faxing t he alert form for SAE (specifi c form forthe tri al, see annex 3) and/ or by telephone communicat ion.
The invest igator should send promptly, wit hin fi ve working days, t he serious
adverse event report form (see annex 4), by fax or express mail, to the TDR clini-
cal monit or, t he TDR cli nical coordinat or and/ or t he TDR product manager, and,
when appropriate, to the other sponsors.
Any relevant in format ion concerning the SAE that becomes avail able after the
SAE report form has been sent (outcome, precise description of medical history,
results of the investigation, copy of hospitalization report, etc.) should be for-
warded as soon as possible to the TDR clinical monitor, the TDR clinical co-
ordinator and/ or the TDR product manager, and when appropriate, t o the other
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ESTIGATORSSECTION2 sponsors. For reports of deaths, t he investigat or should provide TDR and/ or ot her
sponsors/ I EC/ I RB wit h any addit ional requested informat ion, e.g. autopsy re-
ports and terminal medical reports.
Completion and validation of the case report form
The investigator must ensure the accuracy, legibility and completeness of data entry
in t he case report forms (CRFs) and in all other required report forms/ logs. All CRFs
and other required forms will be vali dated by the TDR clinical moni tor during moni-
toring visits.
Completion
Only authorized study staff (names shown in the authorized signatory form, see
annex 2) are allowed to enter data into the CRF and other required report forms.
Ballpoint pen must be used.
Capital letters must be used for all entries in the CRF.
All items must be completed by entering a number or text in the space provided.
When a subject is recruited to the trial, the initial and allocated numbers are
entered in the CRF against the subjects name on the subject identification code
li st. The subjects name should never be entered in t he CRF to protect conf iden-
tiality.
As far as possible, the results of assessment should first be entered into the sub-
ject fi le and then t ranscribed int o the CRF. This will allow data t o be veri fi ed during
the process of source data verification.
The CRF should be completed during subject participation in the trial.
Data reported on the CRFs that are derived from source documents should be con-
sistent with the source documents or the discrepancies should be explained.
Case report form corrections
Only authorized study staff can make corrections.
Do not al low t he cli nical monit or/ sponsor to make correcti ons in the CRF.
Corrections should not obscure the original entry:
Do not erase.
Do not overwrite.
Never use correcting fluid.
To make a correction:
Cross out t he wrong ent ry wit h a single line.
Writ e the correct ent ry alongside, above or under the wrong entry.
Date the correcti on.
Ini t ial t he correction.
Explain t he correction ( if necessary).
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ESTIGATORSSECTION2
Source data and documents
ICH international guidelines for good clinical practice, and other applicable regula-
tory guideli nes pertaini ng to clin ical t rials, require direct access to source data and
documents for t rial related monit oring, audit s, I EC/ I RB review, and regulatory
inspection.
Source documents are all original documents, or certified copies containing data
related to clinical trial activities (source data), necessary for reconstruction and
evaluation of the trial.
Source documents ( non-exhaust ive list )
Informed consent form.
Subject medical file:
Medical and medicat ion history.
Outpati ent or inpatient chart.
Serious adverse event form.
I nstrument printouts. Traces and laboratory result s.
Subjects visit dates.
Subject identification list.
Clinical and office charts.
Product dispensing records, accountability.
Laboratory notes.
Trial agenda.
Memoranda.
Example:
PAZ
PAT jk29/ 03/ 02
Sex 1Male: 1 Female: 2 2 jk29/ 03/ 99
Date of vaccinat ion 2/ 10/ 95
2/ 10/ 01 jk
Site of inject ion: Left Right
Missing data M.D. jk
29/ 03/ 02
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ESTIGATORSSECTION2 Source data
The subject source documents should contain at least the following original data:
Subject identi fi cat ion: last name, fi rst name, date of bi rth, sex, and identi fi ca-
tion number in the trial.
Protocol identi ficat ion number/ study reference.
Name of product on test.
Date of f irst screening and/ or enrolment i n the t rial.
Dates of product administrati on and dosage.
Dates of assessment visit s and name of i ndividual responsible for making t he
assessment .
Serious adverse event (s) and related medicati on.
Dates of laboratory sample collect ion.
Note
Before initiating the trial, the source document and source data will be clearly
defined with the TDR clinical monitor. If no source documents exist at the centre,
one should be created.
