Introduction

This article provides an overview of currently accepted quality requirements for the conduct of clinical trials and is intended to serve as an introduction to that area of the regulated environment recognized as the quality standards employed in clinical trials around the world and referred to collectively as Good Clinical Practice (GCP).

Good Clinical Practice can be defined as:

“A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected.”¹

In the United States, clinical trials on nonapproved, formulated, new chemical entities are required to be performed in accordance with Investigational New Drug regulations as promulgated under Code of Federal Regulations (CFR) 21 Section 312. When a sponsor believes that it has sufficient data to show that a new chemical entity is safe, based on adequate data from prior non-clinical studies in research animals, the sponsor assembles and submits an Investigational New Drug application (IND).

The IND is the vehicle through which a sponsor seeks an exemption from the statutory provision that prohibits unapproved drugs from being shipped in interstate commerce. The IND is essentially a proposal through which a sponsor obtains Food and Drug Administration’s (FDA) permission to initiate testing of an investigational study drug in human subjects. Several regulations have historically governed what is recognized today as Good Clinical Practice (GCP) regulations that serve as the quality standard to be used during the conduct of clinical trial studies.

The FDA established the U.S. GCPs over a number of years in response to inspectional findings that cast doubt on the validity of some clinical trials. Problems identified in these early years by FDA, included: inadequate or missing subject records; serious adverse event not reported; significant clinical study protocol deviations; clinical studies performed without appropriate ethics committee (or, as referred to in the U.S., Institutional Review Board - IRB) approval; failure to obtain informed consent; and in some cases, fraudulent data. As a result of such past events and the introduction of established GCP quality standards, clinical research investigators have been subject to intense scrutiny by sponsors (e.g., clinical site monitoring visits and quality audits) as well as FDA clinical site inspections.

The GCP regulations, relevant to the conduct of clinical trials, include: 21 CFR 50, Informed Consent; 21 CFR 56, Institutional Review Boards or IRBs; and 21 CFR 54, Financial Disclosure. Perhaps also to be included in these sets of regulations would be 21 CFR 11, as it pertains to Electronic Records and Electronic Signatures used in the conduct of clinical trials; however, there continues to be substantial discussion on FDA’s actual intent of 21 CFR 11 in the hospital or research center clinical setting. Finally, in the late 1990s, the International Conference on Harmonization (ICH) published E6: Good Clinical Practice. The ICH GCP guidance is similar to, but more detailed than U.S. GCPs. The ICH E6 guideline continues to be the most recognized document to date and provides the standard for Good Clinical Practice. It is consistent with 21 CFR Parts 50, 54, 56, and 312 GCP regulations, and strict adherence to GCP and IND rules ensure that established quality processes are being followed.

In addition to FDA’s GCP regulations and guidelines, several other documents are often discussed in the context of clinical research standards, including the Declaration of Helsinki, the afore mentioned ICH GCP Guideline E6, the Department of Health and Human Services (DHHS) so-called “Common Rule” and the World Health Organization (WHO) GCP guidelines. Figure 1 depicts the general hierarchy of GCP quality standards.

The “Common Rule,” also referred to as the Health and Human Services (HHS) regulations or the “Basic DHHS Policy for Protection of Human Subjects,” is the U.S. federal policy that provides regulations for the protection of human research participants in research conducted, supported by, or otherwise subject to regulation by a federal government agency that has formally adopted the policy. The HHS Office of Human Research Protection (OHRP) administers the common rule, which has no direct applicability to purely commercial research regulated by the FDA.

Figure 1: Levels of GCP Standards

Standard	Basis
GCP Best Practices	Industry, Academic, and Regulatory Agency Current Thinking
International Conference on Harmonization	GCP Guideline E6
Food and Drug Administration	GCP Regulations and Guidance

Sixteen government agencies, including the National Institutes of Health (NIH), the Department of Justice, the Department of Education, etc., that conduct, regulate, or fund human research have signed on to comply with the provisions of the common rule. When studies involving FDA-regulated products are funded or supported by HHS, the research must comply with both FDA GCP standards and the common rule. The common rule, which focuses on Institutional Review Board or IRB standards and informed consent, is similar to FDA requirements for IRBs (21 CFR Part 56) and for Informed Consent (21 CFR Part 50).

Clinical Study Design Features

Clinical studies are the most critical and demanding stage in the drug development process. The principle restrictions facing an IND holder is that an investigational drug may be shipped and supplied only to those Clinical Investigators (CI) identified in the IND for use exclusively in those experiments described in the clinical controls section of the IND application or its amendments subsequently submitted to FDA.

Phase I

Clinical studies are essentially conducted in several recognized, distinct phases. These include Phase I trials, which typically involve initial safety and human pharmacology studies. Phase I clinical trials start with the initial administration of an investigational new drug to humans. Although human pharmacology studies are typically identified with Phase I studies, they may also be indicated at other points in the development sequence. Studies in this phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer subjects or certain types of patients, e.g.: patients with mild hypertension. Drugs with significant potential toxicity, e.g.: cytotoxic drugs, are usually studied in patients. Phase I studies can be open and baseline controlled, or may use randomization and blinding to improve the validity of observations. Phase I studies typically involve one, or a combination, of the following: estimation of initial safety and tolerability, after both single and multiple dose administration; pharmacokinetics; assessment of pharmacodynamics; and early measurement of drug activity, if possible. Phase 1 trials typically involve 20 to 80 subjects and last, on average, six months to one year.

Phase II

Phase II clinical trials are designed as therapeutic exploratory trials, and are usually considered to start with studies in which the primary objective is to explore therapeutic efficacy in subjects. In initial studies, a variety of designs may be used, including concurrent controls and comparisons with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication.

Phase II studies are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population and are closely monitored. An important goal is to determine the dose(s) and regimen for Phase III trials. Early Phase II studies, also referred to as Phase IIa trials, often utilize dose escalation designs to give an early estimate of dose response. Later studies may confirm the dose response relationship by using recognized parallel dose-response designs. Additional objectives of Phase II trials may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications), additional safety data, as well as target populations (e.g., mild versus severe disease) for further study in Phases II or III. These objectives may be served by exploratory analysis, examining subsets of data, and by including multiple endpoints in trials. Phase II clinical trials typically involve 100 to 200 subjects.

