20th July 2018

Section 5.2.2 in ICH E6 (R2) says: the sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial related duties and functions that are sub-contracted to another party by the sponsors contracted CRO(s).

This is a is wonderful opportunity for Sponsors, especially those with limited resources, to regain some of the control they have lost in the shift to outsourcing of clinical trial operations. How, as a Sponsor, might you plan for this oversight?


1.       Create a Quality Management plan before the study starts, review it periodically and update it when/if an unforeseen quality issue is identified. It should include key risk indicators, the rationale for your strategy, the threshold for action and steps that will be taken to mitigate risks to quality. You can minimize risk by planning.


2.      Make a seasoned CRA part of your oversight team. Ideally, they will have a broad clinical background, be a certified research professional, and have experience making sure sites are inspection ready. They should be diplomatic but unafraid to push back on either the CRO team or site personnel if they see any quality issues. They need to know the protocol and be able to reach the in- house study team when/if a Principal Investigator has a question that the CRO team cannot answer.  Depending on the size of the trial, you may need a dedicated team of CRAs fulfilling this role.


3.      Meet all the stakeholders in person when you can.

a.      This includes the CRO CRAs who will be representing your trial at the site. Your representative should get to know these CRAs and advise them that they will be accompanying them for a co-monitoring visit at their sites at some point during the trial.

b.      This also includes the Principal Investigators (PI) and their research coordinators (RCs). Set expectations at the site selection visit and Investigator meeting that data entry is expected to be real- time and that sites must always be inspection ready. Reinforce this message each time your representative makes a visit to the site. The added value of this kind of visit to the site, whether it is a co-monitoring visit or simply because a PI has reached out, is that relationships are strengthened. A PI who feels his comments about the challenges inherent in the protocol, are being taken seriously will vest time in that study. Getting feedback from a PI or two prior to finalizing the protocol is optimal. But if you failed to do that, don’t let months pass before you decide to do an amendment. Engage the PIs and RCs from the start. Protocols are increasingly complex. Phone calls that are not returned promptly result in missed opportunities.


4.      Make use of available technology and other resources. In this era of risk- based monitoring, the Sponsor CRA should have access to the study dashboard and be able to see in real time where there might be issues. It could be a high screen failure rate at sites, withdrawals, or many protocol deviations. Protocols have become much more complex. If something can go wrong, it will.  Consider joining organizations like the Avoca Quality Consortium. They have quality oversight guidelines and tools for qualifying technical services providers and preparing sites for inspection. TransCelerate has developed an RBM tool and a common protocol template. There is no need to re-invent the wheel when there are resources available. (I am not affiliated with either).


5.      Communicate, communicate, communicate! Build trust. It is a two- way street. Don’t always rely on e-mail. People read tone where none may be intended. If you see a trend, pick up the phone and talk to people on the ground. Host a teleconference and invite PIs and RCs to dial in. Ask for their opinion on why enrolment is a challenge. Has CMS (Centres for Medicare and Medicaid Services) guidance on reimbursement changed thus changing local practice? Is there a competing protocol? Do patients need transportation? Should home visits be considered? Schedule face to face meetings with the various vendors. Actively listen to what people say. Observe their body language, listen for feelings, ask for clarification. Put your mobile away! It should go without saying that you document these interactions. If it wasn’t documented, it wasn’t done.


Often in the rush to get first patient enrolled, plans addressing quality, risk, communication and even monitoring have not yet been finalized. You don’t yet have access to the promised dashboard. The focus is on getting sites activated and meeting timelines like first patient screened, first patient randomized. Nobody is looking at the big picture yet. But with multiple inclusion/exclusion criteria, wash out periods, and sick patient populations with multiple co-morbidities, the chances of inappropriate study subjects being enrolled is very high. That will be costly in the long run.

‘The fastest way to go slow is poor quality’ (not sure who to attribute this quote to but you get the picture).  In the event of an inspection you want to be able to demonstrate that your approach to quality has been thoughtfully considered and implemented.

You can have the best tools and processes in place but ultimately it comes down to the people who are using those tools and processes. At G&L we pride ourselves on our great people. We are happy to support your commitment to quality and the successful conduct of your trials.


This article was written by Brigid Flanagan, Vice President, Clinical Operations, G&L Scientific.


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