DIRECTORATE GENERAL OF DRUG ADMINISTRATION

CLINICAL TRIAL INSPECTION

LINICAL TRIAL INSPECTION

Date: 01.11.2010
Page 1 of 19

GUIDANCE ON CLINICAL TRIAL

INSPECTION

DIRECTORATE GENERAL OF DRUG ADMINISTRATION

Ministry of Health and Family Welfare, Government of the People’s Republic of Bangladesh
105-106, Motijheel Commercial Area, Dhaka-1000.
Tel:+880-2-9553456, +880-2-9556126, Fax:+880-2-9568166,
Email:drugs@citech.net, Website:www.ddabd.org

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DIRECTORATE GENERAL OF DRUG ADMINISTRATION
CLINICAL TRIAL INSPECTION

CLINICAL TRIAL INSPECTION

Date: 01.11.2010
Page 2 of 19
INDEX CONTENT PAGE NO

1 OBJECTIVES
2 SCOPE AND EXTENT OF THE PROGRAMME
3 PLANNING FOR INSPECTION
3.1 SELECTION OF STUDIES
3.2 INSPECTION ASSIGNEMENTS
3.3 PREPARING FOR INSPECTION
3.4 SCHEDULING THE INSPECTION
4 CONDUCTING THE INSPECTION
4.1 CLINICAL TRIAL SITE
4.1.1 OPENING INTERVIEW
4.1.2 ORGANISATION AND DELEGATION OF RESPONSIBILITIES
4.1.3 STUDY PROTOCOL
4.1.4 SUBJECT RECORD & INFORMED CONSENT
4.1.5 SOURCE DOCUMENTS AND CASE RECORD FORM (CRF)
ETHICS COMMITTEE (EC)/INDEPENDENT ETHICS
4.1.6 COMMITTEE (IEC)
4.1.7 SPONSOR
4.1.8 TEST DRUG ACCOUNTABILITY
4.1.9 RECORD RETENTION
4.1.10 CONCLUDING THE INSPECTION
4.2 INSPECTION OF CRO/SPONSOR
DOCUMENTS SUBMITTED TO DGDA AND REGULATORY
4.2.1 APPROVALS OBTAINED
4.2.2 ORGANISATION AND PERSONNEL
4.2.3 SELECTION AND MONITORING OF INVESTIGATORS
4.2.4 QUALITY ASSURANCE (QA)
4.2.5 ADVERSE EVENTS (AE) REPORTING
4.2.6 DATA COLLECTION AND HANDLING
4.2.7 ELECTRONIC RECROD AND CLINIAL DATABASE
4.2.8 DATA COLLECTION
4.2.9 COMPUTEIZED SYSTEM SECURITY
4.2.10 INVESTIGATIONAL PRODUCT (IP)
5 REPORTING OF INSPECTION

CLINICAL TRIAL INSPECTI

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CLINICAL TRIAL INSPECTION

ABBREVIATIONS
AE Adverse events
CRO Clinical Research Organisation
CRF Case Record Form
CT Clinical Trial
CV Curriculum Vitae
EC Ethics Committee
ICF Informed Consent Form
IP Investigational Product
SOP Standard Operating Procedure
DGDAA Directorate General of Drugs Administration

ON
Date: 01.11.2010

JANUARY, 2011
DIRECTORATE GENERAL OF DRUG ADMINISTRATION
CLINICAL TRIAL INSPECTION

AL TRIAL INSPECTION
CLINICAL TRIAL INSPECTION PROGRAMME:

1. Objectives :

The aims of the programme are:

a. To verify GCP compliance to protect the rights, safety and well being of
the subjects involved in clinical trial.
b. To verify the credibility and integrity of clinical trial data generated.
c. To verify the compliance with various regulatory provisions as per Drugs Act, 1940 and
Rules their under, The Drugs (Control) Ordinance 1982 & it’s amendment.

