Published on January 12, 2009
Zagzoug, CRA 209 Monitoring Clinical Research MONITORING CLINICAL RESEARCH: An Investigator’s Approach to Effective Strategic Monitoring In the field of research and development, the U.S. maintains what some may call the most demanding drug regulatory and approval process. In this lucrative pharmaceutical market, companies compete fiercely for innovation and to be at the cutting edge of new advancements in health care. These firms are under enormous pressure to control the mounting costs of research and development while still being able to make significant discoveries for effective therapeutic treatments. As a result, the clinical research field has evolved and experienced many changes to keep up with industry and regulatory demands. Through these changes, the industry has placed greater emphasis on monitoring as they have recognized the value it serves in raising the quality of clinical research. While there are various dimensions in clinical research monitoring, the scope of this paper is to examine monitoring from the investigator’s view and explore its significance in the research process. The Value of Monitoring Clinical research monitoring is a comprehensive, all-inclusive effort that requires the involvement of many industry key players. At the base of the hierarchy of clinical research monitoring, investigators monitor their studies by following the approved protocol, adhering to the regulations, and safeguarding enrolled subjects throughout their participation in the trial. Meanwhile, Institutional Review Boards (IRBs) monitor investigators and their investigative sites to preserve subject safety and ethical conduct of research. Likewise, sponsors monitor their investigators and research teams as they carry out clinical trials to make sure all aspects of the study conduct are within compliance with SOPs, GCPs, and applicable regulations. Finally at the highest level of the monitoring hierarchy, the FDA stands at the top of the monitoring watchtower. Keeping an eye on the industry as a whole, including all key players and stakeholders, the FDA maintains its mission of protecting public health by meticulously evaluating the safety and efficacy of drugs before they are given approval for market. Although the roles and activities may differ in each stage, monitoring plays a critical impact that is evident throughout every stage of the clinical research and development process. This impact can be best described as a ripple effect that starts with the clinical research investigator.
Zagzoug, CRA 209 Monitoring Clinical Research Initializing the Process: the Investigator’s Role In the core of monitoring, the process is set in motion when the actual conduct of the clinical research study goes into effect. This aspect is essentially achieved by the clinical investigator. This individual is the primary player in charge of overall operations of the clinical study. The FDA’s Code of Federal Regulations defines the investigator as An individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. quot;Subinvestigatorquot; includes any other individual member of that team. (21 CFR 312.3) Conducting a clinical research study demands a collaborative effort. For this reason, the investigator works with a diverse yet sophisticated group of professionals, each of whom specializes in their respective fields. This group may generally include research coordinators, site managers, laboratory personnel, technicians, analysts, statisticians, data managers, pharmacists, research assistants, recruiters, regulatory experts, quality assurance personnel, and many others. Although each member of the research team has certain duties to carry out, it is ultimately the investigator who is held accountable for all aspects of the study. This means that the investigator is responsible for maintaining and supervising the trial while ensuring that all legal, medical, ethical, and regulatory aspects are followed. Indeed, the investigator must be a well-qualified professional who holds the proper credentials, experience, and training necessary to meet the challenges and enormous responsibilities associated with undertaking a clinical research study. As the investigator and research team work on the study, there is a certain level of interaction that occurs between them, the sponsor, the IRB, and the FDA. The interrelation between the research team and the sponsor is driven by the common goal of completing the study and obtaining results that may lead to an approval. The interrelation with the IRB is to ensure that the study will be conducted ethically while preserving the safety and wellbeing of subject. Thus, if the research team conducts the study successfully, the sponsor will be able to obtain the information needed to submit the necessary documents to the FDA, bringing them one step closer to gaining approval.