Phase III

Phase III, or therapeutic confirmatory clinical studies, usually is considered to begin with the initiation of studies in which the primary objective is to demonstrate, or confirm, therapeutic benefit. Phase III studies are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies, also referred to as “pivotal” clinical trials, are intended to provide an adequate basis for marketing approval. Phase III studies may also further explore the dose-response relationship, or explore use of the drug in wider populations, in different stages of disease, or in combination with another drug. Trials involving extended exposure to a drug are ordinarily conducted in Phase III, although they may be started in Phase II. Studies carried out in Phase III complete the information needed to support the labeling for use of the drug. Phase III trials involve, in some cases, thousands of subjects and are conducted at multiple clinical research sites or centers by the IND sponsor.

Phase IV

There are clinical trials referred to as Phase IV studies, also called “quality of life” trials, and include a variety of studies for therapeutic use. Phase IV trials typically begin after drug approval. Therapeutic use studies go beyond the demonstration of the drug’s safety, efficacy, and dose definition. Phase IV activities are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are not considered necessary for approval, but are often important for optimizing the drug's use and are often driven by the sponsors’ Marketing and Sales Departments. Commonly conducted studies include: additional drug-drug interaction, dose-response or safety studies, and studies designed to support use under the approved indication, e.g.: mortality/morbidity studies, and epidemiological studies.

Operational Factors

When considering operational systems to meet Good Clinical Practice requirements, there are essentially three main “customers” to be considered. These include: the clinical research study subjects, or patients enrolled in a clinical study at the established clinical investigational site(s); the clinical study site personnel; and the IND sponsor of the clinical research for the investigational drug. It should also be noted that typically the “sponsor” of the clinical research study is a pharmaceutical or medical device company, but sometimes the sponsor can be an independent research body.

At a clinical research site, there are essentially two distinct identities that are considered key personnel, the Principal Investigator (PI), and equally important, the Study Coordinator (SC). The PI, also referred to as the Clinical Investigator (CI), must be suitably trained, qualified, and have the appropriate experience that demonstrates that he or she is an expert in the clinical investigation of the study drug or device for use under the clinical investigational plan. This qualification requirement is made by the submission of an up-to-date Curriculum Vitae (CV), which is requested and reviewed by the clinical trial sponsor.

The CV should show the CI’s current appointment, knowledge of GCP, and appropriate regulatory requirements. PIs are almost always licensed medical doctors. However, it is important to note that a person qualified to conduct a clinical research trial can also be a non-physician, such as Ph.D., Pharm. D., D.O. or D.D.S. FDA GCP regulations under 21 CFR 312.53(a) require that clinical research investigators: “…be qualified by training and experience as an appropriate expert to investigate the study drug in humans.” The ICH E6 GCP guideline states that an investigator

“should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial and should meet all the qualifications specified by the applicable regulatory requirements.”

Moreover, although the FDA GCP regulations make no reference to a medical degree or other specific education and training, the ICH E6 guidance, adopted by the FDA in 1997, under Section 2.7, states that:

“The medical care given to, and medical decisions made on behalf of subjects, should always be the responsibility of a qualified physician or, when appropriate, a qualified dentist.”

Beyond the review of these basic GCP requirements, it is imperative that the PI assigned to a clinical investigation trial:

1. Allows time for regular meetings with the sponsors’ clinical study site monitoring personnel.
2. Is able to identify and screen suitable study subjects.
3. Obtains informed consent from trial subjects prior to subject entry in a clinical study.
4. Spends time with trial subjects.
5. Is able to continually brief study site research team members and review progress of the trial.
6. Completes paperwork, such as case report form (CRF) data entry.
7. Is available to participate in sponsor quality site audits and FDA site inspections.

Clinical Research Development

Clinical trial studies are required to have access to adequate study subjects and facilities, appropriate and secured storage areas for the investigational drug, suitable equipment, and the necessary time a CI will need to carry out a clinical trial efficiently. We have already identified that a clinical research site is required to have a PI who is ultimately responsible for the coordination and conduct of the clinical study. The PI will often be accompanied at the research site by sub-investigators and a study coordinator. The “Sub-Investigators”(SIs) almost always hold medical degrees and have established roles and responsibilities defined at the site. SIs are defined as anyone “that significantly contributes to the study.”

The PI and SIs who treat and evaluate patients must be willing to follow all trial procedures even when they differ from normal practices at the site, e.g.: maintaining drug accountability records, not using certain concomitant medications, more frequent patient visits with increased documentation demands, and more or different testing than usual. Clinical study protocol compliance is especially important in multi-center study trials because chronic non-adherence to the protocol can make combining data inappropriate for later analysis by the study sponsor.

It is important to note that Industry has categorized protocol non-adherence with their own developed nomenclature, such as: “protocol departure,” “exception,” or “violation,” etc. FDA, on the other hand, has always viewed any non-adherence to the clinical study protocol as a protocol violation, period. Not following the clinical study protocol at a clinical site is one of the most common findings from FDA inspections. If FDA considers protocol non-compliance to be substantive, it can result in significant problems for the PI including the site’s data being dropped from consideration.

In Figure 4, one of the top five bioresearch monitoring FDA483s is listed as follows: “an investigation was not conducted in accordance with the signed statement of investigator or investigational plan….” This FD483 (written in FDA’s new Turbo format) can be written when, during an inspection, the FDA investigator determines protocol violations occurred during the course of the study. Whether or not a protocol deviation was planned, unplanned, or is of minor significance, FDA considers all of these as simply, protocol violations. The sponsor should have developed systems and procedures that ensure protocol exceptions (intentional, planned deviations) and unplanned deviations are reviewed, evaluated, and if acceptable, approved by the IND sponsor’s medical monitor.

