Participants’ written informed consent in low-risk pragmatic clinical trials with medicines

ABSTRACT

Introduction: An important gap within modern medicine is the lack of enough comparative effectiveness research of marketed medicines. Low-risk pragmatic randomized controlled trials (pRCTs) are those conducted resembling usual clinical practice that poses no or minimal incremental risk compared with normal clinical practice.

Areas covered: This review addresses one important hurdle in the conduct of low-risk pRCTs: the need to seek participants’ written informed consent.

Expert opinion: The CIOMS ethical guidelines consider that any research that (a) would not be feasible or practicable to carry out without the waiver or modification, (b) has important social value, and (c) poses no more than minimal risks to participants, and that is approved by the relevant research ethics committee, could be conducted without participants’ consent. It is clear that these provisions are applicable to some low-risk RCTs. Recently a research on the EU-CTR registry showed that only 2% of all ongoing phase 4 RCTs could have fulfilled the CIOMS provisions following the investigators’ assessment. The EU clinical trial regulation – and that of other jurisdictions – should be debated on the suitableness of the conduct with an alteration or waiver of participants’ consent of those low-risk pRCTs that fulfill the three CIOMS provisions.

KEYWORDS:

• CIOMS guidelines
• clinical trials regulation
• informed consent
• low-risk pragmatic trials
• medicines
• waiver of informed consent

Article highlights

• Almost all randomized controlled trials (RCTs) assessing medicines have explanatory and pragmatic features. Pre-licensing (phases 1–3) trials are definitely more explanatory (conducted in ideal controlled conditions), whereas some post-licensing (phase 4) trials are more pragmatic (conducted mimicking real-world conditions).

• Very few pragmatic RCTs with medicines are currently conducted. Seeking participants’ written informed consent is a hurdle for the conduct of pragmatic RCTs.

• Low-risk pragmatic RCTs pose no or minimal incremental risk compared with usual clinical practice.

• The CIOMS ethical guidelines and both the USA and Canadian regulations allow the conduct of any research in humans with a modification or waiver of participants’ consent if certain requirements are met.

• The CIOMS ethical guidelines provisions to be fulfilled are (a) the research would not be feasible or practicable to carry out without the waiver or modification; (b) the research has important social value, and (c) the research poses no more than minimal risks to participants. The research must be approved by the relevant research ethics committee.

• An open debate is needed on whether it would be appropriate to amend the EU clinical trials regulation – and that of other jurisdictions – to allow the conduct of low-risk participant-level pragmatic RCTs with a modification or waiver of participants’ written informed consent.

Declaration of Interest

R. Dal-Ré has received speaker fees from Palex Medical. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from the one disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that he/she was the Chair of the revision committee for the CIOMS guidelines. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.