Zagzoug, CRA 209 Monitoring Clinical Research Investigator Responsibilities Being the investigator of a trial is not only a title, but it also implies assumption of major obligations and duties. The general responsibilities of the investigator call for “ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation” (21 CFR 312.60). As part of their responsibilities, the investigator should strive to meet the high standards of good clinical practice especially those listed by the International Conference on Harmonization (ICH) in order to provide public assurance that the rights, safety, and well being of subjects are protected; that the data generated is accurate; and that the reported results are credible. The investigator’s ability to carry out their duties as indicated in the regulations requires that they commit to the constraints of the investigator statement Form 1572. Abiding to the commitments of Form 1572 involves fulfilling the following tasks: Conduct the study according to the protocol • Comply with the regulations • Personally conduct or supervise the trial • Obtain informed consent from subjects • Report adverse events properly • Read and understand the material in the Investigator Brochure before • starting the trial Assure that other people assisting in the trial are aware of their obligations • A great deal of preparation goes into developing a drug and having it tested in a clinical trial. During the course of the development progression, highly skilled investigators are selected to run the trial, well trained research personnel are hired to spot and eliminate errors, and a solid protocol containing all the information needed is utilized to complete the study correctly. The execution of the trial also goes through lengthy groundwork from framing a hypothesis based on present knowledge, designing a study to test the hypothesis, writing a detailed plan of the study protocol, obtaining ethical review and approval, conducting the study while adhering closely to the protocol, collecting relevant data elements, ensuring that the data is of the highest quality possible, analyzing the data and finally drawing
Zagzoug, CRA 209 Monitoring Clinical Research legitimate conclusions. With so much at stake, careful evaluation of the process must be made to ensure proper performance for gaining approval for the drug. Given the extensive measure of planning and effort involved in the actual conduct of clinical trials, it only makes sense that at least an equivalent amount of preparation should be placed in establishing a monitoring plan for a trial. After all, monitoring provides a means of keeping the study in check while minimizing headaches and problems the study may otherwise encounter in the long run. With this in mind, the next few sections will cover the planning criteria and what is expected of the investigator’s role in monitoring. Great Expectations: Understanding what is expected of the Investigator for Proper Monitoring To keep a study in compliance, the investigator should generally have a good working knowledge of the regulations and a well rounded understanding of the necessities of GCP. This is suitable if the investigator merely wants to get a study through to completion. However, if completing a good quality study is the objective, then the investigator should familiarize themselves with the expectations of the sponsor, IRB, and FDA for good and adequate conduct of a study. Understanding these expectations leads to better monitoring which leads to enhanced research performance. Most of these expectations are generally based on the responsibilities assigned to the investigator. The expectations which impact the study are discussed below. Patient protection: It is expected that the investigator will protect the rights, safety, and wellbeing of subjects throughout their participation in the clinical trial. Research participants are under the immediate care of the investigator and subject to the judgment and professional abilities of the investigator. This is why investigators must be qualified through training and experience before beginning a clinical trial. This is supported by 21 CFR 50 Protection of Human Subjects which states how research must be conducted in order to protect all human subjects involved in research. It is also supported by ICH GCP Guideline in section 4.2.3 on having adequate resources and staff to conduct the trial safely and section 4.3 which covers medical care of trial subjects. Obtaining informed consent: It is expected that investigators are to obtain informed consent from subjects with the most current IRB approved consent. Outdated or expired consent forms should not be used and consent must be obtained
Zagzoug, CRA 209 Monitoring Clinical Research in a matter that is voluntary and without coercion. This is supported by 21 CFR 50.20 General Requirements for Informed Consent Subpart B which states that no investigator may involve a human as a research subject without proper legal informed consent as stipulated within this regulation. This requires informed consent free from coercion or undue influence. This regulation also stipulates the investigator must allow sufficient time for the subject to decide on participation. ICH GCP Guideline section 4.8 also supports this expectation. Documenting the informed consenting process: As mandated in 21 CFR 50.27, investigators are expected to document the informed consent process and keep the consent form with the original subject's signature in the study records. It is also expected that the informed consent will also contain documentation that the subject or subject’s legal representative was given adequate time to read and understand it prior to being signed. Investigator reports: Throughout the duration of the trial, investigators are expected to provide certain documents which serve as status reports to the sponsor (21 CFR 312.64). Among these documents, the investigator should have up-to-date reports and case report forms (CRFs) on the