The purpose of this programme is to provide direction to inspectors/DGDA officers for

conducting inspection of site of clinical trial, sponsor / CRO’s facilities involved in clinical
trial and information to investigators, sponsor/ CRO’s about procedures for inspection and
follow up of action.

2. Scope and extent of the programme:

Clinical trial inspection programme covers all clinical trial sites and sponsor / CRO’s
facilities involved in clinical trial of drugs including biological and medical device covered
under Drugs Act, 1940 and Rules their under, The Drugs (Control) Ordinance 1982 & it’s
amendment.

3. Planning for Inspection:

Inspection can be conducted before, during or after a clinical trial is completed.

3.1 Selection of studies:

Inspection can be carried out as a routine surveillance or for any specific cause(s).Study
may be selected for inspection based on, but not restricted to the following criteria:

3.1.1 Nature of study

3.1.2 For regulatory decision based on clinical trial data

3.1.3 Data irregularities

3.1.4 Complaints

3.1.5 Vulnerability of subjects

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3.1.6 Number of CT including number of subject enrolled at a particular site

3.2 Inspection assignments:

DGDA will issue instruction to the officers /Inspectors to conduct the inspection identifying
the Clinical trial, name, address, contact number of clinical trial site, sponsor / CRO’s
facilities to be inspected. It may also identify the type and purpose of the inspection and
provide background materials like study protocol, CRF etc.

3.3 Preparing for inspection:

The inspector shall go through the information provided by DGDA and develop a plan for
conducting the inspection.

AL TR3.4 Scheduling the inspection:

Inspection of clinical trial site would generally be pre-announced to ensure availability of

the Investigator / Sub- Investigator and other personnel along with study records at the
time of the inspection. The date of inspection and other arrangements would be finalised
by the DGDA Officers / Inspector(s) in coordination with the investigator /sponsor/ CRO.
Under some specific circumstances unannounced inspection of clinical trial sites can be
carried out as per the direction of DGDA. Inspection of CRO/Sponsor can be conducted
without prior notice.

4. Conducting the inspection:

4.1 Clinical Trial Sites:

The inspection includes verification of essential documents to determine whether the trial
related activities were in accordance with the protocol, GCP guidelines published by
DGHS, Govt. of Bangladesh and Drugs Act as well as other applicable regulatory
requirements. When inspection is carried out after completion of the clinical trial, it will
include comparison of data generated by the sponsor with source documents at the
clinical trial sites and Case Record Form (CRF) in the investigator’s files. If it is a routine
surveillance or “for cause” inspection of an ongoing clinical trial, the comparison will
generally include source documents and CRF.

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4.1.1 Opening interview:

Inspector should meet investigator / key person of Sponsor and present his / her identity
card. The inspector should provide verbal summary of methods and procedures to be
followed during the inspection.

CLINI During opening interview following main activities should be carried out:

4.1.1.1 Investigator prior education and GCP experience, GCP training provided by the
sponsor.

4.1.1.2 Who did what, when, where and how with respect to following:

• Obtaining Informed consent of subjects,

• Screening and admission of subjects to the study,
• Receipt, handling, administration, return of investigational product,
• Collection and analysing of data,
• Recording, transcribing and reporting of data to sponsor,
• Archiving the data

4.1.1.3 How did the investigator identify the subjects for the study,

4.1.1.4 Date of enrolment first and last subject

4.1.1.5 About Ethics Committee the site is using

4.1.1.6 Whether the investigator has copies of protocol, permission from DGDA,
undertaking by the investigator etc.

4.1.1.7 Information about unexpected and serious adverse events (if any) occurred at the
site,

4.1.1.8 Information about monitoring/auditing of the site by sponsor/CRO.

During the interview other relevant facts may also be found out.