Figure 4: Top Five Bioresearch Monitoring FDA Inspectional Observations for Clinical Research Site Inspections

21 CFR Citation	Observation
312.60	An investigation was not conducted in accordance with the signed statement of investigator or investigational plan
312.62(b)	Failure to prepare or maintain adequate or accurate case histories with respect to observations and data pertinent to the investigation or informed consent
312.60	Failure to obtain informed consent, in accordance with 21 CFR Part 50, from each human subject prior to drug administration or conducting studyrelated tests
312.62(a)	Investigational drug disposition records are not adequate with respect to dates, quantity, or use by subjects
312.66	Failure to report promptly to the IRB all unanticipated problems involving risk to human subjects or others

Of course, trend analysis of protocol violations is a very important quality tool at the IND sponsor company that ensures protocol violations are not rampant or indicative of a poorly designed protocol or of inadequate clinical site training. Indeed, it is to the credit of the savvy clinical research sponsor team to develop clear instructions in the study protocol, provide adequate training of the protocol at the time of site initiation, as well as “benchmark,” at predefined intervals during the clinical trial, the number, type, site trends, etc., to determine whether action should be taken during the trial to minimize protocol violations before they get out of hand. Compliance is then an important factor at a clinical site because of the GCP requirement that, should a sponsor find that the PI is not following the protocol or regulations, they must “promptly” either secure compliance or end the PI’s participation in the trial.

The clinical study site Study Coordinator (SC) is usually a Registered Nurse (RN) and has a significant role in ensuring day-to-day study requirements are met. The Study Coordinator is usually responsible for ensuring records and reports, such as patient charts and specific clinical study “data capture instruments,” including sponsor designed Case Report Forms (CRF), are completed and updated in a timely manner.

Several key principles in regard to data collection are required under Good Clinical Practice regulations. FDA expects that data acquired during a clinical study follow the acronym ALCOA (see Figure 2). That is, clinical trial data is required to be Attributable, Legible, Contemporaneous, Organized, and Accurate.

Probably the two least understood of these GCP data collection quality requirements include attribution and “contemporanity.” The first involves ensuring that clinical trial data, such as data that supports an efficacy assessment is documented in the patient record as being attributable to someone who is responsible for the oversight of the study, i.e., the PI or an SI, who is qualified to obtain, review, or interpret subject test results or diagnostic information. The other critical factor of effective clinical trial management is that clinical data must be reviewed and recorded as it is observed, i.e., “contemporaneously,” and not posted to the established record and reports, days, weeks, or months after the fact. The documentation audit trail is heavily scrutinized during routine sponsor monitoring and quality audits, as well as during FDA site inspections.

Research Subject Recruitment

The success of any clinical study depends on the recruitment of a protocol-specified number of suitable patients within an agreed upon timeframe. If the protocol specifies a maximum number of patients at a site, that number must not be exceeded without sponsor approval. Although it is a common problem, it is important not to overestimate the recruitment rate. If patients are to come from the PI’s own practice, it should be possible to demonstrate, with retrospective data, the potential to meet recruitment goals. Patients who meet most, but not all, entry criteria, referred to as “inclusion and exclusion criteria,” may still be able to participate in the trial with a pre-approved waiver from the sponsor’s medical monitor. Many sponsors publish clinical study newsletters that are sent to all clinical sites involved in a study to communicate the subject recruitment statistics and the status of CRFs, as well as hold Study Investigator meetings to discuss site issues, present feedback to all sites of what GCP and study-related issues are surfacing, and explore remediation measures. This communication goes a long way to ensuring a trial ends on time and top-line clinical research study results are available to the sponsor.

Institutional Review Board Approval

Institutional Review Boards or IRBs, serve an essential and important requirement to ensure patient protection during a clinical trial. It should be noted that the name “Institutional Review Board” is only used in the U.S. Outside the U.S., the term “Independent Ethics Committee” or “IEC” is used. The requirements of IRBs and IECs are very similar and the use of IECs for ex-U.S. IND trials is acceptable to FDA after the IEC complies with the International Conference on Harmonization’s (ICH) E6 requirements. Investigators must have an independent IRB’s written approval of the protocol, the Informed Consent Form (ICF), and any advertising for subject recruitment prior to initiating a clinical trial. The role of the IRB is to ensure the rights and welfare of the trial subjects by providing initial and ongoing review and approval (or disapproval) of clinical trials.

The composition of an IRB requires five members, which includes at least one non-medical person. If the CI is conducting research at a site that does not have a local IRB, a commercial IRB can be used.

Prior to initiating a clinical research trial, the CI must submit the protocol, the ICF (and any other information that will be provided to potential study subjects), the Investigator’s Drug Brochure (IDB) and any advertising to the IRB. It is required that all correspondence to and from the IRB be retained by the CI and that at least copies of all IRB approvals be given to the sponsor.

The sponsor’s Quality Assurance (QA) Department, on occasion, may conduct an assessment of an IRB under consideration for use. Selection criteria for these assessments are based on whether the site will use a local or commercial IRB, and upon the IRB’s past inspection history with the FDA. FDA typically inspects IRBs approximately every three years, or as a need is determined. While FDA IRB inspections are not a rule, the savvy quality professional will obtain Freedom of Information (FOI) redacted Establishment Inspection Reports (EIR) of past FDA inspections of the IRB that will be involved in the sponsor’s study and review FDA’s inspectional findings and remediation. Whether or not the sponsor’s QA Department determines an assessment is needed, it is important to ensure that the IRB has written procedures on how they review initial protocols, protocol amendments, requirements for review of reported Serious Adverse Events (SAE) and IND safety reports submitted by the CI.

Informed Consent

It is essential that each research subject or patient be fully aware of the details of the trial before agreeing to participate. Information should be given in both written and oral form. Although not required by GCP (see Figure 3), it is always a good practice to allow subjects to take an unsigned ICF home to read prior to signing. This allows the patient and interested family members to be well informed about the trial before the formal consenting process.

