Conducting ePRO being used. · Investigational product:

Conducting large, multi-centre, multi-country
clinical trials involve intense cost and labour resources. Also associated, is a
variable degree of risk; not only in terms of achieving the desired outcomes
but, more importantly, in terms of ensuring the safety of study subjects. The
ability to adequately balance cost, benefit and risks when facing unexpected
issues during the study conduct is a key element for ensuring compliance with
applicable regulations and ethical standards and protecting subjects’ safety and data integrity.


This essay aims to outline an action plan
indicating the steps that could be taken on an on-going study, following the
decision to withdraw a marketed product of the same class as the study drug
from the market.

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The action plan has been split into short,
medium and long term actions, which are based on assumptions highlighted


General assumptions:

population: potentially mature, due to indication of osteoarthritis (increased
cardiac/liver function risk).

Maximum time
difference between participating countries = 12 hours (consider forms of instant

eCRF and ePRO
being used.

product: subcutaneous injection – administered at site every 4 weeks.

Data Safety
Monitoring Board (DSMB)/Trial Steering Committee (TSC) implemented from the
start of the study. Last meeting / review was held after the first 2000
subjects completed the study. No concerns were raised.

The study
protocol included full blood biochemistry/ECG at the end of study visit.

Assumption “A”: Following
the decision to withdraw the marketed product, an investigation starts involving
global cross functional sponsor representatives aiming to confirm / discuss the
root cause for the safety concerns and impact on the study drug. The full outcome
of the investigation will be available within 30 days.






Short term


Within 24

communication to whole study team to ensure the message regarding the
withdrawal of the marketed product is received and notify them to expect
further information, in the event they were unable to attend the initial

Initiate urgent
ad-hoc meeting with Chief investigator (CI) and DSMB/TSC. Decision: continue the study based on positive outcome from the
previous DSMB meeting/review.

Initiate a
blinded review of all study safety information gathered to date as a matter of
urgency to identify trends in
the study population.


Within 5

Convey a new
meeting with CI and DSMB/TSC to review output of preliminary safety analysis of
completed and ongoing subjects. Decision:
potential concerns within a small subset of AEs/SAEs identified but do not
grant study halt at this stage. Study can continue until full analysis complete
(Day 31).

CI to send
communication (as agreed with Sponsor) to inform all Investigators about the
potential concerns, requesting them to:

Arrange an
unscheduled visit for all ongoing subjects immediately, to include additional
safety assessments.

Inform EC/CA
as applicable for each country (as the action above would classify as urgent
safety measure).

Expect more
detailed Sponsor’s communication.

Action the ePRO
vendor to send a message to all subjects via the ePRO application to:

Make them
aware of potential symptoms relevant to the safety issues seen on the marketed
drug (as part of the urgent safety measure process).

Notify them
to contact their Investigator/site staff upon experiencing any

Expect to be
contacted by the Investigator/site staff to arrange an unscheduled visit.

o   Prepare overview of trial status –
number of subjects screened, randomised, progress by visit, completed,
withdrawn, to understand and quantify risk.


Medium term actions (Day 6 to Day 30)


Following the immediate actions taken, preparation
activities for 2 possible scenarios are proposed to take place in parallel, to
ensure efficient implementation of actions once the outcome of the
investigation is announced on Day 31.


Scenario 1
Investigation shows that safety
concerns directly apply to
the study drug.

Scenario 2
Investigation shows that safety
concerns do not pose unacceptable
risk to the safety of study subjects, however extra safety assessment
is required to be implemented.

termination letters to Investigators, Ethics Committee / Competent Authority
(EC/CA), vendors.
meeting with global cross functional representatives to plan arrangements
related to subject’s care following study termination as per exit strategy.

documents (statements, cover letters) related to notification of substantial
amendment to EC/CA.
Assess subject’s
progress on study to evaluate impact of the temporary halt on protocol
population for the efficacy analysis, recruitment and IMP supply.



Long term actions (Day 31 to Day 90)


Assumption “B”: on Day 31,
the DSMB/TSC holds a meeting with the study lead and other sponsor
representatives to share the outcome of the full investigation and safety data
review to date; the study can continue, providing increased safety monitoring
aspects are incorporated. Therefore, only Scenario
2 is further developed and the other scenario is disregarded. In
continuation to Scenario 2 activities described above, the following activities
are initiated:


protocol amendment containing additional safety checks (laboratory/ECG) and procedures
deemed necessary by the DSMB/TSC and updated drug safety related information.

Engage with
ECG/Laboratory to align on new study safety requirements.

DSMB/TSC oversight and assign medical monitor.

Informed consent form to reflect changes made to the protocol.

Update Investigator’s
Brochure as applicable.

Submit amendment
package to EC/CA as per countries requirements.

Upon EC/CA
approval on each country, CRAs/country leads to train Investigators/site staff
on changes to the protocol and updated safety information.

Sites will
be instructed to use the new version of the ICF for re-consenting ongoing and for
any new subjects.

Update budget
and timeline projections.

with the safety review meetings on increased frequency.


The above action
plan has been developed with subjects’ safety as the primary area of concern. Key assumptions have been
outlined to support determination of what is deemed the most appropriate and
well informed course of actions. This case also illustrates the strength of
digital solutions in managing such issues.