Clinical Studies Procedure Example

105010228.
doc
Document: Procedure Date: Jul 27, 2009 Revision: XX
CLINICAL STUDIES PROCEDURE

Approvals: Name Author Reviewed by Approved by Title Signature Date
Change control: Rev.

01 02 03
Description of change
Approved by DCN
Signature
Date
QP-02-08
Page 1 of 16
Proprietary and Confidential
105010228.doc
1.
Objective
To define the activities related with the performance of Clinical Studies by [company].
2.
2.1. 2.2. 2.3.
General
Clinical studies are conducted by [company] as part of the validation activities. This procedure applies to all clinical studies, sponsored by [company]. The purpose of this document is to ensure that clinical investigations are properly monitored and documented, and meet international regulatory requirements (section Documents). Reference
3.
3.1. 3.2. 3.3. 3.4. 3.5. 3.6. 3.7. 3.8.
Applicable Documents
Requirements stated in the following documents apply as appropriate to the context: Procedure QP 00-02 - Quality Manual. Procedure QP 00-03 - Terms & Definitions. Procedure QP 01-01 - Quality Policy. Procedure QP 02-01 - Design and Development Planning. Procedure QP 02-02 - Project Planning and Management. Procedure QP-03-03-01 Controlled document types & control Procedure QP 12-01 - Record Types and Retention. [company] clinical study forms (QF-02-08)
4.
4.1. 4.2. 4.3. 4.4. 4.5. 4.6.
Reference Documents
Information contained in the following documents is relevant as appropriate to the context. 21 CFR Part 820 Quality System Regulation. ISO 13485 Medical Devices Quality Management System Requirements for regulatory purposes Directive 93/42/EEC for medical devices EN ISO 14155-1, Clinical investigation of medical devices for human subjects Part 1: General requirements. Guidance for Good Clinical Practice, ICH Harmonized Tripartite guideline, 1996 Helsinki declaration
QP-02-08
Page 2 of 16
105010228.doc
4.7. 4.8. 4.9.
FDA publication Perspectives on Clinical Studies for Medical Device (Statistical).
Submissions
FDA publication Guidance for Industry: Computerized Systems Used in Clinical Trials. FDA publication A Regulatory Perspective for Bayesian Clinical Trials.
5.
Definitions and abbreviations

5.1.
5.1.1.
Documents
Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocols 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 sponsors headquarters. (See detailed list of primary essential documents for the conduct of a clinical study in ref. 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 subjects 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.
5.2.
QP-02-08
Personnel
Page 3 of 16
105010228.doc
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. 5.2.3.
Investigator A person responsible for the conduct of the clinical trial at the trial site. 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. 5.2.5.
Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. Contract Research Organization (CRO) - A person or an organization (commercial, academic or other) contracted by the sponsor to perform one or more of a sponsors trialrelated 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 sponsors 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.
5.3.
Other
QP-02-08
Page 4 of 16
105010228.doc
5.3.1. 5.3.2. 5.3.3.
Adverse Event (AE) - Any undesirable experience occurring to a subject during a clinical study, whether or not considered related to the investigational product. Serious Adverse Event (SAE) - means an adverse experience that is fatal, lifethreatening, or which results in hospitalization or prolongation of hospitalization. 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, sponsors standard operating procedures (SOPs), 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.
6.1.
Application
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 sponsors headquarters. This does not apply to the completed CRF.
6.3.
6.3.1.
Study Initiation
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 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.
QP-02-08
Selection of Investigators
Page 5 of 16
105010228.doc
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 The investigator understands his/her responsibilities for ensuring that the clinical study and is able to undertake all the activities specified in the protocol. 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 investigators site meets the study The investigators site has access to adequate staffing, facilities, and 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
objectives. equipment for the proper conduct of the study.
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 . 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 CRFs 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 protocols table of contents is shown in Appendix 1. 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
QP-02-08 Page 6 of 16
105010228.doc
[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 investigators 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 CRFs 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 sponsors headquarters. 6.3.5. Investigators Brochure An Investigators 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 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
QP-02-08
Page 7 of 16
105010228.doc
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. 2. 3. 6.3.7. Original signed ICF is kept in the site file. Copy of the signed ICF is provided to the patient Additional copy of the signed ICF is kept in the patient medical records.
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 Investigators 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. 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 sponsors clinical department and in the site file.
QP-02-08
Page 8 of 16
105010228.doc
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.
6.4.
6.4.1.
Conduct of Study
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-
QP-02-08
Page 9 of 16
105010228.doc
site meeting at a location decided upon by the sponsor. The investigator(s), study coordinators, monitors and the sponsors 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-0208z 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 sponsors 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, CRFs 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 investigator. During monitoring visits, the CRFs shall be checked against source data (e.g., patient hospital files) to verify that the CRFs accurately reflect the cases in question. 6.4.2.6. Data collection: The monitor shall collect all CRFs that have been completed.
QP-02-08 Page 10 of 16
105010228.doc
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 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.
QP-02-08 Page 11 of 16
105010228.doc
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.
6.5.1.
Study Closure
Close out visit 6.5.1.1.The monitor or clinical affairs manager should ensure that all patients 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 CRFs 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 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.
QP-02-08
Page 12 of 16
105010228.doc
7.
7.1. 7.2.
Allocation Of Responsibilities
The clinical affairs manager is responsible for the conduct and documentation of clinical studies at [company]. The Clinical Research Associate (CRA) is responsible for monitoring the studies and ensuring that they are conducted according to the protocol, SOPs and GCP principles, as applicable. 7.3. 7.4. The QA manager is responsible for assuring full traceability on the study and for auditing the site(s), as applicable. The PI is responsible for the conduction of the study at the site according to the protocol, SOPs 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 Ethics Adverse events Risk to benefit analysis Investigation administration CRF handling and data management (including statistical consideration)
enrollment, patient identification, baseline variables, study procedures)
Appendix 2: Investigators brochure table of contents (as appropriate)

QP-02-08
Device description and function Processing information Risk analysis

Page 13 of 16
105010228.doc
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 (CRFs) may be submitted as a draft Informed consent form(s) + translations Any other written information to be provided to patients Investigators brochure Investigators current CV 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: QP-02-08
Investigators brochure
Page 14 of 16
105010228.doc
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 Investigators brochure updates Amendments to the protocols, CRFs, informed consent Approvals of IRB/EC to the amendments submitted Monitoring visit reports Relevant communications other than site visits (letters, meeting notes, regular authorities) Signed, dated and completed CRFs. Note the original CRF should be kept at the sponsors
During the clinical conduct of the trial
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

QP-02-08 Page 15 of 16
105010228.doc
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
QP-02-08
Page 16 of 16

Clinical Studies Procedure Example

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Clinical Studies Procedure Example

Uploaded by

Copyright:

Available Formats

105010228.

Document: Procedure Date: Jul 27, 2009 Revision: XX