Assessment of Interchangeable Multisource Medicines Quality of BE Data Dr. Henrike Potthast...

Assessment of Interchangeable Multisource Medicines

Quality of BE Data

Dr. Henrike Potthast ([email protected])

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

Quality of Bioequivalence StudiesQuality of Bioequivalence StudiesQuality of Bioequivalence StudiesQuality of Bioequivalence Studies

Citation from Directive 2001/20/EC:

“The verification of compliance with the standards of good clinical practice and the need to subject data, information and documents to inspection in order to confirm that they have been properly generated, recorded and reported are essential in order to justify the involvement of human subjects in clinical trials.”

GCP & GLP

finding/definition of inspection triggers



General Requirements

BE studies as a substitute for clinical and preclinical data

Quality of the BE study is of decisive importance for approval of the product



Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are

protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.



Basic Responsibility - Sponsor

An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.



Montoring

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).



Purpose

The purposes of trial monitoring are to verify that:

a) The rights and well-beeing of human subjects are protected.

b) The reported trial data are accurate, complete, and verifiable from source documents.

c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).



Selection and Qualifications of Monitors

a) Monitors should be appointed by the sponsor.

b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitors qualification should be documented.

c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsoris SOPs, GCP, and the applicable regulatory requirement(s).



Monitor´s Responsibilities

Acting as the main line of communication.

Verifying that the investigator has adequate qualifications and resources.

Verifying complete track of the investigational product(s).

Verifying that the investigator follows the approved protocol and all approved amendment(s).

Verifying that written informed consent was obtained before each subject´s participation in the trial.



Monitor´s Responsibilities ctd.

Ensuring that the investigator receives the current Investigator´s Brochure, all documents, and all trial supplies needed.

Ensuring that the investigator and the investigator´s trial staff are adequately informed.

Verifying that the investigator is enroling only eligible subjects.

Reporting the subject recruitment rate.

Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.



Monitor´s Responsibilities ctd.

Verifying that the investigator provides all the required reports.

Checking the accuracy and completeness of the CRF entries.

Informing the investigator of any CRF entry error, omission, or illegibility.

Determining whether all adverse events (AEs) are appropriately reported.

Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements.



Audit

A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor´s standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).



Audit

The purpose of a sponsor´s audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

Done by individuals, who are independent of the clinical trials/systems.



Reg. project-related inspections

Evaluation phase – examples

protocol gives incomplete/illogical information

numerous protocol violations

unsatisfactory explanation for protocol violations

data too clean/too messy

number of missing values/drop-outs/nds….

Findings due to knowledge from literature and other studies; type of generic product already known



Reg. inspections…

Evaluation phase – ctd.

conflicting (PK-)results as compared to known data without any comment

insufficient documentation (clinic, analytics, statistics)

missing documentation

implausibility/inconsistency of clinical or analytical data

(e.g. long half-life – short wash-out – no carry-over?!)

doubtful statistics or change in the analysis….



Reg. inspections…

Evaluation of source data/raw data

e.g.

print-outs of chromatograms

signed CRFs

analytic protocols

time schedules

list of providers …….



Reg. inspections…

Data verification & QA issues

GCP compliance statement available?

audit/monitoring reports available?

protocol valid, i.e. signed (incl. amendments)?

was the protocol followed?

genuine study subjects/volunteers?

archiving of source/raw data?

violations of the protocol justified? ….



Reg. inspections…

Data verification & QA issues ctd.

excluded subjects - traceable?

consistent trial results?

final responsibility of investigators (signing)?

source of investigative products?

batch information available?

handling of investigative products?



Reg. inspections…


validation of bioanalytical method? timing validation characteristics adherence to GLP SOPs available……

calibrated equipment?

computer systems?

archiving of bioanalytical raw data



Reg. inspections….


statistical plan adhered to? transfer of analytical data to statistics main pharmacokinetic characteristics method of determination nd values considered?

statistical outcome and conclusions consistent?

archiving of statistical raw data



Reg. inspections

Regulatory & ethical issues

independent ethics committee?

ethical approval based on appropriate documentation? protocol amendments investigators brochure; SPC subjects information informed consent

approval of competent authority in time?

subjects from vulnerable populations? e.g.

signing of subjects available?



Reg. inspections

Regulatory & ethical issues ctd.

insurance of subjects adequate?

adequately instructed personnel? investigators technicians suppliers…..

safety evaluation assured throughout the trial?

retention samples sufficient?

storage of retention samples?



Example 1 (publ. data): Verapamil















Example 4 (publ. data): Glibenclamide












THANK YOU

FOR YOUR ATTENTION

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