Clinical Studies Procedure Example

document.docDocument: ProcedureDate: Jul 27, 2009Revision: XX

CLINICAL STUDIES PROCEDURE

Approvals:

Name Title Signature Date

Author

Reviewed by

Approved by

Change control:

Rev. Description of change Approved by DCN Signature Date

01

02

03

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Proprietary and Confidential


1. Objective

To define the activities related with the performance of Clinical Studies by [company].

2. General

2.1. Clinical studies are conducted by [company] as part of the validation activities.

2.2. This procedure applies to all clinical studies, sponsored by [company].

2.3. The purpose of this document is to ensure that clinical investigations are properly

monitored and documented, and meet international regulatory requirements (section 4

Reference Documents).

3. Applicable Documents

Requirements stated in the following documents apply as appropriate to the context:

3.1. Procedure QP 00-02 - Quality Manual.

3.2. Procedure QP 00-03 - Terms & Definitions.

3.3. Procedure QP 01-01 - Quality Policy.

3.4. Procedure QP 02-01 - Design and Development Planning.

3.5. Procedure QP 02-02 - Project Planning and Management.

3.6. Procedure QP-03-03-01 Controlled document types & control

3.7. Procedure QP 12-01 - Record Types and Retention.

3.8. [company] clinical study forms (QF-02-08)

4. Reference Documents

Information contained in the following documents is relevant as appropriate to the context.

4.1. 21 CFR Part 820 – Quality System Regulation.

4.2. ISO 13485– Medical Devices – Quality Management System – Requirements for

regulatory purposes

4.3. Directive 93/42/EEC for medical devices

4.4. EN ISO 14155-1, Clinical investigation of medical devices for human subjects – Part 1:

General requirements.

4.5. Guidance for Good Clinical Practice, ICH Harmonized Tripartite guideline, 1996

4.6. Helsinki declaration

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4.7. FDA publication “Perspectives on Clinical Studies for Medical Device Submissions

(Statistical).”

4.8. FDA publication “Guidance for Industry: Computerized Systems Used in Clinical Trials.”

4.9. FDA publication “A Regulatory Perspective for Bayesian Clinical Trials.”

5. Definitions and abbreviations

5.1. Documents

5.1.1. Case Report Form (CRF) – A printed, optical, or electronic document designed to

record all of the protocol’s required information to be reported to the sponsor on each

trial subject.

5.1.2. Essential documents – Documents which individually and collectively permit

evaluation of the conduct of a study and the quality of the data produced that are to be

held in the ‘regulatory binder” kept at the study site and at sponsor’s headquarters. (See

detailed list of primary essential documents for the conduct of a clinical study in ref. 6.4

and appendix 5).

5.1.3. Informed Consent Form (ICF) –A process by which a subject voluntarily confirms

his or her willingness to participate in a particular trial, after having been informed of

all aspects of the trial that are relevant to the subject’s decision to participate. Informed

consent is documented by means of a written, signed and dated informed consent form

(ICF).

5.1.4. Investigator Brochure (IB) – A compilation of the clinical and non-clinical data on the

investigational product(s) which is relevant to the study of the investigational product(s)

in human subjects.

5.1.5. Protocol (CIP- Clinical Investigational Plan) – A document that describes the

objective(s), design, methodology, statistical considerations, and organization of a trial.

The protocol usually also gives the background and rationale for the trial, but these

could be provided in other protocol referenced documents.

5.1.6. Protocol Amendment – A written description of a change(s) to or formal clarification

of a protocol.

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5.2. Personnel

5.2.1. Principal Investigator (PI) – A person responsible for the conduct of the clinical trial

at the trial sites. The PI is responsible for ensuring that the investigation is conducted

according to the signed clinical study agreement, the investigational plan, and

applicable regulations; for protecting the rights, safety, and welfare of subjects under

the investigator's care; and for the control of device under investigation. If a trial is

conducted by a team of individuals at a trial site the PI is the responsible leader of the

team.

5.2.2. Investigator – A person responsible for the conduct of the clinical trial at the trial site.

5.2.3. Monitor or Clinical Research Associate (CRA) - A person, appointed by the sponsor,

whose responsibility it is to oversee the progress of a clinical trial, and ensure that it is

conducted, recorded, and reported in accordance with the protocol, Standard Operating

Procedures (SOP), Good Clinical Practice (GCP) principles and the applicable

regulatory requirements.