progress of the clinical study made readily available. It is also expected that the investigator is to provide safety reports on all adverse experiences that may reasonably be regarded as caused by, or probably caused by, the drug. In addition, adequate reports shortly after the completion of the investigators participation in the study are expected. Collecting, retaining, and reporting quality data: In accordance with 21 CFR 312.62, the investigator is expected prepare and maintain accurate records of all documentation related to the study. Such documentation should contain adequate drug accountability records, complete and accurate records of all observations, and data pertinent to the investigation including patient charts, consent forms, and case histories for each subject. These records must be kept for at least two years past the date of the NDA approval or until 2 years after the investigation is discontinued and the FDA is notified. In addition, 21 CFR 312.68 states that these records are expected to be made accessible to the sponsor and the FDA for inspection and verification. This requirement is also supported by ICH GCP Guideline sections 4.9, 4.10, and 4.13. Reporting all expected and unexpected adverse events: As affirmed in 21 CFR 312.64 (b) in the regulations and section 4.11 of the ICH GCP document, safety reports must be made promptly available to the IRB and sponsor. These reports should contain sufficient information including laboratory abnormalities. Reports of
Zagzoug, CRA 209 Monitoring Clinical Research death or serious adverse events (SAE) should also include autopsy and any terminal medical reports. Financial Disclosure: It is expected that the investigator must certify that they have no financial interests. If there is financial interest, this must be disclosed as indicated in 21 CFR 54. Financial disclosure helps to prevent bias in the outcome of the clinical trial being conducted. A disclosure statement from each investigator listed on the 1572 must be provided as part of the marketing application submitted to the FDA (21 CFR 312.53). Show involvement: The investigator should take care to demonstrate involvement by personally conducting the trial and by supervising all sub- investigators, coordinators and support staff involved in the clinical trials within this institution. This is clearly indicated in 21 CFR 312.53 (c). A signed 1572 holds the investigator responsible for supervising any clinical trial within his institution. The guidelines also confirm the need for the investigator to assure involvement throughout the study (ICH GCP Guideline 4.2.4). Assurance of IRB Review & Submission of reports to IRB: The investigator must assure that an IRB complying with regulatory requirements will be responsible for the initial and continuing review and approval of the proposed clinical study (21 CFR 312.66). The investigator must also provide prompt notifications and report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects. No changes in the research can be made without IRB approval, except when necessary to eliminate apparent and immediate hazards to human subjects. Control and handling of study drug & study drug accountability: The investigator is expected to maintain control of the investigational drug at all times (21 CFR 312.69). The drug should only be dispensed to trial subjects under the supervision of the investigator or sub-investigator. The regulations do not allow an investigator to supply or administer the drug to persons not authorized to receive it. Records of the drug should be maintained including inventory, how much was dispensed, and how much was returned or unused. If the investigational drug falls under the Controlled Substances Act, then the investigator must take adequate precaution by keeping it in a locked area with limited access to prevent theft or diversion of the product into illegal channels of distribution.
Zagzoug, CRA 209 Monitoring Clinical Research Building the Investigator Monitoring Strategy The elements of successful investigator monitoring depend on several factors that effect frequency, intensity, duration, and adequacy of monitoring. When referring to the FDA regulations and ICH guidelines on GCP, there is no clear reference or formal “set of standards” in monitoring frequency. Nevertheless, it should be noted that the frequency of monitoring is less important than the quality of monitoring. A rushed, perfunctory inspection that includes only a cursory review of source documents is worthless. To achieve proficient monitoring and positive site performance, a well formulated assessment strategy should be implemented to determine the right amount of frequency, intensity, duration, and adequacy called for in monitoring. Based on the FDA’s Guideline for the Monitoring Clinical Investigations (1998), the following covers some of the factors that should be considered to best approach monitoring. Protocol complexity: The protocol generally dictates the conduct of the study by establishing the procedures that will be performed on subjects during their participation. The more activities and tests that a protocol requires, the more risks involved in the study which means more monitoring may be needed. Disease or condition being evaluated: The disease or condition under investigation is also a determinant of the degree of monitoring. For example, a study on a cholesterol-lowering drug will require a greater treatment period than an infectious disease study. Thus the amount of monitoring required will vary depending on the type of disease or condition and how serious it is. Experience of the investigative site: A simple way to determine monitoring frequency is to evaluate the experience of the research staff. If the investigative site is less experienced, more training and greater supervision may be required which also leads to more frequent, extensive, or lengthier monitoring. On the other hand, the more experienced the staff, the less monitoring may be needed.