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4.1.2 ORGANIZATION & DELEGATION OF RESPONSIBILITIES:

Inspector shall verify / obtain following:

4.1.2.1 Brief about study site.

4.1.2.2 Status of the study.

4.1.2.3 Investigator has agreement with sponsor for the study.

4.1.2.4 Financial & Confidentiality agreement with Investigator and concerned laboratory
(ies) in place.

4.1.2.5 In Investigator undertaking protocol title, Investigator’s name, address, telephone

no of site, qualification, Name & address of laboratories, Name of Sub-Investigator
etc are in-compliance with Drugs Act.

CLINI 4.1.2.6 Obtain list of all clinical trials performed by investigator.

The list should have information such as

• Protocol Number
• Protocol Title
• Name of Sponsor/CRO
• Study date

4.1.2.7 Determine whether authority for conducting various Clinical trial related activities
were delegated properly by the Investigator to the competent personnel so that
investigator was able to supervise the study adequately. Obtain a list of personnel
with delegated activity.

4.1.2.8 Documents following;

• Date of EC / IEC approval including initial review of protocol, amendment
the ICD etc.
• Date of screening of first subject,
• Date of signing ICF by the first subject
• Date of first administration of IP,
• Date of last follow up of any subject,

4.1.2.9 List the name and address of facilities involved in laboratory test required by
protocol. Verify accreditation status and adequacy of these facilities to perform the
specified test,

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4.1.2.10 Obtain a copy of site enrolment log,

4.1.2.11 Determine whether SOP’s for various activity are established and documented,

4.1.3 Study Protocol

4.1.3.1 Determine if, there are any difference between protocol provided to DGDA and the
protocol in the Investigator’s file with respect to following:

 Version number and effective date

 Eligibility of Subject (Inclusion/ Exclusion Criteria)
 No of Subject
 Dosage
 Route of administration
 Frequency of dosage
 Randomisation & Blinding process
 Verify whether Investigator follow the protocol as approved
 Version number and EC approval of amendments

4.1.4 Subject record & Informed consent:

4.1.4.1 Review the Informed Consent Form (ICF) signed by the subjects. If the number of
subjects at site is relatively small (e.g.20 or less) 100% of the ICF can be reviewed.

Determine the following:

4.1.4.2 whether ICF have all the elements enlisted in Drugs Act or WHO guidelines,

4.1.4.3 whether IC has been obtained from each subjects prior to participation of the
subject in the study,

4.1.4.4 whether signature/thumb impression of the subjects have been affixed with date,

4.1.4.5 whether in case of illiterate subjects or illiterate representative of a subject, there

are signature and details of an impartial witness,

4.1.4.6 Have witness/ signature being personally dated,

4.1.4.7 Have patient/witness signature been personally dated?

4.1.4.8 Has the dated signature of the designated person for administering informed
consent (IC) been affixed?

4.1.4.9 Is the designated person for administering IC medically qualified?

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CLINICAL TRIAL INSPECTION

4.1.4.10 If IC has been administered by a designated person who is not medically

qualified, is there evidence that subject's queries of a medical nature were
answered by a medically qualified person or the investigator?

4.1.4.11 Is the completed ICF signed and dated by the investigator?

4.1.5 Source Documents and Case Record Form

4.1.5.1 Verify condition, completeness, legibility, accessibility of the investigators source

data file.

4.1.5.2 Determine whether subjects who were enrolled and /or completed the study meet
inclusion and exclusion criteria;
INICAL TRIAL INSPECTION
Date: 4.1.5.3 Determine whether subject received the test drug with respect to dose and
frequency specified according to the protocol;

4.1.5.4 Determine whether safety/ efficacy end point data was collected and reported in
accordance with the protocol;

4.1.5.5 Does medical record mentions subject ID/ name /hospital registration number /
and indication that subjects are participating in a clinical trial

4.1.5.6 Whether all adverse events were reported in CRF;

4.1.5.7 Compare the source document with CRF and determine whether source data have
been correctly transcribed in CRF;

4.1.5.8 Verify whether all SAE’s have been reported to the sponsor (within 24 hours) and
EC (within 7 working days);

4.1.5.9 Verify whether adequate medical care have been given to the subject especially in
the event of inter current illness, adverse events including abnormal lab
parameters;

