Standardizing EU Investigative Sites

ICH/GCP guidelines, the Declaration of Helsinki, and the recent European Union (EU) laws originating from Directive 2001/20/EC are the currently accepted gold standards of Good Clinical Practice (GCP) for research in Europe.^1,2 The importance of the suitability of investigators and the quality of facilities at clinical trial sites has for the first time been given legal recognition in these laws. The Detailed Guidance text of the EU Directive states that information on the qualification and training of the principal investigator in GCP or experience obtained from work with clinical trials and patient care must be sent to the ethics committee (EC) for their approval of this person in such a role.³ In addition, the EC must also approve the quality of the facilities (including the availability of adequate resources, personnel, and laboratory facilities) at clinical investigative sites.

Photography: Comstock Illustration: Paul A. Belci

The process and discipline of the clinical trials environment are not for the faint-hearted, and any idea that the ethical, scientific, and practical dimensions of clinical trials can simply be grafted onto a clinical setting without the specialized personnel and appropriate infrastructure is an error. Investigators and their teams are responsible for the conduct of the most fundamental acts performed in clinical trials: giving adequate information to study participants, getting informed consent, the administration of experimental medication, toxicity surveillance of these participants, and the production of credible, quality data.

There is increasing complexity of study design. Sponsors of clinical trials have constraints (regulatory and financial), and expectations (studies must often respond to efficacy, safety, pharmacological, quality of life, and adherence questions, all in one protocol). There is therefore a need for efficient clinical investigative teams who have technical, administrative, and organizational skills to deliver a quality product in an efficient and timely manner.

Clinical trial protocols originate from pharmaceutical companies or from the noncommercial sector; i.e., they are developed by clinical investigating teams or by national/international collaborating investigators or research organizations. With investigative sites receiving protocols from such diverse origins, there is need for an adequate number of professional team members experienced in research rules and practice. These members evaluate the ethical, scientific, and practical acceptability of studies at the investigative site prior to their submission to the EC.

Investigative sites are already graded by sponsors on a number of parameters:

• quality of data

• recruitment speed

• enrollment numbers

• numbers of protocol violations

• adequate personnel with training and experience

• respect of deadlines for data collection

• numbers of data clarification requests

• administrative tardiness

• audit reports.

In addition, investigative sites should now be able to demonstrate quality practices with job descriptions for study personnel and standard operating procedures for all activities performed in the clinical trial process, for instance the process of obtaining informed consent from study participants.⁴

According to new EU law, investigators who themselves wish to coordinate noncommercial academic interventional trials must assume the responsibilities of sponsors of these studies with the consequent administrative, financial, and legal obligations.

Figure 1. Study coordination at clinical investigation sites.

The coordination of today's clinical trials has become a complex and professional activity. Figure 1 illustrates the multiple partners involved in the smooth running of a clinical trial. There needs to be collaboration with other departments within the institution in which the study is being conducted and with companies subcontracted by the sponsor for their specialist contribution to the trial process. Examples of such include central laboratories, study drug suppliers, interactive voice response systems (IVRS) via telephone or the newer interactive Web response systems (IWRS), clinical research organizations (CROs), and couriers for the transport of medication or biological specimens.

Coordination of these processes requires organization of personnel and facilities in order to respond to the needs of study participants, and the pressures from sponsors as well as compete in the present day clinical trials arena.

Personnel

The biggest single investment and necessity at any clinical investigational site is personnel. Competent, committed and professional staff members are needed in order to meet the high ethical, scientific, regulatory, and practical requirements of clinical trials.

Princical investigator

The principal investigator (PI) assumes overall responsibility for the conduct of the study. In accordance with new EU law, this person may also need to take on the administrative and legal responsibilities as sponsor of academic noncommercial studies.

Research physician

A dedicated research physician would be solely responsible for the enrollment and follow up of all patients participating in clinical trials.

Study participants might be referred by their treating physician to the research physician who could be responsible for:

• giving detailed information on the study to the participant

• determining the eligibility of participants

• the informed consent process

• medical follow up of participants during the study and review of examination/test results

• safety surveillance with decisions on biological retests and the (dis)continuation of the study medication if appropriate.

• Serious Adverse Event reporting, though this activity is not exclusive to a research physician.

Study participants would be seen by the research physician at the screening, baseline, and follow up visits of the study (and unscheduled toxicity visits if necessary). In parallel, they could continue to see their treating physician (who initially referred them to the research physician and the research team) at regular intervals, and at the end of the study the patient will then continue to receive care from their treating physician. (This scenario could be used for participants of Phase II, III, and IV studies.)

The advantage of a dedicated research physician in addition to the treating physician is that it provides some degree of a solution for physicians with potential difficulties in reconciling the dual roles of investigators and carers of their patients.⁵

The research physician may be the most appropriate person for the supervision of case report form (CRF) completion. Another repsonsibility is reviewing and summarizing the multitude of The Council for International Organizations of Medical Sciences (CIOMS)/Dear Doctor reports arriving daily at investigative sites for the other members of the research and clinical teams.