5.2.4. Sponsor – An individual, company, institution, or organization which takes

responsibility for the initiation, management, and/or financing of a clinical trial.

5.2.5. Contract Research Organization (CRO) - A person or an organization (commercial,

academic or other) contracted by the sponsor to perform one or more of a sponsor’s

trial-related duties and functions.

5.2.6. Study coordinator - a person at the study site that works together with the sponsor

representatives to assure that the data collection and the study execution is performed

according to GCP, site SOPs and sponsor’s SOPs.

5.2.7. Institutional Review Board / Ethics Committee (IRB / EC) – An independent body

constituted of medical/scientific/non-scientific members, whose responsibility it 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

trial protocol and amendments and of the methods and material to be used in obtaining

and documenting informed consent of the trial subjects.

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5.3. Other

5.3.1. Adverse Event (AE) - Any undesirable experience occurring to a subject during a

clinical study, whether or not considered related to the investigational product.

5.3.2. Serious Adverse Event (SAE) - means an adverse experience that is fatal, life-

threatening, or which results in hospitalization or prolongation of hospitalization.

5.3.3. Audit – A systematic and independent examination of trial related activities and

documents to determine whether the evaluated trial related activities were conducted,

and the data were recorded, analyzed and accurately reported according to the protocol,

sponsor’s standard operating procedures (SOP’s), Good Clinical Practice (GCP), and

the applicable regulatory requirements.

5.3.4. 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 confidentiality of trial subjects are protected.

6. Application

6.1. Confidentiality

All patient records shall be maintained confidential and information released shall conceal the

identity of individual patients except where the identity must be disclosed legally or is

otherwise necessary. Confidentiality policy will be explained to the patient in the ICF.

6.2. Documentation

Unless otherwise stated, all original copies of [company] forms to be filled-in and signed

during the study, and the informed consent form, should be kept at the site regulatory binder. A

copy of the signed forms should be kept at the sponsor’s headquarters.

This does not apply to the completed CRF.

6.3. Study Initiation

6.3.1. Study Design

Clinical investigations shall be designed to yield scientifically valid results. Statistical

considerations shall be taken into account in designing the study, in particular for

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determining the number of patients required. In case of feasibility or FIM (First In Man)

studies statistical considerations or analysis may not be required.

6.3.2. Selection of Investigators

The Clinical Affairs Manager shall assess and document in writing the approval of the

inclusion of each investigator by the PI. The following criteria are examples for this

assessment:

The investigator has appropriate qualifications and experience to carry out the

clinical study and is able to undertake all the activities specified in the protocol.

The investigator understands his/her responsibilities for ensuring that the study is

conducted in accordance with the protocol and GCP, and that accurate results are

recorded and reported within the agreed timetable.

The investigator has sufficient interest and time to participate in the study.

The anticipated recruitment rate at the investigator’s site meets the study objectives.

The investigator’s site has access to adequate staffing, facilities, and equipment for

the proper conduct of the study.

The investigator agrees to provide his/her CV

The Principal Investigator signs the Clinical Study Agreement.

The investigator is obligated to allocate proper conditions for monitoring and to

cooperate with the monitor.

6.3.3. Regulatory Aspects

The clinical affairs manager will obtain confirmation that all clinical sites are in

conformity with laws and regulations of the country in which the site is located, in

addition to the documents specified in section 4. This is usually part of the clinical

study agreement.

6.3.4. Protocol and Case Report Forms (CRF)

6.3.4.1. A clinical study protocol and a set of CRF’s shall be prepared and approved

prior to the initiation of the study. Medically qualified input is required during

the drafting of the protocol and CRF's. A recommended protocol’s table of

contents is shown in Appendix 1.

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6.3.4.2. Once the protocol is signed and approved by the IRB/EC any alteration to

the protocol is documented as ‘amendments’, which should be agreed upon and

signed by the PI and the Clinical Affairs Manager and implemented via

[company] QP-03-03-01 Controlled document types & control. If the change is

significant, the amendment should be submitted to the Ethics Committee who

originally approved the study for re-approval. Minor changes in the study

protocol should be delivered to the EC via a protocol notification form at the

next formal contact with the EC, or according to the EC SOPs, as appropriate.

6.3.4.3. Amendments to the protocol are valid in all clinical sites except for cases in

which it is clearly written that the amendment will be activated in specific

clinical sites.

