Good Clinical Practice in Clinical Trials: What Does It ...

Editorial Cornelis

van Kuijk,

Good What Good

MD,

PhD

Clinical Practice Does It Mean for

Clinical

Practice

internationally

(GCP)

adopted

refers

standard

to an

to de-

sign, conduct, record, and report clinical trials. GCP guidelines have several objectives. Not only do they provide a framework for protecting the rights of participating patients or volunteers, but they also set standards to safeguard the integrity of data that are submitted to regulatory agencies around the world. GCP guidelines are now implemented worldwide in clinical trials conducted and sponsored by the pharmaceutical and medical device industries. These companies have responded to the GCP guidelines by gradually increasing the size and influence of their internal and external quality assurance departments.

It used ments

to be the

between

those

practice

those

in industry

were

made

tween the investigators directors or managers. ever, those in industry with a contract research

1

From

1998;

and

directly

be-

departmental

and radiologists,

Radiology

agree-

sites

and the medical Nowadays, howtend to contract organization to

Index terms: Editorial Radiology and radiologists, management

Radiology

that

at clinical

209:625-627

the Department

ofRadiology,

Univer-

sity of California San Francisco. Received February 12, 1998; revision requested April 22; revision received May 22; accepted August author,

223,

3. Address Department

Academic

of Amsterdam,

Amsterdam,

CRSNA,

1998

reprint requests of Radiology,

Medical

Center,

Meibergdreef

the Netherlands.

9,

actually conduct a study, or part of a study. These contract research organizations have completely adopted the GCP guidelines and expect the same from the participating investigators. Furthermore, the quality assurance departments, where GCP guidelines are preached as the commandments for clinical trials, expect complete compliance with these guidelines as well. Contract research organizations, as well as the pharmaceutical and medical device industries, have quality assurance

auditors

to the Ste Gi-

University 1105

AZ

who

make

sure that

a clinical

site

is GCP compliant. GCP guidelines have also been adopted and are overseen by the International Committee of Harmonisation (ICH). This committee generates guidelines in consultation with the regulatory agencies and recommends the final drafts to the regulatory bodies of the United States, European Union, and Japan. The ICH was established in 1990 and has been very active since. A total of 45 guidelines have been issued, among which is the Guideline for Good Clinical Practice (1). The tripartite harmonized GCP guidelines were finalized in May 1996 and adopted by the European Community in July 1996, by Japan in March 1997, and by the United States (Food and Drug Administration) in May 1997. The GCP philosophy itself was gradually introduced into

clinical

research

in Clinical a Radiology

trial management

in the 1990s

but

became mandatory only recently. The GCP guidelines include a set of rules for the institutional review board or independent ethics committee, for the investigator, for the sponsor, for the clinical trial protocol and protocol amendments, and for the investigator’s brochure. In addition, the guidelines define the essential documents necessary for conducting a clinical trial. The list of essential documents totals 53; 41 of these are

required investigator

to be located or institution.

in the

files of the

Trials:

Physicians

who

refer

patients

or volun-

teers for clinical trials have been made aware of the GCP guidelines over the past few years and have experienced the tremendous increase in requirements and related workload, especially documentation. For many clinicians, Case Report Forms (forms used to document virtually everything that happens to a patient or volunteer in a study) have become so numerous for all new protocols that a full-time administrative person or dedicated research nurse is necessary to cornplete all of the required documentation. In addition, the maintenance of documentation other than Case Report Forms has become quite a tedious task. This level of documentation transcends what is mandated by the Health Care Financing Administration and other insurers. Furthermore, appropriate staffing becomes difficult. Although quite a few of us provide imaging services for clinical trials, there is a general unawareness of these GCP issues and their consequences among radiologists. These issues become (suddenly) very important when imaging provides the primary efficacy parameter of a clinical trial. Since this parameter will define if a drug or device makes it onto the market, adherence to GCP guidelines is mandatory. In this editorial, I attempt to analyze the implications of GCP guidelines and philosophy for a radiology department

involved

in a clinical

General

Requirements

trial.

In the following paragraphs, some of the general GCP requirements are discussed. When an auditor visits a radiology department, she or he will look for these documents. Bear in mind that a lot of the GCP requirements relate to proper

documentation, auditor

can

because evaluate

this and

is what assess

an

objec-

625

tively. The performance of investigators in clinical trials will be judged mainly their maintaining the proper documenta-

by

tion.