Zagzoug, CRA 209 Monitoring Clinical Research Size of subject enrollment: A study with a large number of subjects will require more monitoring to ensure subject safety. More subjects lead to more data generated but they also lead to more opportunities for risks and safety problems to arise. This can be combated with increased careful monitoring. Rate of subject enrollment: A study with rapid enrollment will generate greater data and this can call for more monitoring to ensure data integrity and validity. At the same time, a study with slow or non-existing enrollment may also require greater monitoring since poor enrollment impacts site performance. This may indicate lack of enthusiasm or poor commitment to study execution. Implementing the Monitoring Strategy: How Investigator Monitoring Gets Accomplished Once a monitoring strategy has been established, the next step that the investigator should consider is what to monitor for. The criteria for monitoring should be laid out so that the investigator knows what to do when a red flag appears. This helps the investigator to be better prepared and able to modify the monitoring plan based on assessment of the study’s needs. Monitoring takes on a variety of forms. The following demonstrates some of the main forms that the study site would benefit in utilizing. Monitoring Trial Oversight: The objective of this form of monitoring is to provide overall supervision of the trial and ensure that it is being conducted in accordance with the highest scientific and ethical standards and regulations which pertain to the principles of Good Clinical Practice. Monitoring Trial Management & Steering: This type of monitoring allows systematic review of the progress of the trial in terms of recruitment, data completeness, losses to follow-up, and assurance to protocol adherence. This helps to keep a close eye on trial activities and allows the investigator and staff to take immediate action as necessary for remedial and safeguarding purposes before the trial steers off course. Monitoring Trial Risks: Risk assessment should be done routinely as part of monitoring operations and updated regularly. If the project falls behind schedule for
Zagzoug, CRA 209 Monitoring Clinical Research any criteria, the risk assessment should be updated to indicate the elevated risk and the impact in how the specified site will be monitored in the future. Likewise, if a site is well ahead of schedule, though a rare occurrence, then the risk assessment should be updated to indicate the lower level of risk. However, it should be noted that such sites must still be examined closely even if things are running smoothly since in some cases it may seem “too good to be true.” For instance, it is ideal to have a site that is enrolling well, but a site with high enrollment and no reports of adverse events or even minor problems seems highly suspicious. This can also be a warning sign for protocol violation. Do the subjects really exist? Is information being fabricated? To confirm the site’s performance, a thorough investigation should be done reviewing CRFs and source documents to verify that (1) subjects meet entry criteria, (2) all fields are complete, (3) entries are legible and understandable, (4) values are within range, (5) entries make logical sense, and (5) there are no extraneous comments. If these characteristics are met, then the documents should lead to valid conclusions (Woodin, 2003). Monitoring Trial Data: The purpose of this type of monitoring is to review accruing trial data and assess whether there are any issues that should be addressed in terms of data quality, integrity, and completeness. Some of the key items to look for in data monitoring include missing data, unusual data patterns, repeated measures, and how the data compares with external sources if applicable. This helps to catch any inconsistencies or safety issues early on and promotes good quality data that is accurate and valid. Monitoring Trial Safety: This aspect of monitoring is perhaps the most critical of all. As noted in previous sections, subject safety is of paramount importance which the investigator is responsible for. Every clinical research endeavor begins and ends with the subject and thus safeguarding their well being is imperative. Without subjects, there would be no way to conduct clinical research. Thus monitoring their safety as well as the general safety of all individuals involved in a trial should be of top priority. Adverse Event Reporting: An Essential Facet of Monitoring Adverse event reporting is a major component of monitoring safety. However, often times it is also the most difficult task to complete for the research team. There are many misunderstandings with regards to what is necessary for reporting safety issues. In addition, the regulations charge the investigator with