Site coordinator

The job of site coordinator requires a serious talent for flexibility. Apart from saying that a person of the medical or paramedical profession may hold this position—it is often a research nurse—there is no end to the diverse activities which the site coordinator may orchestrate, e.g., clinical activity, training, standard operating procedures, job descriptions, contacts with monitors, organization, delegation.

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Research nurses/research technician

The role of research nurses/research technicians can simply be summarized as the practical translation of the protocol to the bedside or the clinic setting. Research nurses/technicians are most often responsible for the first-line practical running and management of the study with diverse roles as carer, patient advocate, and study administrator.

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There are very specific acts which are restricted to the profession of nursing—blood drawing and the administration of medications. Many of the other roles can be carried out by other paramedical professions, such as dieticians, laboratory technicians, or pharmacy assistants.

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These activities can include though are not restricted to:

• seeing study participants during the study follow up visits:

–explaining the study procedures and the timing in which these procedures must be performed

–counselling on adherence to drug regimens

–pill counts to assess adherence

–appointment management of the study follow-up visit and procedures

–adverse and serious adverse events/reaction reporting

–quality source documentation of all data during the follow-up visits

–instructions to study participants on diary card or questionnaire completion

–simple encouragement to the patient/participants who have to adhere to protocol requirements and who in many cases also have an acute or chronic illness.

• randomization procedures

• participant screening and enrollment logs

• study drug management (ordering, accountability, temperature surveillance of storage areas, and the security of the storage areas)

• CRF completion.

Administrative coordinator/research secretary

The administrative work attached to a clinical trial is significant both in terms of volume and responsibilities. A research secretary can have the role of administrative coordinator and will have first line of responsibility for the site study file. This person will now need to be conversant with documents for both European and U.S. administrations.

Biostatisticians

Biostatisticians have a role in studies at clinical investigative sites that are initiated and driven by investigator groups or by an individual investigator.

Biostatisticians may contribute to the protocol and its design with:

• description of the statistical methods to be employed

• calculation of the number of participants needed

• preparation of the level of statistical significance to be used

• preparation of randomization lists

• interim analyses (with reports to the data safety and monitoring boards) if these were planned in the protocol

• final analysis of the study.

Laboratory technicians

Laboratory technicians are responsible for the correct and timely processing of laboratory specimens for the clinical study. Sample logs must be kept up to date. Storage must be at the correct temperature (ambient, refrigerated or frozen) and if required samples will be prepared for shipment with the appropriate packaging, documentation, and labelling.

Laboratory personnel must be well-versed and trained in the rules of transport (ground or air) of biological samples and dangerous goods.

Necessary expertise

In recent years, there has been increasing awareness that investigators must have the expertise for the conduct of ethical studies. As Ezekial Emmanuel concisely put it, "Not only must clinical investigators be skilled in the appropriate methods, statistical tests, outcome measures, and other scientific aspects of clinical trials, they must have the training to appreciate, affirm, and implement these ethical requirements, such as the capacity and sensitivity to determine appropriate subject selection criteria, evaluate risk-benefit ratios, provide information in an appropriate manner, and implement confidentiality procedures."

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Training of personnel

Investigative site teams must have enough "protected time" for regular training on the guidelines, rules and the laws governing their practice.

Training could include such subjects as:

• informed consent procedures

• source documentation

• laboratory procedures

• standardization of procedures such as taking of blood pressure or management of study medication

• temperature surveillance of the storage of ambient, refrigerated, frozen medication, and biological samples

• the investigator's file

• serious adverse events (definitions and reporting)

• ethical considerations in clinical trials

• medical emergencies

• statistical considerations in clinical trials

• pharmacokinetics

• study protocol

• CRF completion

• communication plan

• regulations on electronic source data FDA 21 Code of Federal Regulations 11.⁹

Training may be provided by the more experienced site personnel or by invited lecturers from other centers. There should also be training on the pathology under study at the investigative site. A record should be kept on training that the site personnel received.

Space and time infrastructure

A large number of clinical trials are conducted within the hospital/clinic setting. It is important that investigators have the support of their institutions when undertaking clinical trials.

The performance and documentation of procedures in clinical trials take space and time. This is very difficult if clinical research is carried out in departments where no dedicated space has been allocated to participants enrolled in clinical trials.

Study participants have a need and a right to professionals who are available to them for information, support, and encouragement, and also to care for them behind the scenes with (for example) toxicity surveillance of laboratory results and rapid recall for retesting if necessary. They need privacy, space, comfort and time to read the study information and informed consent documents—if they do not wish to do this at home (as may be the case with studies in HIV) and to complete questionnaires on quality of life etc. as part of the study procedures.

Equipment

An investigative team must have access to the appropriate equipment within the institution for the conduct of the procedures required by the study. In addition, all the equipment must be serviced regularly with certification to prove that calibration and function are maintained to the acceptable recognized standards.

