Annex 9: additional guidance for organizations performing in vivo bioequivalence studies.

 
Introduction 
 
1. Scope 
 
2. Glossary 
 
3. Organization and management 
 
4. Computer systems 
   Hardware 
   Software 
   Data management 
 
5. Archive facilities 
 
6. Premises 
 
7. Clinical phase 
 
8. Clinical laboratory 
 
9. Personnel 
 
10. Quality assurance 
 
11. Ethics 
    Independent ethics committee 
    Informed consent 
 
12. Monitoring 
 
13. Investigators 
 
14. Receiving, storage and handling of investigational drug products 
 
15. Case-report forms 
 
16. Volunteers--recruitment methods 
 
17. Dietary considerations 
 
18. Safety, adverse events and reporting of adverse events 
 
19. Sample collection, storage and handling of biological material 
 
20. Bioanalytical data (laboratory phase) 
 
21. Documentation 
 
22. Pharmacokinectic and statistical calculations 
 
23. Study report 
 
References 
 
Appendix 1 
Examples of the list of standard operating procedures at the contract 
research organization 

Introduction

Multisource pharmaceutical products need to conform to the same standards of quality, efficacy and safety as required of the originator's (comparator) product. Specifically, the multisource product should be therapeutically equivalent and interchangeable with the comparator product. Testing the bioequivalence between a product and a suitable comparator (pharmaceutically equivalent or a pharmaceutical alternative) in a pharmacokinetic study with a limited number of subjects is one way of demonstrating therapeutic equivalence without having to perform a clinical trial involving many patients. In such a pharmacokinetic study any statement about the safety and efficacy of the test product will be a prediction based on measurement of systemic concentrations, assuming that essentially similar plasma concentrations of the drug will result in essentially similar concentrations at the site of action, and thus an essentially similar therapeutic outcome. The bioequivalence study thus provides indirect evidence of the efficacy and safety of a multisource drug product. Often this will be the only evidence that the product is safe and efficacious. It is therefore crucial that the bioequivalence study is performed in an appropriate manner. Several guidance documents stress the importance of on-site inspections to verify compliance with standards of good clinical practice (GCP) (1,2).

The WHO prequalification project was started in 2001 to assure that medicinal products supplied for procurement meet WHO norms and standards with respect to quality, safety and efficacy (http://www.who.int/medicines/). Specifically it is a requirement that the submitted product dossier with all its necessary contents is assessed and found acceptable, and that the manufacturing sites of both the finished pharmaceutical product and of the active pharmaceutical ingredient (API), are inspected and found to comply with WHO good manufacturing practices (GMP). Because products submitted to the prequalification project are usually multisource ("generic") products, therapeutic equivalence is generally demonstrated by performing a bioequivalence study, for example in a contract resource organization (CRO). For prequalification of such a product it is vital that, in addition to the above-mentioned requirements, the CRO used by the sponsor to undertake the bioequivalence studies complies with WHO GCP and considers relevant elements from WHO good laboratory practice (GLP) and good practices for quality control laboratories to ensure integrity and traceability of data. Those involved in the conduct and analysis of bioequivalence studies on products to be submitted for prequalification therefore need to ensure that they comply with the above-mentioned WHO norms and standards to be prepared for any inspections by WHO.

1. Scope

The objective of this document is to provide guidance to organizations involved in the conduct and analysis of in vivo bioequivalence studies.

Bioequivalence studies should be performed in compliance with the general regulatory requirements and recommendations on good practices as specified in the WHO bioequivalence guidelines (3), good clinical practices (1) and good laboratory practices (4) guidelines.

The text below lists general recommendations for organizations (including CROs and laboratories) conducting bioequivalence studies and analysis of clinical trial samples. Recommendations for facilities and equipment are listed in the respective paragraphs. Recommended documents and records are listed in Appendix 1.

This document provides information on:

--organization and management;

--study protocols;

--clinical phase of a study;

--bioanalytical phase of a study;

--pharmacokinetic and statistical analysis; and

--study report.

The present guidelines target organizations conducting bioequivalence studies and highlight certain important aspects of the activities of such organizations. This document does not replace the above-mentioned GCP or GLP or good practices for quality control laboratories guidelines, which are more complete. It is, therefore, not a stand-alone document. For further guidance, see the guidelines for GCP for trials on pharmaceutical products (1).

2. Glossary [1]

The definitions given below apply to the terms used in this guidance. They may have different meanings in other contexts.

adverse event

Any untoward medical occurrence in a clinical trial subject administered a pharmaceutical product; it does not necessarily have a causal relationship with the treatment.

audit of a trial

A systematic examination, carded out independently of those directly involved in the trial, to determine whether the conduct of a trial complies with the agreed protocol and whether the data reported are consistent with the records on site, e.g. whether data reported or recorded in the case-report forms (CRFs) are consonant with those found in hospital files and other original records.

bioequivalence test

A test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro approaches.

case-report form (CRF)

A document that is used to record data on each trial subject during the course of the trial, as defined by the protocol. The data should be collected by procedures which guarantee preservation, retention and retrieval of information and allow easy access for verification, audit and inspection.

comparator product

A pharmaceutical or other product (which may be a placebo) used as a reference in a clinical trial.

contract

A document, dated and signed by the investigator, institution and sponsor, that sets out any agreements on financial matters and delegation/distribution of responsibilities. The protocol may also serve as a contract when it contains such information and is signed.

contract research organization

A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing.

ethics committee

An independent body (a review board or a committee, institutional, regional or national), constituted of medical professionals and non-medical members, whose responsibility is to verify that the safety, integrity and human rights of the subjects participating in a particular trial are protected and to consider the general ethics of the trial, thereby …