I f t he subject data are directl y entered int o the provided CRF, t hen t he CRF
becomes a source document. If this is the case, it should be stated clearly in the
protocol in order to avoid problems with verification of source data that may
arise during audits by TDR quality assurance personnel or inspections by regula-
tory authorities.
Where a subjects diary exists (when subjects are asked t o report eventual adverseevent (s), medical consultation and/ or medicat ion t aken during t he trial) , the
diary must be validated by the investigator and kept in the subjects file.
In order to comply with GCP:
The investigator must guarantee that the monitor(s), the auditors and the regula-
tory authority(ies) will have direct access to source data and documents for verifi-
cat ion of t rial procedures and/ or t rial data.
The invest igator must pledge that the study subject wil l be in formed both orally and
in writ ing in t he consent form that the monit or(s), audit ors(s), I EC/ I RB, andregulatory authorit y(i es) wi ll be granted direct access to his/ her origi nal medical
records, wi thout violati ng confident ialit y, for the verif icat ion of cli nical t rial proce-
dures and/ or data. By signi ng the informed consent form, t he t rial subject or legally
acceptable representative is authori zing access to his/ her medical records.
The investigator is required to retain the patient identification list for a minimum
of 15 years after completion or suspension of the trial (or for a longer period if
required by local regulations). The investigator is required to retain all patient files
and source documents for the maximum period of time permitted by the hospital,
institution, or private practice, but for not less than 10 years, in order to meet
international registration requirements (or for longer periods if required by local
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ESTIGATORSSECTION2regulation). The investigator should keep documents in a safe place and take mea-
sures to prevent accidental or premature destruction of source documents.
The investigator should inform TDR and the sponsor of any change of place of
archiving. TDR and/ or the sponsor wil l inform the invest igat or( s) when thedocuments no longer need to be retained.
Product storage and accountability
The invest igat or may assign an appropriate person (pharmacist / nurse) t o be
responsible for investigation product storage and accountability at the trial site.
The investigator should ensure that the investigation product is properly received,
stored and handled.
The invest igator/ designated person must :
Store the product i n the condit ion that has been specifi ed in wri t ing by TDR
and/ or other sponsors and in accordance with the protocol and applicable regu-
latory requirement(s).
Ensure that the storage temperature is maint ained as specifi ed in t he protocol.
There should be a daily temperature log.
Maintain records of t he product s deli very, i nventory and return.
Maintain up to date accountabili t y on the t rial product accountabil it y log.
Ensure that t he product is used only in accordance wit h the approved protocol.
Document t he use of t he product by each subject, and i f appropriate, check at
regular intervals that each subject is following the instructions properly (com-
pliance).
Return any unused product t o TDR and/ or other sponsors at t he end of the t rial.
Premature termination or suspension of a trial
I n t he case of premature terminati on/ suspension of the tri al for any reason, t he
investigator should inform:
The regulatory authority(i es), if applicable.
The t rial subject , assuring him/ her of appropriate t reatment and follow-up.
If the investigator terminates or suspends a trial without prior agreement of the
sponsor, then the institution should:
Promptl y inform and provide the sponsor and the IEC/ I RB wit h a detailed writ t en
explanation of the termination or suspension.
I f t he sponsor t erminates/ suspends a tri al, t hen t he inst it uti on should:
Promptl y inform and provide the I EC/ I RB wit h a detail ed writ t en explanat ion of
the termination or suspension.
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ESTIGATORSSECTION2 I f t he I EC/ I RB terminates or suspends it s approval of a tri al, t hen the inst it ut ion
should:
Promptl y not if y and provide the sponsor with a detailed writ t en explanat ion of
the termination or suspension.
See ICH GuidelinesGuideline for GCP Part. 4.12
Progress and final reports
The invest igator should submit writ t en summaries of t he trial status to t he IEC/ I RB
annuall y, or more frequent ly i f requested by the IEC/ I RB.
The investigator should provide written reports promptly to the clinical monitor/
sponsor and the I EC/ I RB about any changes, which signi fi cantl y affect t he conduct
of t he t rial and/ or increase the risk to the subjects.
The invest igator should provide t he IEC/ I RB, regulatory authori t y(i es), TDR and/ or
other sponsors with a summary outcome and any reports required at the end of
the trial.
References
The clinical study site team: roles and responsibilities. The Barnette International
Self-Instructional Study-Site Curriculum, Barnett-Parexel, Philadelphia, USA, 1993.
