Functional group within clinical operations that is responsible for storing, preparing, and processing data derived from the clinical trials.


Functional group that applies statistical methods to data derived from clinical trials, creates data tables, and writes statistical report to be incorporated into study reports.

Locked Database

Database is secured ("locked") to prevent any further changes from being made. Analysis then can proceed.


Audit is a formal examination and verification of accounts and processes in conduct of clinical trials by sponsor and FDA. Audits of CRFs are common. Audit of safety data is very important to continually monitor safety of subjects in a trial.

Fig. 8.16. Definitions/Terms -3

Fig. 8.16. Definitions/Terms -3

formal statistical tests are ready to be performed, and final tables may be prepared for inclusion in the final report.

An audit is a formal examination and verification of the accounts and processes in the conduct of a clinical trial. Audits typically include examination of some number of CRFs with identification of any missing information and verification of data items against source documents such as medical records. Audits of CRFs are common in a monitoring visit to the investigator's site by CRAs. An audit of safety data is especially important to ensure its accuracy and to continually monitor safety of subjects participating in a trial. The group, quality assurance (QA), is a separate functional area in clinical operations responsible for conducting the formal audits after a study is completed by the sponsoring company. Regulations and company SOPs are used as references for the conduct of studies for the audits. Audits uncover protocol violations and study conduct issues before an NDA/CTD is filed. The regulatory authorities also routinely audit the trials (e.g., pivotal trials) at both the company and the investigative sites once an NDA is filed as part of their compliance function. A major audit problem in the conduct of a study can cause the FDA/EMEA to exclude the whole study from the NDA/CTD filing [15].

Due to the regulatory oversight and scientific nature of the clinical trial process, there are a number of required documents related to the conduct of a clinical trial. Four of the most important of these documents as they relate to the conduct of a clinical trial include the protocol, consent form, case report form (CRF), and final report. Many of the activities occurring within clinical operations are geared toward the completion of each of these documents.

Nine documents are presented in the next two figures (Figs. 8.17 and 8.18). A protocol is a detailed written description of the planned clinical trial. The protocol typically contains

Protocol and Amendments

Protocol is detailed written description of clinical trial, e.g., study objectives, patient selection, design, methods & procedures, and statistical methods that will be used to analyze data. Amendments are protocol changes & must be approved by IRB.

Consent Form

Consent form is provided to prospective study participants that describes benefits / risks, procedures, and study events subjects will experience if they agree to participate. Evidence of informed consent is provided by subject's signature on form.

Investigator Brochure (IB)

IB provides all available information on non-clinical (e.g., chemistry, formulation, manufacturing, pharmacology, toxicology) and clinical results to date. It is essentially package insert before drug is approved. IB must be provided to each investigator and IRB.

(DMP) Data Management / Statistical Plan

DMP is usually prepared by both data management & biostatistical staff before study starts and no later than unblindingof data. Plan describes how data will be managed (e.g., entered, transferred, cleaned) & statistical tests to be used in analysis of data.

IRB Approval

Each protocol and consent form must be approved by an IRB. Documentation of IRB approval is required and must be filed.

Randomization Code

A code typically prepared by biostatistics that directs investigator as to which drug treatment each subject is to receive.

Statistical Report

Report of statistical methods used to generate and analyze data, plus all the results and analyses. It is integrated into final clinical study report.

Site Visit Report

Report of activities, results and accounts of each clinical monitoring visit (e.g., pre-study, initiation, interim, and close-out).

Final Report

Final Clinical Study Report describes study and all results from study and discussion and is submitted to the FDA. ICH E3 provides necessary guidance for completing this report.

at least 10 commonly used sections, including a description of the disease and therapy background, rationale for this study, product description, study objectives, inclusion/exclusion criteria, dosing and product administration, methods and procedures, such as DBPCRPC study (double-blind, placebo-controlled, randomized or parallel, controlled study), patient assignment and randomization code process, and the statistical methods that will be used to analyze the data and report it in what tabular forms. The consent form is provided to the prospective study participant that describes a balanced reporting of the benefits/risks of this new treatment, alternative treatments, patient's rights to stop participating at any time, and the procedures and study events the subject will experience if they agree to participate. Evidence that the subject has provided informed consent is provided by the subject's signature on this form, as well as the signature of the individual administering the consent.

The investigator's brochure (IB) is the document that provides all available information on the nonclinical (e.g., chemistry, formulation, manufacturing, pharmacology, and toxicology) and any clinical results to date. It is essentially the package insert before the drug is approved. It changes over time as new information from studies is gleaned and added and must be updated on a regular basis. The IB must be provided to each investigator and IRB, including any changes over time.

The data management plan is usually prepared by both data management and biostatistical personnel before the study starts, most frequently and no later than the unblinding of the data. The plan describes how the data will be managed (e.g., entered, transferred, and cleaned) and the statistical tests to be used in the analysis of the data and its reporting.

