Example

 

“Guidelines for Delay, Reduction and/or Discontinuation of Study Medications

 

Dose modification for an individual subject is not permitted unless the following ensues. Modification of study medication is allowed in Arm 0 (treatment arm with enoxaparin) if the [creatinine clearance] (CrCl) falls < 15ml/min. In that instance conversion to dose adjusted IV UFH [unfractionated heparin] is acceptable during the time that the CrCl remains < 15ml/min. If the patient cannot be placed on UFH IV (difficult to obtain frequent aPTT [activated partial thromboplastin time] draws, etc), an acceptable alternative is the use of UFH SQ using the fixed-dose weight-adjusted FIDO regimen, 333U/kg SQ, followed by 250U/kg Q12 hours, without the need to obtain [activated partial thromboplastin time] aPTT monitoring. The investigator is then encouraged to convert back to treatment dose enoxaparin as per protocol once the CrCl ≥ 15ml/min. Modification is allowed in Arm 1 (prophylactic group) if the CrCl falls < 15ml/min to use [unfractionated heparin] UFH up to 22,500 U daily (i.e. UFH 5000u SQ BID or TID or 7500IU SQ BID or TID). The investigator is then encouraged to convert back to prophylactic/intermediate dose enoxaparin as per protocol once the CrCl ≥ 15ml/min..."[232]. 

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“5.4.1 Discontinuation of the product under investigation

 

During the research treatment phase, the participant may suspend the product under investigation at any time. Likewise, the investigator may interrupt the product under investigation whenever necessary, either due to an adverse event or to preserve the participant's safety.

 

Participants who discontinue treatment under investigation without an apparent reason after randomization and prior to the completion of the study will be encouraged to return with the medication and continue the study as normal. If the treatment is discontinued, the patient will continue in the research for the collection of information regarding events of the composite outcome. These participants will be treated according to the standard of care.

…

6.6 Modification of drug dose

6.6.1 Adverse reactions when using medications

…

The decision to temporarily suspend medication can be taken at any time by either the participant or the investigator. Whenever possible, the patient should return to use the products under investigation" [233]. 

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Explanation

 

During a clinical trial, situations may emerge that necessitate changes in, or the discontinuation of, the allocated intervention/comparator for a participant. These events can be caused by a variety of factors including harms, improved health status, lack of efficacy, and withdrawal of participant consent [234]. The protocol should predefine standardised criteria for guiding intervention modifications and discontinuations. This information could be particularly important to evaluate the risk of bias due to deviations from the intended intervention/comparator, [235] an important domain of the risk of bias tool developed by the Cochrane Collaboration. Assessing this domain requires a clear understanding of deviations that occur as planned in the protocol and deviations that arise due to the experimental context.

 

Reviews of two samples of 108 and 292 trial protocols from 2016 found that 76% and 82% respectively reported criteria for modification of interventions [9, 10] Regardless of any decision to modify or discontinue their assigned intervention/comparator, study participants should be retained in the trial whenever possible to enable follow-up data collection and prevent missing data (Item 25b) [236].

 

Summary of key elements to address

• Criteria to guide modifications to trial intervention/comparator (e.g., drug dose change in response to harms, participant request, or improving/worsening disease) 

• Criteria to guide discontinuation of trial intervention/comparator