All protocol deviations/violations should be notified to EC

A study has begun and subjects are enrolled in the study at a few sites.  When few more sites are added later, one of the ECs finds a fault/finding in ICF and asks to implement the change. Can we continue enrolling patients with the old ICF, where the study is ongoing and take re-consent after the new version is approved or do we have to stop screening at these sites?

It depends on what error the EC found and what is the change recommended.
If the change affects/impacts, patient's rights, safety and well-being, then screening/recruitment should be suspended till the amended ICF is approved.

During the trial, if site do not obtain consent to the amended ICF, will it be considered as a protocol deviation? After it was realized, subject was called over telephone and informed about the changes in the ICF and the same was documented in the source with reasons to why it was not obtained during the patient visit.

Failure to obtain consent on amended ICF is a critical and serious protocol violation. It is not enough to call the subject on telephone and document in source. The site has to request the subject to visit the site to complete the consent process for the amended ICF.

Please see an excerpt from FDA warning letter. As per the letter dated July 14, 2004, sent by your site to the IRB, you provided information that the use of was associated with the risk of “serious confusion” that had been identified in 23 other individuals, and that based on this possible serious adverse event, the informed consent document was being revised. We note that following notification of the IRB’s approval of this revised consent form in a July 27, 2004 letter, your site failed to re-consent the 6 subjects, who were enrolled prior to the date of the approval of the revised informed consent document and who were still participating in the study. As a result of this failure, those subjects were not provided with an adequate description of the reasonably foreseeable risks of participating in the study.

If the causality of an AE, that occurs during a BE study, (which is not listed under side effects in the reference drug label) is judged as related to the drug by the investigator of the BE study, does the generic drug label get updated with this new AE or it just has to match the reference drug label?  Is it true that the generic drug label should match the reference label in all respects?

The side effects described in the reference package insert are side effects for which a causal relationship exists between the drug and the side effect.  These are Adverse Drug Reactions (ADRs) i.e. adverse events for which causality is established. These depend on the chemical nature/structure of the reference drug. As generic and reference drug are both identical chemically/structurally, the side effect profile of generic should match the side effect profile of reference drug.

The drug label side effect section is derived from clinical trials. As BE studies are usually single dose in healthy volunteers, it is difficult to be sure about the causality of AE. However, if the generic drug is studied a large trial of 500-1000 patients and if new ADRs are reported (ADRs not reported with reference drug label), then regulatory authorities will ask the new side effects to be added to all labels - generic as well as reference. Hence, generic drug labels usually follow the reference drug labels.

Is there any guideline in India on protocol violations? How are these classified? Is the protocol violation notified by sponsor?
There is no guideline in India on protocol deviation/violation.

US FDA has given following definition:
Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical well-being of the subject (21 CFR 812.35(a) (2)), and generally communicated to FDA. “Protocol deviation” is also used to refer to any other, unplanned, instance(s) of protocol noncompliance.

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