EC chairperson can serve as legal expert during the meeting

Please clarify re: patient reported outcome (PRO) instruments:
1) Post translations whose responsibility is it to validate the translated version of the questionnaire?
2) Could the translated version be submitted to the regulatory authority without validation?
3) Whose responsibility is it to submit the translated questionnaire post validation?
4) If any modification is done in the validated translated version then is there a requirement to validate the modified version and then submit the same to the regulatory authority?
5) What if a translated questionnaire is used without validation considering a situation where only English document has been submitted to the regulatory authorities and the translated version have only been submitted to the respective Ethics Committees?

Garima Singh

For 1) & 3) - FDA has released a guidance on PRO in Dec 2009. It is addressed to sponsors. Hence, they are responsible for validation of the PRO instrument - both English as well as translations.
For 2) - The FDA expects the sponsor to submit validated translations (see below appendix to the FDA guidance).
VIII. Language Translation and Cultural Adaptation

• Process used to translate and culturally adapt the instrument for populations that will use them in the trial
• Description of patient testing, language- or culture-specific concerns, and rationale for decisions made to create new versions.
• Copies of translated or adapted versions
• Evidence that content validity and other measurement properties are comparable between the original and new instruments

For 4) - If there is a modification, following documents are required.

• Any change in the original instrument (e.g., wording of items, response options, recall period, use in a new population or indication)
• Rationale for and process used to modify the instrument
• Copy of original and new instruments
• Evidence that content validity and other measurement properties are comparable between the original and modified instruments (including use in a new indication or population).

For 5) - It would be necessary to validate the translated instrument before using it in the patients. So even if it submitted/approved by EC, the validation is a must. Also, as per FDA guidance, the validated translation must be submitted to FDA.

Can EC chairperson act as legal expert during the meeting (dual role)? Please let me know if in this case, EC quorum met as per Schedule Y?

A. Mohammed Asif

The chairperson can serve as a legal expert. However, the person should be officially designated in the EC SOPs as legal expert for all meetings/quorum. The quorum requires the following EC members representing different roles
For review of each protocol the quorum of Ethics Committee should be at least 5 members with the following representations:

• basic medical scientists (preferably one pharmacologist).
• clinicians
• legal expert
• social scientist / representative of non-governmental voluntary agency / philosopher /  ethicist /  theologian or a similar person
• lay person from the community.

 It does not give EC titles e.g. chairperson. Hence, a chairperson serving as a lawyer can fulfill the requirements of quorum.

Protocol requires that when study drug X+Y is to be administered, drug Y is supposed to be administered first, followed by a normal saline flush, then drug X to be administered. In one patient, drug X was administered first then Y. Is it a protocol deviation or violation?

Praveen

There is no official definition of protocol violation / deviation. However, some guidance is given below:

EFGCP Audit Working
Party 2001
Protocol Violation: Serious non-compliance - may lead to exclusion of patients from eligibility analysis and/or their discontinuation from the study
Protocol Deviation: Less serious non-compliance - may not render a patient ineligible
Norman M. Goldfarb J of Clinical Research Best Practices Nov 2005

• Protocol Deviation. A protocol deviation occurs when, without significant consequences, the activities on a study diverge from the IRB-approved protocol, e.g., missing a visit window because the subject is travelling. Not as serious as a protocol violation.
• Protocol Violation. A divergence from the protocol that materially (a) reduces the quality or completeness of the data, (b) makes the ICF inaccurate, or (c) impacts a subject’s safety, rights or welfare. Examples of protocol violations may include:

• Inadequate or delinquent informed consent
• Inclusion/exclusion criteria not met
• Unreported SAEs
• Improper breaking of the blind
• Use of prohibited medication
• Incorrect or missing tests
• Mishandled samples
• Multiple visits missed or outside permissible windows
• Materially inadequate record-keeping
• Intentional deviation from protocol, GCP or regulations by study personnel
• Subject repeated non-compliance with study requirements

Please find out why the protocol requires IP administration in a specific way. Is there any impact on efficacy / safety if the order of administration is reversed? Is there a pharmaceutical / pharmacological / pk interaction between 2 drugs? If so, it will be a protocol violation.  


Source: Pharmabiz