Updated Standards for Bioequivalence Studies: WHO publishes Revised Guidance for CROs

A generic drug has to meet the same requirements for quality, efficacy and safety as the originator. One of the possibilities to demonstrate its equivalence without using data from a complete clinical trial is to perform a pharmacokinetic study with a small number of volunteers. Such a study provides the indirect evidence that a generic drug is efficient and safe. Typically, "clinical research organisations" and "contract research organisations" respectively (CROs) are entrusted with the performance of such studies. As this is often the only way to demonstrate bioequivalence between generic drug and comparator, the quality standards according to which the CRO is working are particularly important.

10 years ago already, the WHO published a document entitled "Additional guidance for organizations performing in vivo bioequivalence studies" (Annex 9, WHO Technical Report Series, No. 937, 2006) setting the quality standards for clinical research organisations. Given the current developments - especially in the management of electronic data - it had become necessary to revise those guidelines. Last year, the WHO first published a draft document for comment. The revised and finalised guideline entitled "Guidance for organizations performing in vivo bioequivalence studies" (Annex 9, WHO Technical Report Series, No. 996, 2016) has been recently released.

All the chapters have been concretised in the revised Guidance and updated. The most extensive changes can be found in the following two chapters:

4. Computer systems

The chapter starts referring to the currently applicable guidelines and official documents from organisations and authorities (PIC/S, FDA, EU etc.). The qualification of networks, data storage systems and interfaces is required. The subsection "Software" is considerably more extensive than in the Guidance from 2006 and contains key requirements from GAMP 5 and other currently applicable guidelines. The following has to be ensured:

• Passwords have to be unique and individual-specific.
• The software programme in place must be validated for its intended use. The CRO's quality unit also has to validate software developed for special purposes and must ensure that the software was developed in a controlled environment in accordance with the QA system.
• The decision about which software components have to be validated should be based on quality risk management and take into consideration the whole lifecycle. For example, if a software programme for HPLC or HPLC MS/MS analysis was decommissioned, the data must remain fully readable at a later time. For this, the software can be installed on a workstation and where it remains available for verification purposes e.g. in case of an inspection.
• Before implementing regular updates, a risk assessment should clarify the potential impact on current data and the validated status i.e. on the programme components.
• The backups data have to be archived regularly before rewriting is done.

5. Quality Management

This section (in the previous version "Quality Assurance") has also been extended in accordance with the current standards. The following points have been concretised with regard to the responsibilities of the quality unit:

• The protocol and SOPs should be accessible to the study personnel. It should be checked whether the requirements laid down in the SOPs are being followed.
• At regular and defined intervals according to an SOP, internal audits should determine if all studies (including those for subcontractors) are performed in accordance with GCP and GLP. CAPAs have to be followed.
• Root cause analyses, tracking for trends, a CAPA system and the monitoring of data integrity have to be an integral part of the QA system.

The updated Guidance contains an appendix also listing 75 SOPs about the procedures with regard to a pharmacokinetic study which should be followed by each CRO. Regarding the content, this SOP list corresponds to that of the previous document from 2006; only a few SOP titles have been reformulated.

The prequalification programme of the WHO has been existing since 2001 with the objective to make qualitative medicinal products for HIV/ AIDS, malaria, tuberculosis and for reproductive health quickly available. The WHO keeps a list of prequalified medicinal products which is principally used by United Nations authorities like UNAIDS or UNICEF to help them take their procurement decisions. In the meantime, many authorities of other countries have also been using this list. To have a medicinal product be put on the list, a dossier must be submitted to the WHO proving that its quality complies with the standards set in different WHO guidances. Regarding generic drugs, the demonstration of the bioequivalence with a pharmacokinetic study is an essential part of the dossier. This demonstration can only be conclusive when the provisions of the new guidance are met. That's why the revised document is important for all companies striving for the WHO's prequalification status for their generic drugs.