Figure 3: Key GCP Compliance Parameters

An IRB approved ICF must be signed and dated by each subject, or their legally authorized representative, and a copy given to the subject or the person signing the consent. This must occur before any protocol-specified tests are performed, including tests performed solely to determine subject eligibility (i.e., inclusion and exclusion criteria). In addition, the ICH E6 GCP requires the ICFs be signed and dated by the person who actually performed the informed consent discussion. Most IRBs however, require the CI’s signature on the ICF.

Typically, the clinical trial sponsor will provide a model ICF to the clinical research site, which will then provide this template to their IRB. Often the IRB will make some changes to the ICF. Moreover, as the trial progresses, the sponsor may make changes to the ICF, based on new safety information acquired through the active study trial period, which again, should be submitted to the IRB, by the CI.

It goes without saying that it is important that adequate version control mechanisms are established upfront at the study site to ensure the current IRB approved version of the ICF is being used to consent subjects. This is probably one of the most significant issues in the informed consent area that QA auditors find during their assessments of clinical sites. Using the wrong version of the ICF to consent subjects can result in the potential elimination of clinical efficacy data, but since the subject was exposed to an investigational study drug, safety information would be retained and reported by the study sponsor as part of the Intent to Treat (ITT) subject population in the clinical trial. Moreover, as a precautionary measure, and to avoid mix-ups, clinical research sites secure critical study related documentation, including the current IRB approved version of the ICF, in what is commonly referred to as a regulatory binder, of which many volumes may exist at the clinical research site during the active phase of the clinical trial.

Documenting the actual informed consent process has been an FDA requirement based on FDA guidance documents issued in the 1990s, and continues to be enforced by the issuance of FD483s by FDA field investigators, for any non-compliance to this important aspect of informed consent. The informed consent process is typically documented in the site’s nurse progress notes. At the clinical research site, clinical site monitors, and later in the study, QA auditors will perform a comparison of ICFs versus the number of subjects currently in the trial, those who have completed the trial, and those who have dropped out. It is important to ensure that the informed consent process includes detailed notes taken that describe: how the clinical study was explained to the subject, the study risks, the duration of required study enrollment, what to expect, whether the trial will be using placebo, as well as responses to any questions the subject had. FDA also recommends that a copy of the signed consent form be included in the subject records.

Failure to obtain informed consent in accordance with 21 CFR Part 50 from each human subject prior to drug administration, or prior to conducting study-related tests, is a common FDA inspectional observation as listed in Figure 4.

Confidentiality

It is the duty and responsibility of the CI and staff to respect the confidentiality of the subject. Care should be taken to ensure only the subject’s study number and initials appear on the CRF.

In the last few years, much confusion has surrounded the U.S. government’s so-called Privacy Rule. Promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA), it took effect in April 2003. While this had an impact on all health-related services, pharmaceutical compacompanies performing clinical research were required to accommodate this initiative in their operations. HIPPA covers health plans, health care clearinghouses, and health care providers that transmit health information electronically in connection with certain transactions that are defined in the HIPAA statute. These firms or organizations are otherwise referred to as “covered entities” under HIPAA. These transactions involve areas such as health care claims, subject enrollment and dis-enrollment, referrals, etc.

Clinical research sponsors are required to obtain HIPAA authorization from the research subject by site via a written authorization form, which may be a standalone document or may be integrated into the ICF based on the site’s policies and choosing. The written authorization should be reviewed and approved by the site’s IRB. This requirement only applies to research conducted within the borders of the United States and does not apply to IND studies conducted outside of United States borders. Under HIPAA, the clinical research sponsor, including the monitor(s) and the auditor(s), the IRB, and the FDA are granted direct access to the subject’s original records for verification of clinical trial procedures and data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written ICF with HIPAA authorization, the subject, or the subject’s legally acceptable representative, is authorizing such access and use.

Investigational Study Drug Controls

Drug accountability is an important part of the study, and inadequate records have been a common GCP deficiency in the past. FDA expects sponsors and CIs to document carefully the dispensing and use of all investigational study drugs. The CI is responsible for ensuring that accurate records (dates, lot numbers, quantities) are maintained for investigational product receipt, dispensing, return by subjects, study coordinator, or floor nurses, and destruction or return of unused investigational product to the sponsor for destruction.

It is a common practice for the hospital pharmacist to perform these duties. The pharmacist is listed on the site delegation and signature log, and in some cases will be listed on the FDA-1572 form, dependent on study sponsor requirements. However, even when the pharmacist performs all investigational study drug handling and record keeping, responsibility for the accuracy of records remains, ultimately, with the CI. Although not a GCP requirement, FDA expects a full running inventory for an investigational study drug to be maintained even when quantities issued to and returned by subjects are documented on the CRF.

Subject Logs and Randomization Codes

The CI is required under Good Clinical Practice to maintain study-related logs - separate from other study data - of all research subjects screened for the study, subjects enrolled in the study, and trial study subject drop-outs. These logs, which are maintained in the site regulatory binder, should contain the study number and codes of the subjects. These logs are created to ensure that subjects can be identified after the trial is completed. The study sponsor and FDA representatives can review these during data review, FDA site inspection, and biometric data interpretation.

The study sponsor’s data management programmers typically develop the clinical trial randomization code scheme as part of the study start-up and design. These subject codes and randomization codes, assign subjects to the trial based on the clinical trial protocol, for example, in a double blind trial, the system will assign which subjects will receive actual study drug and which subjects will receive placebo. It is imperative that these codes, usually stored on a CD-ROM, are not accessible to study-related personnel, including sponsor personnel, during the execution of the trial.

Most firms move this information off-site to a third party archive service provider during the clinical trial execution period. In double blind studies, where the subject and the CI are not aware of who will receive study drug or placebo, the sponsor will provide some means of allowing the CI to “break” the study medication code in the event of an emergency, for example, an unexpected serious adverse event, to ensure subject safety is maintained at all times. Usually, sealed envelopes or more sophisticated “lottery ticket” style systems are employed. Of course, protocol and sponsor site initiation training, would emphasize that CIs should not “break” the code unless absolutely necessary, in accordance with rules described in the clinical study protocol. Moreover, the site’s IRB, as well as the site monitor should be informed immediately if a code is broken. Most clinical study sponsors require that all unopened, randomization codes be returned at the end of the clinical trial study.