With the increasing use of electronic technology for the gathering and storage of source data for clinical trials, investigative teams and the IT departments of their institutions must be aware and adhere to the 21 CFR 11 rules.

Financial stability

Clinical research personnel stipends and money for the general management of investigative sites come from payment for data generated in clinical trials financed by the pharmaceutical industry, national governments, central EU funds, and university grants—though it is generally acknowledged that the greatest proportion of money comes from the pharmaceutical industry.

It is a well-known fact in Europe that compared to the National Institutes of Health resources available to U.S. researchers, central European academic/noncommercial research is poorly financed. In 2004 the European central funding to research is €500 million ($620 million U.S.), of which 15% is allocated to clinical research; this compares to the NIH budget of $28 billion US (€23 billion), of which 31% is allocated to clinical research. (The population of Europe is 453 million; the U.S. population is 293 million.)

Until some time ago, one of the more discreet aspects of any clinical trial site was its financial status and stability. Traditionally (and still the case at many investigative sites), the Prinicipal Investigator is responsible for contracts with sponsors and the financial management of personnel and logistical needs of his/her site. However, there have been changes in this area—over recent years investigators have given governance of the financial aspects of their clinical research activities to their institutions in many cases. This relieves the hard-pressed investigator of a difficult responsibility and responds to a wish by institutions to be aware of the level of clinical research and the financial income from commercial sponsors.

Since the implementation of the new European law, all investigators must inform their ECs of the financial payments proposed for each clinical trial.

Whether it be an individual investigator or the research affairs department of their institution who assures financial stability, this is a difficult area of management because of its dependence on sponsor liquidity, the continued development of promising molecules, and the continued efficacy and toxicology results in a sector necessitating high-caliber personnel having to adapt to a constantly changing regulatory environment.

Conclusion

It is commendable that the new EU law has endorsed investigator suitability and the quality of facilities at clinical trial sites. It is also an excellent start to establishing standardization of these areas across Europe. A good idea for a clinical trial must now be tempered with examination of the availability of suitably trained personnel and the quality of facilities in which the study can be performed at the clinical trial site.

It is our opinion, however, that there should have been even more emphasis on these issues. This was a missed opportunity by the European Parliament to give even more support and recognition to clinical investigative sites. They have laid down the rules, but the clinical investigator is not realistically going to find the funding to respond to the constraints for such laudable initiative. The idea of establishing a network of centers of excellence in clinical research in Europe has been put forward.¹⁰ These centers would receive adequate public funding for appropriate facilities, high standards of research practice, intellectual leadership, and training for other clinical research professionals.

There is still a lot to be done. The participants of clinical trials, investigative site research teams, and the credibility of clinical research should all benefit from the these new laws in Europe.

Elizabeth O'Doherty,* RN, is a research nurse and site coordinator, Stephane Dewit, MD, PhD, is deputy head of department, and Nathan Clumeck, MD, PhD, is the head of department, all at the Department of Infectious Diseases (PL5), C.H.U. St. Pierre, Rue Haute 290, 1000 Brussels, Belgium, + 32 2 535 4374, fax + 32 2 539 3614, email: Elizabeth_odoherty@stpierre-bru.be

*To whom all correspondence should be addressed.

References

1. International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (1996) Good Clinical Practice: consolidated guidance, 62 Federal Register 25692 (1997), http://

www.fda.gov/cber/ich/ichguid.htm

2. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. http://europa.eu.int/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf

3. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the Clinical trial in medicinal products for human use (April 2003): European Commission Enterprise Directorate General, http://www.eudract.emea.eu.int/document.html#userguides

4. E. O' Doherty and N. Clumeck, "Innovations at an Investigative Site," Applied Clinical Trials, 6 (11) 38–46 (2003).

5. F.G. Miller and D.L. Rostensein, "The Therapeutic Orientation to Clinical Trials," New England Journal of Medicine, 348 (14) 1383–1386 (2003).

6. S. Pelke and D. Easa, "The Role of the Clinical Research Coordinator in Multicenter Clinical Trials," Journal of Obstetric, Gynaecologic and Neonatal Nursing, 26 (3) 279–385 (1997).

7. A. Frydrych, J.D. Burrowes, J. Leung, J. Dwyer, S. McLeroy, L. Uhlin, S. Marjoram, D. Cockram, B. Weiss and the HEMO Study Group: "Dieticians as Study Coordinators," Applied Clinical Trials, 3 (11) 60–68 (2003).

8. E.J. Emmanuel, D. Wendler, C. Grady, "What Makes Clinical Research Ethical?" JAMA, 283 (20) 2701–2711 (May 24/31, 2000).

9. FDA, 21 CFR Part 11, Electronic Records; Electronic Signatures; Final Rule. Federal Register Vol. 62, No. 54, 13429, March 20, 1997.

10. N. Clumeck and C. Katlama, "A Call for a Network of Centres of Excellence in Clinical Research in Europe," The Lancet, 363 (9412) (March 13, 2004).