4.1.6 Ethics Committee (EC) / Independent Ethics Committee (IEC):

4.1.6.1 Identify the name , address of the EC/ IEC in the approval letter and compare it
with that with the one stated in investigators undertaking ;

4.1.6.2 Verify if IEC approval letter mention study code , Protocol title and version number
of the protocol, list of other documents reviewed, list of members present at the
meeting, quorum of five members as specified in Drugs Act, Office Orders and
as per relevant WHO guidelines are satisfied, date, time , venue of the meeting,
signature and date of member secretary / Chairman;

4.1.6.3 In case the site does not have an IEC, verify whether following are in place:
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CLINICAL TRIAL INSPECTION

• Statement of the investigator / institution that approval granted by another

IEC would be abided by statement from the approving IEC that they
would take responsibility for ongoing supervision of the site;
CLINICAL TRIAL INSPECTION
Date: 01.11.2010ge• Has the investigator submitted reports of all SAEs to the IEC and apprised
the EC/IEC about the trial progress?

CLINICAL 1.2010
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4.1.7 Sponsor:

4.1.7.1 Verify whether a clinical trial Investigators agreement has been signed for this
study with the sponsor;

4.1.7.2 Whether investigator maintain copies of all reports submitted to the sponsor;

4.1.7.3 Whether all SAE are reported to sponsor within 24 hours;

4.1.7.4 Whether all CRFs were submitted to sponsor after completion of study;

4.1.7.5 Determine whether all dropouts and reasons thereof were reported to sponsor;

4.1.7.6 Determine the method and frequency of monitoring the progress of the study by
the sponsor;

4.1.7.7 Whether a log of onsite monitoring visit is maintained at the site;

4.1.7 Test Drug Accountability:

4.1.8.1 Review individual subject record to verify the correct dose administration with
respect to dose, frequency, route of administration;

4.1.8.2 Determine whether unqualified /unauthorised persons administered/dispensed the

test drug.

4.1.8.3 Determine whether adequate record of qty. of test drug received , dispensed/
destroyed/returned is maintained ;

4.1.8.4 Determine whether storage condition/monitoring method are as per

protocol/recommendation;

4.1.8.5 Whether trial medication are maintained under controlled access;

4.1.8.6 Have un-used trial medications been returned to the sponsor or disposed of
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CLINICAL TRIAL INSPECTION

according to protocol? In case of destruction at site, is a certificate of destruction

on file?

4.1.8.7 Are the drugs dispensing records being maintained properly?

4.1.8.8 Are the records for reconciliation of all IPs received from the sponsor maintained?
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Date: 01.11.2010
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4.1.9 Record retention:

4.1.9.1 Is adequate space available at the site for retention of documents

4.1.9.2 Determine whether documents are maintained properly and for the period as
specified and necessary measures have been taken for accidental and premature
destruction;

4.1.9.3 Determine who maintained custody of the documents and means for assuring
prompt action;

4.1.10 Concluding the Inspection:

The inspector should conclude the inspection with final discussion with the Investigator.
During discussion the inspector should explain inspection finding .The inspector may also
issue a list of observation at the conclusion of inspection.

4.2 Inspection of CRO/Sponsor

The inspection includes verification of essential documents to compare practice and

procedure followed by the CRO/Sponsor to that committed in the clinical trial application
and GCP guidelines published by Govt. of Bangladesh, Drugs Act and as well as other
applicable regulatory requirements as per latest WHO guidelines. Inspection of
CRO/Sponsor can be conducted without prior notice.

During inspection following aspects may be verified.