Winslade J., Hutchinson D. R. Dictionary of clinical research. Surrey, UK: Brookwood
Medical Publications Ltd. 1992.
I CH guideline for good clinical pract ice, recommended for adoption at Step 4 of the
ICH Process on 1 May 1996 by the ICH Steering Committee.
Operational guidelines for ethics committees that review biomedical research, Geneva,
World Healt h Organizati on, 2000, TDR/ PRD/ ETHICS/ 2000.1
A practical guide to FDA GCP for investigators. Neher and Hutchinson, eds. Brook-
wood Medical Publications Ltd, Surrey, UK, 1993.
The trial i nvest igators GCP handbook: a practi cal guide to I CH requirements.
Hutchinson, ed. Brookwood Medical Publications Ltd. Surrey, UK, 1997.
WHO guideli nes for good cli nical practice ( GCP) for t rials on pharmaceuti cal products.
World Health Organization, Geneva, 1995 (WHO Technical Report Series, No. 850:
97-137).
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ESTIGATORSSECTION2Annexes
Annex 1: Invest igators fi le form . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Annex 2: Authorized signatory form . . . . . . . . . . . . . . . . . . . . . . . . 233
Annex 3: Serious adverse event alert form . . . . . . . . . . . . . . . . . . . . 236
Annex 4: Serious adverse event report form . . . . . . . . . . . . . . . . . . . 237
Annex 5: Example of an informed consent form . . . . . . . . . . . . . . . . . 240
Annex 6: Agreement between WHO/ TDR and the invest igator . . . . . . . . 243
Annex 7: Not relevant
Annex 8: Form FDA 1572 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Annex 9: Identi fi cat ion of screened and enrolled part icipants . . . . . . . . 246
Annex 10: Identifi cati on of enrolled participants . . . . . . . . . . . . . . . . 249
Annex A: Good cli nical pract ice laboratory for clini cal t rials1 . . . . . . . . 252
1 Annex A is a separate TDR annex. Annexes 1-10 form part of a global set of TDR annexeson standard operating procedures.
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ESTIGATORSSECTION2 Annex 1
I NVESTIGATORS FILE FORMPROTOCOL TI TLE:
Study ID No.
Sponsor:
Clinical monitor:
Tel: Fax: Email:
Investigation product:
Principal investigator:
Tel: Fax: Email:
Study site:
I NVESTIGATORS and MONI TORS SI GNATURE
To be signed during the closeout visit.
I hereby confirm that I have checked the content of the investigators file against the infor-mation contained in this form and that the file is complete.
Monitors signature: _______________________________ name: ___________________
I hereby agree that t he content of t he investigators fil e matches the information gi ven on thi sform and I agree to retain the documents for the required period of time.
I nvesti gators signature: ____________________________ name: ___________________
I NVESTIGATORS FI LE LOCATI ON
1. Administrati ve and regulatory documents:
2. Correspondence and monit oring:
3. Trial documents:
a) General fi le:b) Data reporting:
c) Products:
d) Samples:
e) Trial material / equipment:
f) Study Subjects data and documents
YES NO NA*
I s/ Are the tri al documents storage room(s) adequate? s s s
I s there a possibi li t y of l ocking t he storage place(s)? s s s
Does/ Do the storage place(s) have li mit ed access? s s s
* NA: Not applicable
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I NVESTI GATORS FILE On File
The investigators file should be checked and updatedfor the whole duration of the trial YES NO NA*
1. ADMINI STRATI VE AND REGULATORY DOCUMENTS
Composit ion of I EC/ I RB who gave final approval s s s
Local regulatory requirements s s s
I EC/ I RB and other authorit ies writ t en approval for alldocuments (protocol, informed consent and any other
s s swritten information including advertisement for studysubjects recruitment)
I EC/ I RB and other authorit ies writ t en approval forprotocol amendments s s s
Correspondence with I EC/ I RB and other authorit ies s s s
Protocol submission s s s
Amendment submission (i f any) s s s
Protocol modification notif icati on (if any) s s s
I nterim report / writt en summaries of t he t rial s s s
Documentati on of serious adverse events report ings s s
to t he IEC/ I RB/ authorit ies
Terminati on of the study s s s
Product importation authorizati on s s s
Correspondence about product i mportation s s s
For studies under IND, copy of t he completed and signedform FDA 1572 s s s
I nvest igator and sub-invest igators curriculum vitae (CV) s s s
Copy of t he up to date authorized signatory form (ASF) s s s
I nvest igator agreement (TSA contract ) signed and datedby both parties
s s s
Payment receipt s s s
Signed confidenti al agreement s s s
Signed agreement t hat products will not be used beforethe clini cal trial ini t iati on monitoring visit and approvalfrom the TDR clinical coordinator
