Introduction  

At first glance, the requirements of the new VICH Guideline appear to be much greater compared to those of the EU CVMP GCP Guideline. In reality much of the VICH Guideline is an expanded version of the CVMP Guideline. Many requirements are common to both Guidelines, but they are explained in greater detail in the VICH GCP Guideline and so the text is longer.  

There are, however, some new concepts, some new definitions in the Glossary and some new words in the text of the VICH document.  

The object of this paper is to highlight the major changes that will be brought about by the adoption of the VICH GCP Guideline, which became operative in July of this year, in terms of their effects on those involved in veterinary clinical trials.  

The following new words appear in the VICH GCP Guideline: “Authenticated Copy”, “Contract Research Organisation”, “Quality Control”, “Quality Assurance”, “biologicals” and “Multicentre Studies”.

 A Matter of “Quality”  

While the implementation of the CVMP GCP Guideline in itself implied the application of a quality standard, the VICH GCP Guideline stresses “quality” to a much greater extent than the CVMP GCP Guideline. The word “quality” appears only twice in the CVMP GCP Guideline, whereas it appears 20 times in the VICH GCP Guideline!  

In paragraph 2.8 under “The Principles of VICH GCP”, the VICH Guideline states “All participants in clinical studies are encouraged to adopt and adhere to generally recognised sound QA practices”. The Guideline then follows this principle later in the document in giving guidance to the Sponsor, Monitor and the Investigator. It becomes apparent that the Sponsor has the overall responsibility for quality assurance. These responsibilities are discharged partly through well-written protocols and SOP’s, and partly through the day to day quality control procedures that are carried out, mainly by the Monitor. Thus the Monitor plays a pivotal role in ensuring the quality of any study.  

Major Changes for:  

1) The Investigator  

There is no doubt that, compared to the CVMP GCP Guideline, the VICH GCP Guideline means more responsibilities and obligations for the Investigator, especially in the production of documentation and increased communication.  

The Investigator has the responsibility of recording and promptly notifying the Sponsor of any protocol deviations ( 2.2.5-6). The Investigator can delegate some trial functions to practice or farm staff where appropriate, but only if the staff have undergone appropriate training ( 3.2.8) for the purposes of the study. In farm studies, the Investigator must supervise the housing, feeding and care of study animals. Also the Investigator must document any health or environmental changes. This infers a regular “on site” presence of the Investigator during a study.  

Any adverse events must be promptly notified to the Sponsor ( 3.2.17). Such adverse events are not confined to Adverse Drug Reactions, but include any happening that adversely affects an animal or the study, either directly or indirectly.  

While clinical samples are regularly handled within any practice, mistakes can easily occur. The loss of identification of a sample can take place temporarily, if, for instance, plasma is being pipetted and transferred to an unlabelled container. It is the responsibility of the Investigator to ensure that the identity chain is not broken (3.2.30) There is also a requirement for the Investigator to store the documentation, generated during the course of a study for the period required by the authorities. The documentation stored by the Investigator may be original, or authenticated copies if the originals have been sent to the Sponsor (3.2.32). Previously, within the CVMP GCP Guideline, storage of the study documentation was a Sponsor responsibility only.

2) The Sponsor  

The Sponsor, before carrying out any study must ensure that there is sufficient scientifically valid information regarding the effectiveness and safety to justify a clinical study (4.2.1). In the EU, we take this for granted, especially as some Member State Authorities require sight of this information before they will grant permission for a trial to be carried out. However, The VICH GCP Guideline is an international guideline and in some countries permission to carry out a clinical study is not required and so an ethical obligation is placed on the Sponsor.  

The appointment of Monitors is the responsibility of the Sponsor (4.2.4), or the Contract Research Organisation (CRO) in cases where this responsibility has been delegated to the CRO. Monitors must also be appropriately trained (4.2.2). This means that Monitorss must have a science background and be trained, not only in GCP, but also in the specifics relating to the study.  

Multicentre studies are not mentioned in the CVMP GCP Guideline. The VICH GCP Guideline assigns specific responsibilities to the Sponsor in relation to these (4.2.8). It would be normal to pool the data collected from individual sites in a multicentre study and so trial procedures must be uniform across sites, particularly in terms of compliance generally, data collection and recording. Importantly it must be apparent from the trial documentation that this objective has been achieved. Under this heading the Sponsor has a duty to facilitate inter Investigator communication (4.2.8.4). This is an important activity, especially in achieving uniformity. Meetings of Investigators prior to, during – if appropriate – and at the end of a study can go a long way to fulfilling this objective.  

Paragraph 4.2.16 of the VICH GCP Guideline reinforces the Sponsor’s duty to ensure the quality and integrity of data by implementing quality audit procedures. Again mainly the Monitors will effect these in their day to day trial activities.  