4.2.1 Documents submitted to DGDA and regulatory approvals obtained.

4.2.1.1 Clinical Trial application and DGDA approval letter

4.2.1.2 Import license application and import licence obtained. Copy of license

4.2.1.3 Export NOC for biological samples

4.2.1.4 List of investigators

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4.2.1.5 Investigator Undertaking CLINICAL TRIAL INSPECTION

Date: 01.11.2010
4.2.1.6 Investigator's brochure

4.2.1.7 Protocol and Protocol amendments

4.2.1.8 Patient Information Sheet and Informed Consent Form

4.2.1.9 Case Record Form

4.2.1.10 Ethics Committee approval and notifications to DGDA

4.2.1.11 Unexpected and Serious Adverse Event Reports

4.2.1.12 Study report

4.2.2 Organisation and personnel:

4.2.2.1 Company profile and overall structure,

4.2.2.2 Organization chart for management of the clinical trial Structure and
responsibilities for all activities involving investigational products Departments, functions,
and key personnel responsible for Protocol development Investigator's brochure, Case
Record Form Informed consent form (ICF), translations and amendments. Selection of
investigators Regulatory approval, Ethics Committee (EC) approval, Monitoring Quality
assurance Adverse Event (AE) Reporting, Data Management , Statistical Analysis
Electronic Records/Clinical Database, Clinical Supplies-Investigational Products (IP)
Archival.

4.2.2.3 Identify and determine the personnel responsible for following:

• Authority to review and approve study documents

• For final evaluations and decisions in the review of study
• For obtaining & reviewing adverse events and reporting to DGDA
• Monitors/CRO’s with job descriptions and qualifications
• Job description of key stake holders
• Verify clinical personnel training record
• To obtain a list of external service providers and contractors and
documentation of the service they provide.
• Verify the SOPs followed for various responsibilities and clinical trial related
activities.

CLINICAL TRIAL INSPECTION

Date: 0115 of 19
4.2.3 Selection and monitoring of investigators

4.2.3.1 Obtain list of all investigators along with Investigator Undertaking, Signed
Investigator Agreements
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4.2.3.2 Criteria for selection of sites

4.2.3.3 Information provided to sites viz.

4.2.3.4 Informed consent form, Protocol, Reports/publications of previous trials,

Investigator's Brochure, Product labelling, Training, All versions and updates etc.

4.2.3.5 Investigator’s non-compliance (If any)

• Deviations from DGDA regulations

• Deviations form protocol
• How sponsor handles serious deviations from approved protocol or Drugs
Act or WHO guidelines.

4.2.3.6 Steps for correction:

• Verify whether any investigators terminated? Review monitoring reports reported

to DGDA,
• Any Non-compliant investigator /terminated? Reasons?

4.2.3.7 Selection of monitor:

• List all monitors for study duration

• Selection criteria for monitors
• Job descriptions/responsibilities
• Qualifications
• Training Records and CVs
• Reporting structure
• Monitoring SOP Frequency, scope and process, Obtain a copy of SOP and
check compliance, If no SOPs, interview monitors to check how monitoring
was done, Monitoring Plan, Monitoring Reports.

4.2.3.8 Review the Pre trial and periodic trial visit report in respect of following content:

• Process of verifying compliance to protocol

• Process of verifying investigator responsibilities
• Ethics Committee Approvals Amendments/Re-approval Communication-
progress reports/SAEs etc Validity/Completeness
• Informed Consents Confirmation of consent and process of consent.
• Use of IEC approved forms.
• Adequacy of consent documentation, Completeness
CLINICAL TRIAL I • Which CRFs were compared to source docs? When and who verified
CRFs against source data (hospital records, office charts, laboratory
reports,etc.) at the study site. Form for data verification
• Check copy of any SOPs and guidelines for data verification
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• Data correction handling, Compliance to Monitoring Plan, Frequency,

Follow up etc.