6.3.4.4. The cover page of the protocol includes the investigator’s signature/s. An

additional first page with a change control table and an identification table will

be kept at [company], attached to the original document. Protocols and CRF’s

are assigned with an internal separate document number per [company]’s

document control procedure.

6.3.4.5. Changes are documented as ‘amendments’, [company] QP-03-03-01

Controlled document types & control. In addition, amendments are signed by

the Clinical Affairs Manager, the PI and if required by the EC. The filled-in

forms are kept in the regulatory binder at the site and at the sponsor’s

headquarters.

6.3.5. Investigator’s Brochure

An Investigator’s Brochure summarizing all relevant data on the investigational

product, including: pre-clinical, clinical (if applicable), and safety data, shall be

prepared and provided to each investigator participating in the study. See Appendix 2

for a list of contents.

6.3.6. Informed Consent

Patients enrolled to the clinical study or, where appropriate, their legal representative,

shall be provided both verbally and in writing with information on the investigational

product and procedures. Their consent to be included in the study shall be expressed by

the fact that they have written their name, signed and dated the consent form, prior to

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the enrollment in the study. A copy of the signed form will be given to each subject.

The informed consent form is considered a controlled document - complete informed

consents forms will be kept as records at the study site/s file and in the patient medical

records, in addition to the copy provided to the patient. A significant change to its

content requires an EC approval (via a submission of an amendment). The principles of

the informed consent form content are detailed in Appendix 3.

ICF signing: the patient will write his/her name, sign and date the ICF. None of this

data will be completed by the physician.

Copies of ICF:

1. Original signed ICF is kept in the site file.

2. Copy of the signed ICF is provided to the patient

3. Additional copy of the signed ICF is kept in the patient medical records.

6.3.7. Indemnities / Insurance

Any indemnification required by investigators or ethics committees shall be arranged

prior to the initiation of the study, as well as the clinical trial insurance that is required

in relevant countries. The Clinical Affairs Manager shall ensure that either these have

been obtained or that [company] has authorized the CRO to obtain them on its behalf.

6.3.8. Agreements

6.3.8.1. Prior to study initiation, a written agreement shall be signed by the PI

indicating his/her willingness to adhere to the protocol, and defining any other

responsibilities or arrangements not covered by the protocol.

6.3.8.2. The PI and all investigators involved with the study should sign a financial

disclosure form, reporting any financial interest in the company or the test

product.

6.3.9. Ethics Committee

6.3.9.1. The study protocol and other relevant documentation, e.g., ICF, IFU, a

sample of CRF and Investigator’s Brochure, shall be submitted to the

appropriate Ethics Committee for review. Normally a separate application shall

be made for each participating center, unless there are arrangements to accept

Ethics Committee reviews carried out elsewhere.

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6.3.9.2. No center may start the study until the appropriate Ethics Committee

approval has been obtained in writing. A copy of the written approval shall be

kept in the regulatory binder kept in the sponsor’s clinical department and in the

site file.

6.3.9.3. The documents to be included in the Ethics Committee submission are

detailed in Appendix 4. Additional documents may be required, according to the

specific EC/IRB SOPs.

6.3.9.4. Note: In countries in which additional requirements apply (e.g., notification

to- or approval from- the EC or Competent Authority, or approval by national

EC / hospital manager), the study may start only after all requirements are

fulfilled.

6.3.10. Supply of the Investigational device

6.3.10.1. Only approved product, sterile if applicable, after the completion of all

relevant manufacturing and quality tests, shall be used for clinical studies. It is

the quality assurance responsibility to verify the completion of the activities and

completeness of the documentation for traceability purposes.

6.3.10.2. All products supplied for clinical study use shall be labeled “For Clinical

Investigation only” and the package will include instructions for use (IFU), as

applicable.

6.3.10.3. Shipment and use of the product will be documented in the appropriate

[company] clinical forms and delivery notes. The filled-in forms and delivery

notes will be kept at the site file and at the sponsor file.

6.3.11. Training

Any clinical study of an investigational product will be initiated only after an

appropriate training has been given. The extent, nature and responsibility of the training

shall be decided by the clinical affairs manager and, as appropriate, by the medical

director and the monitor. In addition, GCP training will be provided to all site

personnel, and a specific training will be provided to the PI, reviewing PI obligations

and responsibilities.

