Keeping an eye on the incubators
pharmafile | October 24, 2003 | Feature | Research and Development |Â Â CRO, contract research, contract research organisationÂ
Pharmaceutical companies are increasingly outsourcing their clinical trials to contract research organisations (CROs). There are more than 1,000 CROs world-wide, offering a range of services from specialist niche activities to full service provision. These include data management, central laboratories, clinical trial management and clinical trial drug supplies.
Impact of ICH/GCP guidelines
The introduction of good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines towards the turn of the last century and the increase in regulatory requirements has led to an exponential increase in the amount of paperwork. These guidelines were introduced to provide the pharmaceutical industry with a structured global format that meets the regulatory requirements of all countries involved in R&D of new investigational drugs for human use, and protect participants in medical research involving human subjects. The impact of these guidelines has increased the need for more rigorous collecting of documentation, validation and inspection by regulatory agencies, with the overall effect on the industry of an increase in head count required to manage and implement the new regulatory requirements. Pharma companies have seen a huge increase in their budgets because of these commitments and now drive towards a faster time to market.
It was for this reason that many large organisations have turned to CROs for help in running clinical trials they simply could not expand their workforce at the same rate as the regulatory requirements mushroomed. The most basic logistics of resourcing assessments is worked around the 'in-house' capacity, in that if staff are available then the activity is handled internally, and if not the task is outsourced, hence the growth and continuing expansion of the CRO industry. Before placing a contract with a CRO, however, it is necessary to conduct audits on those CROs chosen as vendors.
Definition of quality assurance and quality control
Quality assurance: systems and processes established to ensure that the trial is performed and the data generated in compliance with ICH/GCP guidelines, including procedures for ethical conduct. This is provided through in-process auditing of both the clinical process and the data.
Quality control: the operational techniques undertaken within the system of quality assurance to verify the requirements of those involved in managing a particular trial.
Compliance provides public assurance that the rights and well-being of subjects are protected, consistent with the principles that originate in the Declaration of Helsinki, and that the data are credible. The larger pharmaceutical companies have their own in- house quality assurance (QA) personnel, which should be individuals who are independent of the clinical trial systems. The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. The sponsor's audit plan should be guided by the importance of the trial submissions to regulatory authorities.
The need to audit those contractors to whom work is outsourced is of paramount importance and would be carried out by the in-house QA department. This should include all vendors to whom work is contracted out. These may include project management, central laboratories, data management, clinical trial supplies and any other vendor contracted to support the management of the clinical process.
Preparing for an audit of a CRO
A successful system audit requires project management to include preparing the staff (both the audit team and the client/customer groups) and understanding the process and regulatory requirements. It is essential that this begins with an audit brief/scope and that both the auditor and auditee are very clear on the scope, which should be confirmed and communicated prior to the start of the audit. The auditor should be provided with copies of organisational charts (defining the role of those listed), an index of standard operating procedures (SOPs), a list of all studies that are currently in process and their status, specific study indication, relevant SOPs, a study protocol, and job descriptions and CVs of staff involved.
The critical steps and the steps the audit team follow and who is responsible for what activities should be clearly defined. Communication is key, both at the beginning and the end of the audit. These audits usually involve numerous staff from the client QA areas and it is important that all understand the process and roles. It is more realistic to target systems rather than individuals and to ensure that the system audit crosses therapeutic areas, projects and divisions. It is essential to provide mini-debriefs each day with the staff involved and a need to be flexible around the availability of those being audited. The auditor needs to be willing to reschedule any of the activities around the timeline of the total audit and to ensure that all are conducted.
The introductory meeting with the personnel is very important and all those involved in the audit should attend if possible to ensure the aims of the audit are clear and any questions can be clarified. At this point any changes to the plan can be identified. Separate meetings with key personnel are vital to the audit and usually the time in-between gathering information and conducting the next interview are vital for the auditor to gather his thoughts. Audits should be conducted before a study commences and again at midpoint of the study start. This ensures that the procedures defined at the study start remain in place and are still being adhered to. Any changes in staff should be noted and problem areas encountered by the CRO and sponsor recorded.
Conducting the audit
The following should be reviewed:
- roles and responsibilities of personnel
- staff training and related records
- SOPs
- QA procedures
- archiving procedures
- data management.
