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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

8 TDR/ PRD ( SOPs) and guidelines CT 05 Investigators Responsibilities

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ESTIGATORSSECTION2


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TDR/ PRD ( SOPs) and guidelines CT 05 Investigators Responsibilities 199

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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


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


Probable

The experience:


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


Most probable

The experience:


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


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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ESTIGATORSSECTION2

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



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I NVESTIGATORS FI LE On File


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



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I NVESTI GATORS FILE On File


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


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


Annex 1 continued



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ESTIGATORSSECTION2 Annex 1 continued

I NVESTIGATORS FI LE On File


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:



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ESTIGATORSSECTION2Annex 1 continued


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


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)



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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


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)



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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


Date_____

/_____

/_____

Page

No

Lastname

Firstname

Function

Roleint

hetrial


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


Date_____

/_____

/_____

Page

No

Lastname

Firstname

Function

Roleint

hetrial


Signature

Initials

documents?

Yes|_

__

|

No|_

__

|

Ifyes,

specify:

Dateofsignature:

_____

/_____

/____

Yes|_

__

|

No|_

__

|

Ifyes,

specify:

Dateofsignature:

_____

/_____

/___

_

Yes|_

__

|

No|_

__

|

Ifyes,

specify:

Dateofsignature:

_____

/_____

/____


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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



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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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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