GUIDELINES FOR GOOD PRACTICE IN THE CONDUCT OF CLINICAL TRIALS IN HUMAN PARTICIPANTS IN SOUTH AFRICA
APPENDIX C
DETAILS OF AN MCC INSPECTION
The inspection may involve;
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a comparison of the practices and procedures of the clinical investigator with the commitments made in the application to conduct a clinical trial and/or
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a comparison of the data submitted to the sponsor and regulatory authority with the source data.
THE INSPECTION
PRE-INSPECTION CONTACT
Where appropriate, appointments for inspection of an investigational site should be made telephonically. The Medical Director of the relevant pharmaceutical company also need to be contacted, as the clinical research associate (CRA) of the company responsible for the monitoring of the specific study needs to be present during the inspection.
The MCC official should, however, keep the time span between initial contact and actual inspection as short as possible. What appears to be undue delay of the inspection on the part of the clinical investigator needs to be investigated.
PRE- INSPECTION MEETING
The purpose of this meeting is for the MCC official(s) to explain the purpose of the inspection, i.e routine or for -cause, and to establish whether the investigator has fulfilled his/her GCP responsibilities. The latter includes:
Whether the investigator is thoroughly familiar with the properties of the investigational medical product(s) as described in the investigator’s brochure.
to ensure that he/she has sufficient time to conduct and complete the clinical study, has adequate staff and appropriate facilities (including laboratories) available for the duration of the study, and to ensure that other studies do not divert essential subjects/patients or facilities away from the study in hand.
the investigator needs to provide retrospective data on numbers of subjects/patients who would have satisfied the proposed entrance criteria during preceding time periods in order to assure an adequate recruitment rate for the study.
the investigator needs to provide an up-to-date curriculum vitae.
to establish whether the investigator has studied the protocol and whether the assisting personnel have been adequately informed of their responsibilities.
to determine if Ethics Committee approval has been obtained.
to determine in what manner the investigational products are handled and stored, and that investigational products are dispensed to study subject/patient in accordance with the protocol and that any unused products are returned to the Sponsor. Reconciliation of trial medication must be provided.
to ensure that the confidentiality of all information about subject/patients is respected (by all persons involved). to ensure that the investigator observes the following points particularly related to patient care:
if appropriate, fully functional resuscitation equipment should be immediately available in case of emergency.
the Investigator is medically responsible for those subjects/patients who are under his/her care for the duration of the study and must ensure that appropriate medical care is maintained after the study.
clinical significant abnormal laboratory values or clinical observations must be followed up after completion of the study.
THE INSPECTION
SITE MASTER FILE
The following original documents or certified copies thereof must be available at the investigational site:
Investigator’s Brochure
Protocol, including all amendment
MCC approval for original application and all the amendments
Ethics Committee approval, including approval of all amendments
Trial subject informed consent
Investigator’s CV
CRFs
INSPECTION PROCEDURES
This part identifies the nature of the information that must be obtained during each inspection to determine if the clinical investigator is meeting his/her obligation as trialist. This outline provides only the minimal scope of the inspection and the MCC official should extend the inspection as the facts involve. The inspections conducted should be sufficient in scope to determine compliance with GCP. The MCC official should not attempt to evaluate scientific data during the inspection, but only verify documentation and validate data.
The protocol, included and amendments must be signed by the investigator.
Documentation Ethics Committee and MCC approvals must be verified.
Signed informed consent documents must be validated. The signatures need to be checked against evidence on patient files. Date of consent must be prior to date of initiation of trial. If oral consent was obtained, it must be determined whether this was recorded in the subject’s medical records. A copy of the information presented orally must be obtained.
Subject records must be verified.
The condition, organisation, completeness and legibility of the investigator’s raw data files need to be described.
It needs to be determined whether there is adequate documentation to assure that all audited subjects did exist and were alive and available for the duration of their stated participation in the study.
The raw data in the clinical investigator’s records needs to be compared with the completed case reports.
The following needs to be determined:
whether the number and type of subjects entered into the study were confined to the protocol limitations.
whether the criteria (e.g age, sex, reproductive potential, disease condition) for exclusion of subjects from the study, as specified in the protocol were followed
observations, information, and data condition of the subject at the time the subject entered into the trial.
observations and data on the condition of the subject throughout participation in the investigation, including results of lab tests, development of unrelated illness and other factors which might alter the effects of the test article.
Records of exposure of the subject to the test article.
Whether clinical laboratory testing (including ECGs X-rays and other special investigations), as noted in the case reports, can’t be evaluated by the presence of completed laboratory reports in the source documents.
The occurrence of adverse reactions must be determined. The reporting of these events to MCC and the Ethics Committee must be documented.
All persons obtaining raw data or involved in the collection or analysis of such data need to be identified.
It needs to be determined whether all products, and the reasons therefore were reported to the Company.
TRIAL MEDICATION
Accounting procedures for the test and comparator drugs must be determined.
Dates and quantity of trial medication dispensed as well as the recipients must be available as well as corroboration by raw data notations.
The blinding of medication, if appropriate, must be validated to ensure protection of the study from bias.
It needs to be determined whether distribution of the article was limited to those persons under the investigator’s direct supervision.
The storage area may be inspected.
It needs to be determined whether the test article is a controlled substance and whether it is securely locked.
Access to the controlled substance must be restricted to the investigator and the responsible pharmacist.
COMPUTER ELECTRONIC DATA SYSTEMS
If electronic data systems are involved in gathering data, storing data, or transmitting data to the sponsor, these need to be identified and their capabilities established.
The following are important:
What is the source of data entered into the computer?
Who enters data ?
When
Who has access to computer? Security codes?
How are data previously entered changed? Audit trial? By whom?
How are data submitted to sponsor? (hard disk, floppy disk, fax, modern network, mail, messenger)
How are errors, omissions, etc., in the data received corrected and how are they documented?
POST-INSPECTION MEETING
At this meeting the MCC official(s) will convey the findings of the inspection to the investigator and the representative of the pharmaceutical company or contract research organisation. The matters discussed at this meeting will be in line with the report written by the official.
Important matters include:
When significant violations of GCF are suspected, reports must contain sufficient narrative and accompanying documentation to support the findings. These findings also need to be presented to MCC.
When it is apparent that the study has been conducted in substantial compliance with the guidelines, an abbreviated report may be submitted.
The following is a guideline as to what should be included in an abbreviated report:
The comparison of raw data recorded on the case report forms to that of the source data, including the number of records compared and what was compared (patient charts, hospital records, lab slips and etc.)
There should be a statement about the trial medication accountability records was not sufficient to reconcile the amount of medication received, dispensed and/or returned.
There should be a statement about protocol adherence, which should be characterized and quantified.
There should be a statement about the obtaining of informed consent from each patient
There should be a statement identifying the specific individual responsible for each significant aspect of the study (who saw the patient, who administered the test medication, etc.).
There should be a statement on follow-up of adverse experiences (including death) if any occurred.
If deficiencies are found during the inspection in any of these or in any of the areas it needs to be explained and documentation attached as exhibits.
A copy of the consent form and protocol actually used needs to be attached.
It is important to note that the above deals with an abbreviated report, not an abbreviated inspection.
All clinical investigator audits conducted for cause must have full reporting.
A for-cause inspection may be the result of prior knowledge or suspicion of alleged violations of the act and/or guidelines. A for-cause inspection may concentrate the data audit on specific areas of the study or may expand the data review to cover multiple studies. This inspection may also result when a study is of singular importance to the approval of registration of a medicine, i.e one of two adequate and well controlled studies
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