Introduction:

Good Clinical Practices

After reading this you will be able to understand the basic principles of Good Clinical Practice (GCP); an international standard on how clinical trials should be conducted. The basic ethical principles of GCP are:• Well-being of participants• Benefits versus Risk• Ethics committee approval• Voluntary informed consent • Confidentiality of participants

Who Can Be An Investigator?

Good Clinical Practice mandates:

Quality and Experience - The investigator must...

be suitably qualified and have the appropriate experience

have an up-to-date CV: this should describe the investigator’s current appointment as well as provide any other relevant evidence of suitability to undertake the study

have knowledge of GCP and the appropriate regulatory requirements

Good Clinical Practice mandates:

Time and Availability - The investigator must have time to do the study. Time is needed…

for regular meetings with the sponsor monitor

to identify and screen suitable subjects to spend adequate time with study

subjects to obtain consent, answer questions and to carefully implement the study protocol

to brief research team members and review the progress of the study

to meet with auditors and inspectors

Good Clinical Practice mandates:

Commitment - The investigator should also have:

appropriate facilities and equipment

suitable co-workers

reliable number of suitable subjects to enter the study

commitment to comply with principles of GCP

Communication is the key to the success of any clinical study.

Keep others informed…

…and be informed!

Rules of Good Clinical Practice

1. Know and Follow the Protocol

2. Select and Train Personnel

3. Recruit Subjects

4. Record Data Carefully

5. Maximize Study Subject’s Protection • IRB Approval• Consent• Assent

6. Product Accountability

7. Laboratory Requirements

8. Safety Reporting

RULE 1 - Know and Follow the Protocol The protocol is a unique document describing in detail how the study

should be performed.• READ – all research team members should read and be familiar with the

protocol• AGREE – the investigator should discuss any areas of concern with the

sponsor before the study starts• SIGN – by signing the protocol, the investigator is making a formal

agreement to adhere to it at all times

• FOLLOW – non-adherence to the protocol, no matter how minor, may have a major effect on the study outcome. All deviations from the study protocol should be recorded. Protocol violations reflect poorly on the quality of the investigator and research team and cost time and money.

• MAKE AVAILABLE – the protocol should be kept in a central location so that it is available to each member of the study team. Each team member should be given a copy. However, since the protocol is a confidential document, its distribution should be controlled and recorded.

• FILE – a copy of the final protocol should be placed in the study file. Old versions should be clearly marked as being out of date and filed away from the current version to avoid confusion.

RULE 2 - Select, Train and Log Suitable Study Personnel

• SELECT – The principal investigator should be a qualified physician or other healthcare provider and is the responsible leader of the research team. Sub-investigators may be other members of the team who are supervised and designated by the investigator to perform study related procedures and/or to make important study-related decisions.

• TRAIN – Investigator should have available an adequate number of qualified staff for the proposed duration of the study to conduct the study safely and properly. All study personnel and members of supporting departments (e.g. pharmacy) need to be fully informed about the protocol, the investigational product(s) and their study-related duties. Regular team meetings should be held to review activities and progress.

• LOG – A log of all personnel with significant study-related duties is required. This “delegation of authority” should be kept with the permanent study regulatory files. This should list each person’s name, job title, role and dates of involvement in the study (no matter how short). CVs should be kept in the study file for all investigators and sub-investigators.

RULE 3 - Subject Recruitment

• PREDICT ACCURATELY – Predict subject recruitment using both past and current information. DO NOT GUESS.

• SELECTION – Choosing suitable subjects is important. Remember some subjects may not want to participate. Follow the protocol’s inclusion and exclusion criteria exactly. Keep a log of screened and recruited subjects. Be supportive of patients who chose not to participate in order to alleviate worries that they have not been a “good” patient by refusing the invitation to participate.

• WITHDRAWALS – Subjects may withdraw at anytime. If they decide to do so, try politely to obtain and record reason.

Test Your Knowledge

• If you don’t have past and/or current patient information to predict subject recruitment, estimating the number of potential subjects is an acceptable practice.o True False

RULE 4

Record Data Carefully

• Source Documents

• Case Report Forms (CRF)

• Study Files

• Source Data Verification against CRF

SOURCE DOCUMENTS – The place where data is recorded or written for the first time is considered a source document and MUST BE KEPT as part of the permanent records. (Source documents may include items such as clinic notes, x-ray reports, lab reports, etc.) Data reported on the CRF, that are derived from source documents, must be consistent with source documents or the discrepancies must be explained.