Adverse Event Reporting

For clinical study trials performed under GCP, Adverse Events (AE) or experiences are defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered associated with the use of the study drug. This includes any signs, symptoms, inter-current illnesses, clinically significant alteration in laboratory values, and any significant worsening of the disease under study, regardless of whether the event is considered to be related to the investigational study drug or to a concomitant medication.

Ensuring accurate adverse reporting during a clinical trial remains one of the most challenging roles for the IND sponsor. The reason for this is the natural tendency to not report AEs that are considered minor or that are not considered related to the investigational study drug. However, GCP requires that all AEs be reported on the sponsor provided CRF, regardless of whether or not they are considered related to the study drug, including: accidents, headaches, colds, etc.

When a study subject is hospitalized during the study period, including a defined period of time after the subject has completed the trial, the sponsor’s Drug Safety Department should review all records of the hospitalization for reportable AEs.

For reporting purposes, a Serious Adverse Event (SAE), is defined as:

“Any adverse event occurring at any dose that results in one of the following outcomes:

• Death
• A life-threatening adverse event experience
• In-patient hospitalization or prolongation of existing hospitalization
• A persistence of significant disability”

Under the U.S. GCPs, SAEs are further defined as:

“Important medical events that may not result in death, be life-threatening, or require hospitalization (but) may be considered a serious adverse event drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or the home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.”²

CIs are required to “immediately” inform the study sponsor of all SAEs, regardless of causality assessment. Typically, this is defined in the clinical study protocol as “within 24 hours.” In turn, the study sponsor is required to submit SAEs that are considered unexpected and determined to be related to the investigational study drug to FDA within 15 working days of receipt; and SAEs resulting in death, within 7 working days. This reporting scheme for SAEs is referred to as “expedited” reporting. In addition, the study sponsor is required to inform all other CIs involved in the study of these SAEs as they occur through the study. These reports are referred to as “IND Safety Reports.” The CI must “promptly” report all SAEs from study site subjects and all IND safety reports to the site’s IRB. “Promptly” is usually defined as “within two weeks,” unless the study site’s IRB requires more rapid reporting.

When reporting an SAE, a CI is requested to give an assessment of the relationship, referred to as “causality,” of the event to the investigational study drug. This determination of “relatedness” of the investigational study drug to the SAE is often expressed as: “probably not,” “possibly,” “probably,” or “definitely.” The U.S. GCP definition of investigational study drug relatedness, that is, associated with the use of the drug, is “…a reasonable possibility that the experience may have been caused by the drug.” Therefore, for the study sponsor’s regulatory reporting purposes, an SAE is considered “investigational study drug-related” if it is classified as “possibly related” or higher in the evaluation scheme.

Delay in reporting an SAE, that is waiting longer than 24 hours, is unfortunately, quite common during clinical trial studies and is also considered a significant non-compliance GCP issue with FDA. As listed in Figure 4, failure to report promptly to the IRB all unanticipated problems involving risk to human subjects or others, is a top bioresearch monitoring FDA 483 inspectional observation.

Clinical Study Site Control Record>/h2>

As discussed previously, clinical study sponsors, e.g., a pharmaceutical or medical device company that is holding an active IND or Investigative Device Exemption (IDE), respectively, are required to obtain some upfront, pre-study information from the site, before the study drug can be sent to the research site. This includes obtaining the CI’s and SI’s up-todate curriculum vitae (CVs) and confirming that they have the training, education, and experience to conduct the intended trial. Moreover, it should be confirmed that the CI maintains a list of study personnel at the research site that also includes delegated duties, exact times (dates) the individual provided services to the clinical site trial, and sample signatures and initials. This “site log” is often referred to as the “site delegation of authority – signature log.”

The other key documents that designated study site personnel are required to complete are the FD-1572 or “Statement of Investigator” forms.³ While there can be considerable interpretation and confusion over who should be listed on the FD- 1572, most sponsors require, at the minimum, that the name of the PI and sub-Investigators be listed. However, ancillary operational staff, such as radiology, pharmacy (if the study is single blinded, the pharmacist should be listed on the FD-1572), and other departments, such as the Surgery Department, if involved in the clinical study, are usually not required to be listed on the form FD-1572; instead, the hospital or research center itself is listed as the entity at which research subjects are evaluated. Moreover, “third party blinded assessors,” such as radiologists, cardiologists, or pathologists, who evaluate diagnostic media for efficacy and safety based on clinical study protocol parameters, do not compromise an investigational site and are considered CIs. Based on FDA interpretation, they are not required to be listed either on the FD-1572 or on the site delegation of authority – signature log. Although key clinical study subject records and reports, such as EKG readings, X-rays, and other diagnostic tests are procured or evaluated by these personnel, they are not considered under GCP to be directly involved in the examination or treatment of study patients.

The PI or CI, as already mentioned, usually appoints a Study Coordinator (SC) to assist with the completion of CRFs and other administrative aspects of the trial. In some cases, a study site might “contract” various portions of the clinical study management responsibilities to a third party, commonly referred to as the application Site Management Organization (SMO) or the Trial Management Organization (TMO). The CI is required to be thoroughly familiar with the sponsor-approved clinical study protocol and properties of the Investigational Product (IP) or study drug.

The sponsor’s Medical Monitor (MM), an M.D., is usually required to review the protocol with the PI and obtain sign-off to the effect that the PI understands the clinical study investigational plan. The sponsor is required to provide an Investigator’s Drug Brochure (IDB) as well as periodic updates that describe the chemical and pharmaceutical properties of the IP as well as up-to-date previous and ongoing animal and clinical trials that have been conducted on the study drug. All study-related staff, not just the PI, should review applicable sections of the sponsor provided IDB and clinical protocol. For example, the clinical research site Pharmacy Department, responsible for meeting IP storage and dispensing requirements, should also be provided with an up-to-date copy of the IDB to ensure the IP or study medication is properly maintained.