4.2.4 Quality Assurance (QA):

4.2.4.1 Verify SOP for QA audits and operation of quality assurance unit

4.2.4.2 Describe how the audit and monitoring are separated

4.2.4.3 Obtain list of audited trial

4.2.5 Adverse events reporting:

4.2.5.1 Verify sponsor’s method for following up of adverse events and for dissemination
of AE information to others Investigators

4.2.5.2 Obtain list of SAE reported, Including death.

4.2.5.3 Verify the timeline for reporting the SAE to DGDA and other Investigators /EC;

4.2.6 Data collection and handling

4.2.6.1 Study tabulations: List of all studies for marketing Authorization

4.2.6.2 Data Tabulations: Number of subjects. Verify if number in CT application same as

marketing Authorization application(compare to CRFs submitted)

4.2.6.3 If any subjects not included in the marketing Authorization application? Why not
included?

4.2.6.4 Review of SOPS to verify compliance to assure the integrity of safety and efficacy
data collected from clinical investigators

4.2.6.5 Verify that the SOPs were followed and document any deviations

4.2.6.6 Deviations/Data queries resolutions

4.2.6.7 Statistical processes

4.2.6.8 Primary endpoints compare the tabulations with CRFs and source documents
CLINI11. 17 of 19
4.2.6.9 Record retention

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4.2.7 Electronic Record and Clinical database:

4.2.7.1 Person responsible for designing and developing data base

4.2.7.2 Can it be modified, or has it been modified? If so, by whom?

4.2.7.3 If the clinical investigator can modify it, how would the sponsor be aware of any
changes?

4.2.7.4 Validation :Person responsible, Process, Documentation of process

4.2.7.5 Error logs maintained for errors in software and systems?

4.2.7.6 Do error logs identify corrections made?

4.2.8 Data collection:

Following aspects may be verified:

4.2.8.1 Responsibilities : Authorization to access the system, to enter data and to change
Data.

4.2.8.2 Use of electronic data capture or data transcription from paper CRFs into an
electronic record

4.2.8.3 Audit trail : to record Changes to electronic records, Person Responsible for the
change and Time of the change

4.2.8.4 Process of data transmission from the clinical investigator to sponsor or CRO

4.2.9 Computerized System Security:

Following aspects may be verified:

4.2.9.1 Management of system access e.g. access privileges, authorization/de-

authorization procedures, physical access controls

4.2.9.2 Records of authorized personnel, Names, Titles. Description of their access

Privileges

4.2.9.3 Access methods e.g., identification code/password combinations, tokens,

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biometric signature, electronic signatures, digital signatures

4.2.9.4 Data security in case of disasters, e.g., power failure

4.2.9.5 Contingency plans and backup files

CLINICAL TRIAL INSPECTION
Date: 4.2.9.6 Controls in place to prevent data from being altered, browsed, queried, or reported
via external software applications that do not enter through the protective
system software

4.2.10 Investigational Product (IP):

Following aspects may be verified:

4.2.10.1 Transferred data from central lab to sponsor

4.2.10.2 Integrity Procedures to ensure integrity of IP from manufacturing to receipt by the

clinical investigator.

4.2.10.3 If IP met required release specifications by review of the Certificate of Analysis?

4.2.10.4 Storage of IP and the conditions of storage

4.2.10.5 Process of verification of IP integrity during shipment to investigator.

4.2.10.6 IP label

4.2.10.7 If the test article was recalled, withdrawn, or returned?

4.2.10.8 Accountability:

Following aspects may be verified:

• Names and addresses of clinical investigators receiving IP Shipment, date (s),

quantity, batch number.

• Final disposition of the test article.

• Detailed audit if serious violations are suspected.

• Sufficient records to reconcile IP usage (compare the amount shipped to the

investigators to the amount used and returned or disposed of).

• Check whether all unused or reusable supplies of IP returned to the sponsor

when either the investigator(S) discontinued or completed participation in the
clinical investigation, or the investigation was terminated. If the test article was
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not returned to the sponsor, describe the method of disposition and determine if
adequate records were maintained.

6. Reporting of inspection

The Inspection should be documented in writing in both during and after inspection. After
the inspection a narrative report containing details of inspection finding should be
prepared and submitted to DGDA.

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