Each protocol and consent form must be approved by an IRB (Fig. 8.18). Documentation of the IRB approval is required and must be filed with the investigator at each site and the company for each trial. The IRB file at the site must also contain the membership of the IRB. The randomization code is a coding process typically prepared by biostatistics that directs the investigator as to which drug treatment each subject is to receive. For multicenter studies, the randomization is centrally controlled with investigators calling the center for their patient's assignment to treatment groups. Often, this call center process for the code is automated as each investigator calls for each of their study patients. After a study is closed and the data is locked, a report of the statistical methods used to generate and analyze the data is integrated into a final clinical study report. The rationale for the selection of the particular tests to be used is provided. A description of the tables and graphs to be used is provided. This statistical report is integrated into the final clinical study report.

A site visit report provides the results and accounts of each clinical monitoring visit (e.g., prestudy, initiation, interim, and close-out). These visits and reports are conducted and written by clinical research staff from the company, also called "monitors or CRAS." The content of these reports includes, for example, the dates and times of visits, who was met with, what protocol violations were found, storage conditions of the product, what records and how many were reviewed, storage conditions of study records, and how were discrepancies found and rectified. The PI or at least the Co-I should be available for all site visits, especially because an assessment of the site and its staff is being made and also to address protocol questions.

The final report of a clinical study describes the protocol, especially design features, clinical conduct and results of the study, such as profiles of the patients (demographics and disease and treatment status), outcomes for the key end points, data analyses that were conducted for efficacy and adverse events, and conclusions drawn from the study. These reports must be submitted to the regulatory authorities in a timely manner. ICH E3 provides the necessary guidance for completing this report [22].

As important as the design of the clinical trial itself is the selection of the site(s) and investigator(s) in which the study will be conducted (Fig. 8.19). Some criteria that are important when selecting a study site and investigator include qualifications and experience of the investigators and staff (PI, Co-I, and especially study coordinators) and the site's ability to conduct the study in a clinically competent and GCP compliant fashion [16]. A prestudy site visit form will provide an outline for this evaluation. The characteristics of the personnel at the site that will be involved in the study include:

• Dedication: Will you be able to get in touch with the site when needed? Do the individuals enjoy their work and demonstrate a commitment to their work? Is quality exemplified in the work?

• Education: A curriculum vitae (CV) should be requested from each person who will be involved with the study. Do each of the individuals have a degree in their given profession? A physician (M.D. or D.O.) must be a co-investigator or principal investigator for medical ethics and legal reasons. Other researchers and clinicians in other disciplines can be a PI: Pharm.D., Ph.D., D.Nurs.

• Training: Are the medical staff board certified in their specialty? Has each person received specific training to perform their research job and has it been documented? Have they been trained in the regulations and guidelines related to conducting a study? Do they need training on the protocol? This is almost always necessary because of the novelty of the products and the nuances of the specific study that are important for trial conduct and appropriate data collection.

• Experience: How long has each person been doing their particular job and how long have they been involved with the conduct of clinical trials? What is their experience base with the target disease?

r Criteria important for selecting a study site and investigator: c Qualification and experience of investigators. c Site's ability to conduct study in clinically competent and GCP compliant fashion. Pre-study site visit will provide for this evaluation.

o Characteristics of personnel at sites involved in study including:

> Dedication S> Education

> Training

S> Experience o Availability of specific equipment that may be required by study o Geographic location (opinion-leader representation) r Thought leaders or investigators: c Known to have committed significant time to studies of the disease at interest c Considered early on in development of drugs.

The availability of specific equipment that may be required by the study is needed. Local laboratories that are up to national standards may be needed, but often samples are obtained, stored, batched, and sent to a central lab to ensure consistency and accuracy of testing, especially for any sophisticated tests, such as genetic analyses.

The geographic location of the site may provide some insight to the population that may be recruited at the site as well as a general idea of the cost. For example, sites located in more heavily populated areas (West and East Coasts) generally have a higher cost of living, and the cost of the study will typically be higher. How far is the site from the sponsor and the monitor? Is the site easy to access from the airport?

Do they have the patients in their practice or geographic area for the study, regarding not just numbers, which of course is very important, but also the type of patients in their diagnosis, severity, and availability for the study? Are there geographic, language, or other barriers to patient participation? Do the patients need assistance (financial, logistical) in participating in the study because of the extra time to perform all the tests?

Typically, thought leaders or experienced practitioners with many patients with the disease of interest are considered that are known to have committed significant time to the study of the disease at interest. A thought leader often will have a track record of studies done previously for drug development with other companies. A limit to too much thought-leader involvement as investigators is their usual location at universities, tertiary health care centers, that will have more sick and complicated patients that are not representative of typical patients and may not fit the study. Thought leaders are important to bring onto the project team early in the development of the product (e.g., before the IND is filed). A review of the literature and attendance at therapeutic-specific professional meetings will often dictate who the thought leaders are. These science-based individuals can assist in study design of existing protocols, suggest new studies that need to be done for the clinical plan, discuss competitive products, provide feedback on proposed product profile and package insert, provide access to other possible investigators, add credibility to your research program, and help understand any health care issues for this disease.