s s s
Copy of the insurance cert ifi cate/ other insurancedocuments s s s
ICH GCP Guideline s s s
TDR/ PRD invest igators SOPs s s s
Other administrative and regulatory trial documents s s s
I f yes, please specif y _______
Annex 1 continued
* NA: Not applicable
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I NVESTIGATORS FI LE On File
The investigators file should be checked and updatedfor the whole duration of the trial YES NO NA*
2. CORRESPONDENCE AND MONI TORING
Correspondence wit h TDR and/ or ot her sponsoring agencies s s s
Notes of meetings wit h TDR and/ or other sponsoringagencies
s s s
Copy of t he summary list of sit e visit s s s s
Trial initiation monitoring report s s s
Notification by the investigator to TDR and/ or other
sponsors of serious adverse events and related reports
s s s
Documentation of serious adverse event reporti ng by TDRand/ or other sponsors to ot her invest igators
s s s
Correspondence about important requests s s s
I nvesti gator interim report / summaries of the tri al for TDRand/ or other sponsors
s s s
3. TRI AL DOCUMENTS
a) General documents
Copy of the invest igators brochure (version no. ) s s s
Copy of the approved protocol, signed and dated by allinvest igator(s) and sponsoring agencies (version no. ) s s s
Copy of the approved protocol amendment(s), signed anddated by all investigator(s) and sponsoring agencies
(version no. ) s s s
One blank copy of the approved informed consent (IC) andany other written information including all translationsand the advertisement for study subject recruitment s s s
One blank copy of t he approved revision of t he informedconsent (IC) and any other written information amendmentsincluding all translations and the advertisement for studysubject recruitment s s s
I nformed consent procedure s s s
b) Data reporting
One blank copy of t he CRF (version no. ) s s s
One blank copy of t he SAE Forms (version no. ) s s s
One blank copy of t he source document (version no. ) s s s
Case report form completion procedure s s s
Adverse event reporti ng procedure s s s
Annex 1 continued
* NA: Not applicable
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I NVESTI GATORS FILE On File
The investigators file should be checked and updatedfor the whole duration of the trial YES NO NA*
c) Products
Product cert if icate/ batch release s s s
Cert ifi cate of extension of t he batch expiry date s s s
Product acknowledgement of receipts (copy) s s s
Return of unused product form(s) (copy) s s s
Product destruction certi ficate if dest royed on sit e,and TDR authorization
s s s
Product management procedures (administration, storage, ) s s s
Complete product accountabili t y log (copy) s s s
Complete product management log (copy) s s s
Randomization li st, envelopes and acknowledgementof receipts
s s s
Randomization list, envelopes and ret rieval cert ifi cate s s s
Copy of t he t emperature recording log if appropriate(especially for vaccines)
s s s
Other products related t rial documents s s s
I f yes, please specif y _______
d) Samples
Laboratory certif ication/ normal ranges s s s
React ive acknowledgement of receipt s s s
Specimen management procedures (collect ion, storage,results)
s s s
Temperature recording log if appropriate (e.g. deep freezesample) s s s
Shipment note (if appropriate) s s s
Record of retained laboratory specimens (if any)To document location and identification of retained specimens ifassays need to be repeated
s s s
Other laboratory specimen products-related trialdocuments s s s
I f yes, please specif y _______
Annex 1 continued
* NA: Not applicable
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ESTIGATORSSECTION2 Annex 1 continued
I NVESTIGATORS FI LE On File
The investigators file should be checked and updatedfor the whole duration of the trial YES NO NA*
e) Trial materi al and equipment
Acknowledgement of receipt s s s
Specify
material/ equipment:s s s
s s s
s s s
Return of t rial material/ equipment certif icate (copy) s s s
Specifymaterial/ equipment:
s s s
s s s
s s s
f) Study subjects data and documents
Signed and dated informed consent f orms (f or all subjects) s s s
Ident if icat ion of screened and enrolled part icipants log s s s
Identification of enrolled participants log s s s
All case report forms (wit h copy of t he CRF for t erminatedsubjects) s s s
Copy of the subject assignment l ist s s s
Copy of the laboratory sample log s s s
Copy of all serious adverse event forms s s s
Documentat ion of CRF corrections s s s
Copy of the completed CRFs retrieval cert if icate s s s
All study subjects source documents, including laboratoryresults s s s
COMMENTS AND ACTIONS:
* NA: Not applicable
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ESTIGATORSSECTION2Annex 1 continued