Training

Documents

Operating

and

Standard

Procedures

Auditors

will

documents.

always

They

ask

will

not

for

training

only

ask

for

your curriculum vitae and related certificates (eg, board certification and/or continuing education certificates), but they will also ask about your familiarity with the study protocol. Basically, you have to

document

that

you

have

read

the

entire

protocol and that you have extracted and correctly implemented that part of the study that relates to your responsibilities. The easiest way to do this (although it takes time to do it) is to generate your own standard operating procedure for your task in the study. In this standard operating procedure, document your responsibilities as well as those of your colleagues, participating technicians, and other personnel. Auditors are interested in knowing “who is doing what and do they know what they are doing?” A standard operating procedure can be a singlepage document if your tasks are simple (“Dr X and MR [magnetic resonance] technologist Y will perform an MR study of the hand according to the requirements as stated in the protocol [Title and Date], etc”). But, in more complex studies that involve a variety of people with different responsibilities, the standard operating procedure can be a multipage document. Auditors are especially fond of having version numbers and dates on documents (as well as signatures), because these provide a “clean” paper trail when changes to documents are made.

down the road), the MR apparatus is replaced. The new equipment, however, will not provide the same sequences that you worked with in the past. This is a potential problem because now no guarantees of a reliable comparison with baseline data can be given. The study is thus at jeopardy because it has to be documented that what you do now is comparable to what you did in the past. In general, equipment changes have to be avoided in trials as much as possible. Standardization is the key word in GCP. The same holds true for equipment upgrades and even regular maintenance. I have done studies in the past in which we discovered that “fine-tuning” of equipment led to substantial differences. As such, maintenance records and, if applicable, quality control charts of the equipment used in the trial have to be maintamed.

Image

Acquisition

Because many current studies are multicenter studies (from five to 200 sites), it has become extremely important to standardize image acquisition protocols. Ev-

eryone

who

works

Not

Device only

must

Quality the

Control

investigator

and

the

co-investigators and study coordinators be certified and demonstrate competence in their respective areas, but also the equipment on which they work will be checked. This is especially true if a study warrants that a certain type or version of the device be used for the duration of the trial. Consider, for example, the following scenario: You are asked to participate in a study that uses MR imaging with a protocol prescribing certain imaging sequences. The patients in this study will have a baseline study and several follow-up studies over a specific time period. After the study has started (somewhere

626

Radiology

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depart-

ment knows how difficult that is. Radiologists trained at different institutions can have very different opinions regarding the “best” protocol. With standardization as the key issue in GCP, because it ensures comparability of data, a single protocol is typically prescribed in multicenter studies. This protocol is usually a compromise between several expert opinions, which as we all know can be quite different. Furthermore, the protocol should be feasible in all the participating clinical sites. As such, it is not always the “best” acquisition protocol but it should be the “best compromise” that

can be implemented Imaging

in a radiology

have

to be

tant that you are completely aware of the imaging requirements. If you have any doubts or questions, you should contact the quality assurance center. An undesirable situation is one in which clinical investigators from a hospital receive many notices that the acquired images are of unsatisfactory quality and that their work is below standards not informed or

just were

because they incompletely

were in-

formed about the specific requirements for that study. If the imaging part of the study provides the primary efficacy parameter (consider, for example, incidence of vertebral deformities in osteoporosis, progression of erosions and joint space narrowing in arthritis, or tumor volume changes in oncology), you and your department play

a key role in that study. Even if a (research) clinician referred the patients for the study and also performed the clinical evaluation of these patients, there is no reason why you should position yourself just as a service unit. If you are to play a key role, do so, but make sure you deliver quality work.

As the

radiologist

and/or

technician

involved in such a study, you should always be invited to start-up meetings. It is unacceptable that only the clinicians who are responsible for the patients (eg, endocrinologists, rheumatologists, oncologists, etc) attend such start-up meetings when imaging is a primary efficacy

parameter.

at all participating

sites, which in large-scale trials can be at sites worldwide. Nowadays, it is becoming more common for imaging quality assurance centers to provide quality assurance services to the industry. They can be involved in designing the protocol, in training of all participating clinical centers, in providing standardized manuals and guidelines, as well as in providing centralized quality assurance of imaging data and centralized analysis (reading) of the imaging data. These centers have become very popular in large-scale osteoporosis, arthritis, oncology, cardiovascular, and some neurobiology studies. This means that you and your department

differently than what you are used to doing. You need to have flexibility within your organization. Furthermore, you have to accept that your work will suddenly be quality assured by outsiders, who may be telling you they do not like the quality of your work. When your imaging work undergoes quality control by an imaging quality assurance center, it is very impor-

prepared

to

do

things

Record

Keeping

All relevant have to be

records maintained

relating and

to a study archived.

