Dose Escalation - is it GCP compliant?

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

A new post, "Dose Escalation - is it GCP compliant?" has just been published on the MHRA Inspectorate blog emphasizing that according to Good Clinical Practice (GCP) dose escalation (DE) practices, especially between first in human (FIH) healthy volunteer trials and those in patients (FIP) should be the same. Good quality data and sound procedures are vital to ensure the safety of all trial subjects.

According to the MHRA, there should be a DE process where the PI(s) and the sponsor review all the data and make a documented decision. This meeting, together with the data used (including evidence of QC) and the decision, should be clearly documented and the decision circulated to all relevant parties (such as clinical and pharmacy teams) in advance of the next dosing occasion. For DE to be GCP-compliant, there should be a formalized procedure detailing how the dose escalation process will be undertaken (in the form of SOPs and transparency in the protocol).

In summary the blog states:

• The MHRA Clinical Trials Unit (CTU) approving the trial protocol will assume a GCP-compliant DE plan. This means that all subjects in the cohort and all their data at all the timepoints will be reviewed in the DE decision meeting unless the protocol states otherwise.
• The MHRA GCP inspectors inspect against the legislation and the relevant early phase guidance. They expect to see a formalized procedure for DE and for a specific clinical trial to be able to reconstruct the dose escalation as described in the formalized procedure together with the approved protocol. This will verify that the trial was conducted in a GCP-compliant manner.
• In addition, the MHRA will expect to see:
  • evidence that the relevant data has been collated, verified for accuracy and provided to the DE committee,
  • the DE meeting minutes,
  • the DE decision agreed by the DE committee (including the PIs),
  • circulation of the DE decision to all relevant team members.
• In view of today’s complex trial design and expansion to the patient first in human trials, it should be considered whether current procedures are in line with new technology for collecting and using accurate and reliable data for safety decisions.
• Quality by design (QbD) should be built into the protocol, the trial design should be risk assessed and it should be ensured that decisions are transparent to the regulators and ethics committees reviewing the protocol.
• The trial master file (TMF) should enable to reconstruct the dose escalation process easily.

For more information please also read the MHRA Inspectorate blog "Dose Escalation - is it GCP compliant?".