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6.4. Conduct of Study

6.4.1. Site initiation visit

6.4.1.1. Before any site(s) begin the study, a study initiation visit shall be carried out. The

site initiation visit may take place either at the specific study site or as a multi-site

meeting at a location decided upon by the sponsor. The investigator(s), study

coordinators, monitors and the sponsor’s representatives shall participate in the

visit.

6.4.1.2. The issues to be discussed during the site initiation visit include issues such as:

protocol design adherence, training of the use of the investigational product,

recruitment methods, study timelines, SAE reporting, data documentation (CRF),

informed consent procedure, monitoring and GCP adherence.

6.4.1.3. Site initiation visit shall be documented in a report (using [company] QF-02-08z

form). The report should detail all topics covered during the visit, including training

on specific procedures and decisions as to study specific requirements.

6.4.1.4. The report shall be filed at each study site and shell be kept at the sponsor’s

headquarters and at the site file.

6.4.2. Monitoring visits

6.4.2.1. Monitoring visits shall be conducted on a regular basis as defined by the sponsor.

6.4.2.2. The investigator and other staff members (optional) shall participate in the

meeting at the beginning of each visit.

6.4.2.3. Prior to each monitoring visit, the monitor should review previous reports /

communication, identify outstanding issues and be familiar with the status of the

site(s).

6.4.2.4. The visit shall start with a short update about the progress of the study and a

report of the pros and cons of the study proceeding.

6.4.2.5. Verification of clinical data: The monitor shall verify completeness, legibility,

clarity, obvious errors, and protocol compliance of signed inform consent forms,

CRF’s and essential documents to be held in the regulatory binder kept on site. All

reasonable attempts to clarify and complete these data shall be made with the

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investigator. During monitoring visits, the CRF’s shall be checked against source

data (e.g., patient hospital files) to verify that the CRF’s accurately reflect the cases

in question.

6.4.2.6. Data collection: The monitor shall collect all CRF’s that have been completed.

6.4.2.7. Monitor report: After each monitoring visit, the monitor shall write a

monitoring report including site performance and study progress and problems. The

report should include corrective actions and steps for avoiding future violations. The

report shall be sent to the investigator. Each monitoring visit shall be documented in

the appropriate [company] monitoring log.

6.4.3. Adverse Events, nonconformities and customer complaints

6.4.3.1. Information concerning serious adverse events and product-related adverse

events shall be reported immediately (within 24 hours) to the sponsor. The event

may be reported by telephone but it should always be followed by a written and

signed report.

The Clinical Affairs Manager will ensure that:

Any regulatory requirements for reporting adverse events are met.

Any requirements to inform Ethics Committees of adverse events are met.

All the investigators participating in the study are notified.

Consideration is given to any necessary modifications to the study, including its

possible discontinuation, consequent to the reported adverse event.

6.4.3.2. Complaints that are outside the scope of adverse events (e.g., complaints on

device malfunction, lack of equipment, inadequate training) shall be reported to

[company] and handled by the Clinical affairs Manager. The event details shall be

documented in [company] form QF-02-08u-01. The event discussions, conclusion,

action suggested and taken shall be summarized on ‘CAPA form’.

6.4.3.3. Nonconformities that are found by [company] during the study are documented

using the ‘nonconforming product’ procedure [company] QP-09-01-01 (NCR) Non

Conforming Material Procedure.

6.4.4. Audits

6.4.4.1. Audit shall be independent of and separate from routine monitoring, and shall be

under the responsibility of the Quality Assurance department. The QA department

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may conduct the audit or appoint an individual on its behalf to conduct the audit.

The QA department should ensure that the auditors are qualified by training and

experience to conduct audits properly.

6.4.4.2. Performance of audit is the sponsor decision.

6.4.4.3. The audit(s) shall, preferably, be conducted at a mid-point of the clinical trial.

6.4.4.4. The observations and findings of the auditor(s) should be documented in a final

audit report and shall be kept as a quality record at [company]. The report shall not

be part of the regulatory binder of the trial that will be submitted to the authorities.

6.5. Study Closure

6.5.1. Close out visit

6.5.1.1. The monitor or clinical affairs manager should ensure that all patient’s data are

documented and recorded (files and CRF copy on site).

6.5.1.2. The monitor or clinical affairs manager shall discuss with the investigator GCP

requirements for storage and archiving of study material, responsibility to inform

the EC of study termination and publication policy of study results and data.

