WHO Expert Committee (Fiftieth report): Clinical recommendations for the organizations performing in vivo BE studies
08 Jul 2019
WHO has recently released a guideline for performing in vivo bioequivalence studies (WHO Technical Report Series 996, 2016). The guideline mainly emphasizes on the subject safety, including data integrity. The objective is to provide guidance to the CROs that are involved in conduction and analysis of BE studies.
This guideline supersedes the version of WHO technical report series, no.937, 2006 (4).
The guidelines provide recommendations on the organization, study protocol, clinical phase, bio-analytical phase, pharmacokinetic/statistical analysis, study report and QA system.
The recommendations on the clinical section are as follows:
- A CRO should have adequate premises with sufficient space/bed to accommodate the study subjects, and to perform other activities by study personnel. There should be a system so that the subject can alert the study personnel in case of need/emergency. The toilets for the subjects should be designed in such a way that they can be opened even from outside in case of medical emergency. Appropriate vehicle/ambulance should be ready in advance for the urgent transportation.
- Restriction: Access to the key documents (like randomization list), pharmacy should be restricted to concerned authorized person/personnel only.
- The equipments/emergency use equipment that are used in the study should be appropriately calibrated at predefined intervals.
- The laboratory for analysis of the samples should be an accredited laboratory and the safety laboratory test should be performed as specified in the protocol. The Lab report should be individual for each subject. The source data should be adequately protected from modifications or deletions.
- The trial must be approved by the IEC and legislation in force. The IEC should be given sufficient time to review the protocol, ICF and related documents.
- The clinical study monitoring is an essential part to ensure the quality of the trial. The monitor should be adequately qualified, and the monitor should ensure that the study is conducted in compliance with the protocol, GCP and applicable regulatory guidelines. The monitoring can be delegated to a CRO also; in such case a monitor should be independent from the personnel performing the study. There should be SOPs which describe the designation of the monitor, procedure of monitoring visit, initiation visit, and study close-out visit. A monitoring report should be provided to the sponsor.
- The principal investigator is overall responsible for the clinical study including the design, conduction, report, safety, and communication with the IEC and local authorities. The investigator should be appropriately qualified, experienced with clinical studies, and at least one investigator should be a medical practitioner.
- The information regarding the receipt, storage, handing and accountability of the IMP should be appropriately documented. The information of shipment, delivery, receipt, description, storage including each movement of the study drug should be documented and in knowledge of the CRO. The study drug should be stored under appropriate condition and labeled with the necessary details. The label should be pasted on the container, not on the lid. This is to ensure the information will not be lost even if the lid of the container is opened. During dispensing of the study drugs, it should be ensured that the surface area is properly cleaned, and if there are two investigational products (like test product and reference product), they should never be dispensed at the same time. A second person should verify the process. Sample of the study drug should be retained in the original drug container for at least one year of the expiry date of the newest product, or as per applicable regulatory authority requirement.
- Dosing should be done in accordance with the SOP and protocol requirement under supervision of the trained study personnel followed by performing dosing compliance. The exact time of dosing should be documented.
- To record the data of each subject, CRF should be used. The CRF should be prepared as per the protocol requirement and pertaining SOP requirement. The data to be captured in the CRF should be specified in the protocol. A CRF should reflect the actual result obtained during the clinical study.
- The selection of the subjects should be done in advance as last minute recruitment of a subject may lead to non compliance with the inclusion/exclusion requirement. The data base of each subject should be monitored by the CRO. Medical screening record should also be monitored for each subject to avoid cross participation of the subjects in the clinical studies.
- The meal provided to the subjects during the study, should be standardized (by dietician), adequately controlled and scheduled in the study. Record of meal consumption (including timing, duration, amount of food and fluid consumed) should be documented.
- The clinical study should be planned, organized and performed in a way that the adopted safety profile is acceptable to all stakeholders. The CRO should have all the relevant formed like adverse event form and reporting form etc.