GCP Refresher for Investigator

IP Management

Malaysian Guideline for Good Clinical Practice, 4th Ed, 2018

Overview
• Definition of Investigational Product (IP)/
Investigational Medical Product (IMP)
• IP management at site
• What to look out for?
IP…?
“ A pharmaceutical form of an active ingredient including
plant/animal-derived medicinal products or placebo being
tested or used as a reference in a clinical trial, including a
product with a marketing authorization when used or assembled
(formulated or packaged) in a way different from the approved
form, or when used for an unapproved indication (off-label use),
or when used to gain further information about an approved
use.”

- Malaysia GCP Edition 4, 2018

How many IP?

What is IP?
What is IP?
What is IP?
Non-Investigational Medicinal Product (NIMP)

Medicinal product supplied as part of the study but is not

the medication being investigated.

Example:
▪ support or rescue medication,
▪ diagnostic, or preventative treatment, or
▪ part of standard medical care.
IP Management
IP Management

Regulatory Investigator’s Brochure/

Drug manufacturing Package Insert
requirements

Supply chain Quality Control SOPs

Management system Training Storage

IP Accountability
IP Accountability

Inventory records document that IP was used only:

In the clinical trial
What ▪ For eligible subjects
▪ In accordance with the latest approved protocol

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IP Accountability

Maintaining records of:

▪ Product delivery
How ▪ Inventory at site
▪ Use by each subject
▪ Return to sponsor/ disposition of unused product
(GCP 4.6.3)

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IP Accountability

The records should include

▪ Dates
▪ Quantities
▪ Batch/ serial numbers
How
▪ Expiration date (if applicable)
▪ Unique code numbers assigned to the IP
▪ Subject was provided with specified dose
▪ Reconciliation of IP received from IP

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IP Accountability

The records should include

▪ Dates
▪ Quantities
▪ Batch/ serial numbers
▪ Expiration date (if applicable)
How ▪ Unique code numbers assigned to the IP
▪ Subject the IP was dispensed to
▪ Etc

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IP Accountability

Investigator/Institution- Responsible for drug accountability

at site (4.6.1)
Who?
Can delegate responsibilities to pharmacist or other
appropriate personnel under supervision of PI (4.6.2)

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IP Management at site

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 Typical study flow..

Site Study Start- Site Study Study Close

Feasibitliy
Confirmation Up Activation Conduct Out

When does IP management starts @ site?

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 Process.. When does it starts?

Site Study Start- Site Study Study Close

Feasibitliy
Confirmation Up Activation Conduct Out

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 IP
preparation?
Cost to include
in budget? Safety
precaution?

Feasible?
 Site Study Start- Site Study Study Close
Feasibitliy
Confirmation Up Activation Conduct Out

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Start-up: First IP Shipment
Dr Ming is the Principal Investigator (PI) of study ABC. He plans to have his
study coordinator, Amin, to be in charged of IP management.
On 27 Jan 2020, the study monitor contacted Dr Ming to arrange for the
first IP shipment to site. The IP is expected to arrive on the next day.
The study Site Initiation Visit (SIV) date is planned on 01 Feb 2020, and the
site is expected to screen the first subject the very next day.

What does Dr Ming need to make sure are in place before receiving the
first IP?

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Start-up: First IP Shipment

Trained &
NPRA Approval
CTA signed EC Approval Delegated
(CTIL/ CTX)
Personnel

Availability of
IP Quantity- Storage
delegated Access to IWRS
Storage Space temperature stable
personnel

Calibration of Investigator’s
Accountability Log
thermometer Brochure

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Start-up: First IP Shipment
• The investigator should ensure that all persons assisting with the trial are
adequately informed about the protocol, the investigational
product(s), and their trial related duties and functions.
Malaysia GCP Edition 4, 2018,4.2.4

!! Training & Delegation Log for pharmacist prior to first IP shipment

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 Site Study Start- Site Study Study Close
Feasibitliy
Confirmation Up Activation Conduct Out

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 Study Conduct

Management of
Storing and
Ordering IP Receiving IP Temperature
Securing of IP
Excursion

IP Dispensing and Dose

Transferring of IP IP Recall
Administration Modification

Management of
Unused IP IP Destruction
 Study Conduct

Management of
Storing and
Ordering IP Receiving IP Temperature
Securing of IP
Excursion

IP Dispensing and Dose

Transferring of IP IP Recall
Administration Modification

Management of
Unused IP IP Destruction
 IP Supply Process
▪ Is supply auto-triggered?
▪ Expiry Alert?
▪ How to Order?
▪ Turn Over time?
Ordering IP

Ordering Process

▪ Consignee’s availability
▪ Approval timeframe
▪ NPRA Approved amount
 Management of
Storing and
Temperature
Securing of IP
Excursion

Activity
 7 Rights
▪ Right Subjects
IP Dispensing ▪ Right Drug
and ▪ Right Time
Administration ▪ Right Dose
▪ Right Route
▪ Right Form
▪ Right Dispenser
 Subject Training
▪ Compliance
▪ Usage
IP Dispensing and ▪ Dosing
Administration ▪ Storage
▪ Accountability
▪ Supporting materials
(diary, ice bags, syringes
etc)

DOCUMENTATION!
Corrective & Preventive Action?