Delegation of study related tasks to a CRO by the Sponsor are specifically mentioned (4.3). Two specific points emerge. If tasks are delegated to a CRO the Sponsor still has the ultimate responsibility for the quality and integrity of the study (4.3.1). Importantly the Guideline states that there must be a contract between the Sponsor and the CRO defining the functions and duties that have been delegated (4.3.2).

3) The Monitor  

The section dealing with the Monitor (5) is relatively short compared to those dealing with the Investigator and Sponsor. Despite this, the Monitor has a crucial role in clinical trials, being the Sponsor’s representative in the field having direct and continual contact with the Investigator. The Monitor must have a scientific background in order to deal with the technicalities of the study. Additionally the Monitor must be trained in quality control procedures and data verification techniques (5.1) to exercise the appropriate level of quality control throughout the study. The Monitor must have a good personal relationship with the Investigator to carry out the necessary quality control procedures, make sure that the Investigator understands the study and is well aware of the role and responsibilities he/she is undertaking (5.2.5).  

Visits by the Monitor to trial sites are an essential activity. These must take place with sufficient frequency to ensure study compliance (5.2.6). Judgement must be applied here, and in a multicentre study it is not unusual for one Investigator to receive more visits than others to ensure compliance and so quality.  

Monitors could inadvertently bias a study by word or deed and must be aware of this constantly (5.2.7). Investigators are acutely aware that they are under scrutiny during Monitor visits, and so may have their clinical judgement influenced by something the Monitor says or does.  

A new and very important Monitor responsibility under The VICH GCP Guideline is the completion of a signed summary report at the end of a study confirming Investigator compliance (5.2.14). This means that the Monitor must have confidence in the QC procedures he/she has carried out during the course of the study and the signing of this document cannot be undertaken lightly. The background work required during the study for the Monitor to sign this report with confidence should not be underestimated.

Communications  

The VICH GCP Guideline requires that both the Investigator and the Monitor “prepare and maintain an accurate record of all contacts….. and should include the date and time”. Much of this communication will be between the Investigator and the Monitor. This may result in two different versions of the same conversation, as in real life! One possible solution is for one party to prepare the contact report, agree it and both sign.

Implications of the Adoption of the VICH GCP Guideline  

The Investigator will have an increased workload under The VICH GCP Guideline compared to The CVMP GCP Guideline. Direct Investigator responsibilities relating to communicating information to the Sponsor and the Monitor will increase bureaucracy. However it must be recognised the GCP is a bureaucratic process and this increase is inevitable. The Investigator must make allowance for this. The organisation of a clinical study within a practice or on a farm means that the practice or farm must itself be well organised in order to absorb the study and carry it out properly. It also means that the Investigator has to commit staff and facilities to the study. Investigator and practice/farm staff training is a pre-requisite to carrying out any study. Training must be at two levels; general training in the principles of GCP and study specific training. Commitment to the study by all these study participants is essential to success. There must also be commitment from those staff not involved in the study, as the study will impinge on their activities also.  

This means that the correct choice of Investigator and practice/farm is critical. The degree of commitment necessary means that it may be difficult to find good potential Investigators and sites.  

To satisfy the requirements of The VICH GCP Guideline, the Sponsor or CRO need additional capabilities. The Sponsor/CRO needs training facilities for Monitors, especially in the area of Quality Assurance. Expertise in drawing up clear contracts with Investigators (and CRO’s) is necessary. For multinational studies, language presents a particular problem, especially in some countries with more than one language or dialect. This must be overcome to ensure quality. This means that trial documentation must be translated accurately and understandably. Collected data then must be translated back again. The Sponsor/CRO must have access to local Monitors to facilitate these processes.  

The requirements and specification for Monitors is more exacting under the VICH GCP Guideline. The Monitor must be a scientist in order to understand the study and product under investigation. Training in QC/QA techniques and a full understanding and experience of GCP are necessary. In order to fulfil the other requirements of VICH GCP, e.g. to ensure that the Investigator has a full understanding of the study and meets his/her study obligations, the Monitor must be a good communicator, presenter and be able to handle people well. The Monitor bears the main responsibility for QA and must be appointed with appropriate care. The cost of inadequate Monitoring can be high.

Conclusion  

The VICH GCP Guideline is more comprehensive and detailed than the CVMP GCP Guideline but many of the requirements are common to both Guidelines. The VICH GCP Guideline, however, increases the overall requirements, responsibilities and obligations in carrying out clinical trials. In particular it demands greater commitment from Investigators and places emphasis on Quality Assurance as an ongoing process, which is implemented mainly by the Monitor