The clinical study sponsor, through routine site monitoring, as well as periodic Quality Control (QC) site visits, has the responsibility to ensure that information recorded in subject medical records forms part of the original or “source” data of the clinical trial. Source documentation verification is an important element of site monitoring, QC assessment, and QA site audits, as well as FDA site inspections. It should always be remembered that source data is the first place one records the measured data in a clinical trial. As in any GXP operational area, source data should never be recorded on scraps of paper or unbound notebook pages.

Source documents include clinical data such as subject files, patient charts, subject diaries, progress notes, medication administration records, original lab reports, X-rays, EKG printouts, trace and equipment printouts from automated machines and diagnostic equipment. It is important that detailed entries in subject files for recording efficacy and safety data, dates of subject visits, results of diagnostic tests taken, and details of adverse events are recorded. As discussed previously, Figure 2 depicts FDA’s ALCOA acronym for recording data and results during clinical trials. Study site personnel must record data to the study-specific CRFs provided by the sponsor.

It is interesting to note that GCP regulations do not indicate a required minimum amount of data to be recorded in subject records. However, FDA typically expects subject records to contain at least the following:

• The date and signature or initials of the person making the record entry
• Study inclusion and exclusion criteria
• Date of data entry into the study with study name and study ID or number
• The study visit number or time (e.g.: week two)
• Subject status at each visit
• All adverse events since the last visit, or in certain instances, the lack thereof
• All changes in concomitant medications
• The date and reason for removal from the study (i.e.: study drop-outs)

If we further examine the GCP regulations, the only statement under ICH E6, on the requirements for the location of original data is found in Section 6.4.9, which states the protocol should include:

“…The identification of any data to be recorded directly on the case report forms (i.e., no prior written or electronic record of data), and considered to be source data.”

However, most sponsors do not allow original entries on CRFs, that is, they require all CRF data to be verifiable by original entries in the subject records. In either case, there should be pre-defined rules from the sponsor to the investigator about where original data will be recorded before a trial is initiated.

In regard to electronic records, some sites may incorporate the use of electronic record keeping and e-data capture, which may include, but is not limited to:

• Subject medical records scanned into hospital systems
• Clinical laboratory values maintained in computer systems at the CI site
• Patient use e-diaries to report clinical signs
• Hospital pharmacy records patient treatment assignments in computer system

Although FDA is currently re-evaluating the application of its Part 11 regulations, any site using e-systems should be assessed to identify the systems that contain GCP regulated records and determine whether the systems that support these records are compliant with 21 CFR 11.

With the intent that a clinical trial be “reconstructable,” it is important that all original data be signed or initialed and dated, either manually or electronically. This includes subject records and other notes, records and reports, or information related to the trial. This goes back to the FDA “rule” for original data: “if it isn’t documented, it didn’t happen.”

Understanding the Role of the Clinical Site Monitor

The clinical site monitor, often under a job title such as, “clinical research associate,” is generally the primary point of contact between the sponsor and the clinical investigation site. The monitor plays several key roles in the clinical trial study. After identification by the study sponsor of potential clinical research sites, a pre-study visit is conducted by the monitor or in some cases, affiliated study sponsor research personnel, such as clinical program manager or clinical research scientist to review the adequacy of the site to perform the intended study, including required equipment and access to patients. Site monitoring is comprised of three key areas: the initiation visit, routine monitoring visits, and the closeout site visit. Under an approved clinical monitoring plan, monitors conduct periodic visits at their assigned study sites and ensure that the study continues to be conducted in accordance with the study sponsors’ investigational plan. Monitoring site reports are issued following each visit, and should identify any site issues or required follow-up actions to be reviewed at the next monitoring visit.

Routine monitoring visits are scheduled at regular intervals once a study site has been initiated. Visit frequency depends on the specific study design, the length of the study, the experience of the site staff, and the amount of site activity since the previous visit. Visit frequency should be addressed in the monitoring plan. In addition to routine visits, a visit may be conducted in response to a specific site need, or to address performance or compliance concerns.

Areas reviewed that:

? The investigative site and site personnel remain in compliance with government regulations, the protocol, and the site’s policies and procedures.
? The investigator(s) and staff are fulfilling their obligations as discussed and agreed upon.
? The study data are being collected accurately and completely in CRFs, and are consistent with all source documentation (source data verification).
? The study medication is being correctly stored, prepared (if applicable), dispensed, and accounted for.
? All serious adverse events are being properly reported.
? The facilities and staff remain adequate.

Monitoring visits should be scheduled with the study site’s Study Coordinator (SC) to ensure the site staff will have adequate time to review patient data (data collected since the previous visit as well as any unresolved issues remaining since the previous visit) and regulatory or safety issues with the monitor. The PI (or sub-investigator) should also be available to meet with the monitor at some time during the visit (preferably toward the end of the visit so the monitor can update him or her on study status and site performance). The monitor must ensure the site staff is aware of the visit objectives and that CRFs, ancillary reports, and source documentation are completed, up-to-date, and available for review.

Prior to each visit, the monitor must review the current status of the clinical trial and study site. Items to be reviewed prior to visits include the following (where applicable):

? Compare current subject enrollment status versus anticipated enrollment status
? Review outstanding data and laboratory issues
? Complete SAE reports
? Review status of clinical and non-clinical supplies
? Revisit outstanding or unresolved study-related needs or issues
? Consider performance and compliance issues (if any, devise plans for resolution)
? Complete and compile site communications (letters, emails, faxes, and telephone contacts) and previous monitoring reports

In certain situations, a study sponsor may “contract out” various responsibilities of the clinical trial study, including site monitoring, to a Contract Research Organization (CRO). This “transfer of obligations” is allowed under regulations found in 21 CFR 312, and the exact roles and responsibilities should be outlined in the contractual arrangements between the CRO and the study sponsor.