1. Subject throw away the empty bottle

2. Subject overdose

3. Subject shared the IP with others

Compliance

What was taken

X 100% = % Compliance
What should’ve been
taken
Compliance

Your study requires subject to take 1 IP tablet twice per day- One in the
morning, and one at night. Subject 001 comes in for study visit on 1st May
2021. After checking that he is eligible to take the IP, you dispensed 100
IP tablets to him. Subject took his 1st PM dose in the clinic as per protocol
instruction before returning home with the remaining tablets.

When Subject 001 return for the next visit on 31st May 2021, his IP bottle
has 10 tablets remaining. His last dose was on 30th May 2021 PM.

What is the subject’s compliance rate during this period?

What was taken / What
Taken= 100-10 = 90 tabs should’ve been taken X
Ideal dose 100%
Full dose (2 tabs): 2nd May – 30 May = 30-2+1= 29 days = 29*2= 58 tabs = % Compliance
Half dose (1 tab): 1 May = 1 day = 1 tab
st

Ideal dose = 59 tabs

Compliance = 90/59 X100= 152%
 Site Study Start- Site Study Study Close
Feasibitliy
Confirmation Up Activation Conduct Out

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Final Reconciliation

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Final Reconciliation

How many used + unused +

How many shipped to site
returned + expired

Good proactice to do reconciliation at regularly schedule intervals!

For each procedure, identify what could go wrong

E.g.:

▪ Long visit intervals: subjects missing doses or misplacing medication

▪ Incomplete logs lead to unaccounted medication

▪ Missing information on logs can lead to impossible reconciliations

▪ Omission of transfer documentation (e.g., shipping receipts) can lead

to unaccounted medication

▪ IP is self-administered by subject at home: subject administered

wrongly

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Case Study #1

Protocol ABC requires subject to take one tablet of the study drug every day.
The IP is dispensed weekly with 14 tablets per bottle. In addition, subject diary
was provided to subjects for them to record their daily IP intake.
Akmin was recently enrolled to this study and was dispensed his first batch of
IP. He was trained on the dosing instruction and how to complete the diary by
SC, Lily.
1 week later, Akmin returned with an empty bottle of IP (there should be 7
tablets remaining). According to the diary, Akmin didn’t missed a dose for
the past 1 week.

What are the possible explanation for the discrepancy?

What should the investigator do next?

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Case Study #2

Study ABC requires subject to come to site every 3 months for follow up and
to receive 3-months supply of IP. Due to immobility, subject is not able to visit
site to receive his 3-months supply of IP. As a result, his IP supply is running low.

CRA, Ah Meng, offered a solution: site to provide subject’s address so that

Sponsor can ship the IP directly from the IP storage facility to subject’s house.

What should the investigator in this scenario do next?

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Case Study #3

At site A, IP room temperature is monitored manually every morning around

8:30am by Ashin, a delegated personnel. Study ABC’s IPs are stored at room
temperature. He will record the temperature into a temperature log.
One day, Ashin was on emergency leave in the morning and is only back
after lunch. On that same morning, SC Ming dispensed IP to Study ABC
subjects.
After reporting to office, Ashin noted that there is temperature excursion at
the IP room. The start time of the excursion is unknown as the latest recorded
data is on the day before. It was assumed that the temperature excursion
happened since morning.

What is the protocol deviation here?

What should the investigator do next?

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Case Study #4

Study ABC is a diabetic study, and the IP was pre-filled insulin pens that must
be stored in fridge.
On 1st Mar 2021, without any prior notice, the study SC received1000 pre-filled
insulin pens IP. The designated storage fridge couldn’t accommodate all
pens. As a result, about half the IPs were stored at other clinic’s fridge. All IPs
were then subsequently dispensed to subjects.
After a year, during MREC audit, the auditors found that the other clinic’s
fridge calibration certificate has expired during the time the IPs were stored
there.

What are the concerns here?

What could have been done to avoid this situation?

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Case Study #5

Akmin, the designated pharmacist, for study protocol DEF, received the first
drug shipment on 01Feb2019. The first subject is scheduled for randomization
visit the second day.

He ensured that the drug’s condition are good, store the drug according to
the pharmacy manual, and update site accountability log.

However, he didn’t register the drug arrival on IWRS because Sponsor has not
provided user access to him.

What are the consequences of not updating the IWRS on a timely manner?

What should Akmin do next?

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Case Study #6

Study protocol ABC is a single blind study where the study team is split into
blinded and unblinded team.

During study feasibility, while reviewing the IP storage space, you realized that
both blinded and unblinded SCs will have access to the same fridge where
the IP is stored.

Your unblinded SCs assure you that they will cover the IPs with an opaque
sheet of paper so the IPs will not be visible to the blinded SCs. Furthermore,
the blinded SCs also assure you that they won’t look at the IPs while using the
fridge.

What other possible solutions are there to ensure there’s no accidental

unblinding?

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Case Study #7

Study protocol requires subject to take one tablet of IP daily.

On 1st May 2022, Subject 001 was dispensed a bottle of IP (kit number: 123,
expiry 31st May 2022). Her next visit is scheduled on 2nd Jun

What potential issues do you foresee?

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Case Study #8

Used bottles of IP was discarded by cleaners when the study coordinator

placed them on the floor to clear storage space. These bottles has not be
reconsolidate by the study monitor.

What will you do next?

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https://www.surveymonkey.com/r/GCPR2_EF_2022