These records include but are not limited to curricula vitae, training records and certificates, maintenance logs, equipment specjfications, Case Report Forms, log sheets, and standard operating procedures. Many auditors require that you

maintain telephone logs. This basically means that you have to document any study-related conversation you had with the sponsor, individuals at the contract research organization, its monitors and auditors, and individuals at other study sites. As this can be extremelylabor intensive, I usually recommend that all com-

van Kuljk

munication be done by facsimile (fax), which always provides a written document. Other documents that can be requested from you are disaster recovery protocols and visitor logs. As mentioned before, participating in a clinical trial under GCP guidelines requires extra administrative work for which you should be reimbursed just as for your imaging services. In addition to the documents outlined previously, it is often requested that you keep patient-specific log sheets for your imaging studies. These log sheets usually contain patient-specific data (number of patients, dates of birth, initials) as well as imaging-specific data (number of studies, date of study, and relevant parameters of the study such as kilovolts peak and milliampere seconds for radiographic studies, repetition time and echo time for MR studies, etc). Please note that both the imaging study itself (radiographs or hardcopy printouts of MR, computed tomographic, or ultrasonographic studies or digital archives) as well as the accompanying log sheets are considered source documents for the study and have to be kept and archived in such a way that they can be retrieved easily by either the sponsor’s auditors or the auditors from the U.S. Food and Drug Administration and/or other regulatory agencies. The following is an overview of required GCP documentation gators: 1 . Study protocol and ments, including sample Forms (signed and dated) 2. Investigator’s brochure

3. Information

given

pants (informed consent formation, advertisements, documents)

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from

investi-

any Case

amendReport

to study form,

partici-

other recruitment

in-

4. Financial documents (budgets, contracts, agreements) 5. Insurance statements 6. Documentation or correspondence for and from the institutional review board or independent ethics committee 7. Curricula vitae, training documents, and/or certification of investigators 8. Signature log sheets 9. Normal values or ranges of parameters for any procedures 10. Certification of equipment or tests (including maintenance logs) 1 1. Trial initiation monitoring report and subsequent monitoring visits reports 12. Relevant communications (letters, fax, meeting notes, telephone calls, email) 13. Any interim or final study reports 14. Any source documents (log sheets, manuals, patient files, reports, radiographs, Case Report Forms) 1 5. Screening, enrollment, and dropout logs 1 6. Standard operating procedures Some of these documents will be provided by the sponsor, while others are the responsibility of the investigator. It is always wise to check this list and ask for the proper documentation from the sponsor if anything is missing.

Is It Worth

It?

I acknowledge the fact that the previous paragraphs were tough reading. As a radiologist myself, I had a difficult time adjusting to all these new demands. And yes, I admit, sometimes the level of documentation currently required to participate in a clinical trial can be overwhelming. On the other hand, it makes you think about the organization of your own department, and you will soon find defi-

ciencies in what you do routinely. Imaging protocols tend to fluctuate, depending on the experience and beliefs of the radiologists involved. A protocol is designed as a standardization tool and should be used as such. Regular evaluations are necessary. Furthermore, standard operating procedures are standardized protocols themselves. It is always enlightening to discover that many things we do routinely are not very well documented. More and more clinicians and radiologists are engaging in clinical trials. There are now several established networks of clinical centers that promote themselves as “big recruiters” for clinical trials. In addition, several private entities have been founded that own and run professional patient recruitment centers for a variety of clinical trials (from osteoporosis to hypertension). As radiology plays a crucial role in a multitude of clinical trials (eg, evaluating new treatments for multiple sclerosis, several neoplasms, angiosclerosis, osteoporosis, arthritis, fracture healing), familiarity with and knowledge of GCP guidelines is a prerequisite for success. Acknowledgment: Thanks to Victoria Vandenberg who converted the original Anglo-Dutch document into plain and readable American English. Reference 1 . International Conference on Harmonisation (ICH)/European Federation of Pharmaceutical Industries Associations. ICH E6 Guideline for Good Clinical Practice 1996. ICH Secretariat do International Federation of Pharmaceutical Manufacturers Associations, Geneva, Switzerland. In the United States: published in Federal Register, Vol. 62, No. 90, 1997; 25691-25709. Available at: http://www.ifpma.org/ich5e.html. Accessedjanuary 4, 1998.

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Clinical

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In CllnlcalTrials

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