Source Data Verification

GCP requires the CI to allow direct access to research subject records for comparison to the CRF. This practice is referred to as “source data verification” (SDV), and serves a critical role in ensuring data is accurate and reliable. During site inspections, FDA will not accept data from a site unless direct access to patient records is allowed. To meet this obligation, sponsors are responsible to ensure that clinical study data recorded on CRFs are traceable to the original source documentation. The site monitor is required to perform source data verification for a pre-determined percentage of data, typically 50-100%, on select CRFs during each visit. Source data verification represents a key responsibility of site monitoring.

Clinical Research Equipment and Facilities

Equipment employed during the conduct of a clinical trial, such as X-ray machines, EKG machines, imaging equipment, spirometers and refrigerators used to store investigational product or bio-samples must be available and in good working order. Traditionally, the acronym “SMAC” has been used to characterize these requirements. SMAC stands for: Suitable, Maintained, Available, and Calibrated.

First, equipment should be verified as suitable for its intended purpose. The CI should be directed to the exact type of equipment to be used during the trial, as listed in the clinical protocol. Equipment should also be maintained on a routine basis to ensure it remains in proper working order. Records should be available for routine review and inspection. Moreover, all equipment should be available for use as directed by the clinical trial study defined time period requirements. Finally, equipment used in a clinical trial should undergo routine calibration to ensure it performs accurately. Again, equipment calibration records should be maintained.

Reporting Clinical Data

All study data recorded on the sponsor’s CRF, after completion and sign-off by the CI are retrieved or “harvested” from the study site and sent to the sponsor. The sponsor’s Data Management Department then carefully enters this critical information into their validated study database, typically using two data entry personnel. This technique is referred to as “double data entry” and is considered a key QC element of data in process control. Often, information (e.g., measurement units) on the returned CRF may not have been recorded correctly, initially, or in some cases, erroneous data may have been input at the clinical trial site, resulting in blank fields or incorrect information. In these cases, a request or “data query” is forwarded to the clinical trial site by the sponsor’s Data Management Department. Under GCP, the CI is required to sign-off on these query forms acknowledging the change to the data recorded on the original CRF. At the end of the study, the sponsor arranges for analysis of the data by qualified statisticians, which is often conducted by the sponsor’s Biometrics Department, according to prospective criteria stated in the clinical protocol. Following this, a clinical study report is put together by a qualified medical writer and eventually, the information is provided to the FDA in the form of IND amendments submitted during the investigational study phases, and in the eventual New Drug Application (NDA) that will be submitted.

Development of Effective Quality Assessment Models for Clinical Studies

It is an ICH requirement that the sponsor of a clinical trial, or the agent of the sponsor of a clinical trial, provide routine monitoring of the participating sites to assure that the investigators are fulfilling their obligations, including quality requirements. Although not required by GCP, it is also an expectation that the sponsor designate an independent team to audit selected sites to evaluate the activities being performed, ensure protection of subjects, and ensure the integrity and reliability of data being generated at those sites.

The most important facet of a clinical trial study is to ensure that a “state of control” is continuously maintained during the entire course of the clinical trial study. Data integrity and subject protection are cornerstones in the conduct of an adequate and well-controlled clinical study trial.

State of Control: “A system is out of control if the recorded clinical study information cannot be verified to source documentation that demonstrates reliability, accuracy, and integrity of the data that supports the clinical study. Documented GCP deficiencies provide the evidence for concluding that a system is not operating in a state of control.”

Figure 6 depicts the operational areas during the conduct of a clinical trial, where QA plays a vital role in ensuring GCP compliance. These traditional quality assessment areas include the trial master file, clinical investigation site, clinical database, and the final clinical study report. These steps in the clinical study process are considered key critical control points. The sponsor’s QA Department will usually manage all aspects of quality assessment needs in support of the clinical trial by development of a comprehensive quality plan at the time of the clinical trial study project start-up. The quality plan may contain provisions for timing and types of audits, audit selection criteria, sampling plans, acceptance criteria, audit report distribution and requirements, auditor qualifications, use of third party auditors, etc.

Figure 6: Quality Assessment Model for the Application of Good Clinical Practice During a Clinical Study Trial

The quality assessment management model of clinical trial studies is based on risk management principles to determine where to conduct meaningful quality audits, when many clinical trial study sites are involved. Quality assessments are conducted during phase 1 and 2 clinical trials, for example: an audit of the “Phase 1 Unit” facility may be typically limited to one or a small number of sites; a multicenter full blown phase 3 on the other hand, may involve 50-100 clinical investigation sites, and hundreds of subjects, requiring development of site selection criteria based on multiple variables.

As a multi-center phase 3 clinical trial study progresses and the recruitment pattern is evident, the number and the identities of the sites to be audited are decided based on the following considerations:

• The status of study progress
• The numbers of subjects recruited at the site
• Information from the company’s Clinical Research or Operations Department’s project leader, or a team member based on concerns that the Investigator is not fulfilling his or her obligations or is non-compliant with protocol or regulatory requirements
• Information from the sponsor company’s Drug Safety Department relating to concern for subject safety or a trend in safety data
• Information from the Clinical Data Management Department, concerning consistently missing CRF data or high rates of data queries
• Information from biostatistics, relating to consistent inaccuracies or noted repetitiveness of data from a site
• Representation of sites monitored by different clinical monitors
• Notification of inspection of a site by a regulatory agency or agencies
• Review of select data in the database

While all of these key GCP audit-related parameters should be evaluated, the selection of clinical investigation sites for quality assessment is almost exclusively driven by subject enrollment as the key attribute, namely, high enrolling sites in a study are the most likely to be eventually inspected by FDA. Quality assessments at CI sites may occur anytime as needed, but usually, are scheduled when 25-50% of the subjects are enrolled for the entire study. When a phase 3 trial’s overall study enrollment reaches this level, anywhere from 20-25% of the sites are audited by the sponsor’s QA Department. For example, a multi-center phase 3 trial with 100 clinical sites, would call for 20 to 25 sites to be selected for an on-site quality assessment. Since these trials are quite large and enrollment totals at individual sites may change as the trial progresses, the site audits are sometimes divided into sets of two, with each “wave” of assessments being comprised of half the total sites selected. Prior to the conduct of the actual site inspections, the quality auditor will also audit the study’s Trial Master File (TMF), which is maintained through the trial at the study sponsor site, or in some cases, by a CRO. Most site audits involve one auditor over a two-day period.