CASE REPORT FORMS – All study data are to be fully, legibly, and accurately recorded in the CRF in a timely manner. All information recorded on the CRF must be able to be validated by information in the source documents. If changes are made, they must be made clearly and dated and initialed and should not obscure the original entry. Ideally, key study-related data will also be recorded in the subject’s files. (This allows reconstruction of the study in the event that CRFs are lost.)

STUDY FILES – need to be stored in a safe, secure and confidential place to control access and prevent important documents from getting lost and/or prematurely destroyed. Once the study has ended, the investigator is obliged to keep the study-related documents for a minimum of two years after FDA review.

The sponsor will notify the investigator when the study-related records are no longer needed. When the study includes an treatment or intervention, a copy of the consent form should be sent to medical records at the beginning of the study. This is done to document the subject’s participation in the study in case the subject requires medical attention in an emergency situation.

SOURCE DATA VERIFICATION Monitoring and auditing by the sponsor and inspection by the appropriate regulatory authorities is for the purpose of performing source data verification (SDV). SDV involves the Clinical Research Associate (CRA), or monitor, comparing entries in the CRF with data recorded in subject files (source documents). The goal is to ensure that all data are correctly and reliably recorded. This is a quality control process.

RULE 5

Maximize Study Subject’s Protection

• IRB Approval

• Consent

• Assent

IRB Approval

Before starting a trial the principal investigator must obtain written and dated approval from the IRB of the following:

• The final protocol• The consent/assent form(s)• The current investigator’s brochure• Any subject recruitment methods (e.g. poster or

advertisement)• And any other documents (e.g. questionnaires,

scripts, etc.) the IRB may need to fulfill its responsibilities.

The principal investigator must inform the IRB of the study status at least annually and when the study is finished or if it is terminated earlier than planned.

CONSENTCONSENT Subjects must be fully informed about the study.

Information should be provided both verbally and in writing. Subjects should understand the purpose of the study, the procedures

they are being asked to undergo, the risks and benefits and the voluntary nature of their participation (i.e., they can stop their participation at any time).

Subjects must be given ample time to ask questions and make a decision.

The subject’s freely given consent should be obtained in writing BEFORE ANY study-related procedures are carried out.

Both the person obtaining the consent and the person(s) giving consent need to sign and date the consent form on the same occasion.

A copy must be given to the subject, and the original should also be placed in the subject’s file or study binder.

Subjects may need to re-consent to taking part in the study if important new information becomes available.

IMPORTANT: Consent is an ongoing process that starts with at the first contact with a potential subject and continues throughout the entire study.

ASSENTASSENTFor ChildrenFor Children

• Except under specific circumstances, assent to participate in a study must be obtained from children (i.e., in North Carolina, subjects aged 17 and under) who are capable of providing assent, which can be written, oral or both. The IRB shall determine that adequate provisions are made for soliciting the assent of the children (this includes proving age specific language to the prospective subjects), when in the judgment of the IRB the children are capable of providing assent.

RULE 6: Product Accountability

RECORD KEEPING - Detailed records of study product (received from the sponsor, kept at the site, dispensed to each subject, returned from each subject, and returned to the sponsor) should be maintained by the study pharmacist.

COMPLIANCE - Correct use of the investigational product(s) should be explained by the investigator, or a person designated by the investigator, to each subject and the investigator should check, at appropriate intervals, that the subject is following instructions correctly.

STORAGE - Investigational product(s) should be stored in a secured area as specified by the sponsor and in accordance with applicable regulatory requirements..

Rule 7: Laboratory Requirements

Documentation– Before the implementation phase of the study begins the

sponsor will need CHCC reference ranges for tests included in the protocol and quality assurance information (certification or accreditation).

Updates– For the duration of the study, updates of these items need to

be provided to the sponsor.

Review– An appropriately trained person must review all laboratory

results.

Results– Any abnormal results should be followed by the investigator

until resolution.

Rule 8: Reporting of Unanticipated Problems

Events that are unexpected in nature, severity or frequency AND related to participation in the research study should be reported to the IRB. Upon review of the report, the IRB will determine if the event places the subject or others at a greater risk than was previously recognized.

Unanticipated problems should be reported to the IRB within 2 weeks of the investigator becoming aware of the problem. Unanticipated problems that are serious adverse events should be reported within 1 week.

You may have other reporting responsibilities (e.g. study sponsor, funding agency, NIH, etc.). You should learn what these are prior to initiating the study.