Roles and responsibilities of personnel
It is important to define the roles of the personnel who will be responsible for the study and define their responsibilities so that any change of personnel can be noted during the course of the study. This is essential to maintain continuity, as studies are often complex in nature. A working knowledge of the therapeutic area under study is essential, and it is therefore important to establish that the project manager has an understanding of the protocol that is being used.
Staff training and related records
A record of staff training should be reviewed and assurance given that it is updated on a regular basis. A record of all courses attended and CVs for all staff involved in the project should be up to date and available for review. It is important to ensure that staffing levels are adequate for the proposed study and an evaluation of current projected workload is assessed.
SOPs
The most important step in assuring that clinical studies are conducted in accordance with ICH/GCP guidelines is the preparation, implementation and enforcement of SOPs. All activities relating to the conduct of clinical research should be documented in the SOPs and reviewed on a regular basis. CROs can use their own SOPs or may work to those of the sponsor. An SOP is a formal document that describes the procedures that will be followed in the accomplishment of various tasks. Employees should write SOPs so that the procedures outlined in them are practicable and attainable. SOPs should never be considered as static documents and should be reviewed regularly and amended if required. Each SOP should include the following sections:
- introduction: a succinct statement of the rationale for the procedures that the SOP describes and a general introduction of the SOP
- contents: the contents of the SOP will follow the order noted in the table of contents.
All current SOPs and their most recent dates of issue should be listed in an index at the beginning of the manual containing all the SOPs. As each new SOP is generated or as an existing one amended, the index should be likewise updated. All SOPs should be reviewed by the SOP committee, approved by title, signed and dated.
QA procedures
The sponsor should review the functions of the CRO QA department. The process of independent auditing is the only way to ensure verification of compliance with the standards of GCP. It is important to establish what processes are in place within the company for QA and QC procedures and that the date of the last audit is recorded. If the CRO has its own in-house QA/QC department the personnel should be interviewed and the QA/QC SOPs reviewed. The CROs should also be prepared for inspections by regulatory authorities.
Archiving procedures
The suitability of storage facilities should be inspected and security reviewed as most of the essential documents required by ICH/GCP guidelines for the proposed study will be kept at the CRO office until the completion of the study. The CRO is responsible for security of all data generated during the course of the clinical study until study closure or database lock. The study documents are then returned to the sponsor. For data that is entered remotely, a signed printout should be retained either as it is or in a microfiche form as an original record.
Data management
Data management is a comparatively new discipline within the pharmaceutical industry. It has its origins in the 1970s and emerged from the medical and computer departments of larger companies such as Merck and Glaxo. Since then it has become a major force in contributing to the speed at which compounds may be brought to market. It is in recognition of this that millions of pounds have been spent over the last decade on the data management process, both manual and electronic. The quantity of data required for a product licence application has escalated with the introduction of stricter regulations and ICH/GCP guidelines. All these data must be checked, validated and incorporated into the analysis. Major companies have devoted enormous resources to their data management division at a time when budgets are being pressed and reduced in other areas. Therefore when data management is outsourced the data audited should confirm that:
- what was done is what should have been done
- what was reported is what was recorded
- the trial was done according to the principles of ICH/GCP guidelines.
A system of formal audit applies routinely to clinical data and provides benefits within and without the company concerned. Internally, it gives assurance to senior management that quality control data are being applied, and externally it shows that attention is being applied to ICH/GCP guidelines.
The quality of the data collected during a study will determine the significance of the study results.
Summary
Prior to any audit, how the audit findings will be presented needs to be clear and understood by all involved. This needs to cover both verbal and reported findings. Findings will also need to be classified in some way, which may be done by the arrangement of findings by risk and urgency needed to address the audit findings. The findings should generate response with agreed actions and should be followed up according to predetermined processes. Choosing a CRO is therefore reliant on the findings of the audit report from the QA department.
Related Content
Crown Bioscience opens new US model development centre
Crown Bioscience, a US global contract research organisation (CRO) that is part of JSR Life …
Symeres announces acquisition of DGr Pharma
Symeres, a Contract Research, Development and Manufacturing Organization (CRDMO) has acquired DGr Pharma, a drug …
Evestia Clinical and Atlantic Research Group merge to create global specialist CRO
UK-based Evestia Clinical will merge with US-based Atlantic Research Group (ARG), forming a leading independent …