The investigators file should be checked and updatedfor the whole duration of the trial YES NO NA*
Composit ion of t he I nsti t utional Review Board/Independent Ethics Committee s s s
Local regulatory requirements s s s
Form FDA 1572 For US studies (under I ND) completed,
signed and dated by all principal investigators who areto part icipate (can be sent before or aft er local I EC/ I RBapproval but a minimum of 45 days before productdelivery date)
s s s
I nvest igator and sub-invest igators curriculum vitae (CV) s s s
Signed investigator SOP s s s
I nformed consent and any other writt en informationincluding all translations and advertisement for studysubject recruitment
s s s
Laboratory certif ication and accreditation s s s
Laboratory technical procedure and normal ranges s s s
Other documents
Please specify:
s s s
s s s
s s s
s s s
COMMENTS AND ACTIONS:
DOCUMENTS TO BE OBTAI NED DURING THE PRE-TRI AL
MONI TORI NG VISI T(or on agreed date ___________ (dd/ mm/ yy) if not obtained during the pre-trial
monitoring visit)
* NA: Not applicable
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ESTIGATORSSECTION2 Annex 1 continued
These documents should be submitted to TDR beforeinitiation of the trial. A copy of the approval should begiven as soon as possible in order to f inalize / print alltrial documents and prepare product packaging.
YES NO NA*
Technical services agreement, signed and dated s s s
Signed approved protocol (can be collected during theinitiation visit) s s s
Composit ion of I EC/ I RB who gave approval s s s
I EC/ I RB and other authorit ies' writ t en approval forall documents (protocol, informed consent and any otherwritten information including advertisement for studysubject recruitment) s s s
Product importation authorization s s s
Signed agreement that products will not be used beforethe written approval by the TDR Clinical Coordinator s s s
Authorized signatory form (ASF) (can be collected duringthe initiation visit) s s s
Other documents
Please specify:
s s s
s s s
s s s
s s s
COMMENTS AND ACTIONS:
Follow up actions Person( s) responsible
DOCUMENTS TO BE OBTAI NED DURING THE PRE-TRI AL
MONI TORI NG VISI T(or on agreed date ___________ (dd/ mm/ yy) if not obtained during the pre-trial
monitoring visit)
* NA: Not applicable
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An
nex2
AUTHORIZED
SIGNATORYFORM
STUDYSTAFFANDAUTHORIZEDS
TAFFFORTRIALDOCU
MENTCOMPLETION
Principalinvestigator:
Centre:
Sponsor:
Ti
tleofthetrial:
In
vestigationproduct:
Inv
estigatorsignatureanddate(tobesignedanddatedattheendofthetrial):............................................
Date_____
/_____
/_____
Page
No
Lastname
Firstname
Function
Roleint
hetrial
Authorizedtofillinthetrial
Signature
Initials
documents?
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/_____
dd/
mm
/yy
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An
nex2
continued
Inv
estigatorsignatureanddate(tobesignedanddatedattheendofthetrial):............................................
Date_____
/_____
/_____
Page
No
Lastname
Firstname
Function
Roleint
hetrial
Authorizedtofillinthetrial
Signature
Initials
documents?
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/____
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/____
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/____
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An
nex2
continued
Inv
estigatorsignatureanddate(tobesignedanddatedattheendofthetrial):............................................
Date_____
/_____
/_____
Page
No
Lastname
Firstname
Function
Roleint
hetrial
Authorizedtofillinthetrial
Signature
Initials
documents?
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/____
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/___
_
Yes|_
__
|
No|_
__
|
Ifyes,
specify:
Dateofsignature:
_____
/_____
/____
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ESTIGATORSSECTION2 Annex 3
Date of report (dd-mm-yy): _________________
Source I nvest igator/ reporter name: _________________/ Signature____________________
Address: ___________________________________________________________________
Tel. no.: _______________ Fax no.: ____________ Email : _________________
Subject ident if ication ( ini t ials of last name, fi rst name): __________
Age (i n years): _____ Date of birt h, if known (dd-mm-yy): _________________
Sex: ______________
Race (whi t e; black; oriental; other): ____________________Hospit al number (i f applicable/ available): _______________
Protocol title: _________________________________________________________
Protocol no.: _______________
Centre: _____________________________________________________________________
Subject number: ______________
Relevant medical history; including laboratory, X-ray or ECG data.