6.5.1.3. Data collection: All remaining used and unused CRF’s will be collected.

6.5.1.4. A written site close out report will be written. The report shall give an overview

of the study conduct and results. The report, together with a follow-up letter shall be

sent to the investigator.

6.5.2. Product Allocation/Return

On completion of the study, the monitor(s) shall collect from the clinical centers all

remaining equipment and return them to [company].

6.5.3. Reporting

A report of the study, which incorporates data from each study site, shall be

prepared. The report shall include a description of the study design and

methodology, data analysis, statistical analysis (if appropriate), and a clinical

appraisal. The final report shall be signed by each clinical investigator, the clinical

affairs manager, and by the CRO representative (if any). (Note: Should any

investigator refuse to sign the final report, an explanation shall be provided.).

6.5.4. For a clinical study report template please see [company] QF-02-08ai-01. Archiving

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All records relating to the study shall be stored in a secure place in [company] and

at the study site for the appropriate period according to the GCP regulations.

7. Allocation Of Responsibilities

7.1. The clinical affairs manager is responsible for the conduct and documentation of clinical

studies at [company].

7.2. The Clinical Research Associate (CRA) is responsible for monitoring the studies and

ensuring that they are conducted according to the protocol, SOP’s and GCP principles, as

applicable.

7.3. The QA manager is responsible for assuring full traceability on the study and for auditing

the site(s), as applicable.

7.4. The PI is responsible for the conduction of the study at the site according to the protocol,

SOP’s and GCP principles, as applicable.

8. Appendices

Appendix 1: Protocol - table of contents (as appropriate)

- Signature page

- Protocol Synopsis

- Introduction

- Device description

- Study objectives

- Study design (contraindications, study duration, inclusion/exclusion criteria, patient

enrollment, patient identification, baseline variables, study procedures)

- Ethics

- Adverse events

- Risk to benefit analysis

- Investigation administration

- CRF handling and data management (including statistical consideration)

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Appendix 2: Investigator’s brochure – table of contents (as appropriate)

- Device description and function

- Processing information

- Risk analysis

- Bench testing

- Biocompatibility

- Animal studies

- Previous clinical studies (if applicable)

- Literature survey

Appendix 3: Informed consent – table of contents

- Purpose of the study

- Description of the research

- Compensation / reimbursements

- Insurance

- Potential risks and discomforts

- Potential benefits

- Alternatives to participation

- Confidentiality

- Voluntary participation

- Termination of participation

- Contact persons

Appendix 4: Items to be included in the Ethics Committee submission file (as

appropriate)

- Protocol / amendments

- Case Report Forms (CRF’s) – may be submitted as a draft

- Informed consent form(s) + translations

- Any other written information to be provided to patients

- Investigator’s brochure

- Investigator’s current CV

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- Instructions For Use

Appendix 5: List of initial essential documents to be kept in regulatory binder (as

appropriate)

Before the clinical phase of the trial commences:

- Investigator’s brochure

- Signed protocol and amendments, if any

- Sample Case Report Forms (CRF)

- Informed consent form (including all applicable translations)

- Any other written information given to trial subject.

- Signed financial agreement of the trial

- Insurance statement (where required)

- Signed agreements between involved parties

- Approval of IRB/EC

- IRB/EC composition

- CV of investigator and sub-investigator

- Certification of medical/laboratory tests – as applicable

- Sample of labels attached to the investigational product

- Instructions for handling of investigational product and trial-related materials

- Shipping records – as applicable

- Site personnel identification list

- Site initiation monitoring report

During the clinical conduct of the trial

- Investigator’s brochure updates

- Amendments to the protocols, CRF’s, informed consent

- Approvals of IRB/EC to the amendments submitted

- Monitoring visit reports

- Relevant communications other than site visits (letters, meeting notes, regular

authorities…)

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- Signed, dated and completed CRF’s. Note – the original CRF should be kept at the

sponsor’s headquarters and a copy of the CRF should be kept at the site file. If the CRF or

part of it is considered source data, a copy should be kept at the patient medical file.

- Documented adverse events reporting

- Subject enrollment list

- Subject identification code list (to be kept only at site)

- Investigational product accountability – as applicable

- Signature sheet

After completion or termination of the trial

- Documentation of investigational product return – as applicable

- Audit report, as applicable

- Site close out visit monitoring report

- Final report by investigator to IRB/EC and to the authorities, as applicable

- Clinical study report

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Clinical Studies Procedure Example

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