Training of investigators and staff is a common and important practice by clinical operations and medical affairs staff at manufacturers for multisite studies. Key training areas include the product, protocol, SOPs, data collection, the definitions and reporting for adverse events, and the investigators' responsibilities as stated in the regulations. Protocol compliance and data quality can be favorably affected by training investigators and their staff in these matters. Areas that can be problems to avoid at multiple sites, regarding excess variability, are the use of inclusion/exclusion criteria, monitoring (what, how, when), drug records and administration, and data collection with CRFs. Separate meetings for the education of the PIs, Co-Is, and study coordinators are a significant investment of time, money, and company staff that is well spent to result in a well conducted and completed study. The duration of such meetings is often 1-2 days at an off-site location to have an audience focused on the training.

Patient selection will be guided by the protocol and the availability of patients to the particular investigator (Fig. 8.20) [17]. It is common for many more patients to be screened and recruited but not selected to participate in the study. Many patients will not be selected due to the inclusion and exclusion criteria of the protocol, which are strict for pivotal trials and usually cannot be waived for individual patients. Some patients may decide not to participate due to the potential risks (e.g., adverse events, blood sampling, placebo groups) or requirements the study may pose on them. Long-term stays in care centers, high number of visits, long-duration studies, and extent of testing may lead to recruitment problems. Ultimately, a certain number of the patients recruited will volunteer to participate and will sign a consent form indicating that they have been informed of the study (including the benefits, risks, commitments). Once the study enrollment begins, it is critical to the success of the trial that the subjects be retained to complete the study. The investigator and the investigational site will influence the retention of study subjects. Trust in the investigator and staff and the facilities themselves will all influence subject retention in the study. The design of the trial will also influence this. Study designs that are demanding of the subject (e.g., require long inpatient stays, multiple visits, long studies, injectable products, frequency of product dosing, or too much invasive or time consuming testing) may lead to greater attrition during the study. Benefits that the study subjects may derive from the study may also influence the retention of subjects. If a subject does not feel that he or she is benefiting sufficiently from participation in the study, they may elect to withdraw. One benefit that a subject may gain is monetary, but it is critical that this benefit is not so excessive to be viewed as coercive. All of these factors must be considered when designing the trial and choosing the investigators and investigational sites. The added medical attention by clinicians and the free care given within the protocol are good incentives for participation and retention. The benefit to mankind in advancing care of this disease is a very good motivator for some patients to participate, but the investigator cannot oversell this situation as to be considered coercive. In the United States, the HIPPA privacy rules for personal information have complicated and added cost to patient recruitment, adding more time and process.

Independent review of clinical research by an institutional review board (IRB) or its equivalent is a universally acknowledged requirement for biomedical research to be conducted in human beings (Fig. 8.21). Documentation of the review and the IRB's approval is required before the clinical trial may begin. The IRB, usually referred to as an independent ethical committee (IEC) in Europe, is an independent body composed of medical, scientific, and lay community representatives that is responsible for protecting the welfare and rights of the research subject. The membership needs to involve experienced clinicians and seasoned clinical researchers with the time commitment to perform all their functions. IRBs confirm that the study is based on sound scientific principles and appropriate interpretation of data and that as designed it is capable of answering the scientific questions it poses with an r Independent body; medical, scientific, and lay community representatives r Responsible for protecting welfare and rights of research subjects r IRBs confirm:

c Study is based on sound scientific principles & appropriate interpretation of data, c As designed study is capable of answering scientific questions it poses, o With acceptable level of risk to subjects Documents that IRB reviews and approves: o Protocol c Consent Form o Investigator Brochure c Advertisements

IRB has ongoing safety oversight responsibility after study is approved:

c IND safety reports c Periodic reports from investigator IRB be available to answer any questions a subject may have

Types of IRBs:

c Most IRBs are associated with hospitals or academic institutions c Commercial IRB or Central IRBs: duly constituted service business k Patient selection is guided by: o Protocol.

o Availability of patients. r Reasons patients may not participate in a study: c Do not meet inclusion/exclusion criteria of protocol o Patient elects not to participate due to: > Risks and Excessive requirements r Subject enrollment begins: r o When subjects sign consent form indicating that they have been informed of study (including risks) and agree to participate.

r Factors important to retention of study subjects r

(critical to success of trial):

c Investigator and investigational site. r c Study design. Studies requiring long interned stays or multiple visits may lead to greater attrition. o Subject benefits (e.g., additional medical attention or monetary).

acceptable level of risk to subjects. The documents an IRB reviews to address these questions consist of:

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