SERI OUS ADVERSE EVENT ALERT FORM
General information
Adverse event
Concomitant medication
Subject history
Description of event: ___________________________________________________
Onset date (dd-mm-yy): ________________
Outcome(s): __________________________________________________________
Relationship t o t est product by t he invest igator / reporti ng physician: __________________
Treatment required: ____________________________________________________
Name of medication: ___________________________________________________
Date started (dd-mm-yy): ________________________
Date discontinued (dd-mm-yy): ___________________Dose: ____________________________
Reason for use: ____________________
Route of admin ist rati on: _____________
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SERI OUS ADVERSE EVENT REPORT FORM
PROTOCOL TI TLE: Protocol I D no: Centre:
Trial information
Subjects I nvestigation product: Report typestudy no. 1=I nitial
2=Follow-up
Adverse event information
Expedited report criteria(Tick all appropriate to event)
Suspected trial product information
16. Suspected product : 17. Dai ly dose at onset 18. Route ofof event administ rat ion
19. Indication for use:
20.Therapy dates ( from/ to, dd/ mm/ yy)
21. Therapy duration until onset (hh/ dd/ mm)
22. Did the event abate after stopping product? 1 = No 2 = Yes 3 = NA*
Concomitant drug(s)
23. Relevant concomi tant drugs and dates of administ rat i on 1 = No 2 = Yes
If yes, then list the name(s) and detailsDose Unit
Drug name
Rout e Schedule
1. Patientinitials
2. Date of birth(dd/ mm/ yy)
3. Age(year)
4. Sex
1 = female2 = mal e
5. Height(cm)
6. Weight(kg)
7. Eventonset
(dd/ mm/ yy)
8. Adverse event in MEDICAL TERMS:
9.Patient diedDate:_______
(dd/ mm/ yy)
10.Life-threatening
11.Prolongedhospitalization
12.Significantdisability
13.Congenital anomaly
14.OtherSAE
15. Description:
Datestarted
(dd/ mm/ yy)
Datediscontinued(dd/ mm/ yy)
Continue1 = No2 = Yes
Reasonfor use
* NA: Not applicable
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Serious Adverse Event Protocol Cent re:Report Form I D no:
Other relevant history, laboratory findings and action taken
24. Other relevant history:
25. Relevant t est / laboratory fi ndings
Laboratory t est Unit Date Value Comments on laboratory(dd/ mm/ yy) f inding
26. Action taken by investigator:
__0 = none __5 = Concomitant drug disconti nued
__1 = Trial dosage change __6 = New drug therapy added
__3 = Trial drug disconti nued __7 = Prolonged hospitalizat ion
__4 = Non-drug therapy
27. Outcome:
1 = Completely recovered on (dd/ mm/ yy) __________________________
2 = Recovered wit h sequel 5 = Condit ion deteriorated
3 = Condit ion improving 6 = Death, autopsy done (attach summary)
4 = Condit ion sti ll unchanged 7 = Death, autopsy not done
28. Causality assessment by investigator (is there any relationship with test product?):
0 = Not related 3 = Probable
1 = Unlikely 4 = Most probable
2 = Possibl e 5 = I nsuffi cient data to assess
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Serious Adverse Event Protocol Cent re:Report Form I D no:
Information source
29. Name, address, telephone and email address of the investigator
Name: ______________________________ Profession (speciality) ____________________
Address: ____________________________________________________________________
____________________________________________________________________________
___________________________________________________________________________
Tel: ________________________ Email : ______________________________
Signature of investigator reporting event ______________________________
Reporting date (dd/ mm/ yy) ___________________
Sponsor information
30. Name and address of reporti ng sponsor/ manufacturer:
Name:Address:
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
31. Date received by sponsor (dd/ mm/ yy) 32. Date of this report (dd/ mm/ yy)
Signature___________________________ _____________________________________
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ESTIGATORSSECTION2 Annex 5
EXAMPLE OF AN I NFORMED CONSENT FORM
The doctor has confirmed that you have the skin disease called salak. As you prob-
ably know, this disease is very common in this area, and is transmitted by the b