Definitions

Adverse Event (AE) - An adverse event is ANY untoward medical occurrence in a study subject who has been administered a pharmaceutical product. The event need not have any relationship with treatment. (e.g. Person slips on icy sidewalk.) ALL adverse events must be reported in the case report form.

If the adverse event has a reasonable causal relationship with treatment, it is defined as an Adverse Drug Reaction (ADR) (e.g. Elderly person slipped on icy sidewalk because she was dizzy from study medication.) “All non-reportable” adverse events (and IND safety reports) should be reported in aggregate to the IRB at the time of annual renewal.

Serious Adverse Event (SAE) -This is defined as any untoward medical occurrence that results in:

death is life-threatening requires inpatient hospitalization or prolongs existing hospitalization results in persistent or significant incapacity/disability results in a congenital anomaly

SAEs must be reported by the investigator to the Sponsor as stated in the protocol (typically, within 24 hours).

During and following a subject’s participation in a study, the investigator should ensure that adequate medical care is provided to a subject for any AE, ADR, or SAE, including clinically significant laboratory values, related to the study.

Protocol Violations and Deviations (minor departures from the approved protocol which has not been approved by the IRB) are considered unanticipated problems because they are unexpected and related to the research.

Reporting requirements are as follows: Within two weeks: violations/deviations that pose a risk to

subjects (e.g.missed safety labs) Within one weeks: violations/deviations that pose a risk to

subject which are more serious (e.g.missed pregnancy test and the subject is found to be pregnant).

Provide list as part of annual renewal application: Violations/deviations for which the risk associated with the event is no more than minimal (e.g. visit completed 2 days outside of window)

Scenario

You are a research coordinator for a study in the NICU that involves infusing patients with a drug to prevent staph aureus. While on the study drug, one of your study patients develops a head bleed and the physician has been made aware of the bleed.

Question: An adverse event has occurred. You are not sure at this time

whether this is related to the study drug or related to the disease process. What should you do?

Discussion: Because this “bleed” has occurred while the patient is on a study

protocol it is important “to document” this as an adverse event (whether or not it was actually caused by the study drug) and report (in writing) to the IRB and the sponsor.

You may take the test now by clicking on the “test” button, or you may leave and return at a later time to take the test by clicking on the “exit” button.

1. The basics of good clinical practice are: 1) protection of the patient; 2) data obtained is timely; 3) data obtained is correct; 4) data obtained is reproducible; 5) protection of the investigator:o 1 and 5o 1, 2, and 5 1, 3, and 4o All of the aboveo None of the above

2. In addition to time and the appropriate experience, the investigator should have:

Knowledge of “Good Clinical Practices”o Proven ability to recruit subjects quicklyo A track record with the company sponsoring the study

3. The investigator is the only member of the research team that needs to be fully informed about the trial and needs access to the protocol.o True False

Test – Good Clinical Practices

4. Prior to taking on the responsibility for a clinical study, the investigator needs to consider whether he/she has a reliable number of suitable subjects.

Trueo False

5. Detailed records of the study product (drug) should be kept by a:o Lab tech Pharmacisto Study Nurseo None of the above

6. Once approval is received by the hospital’s IRB to go ahead with the study, the investigator has fulfilled all his/her obligations to the IRB for the duration of the study.o True False

Test – Good Clinical Practices

7. All abnormal laboratory results should be followed by the investigator until resolution.

Trueo False

8. Obtaining consent ___________ any study-related procedures are carried out is mandatory.

Beforeo Within 24 hourso After

9. The investigational drug can always be stored in the clinic during the study.o True False

10. Subjects may withdraw from the study at any time. Trueo False

Test – Good Clinical Practices

11. The key to the success of any clinical study is:o Making sure the principal investigator does all the worko Making sure the nurse coordinator has read the protocol Communication – keeping the team informedo Recruiting large numbers of subjects

12. Before a study begins, the sponsor needs the following from the laboratory:o A. Reference ranges for tests included in the protocolo B. Proof of a laboratory’s accreditation or certification C. a and bo D. None of the above

13. In order to obtain appropriate informed consent, information needs to be provided both verbally and in writing to the subject.

Trueo False

Test – Good Clinical Practices

14. The principal investigator is the only member of a research team that needs to be familiar with the protocol.o True False

15. It is not necessary to keep source documents if study data is recorded on the case report forms.o True False

16. The only difference between an “adverse event” and a “serious adverse event” is whether or not the event is related to the study.o True False

17. Subjects do not need to be re-consented to take part in a study if important information becomes available after the study began.o True False

Test – Good Clinical Practices

Congratulations!

You have completed the Good Clinical Practices Training Module