Other audits conducted by the clinical study sponsor’s QA group include audits of the clinical database and the final clinical study report. For clinical database audits, after data is retrieved from the clinical investigation site and entered into the clinical data management system database, the quality auditor compares selected CRFs to database entries and identifies any errors. Established error rates are used as acceptance criteria. In some cases, companies have developed database release forms, where, after completion of the database audit by the QA group and the remediation of errors, QA approval occurs as part of the sign-off. At this point, the database is “locked,” the subject randomization codes are broken, and the clinical data is made available to the biostatisticians for data interpretation.

Use of Corrective and Preventive Action (CAPA) in the Management of GCP Quality Issues

Root cause analysis and continuous improvement should be part of the architecture of a welldeveloped quality program for the management of clinical research studies, just as these principles are used routinely in current Good Manufacturing Practice. When a quality audit identifies a deficiency, an investigation should be conducted to understand the root cause and eventual implementation of corrective and preventive action, to minimize recurrence. For example, if a quality audit of a CI site determines that an incorrect version or a non-IRB approved version of the ICF was used to enroll several previous subjects into the trial, the quality auditor should not only ensure that immediate corrective action is taken to remediate this situation, but also identify process-related preventive action steps with the site staff to ensure a process is in place that allows for proper version control and instructions of where the current version of the ICF is maintained. Ideally, in the stated example, the auditor should procure documented evidence in the form, revised procedures, and staff reinforcement training, to close the CAPA for this audit observation.

Preparation and Management of FDA Inspections at Clinical Research Sites

FDA inspections are usually conducted as part of the approval process for a marketing application (e.g., NDA, BLA, or PMA) and occur within a few months of filing the application. While sponsor onsite inspections sometimes occur, the FDA mainly focuses its inspections on the top enrolling clinical investigation sites. In most cases, the top three to four enrolling investigators from the two most important late phase pivotal clinical trials are selected for inspection, but it should always be remembered that any trial or site may be inspected at any time by the FDA. For new drug entities, FDA’s Division of Scientific Investigations (DSI) will contact the sponsor sometime after the NDA is submitted, usually following completion of review of the NDA by the FDA Center. Figure 5 lists some of the typical documentation requested by the FDA DSI from the study sponsor. FDA’s DSI then sends copies of this information to the FDA field districts where the selected clinical investigation sites are located.⁴

Figure 5: Typical GCP Related Documentation Requested by the FDA Division of Scientific Investigations in Preparation for Clinical Study Site Field Inspections

These clinical investigator site “pre-approval” inspections are typically scheduled one to two weeks prior to the inspection by the local FDA field district office. As a proactive approach to a successful investigation, the NDA sponsor’s QA Department should provide training to the CI and site staff on the general rules of handling an FDA inspection. Moreover, clinical site inspection preparation can be facilitated by the sponsor’s providing control copies to the clinical investigation site of the same records and reports provided to the FDA. This will aid tremendously in the site’s preparation efforts and in its overall FDA inspection readiness.

FDA clinical site inspections typically last for one to two weeks, but in some cases may be as short as a few days if conducted by an experienced FDA investigator with a thorough background in GCP. The FDA investigator will review all aspects of the trial to ensure the data submitted in the sponsor’s NDA is accurate and reliable. If any FD483 inspectional observations are issued, the NDA sponsor usually assists the site in responding to these. It is interesting to note that it is considered unconventional for anyone from the sponsor’s company to be physically present at the clinical investigation site during the actual FDA inspection. While daily debriefings with the site by the sponsor are encouraged, the actual presence of personnel on-site from the NDA sponsor company has been viewed as unacceptable to FDA field investigators. FDA wants to be able to conduct an inspection at a clinical investigation site by reviewing records, interviewing site personnel, including the CI and SC, without any interference or coaching by the sponsor. Figure 4 lists the most common FD483 inspectional observations that occur at clinical research sites.

As with GLP or GMP, FDA inspections using the FDA’s new “Turbo EIR” system, FDA investigators now use “canned” CFR references and state the specific observation as evidence of non-compliance to GCP requirements. All FD483s listed directly relate to key GCP principles already covered in this article. The preparation and management of GCP oriented FDA inspections is a critical step for the NDA sponsor to complete in ensuring a successful inspection.

Conclusion

This article provides a general overview of Good Clinical Practice for today’s quality professional. Its intent was to present general operational topic areas that one must consider ensuring that effective quality management principles are utilized during the conduct and evaluation of clinical trial studies. In many ways, the foundation, as well as the utilization of Good Clinical Practice regulations, do not differ dramatically from those quality principles used in Good Laboratory Practices and current Good Manufacturing Practices. Finally, as was indicated in every discussion throughout this article, the study sponsor or CRO, the clinical investigative sites, and the institutional review boards must work as a partnership toward the common goal of successful study conduct. The QA professional plays a vital role in ensuring that this goal is met by ensuring compliance to GCP principles.

References

1. International Conference on Harmonization E6: Good Clinical Practice
2. 21 CFR 312.32(a) IND Safety Reports
3. D. Mackintosh and V. Zepp, “GCP Responsibilities of Principal Investigators: Beyond the 1572,” Applied Clinical Trials (November 1996), pp. 32-40,
4. Basic Clinical Bioresearch Monitoring General Inspection Assignment Process, Society of Clinical Research Associates (SOCRA) Source (August 2005), pp. 25-31, J. Salewski, Deputy Director, Division of Scientific Investigations, Office of Medical Policy, Center for Drug Evaluation and Research, U.S. FDA