Zagzoug, CRA 209 Monitoring Clinical Research protecting the rights, safety, and well being of the subject, yet it does not offer much elaboration on what should be included in actual safety reporting. In fact, the FDA does not assign a specific definition to the term adverse event. However, the ICH GCP guideline has clarified many items that were previously open to interpretation by sponsors, investigators, and site personnel. According to the glossary in the ICH E6 guideline, an AE is defined as: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. In cases of serious adverse events (SAEs), the FDA provides the following definition which is also consistent with the ICH definition for an SAE: An event occurring at any dose that results in any outcomes: death, a life- threatening event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity or a congenital anomaly/birth defect (21 CFR 312.32). As part of safety monitoring, investigators are mandated to report adverse events during clinical trials as required in form 1572. This is also supported by 21 CFR 312.64, which states “an investigator shall promptly report to the sponsor any adverse effect that may be reasonably regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately.” ICH GCPs also adds the following from section 4.11 on safety reporting: All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the
Zagzoug, CRA 209 Monitoring Clinical Research reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC. With the understanding of the critical importance of adverse events reporting, it is important to specify what information should be gathered by the investigator for each event. When making a report for the adverse event, the investigator should include the onset (date/time), duration, severity (mild, moderate, severe), relationship to the study drug, and whether or not it is serious. All events should be recorded on the case report form. In addition, if an event is serious, the investigator must report it to the sponsor immediately and must also report to the IRB as well (21 CFR 312.66). The FDA’s Guidance for Clinical Investigators, Sponsors and IRBs on Adverse Event Reporting (2007) stresses that timely notification is essential in safety monitoring. It is extremely important that the investigator notify the sponsor of each serious adverse event as soon as possible even if all the details are not yet available. An initial report should never be delayed while awaiting further information since additional details can be reported as they become available. Barriers to Effective Monitoring Effective monitoring requires discipline. In a world of constrained healthcare budgets and increasing competition, many difficult decisions must be made with regards to monitoring clinical research. However, in the drug development process, research teams often tend to become attached to their projects, which may lead to certain barriers to effective monitoring. As previously mentioned, one of the requirements of investigators is that they must certify that they have no financial interests. Medical treatments are always in demand so long as disease continues to exist; and where there is demand, there is business, and where there is business there is money to be made. Those involved in clinical research, including investigators, are human. Thus they are not immune to the temptations which lead to conflicts of interest, a major barrier to effective investigator monitoring. If there is financial interest, investigators must disclose this information as it may cause bias in the outcome of the clinical trial being conducted (21 CFR 54.4). This can be through financial interest in the company or patent interest if the drug should become approved. Otherwise the validity of trial is jeopardized and more importantly, subjects are exposed to unnecessary risks. Substandard monitoring leads to inferior research and tolerance of errors, inaccuracy, and unethical clinical research practices including misconduct and fraud.
Zagzoug, CRA 209 Monitoring Clinical Research Martinson, Anderson, and De Vries (2006) note some of the following ways in which monitoring barriers can lead to questionable research integrity: Manipulating or concocting research data. • Failing to disclose financial interest or not properly disclosing conflict of • interest. Plagiarizing or using another’s ideas without obtaining permission or giving • due credit. Failing to present data that contradict one’s own previous research. • Overlooking the use of flawed data or questionable interpretation of data. • Circumventing certain minor aspects of human-subject requirements (e.g. • related to informed consent, confidentiality, etc.). Changing the design, methodology or results of a study in response to • pressure from a funding source. Ignoring details or cutting corners to meet a deadline. • Overcoming barriers to effective monitoring may seem daunting and difficult but through diligence and intelligent observation it can be accomplished. Careful inspection and recognizing suspicious activities during reviews and evaluation of a study is the key, but it has to be done right. Being able to generate good quality data can mean the difference between valid research and wasted efforts and resources. Woodin & Schneider (2003) note that the general characteristics of good quality data include logical information with values that are within range and have the correct units for measurement. They can be evaluated and analyzed with ease. Good quality data in a study is gained by having subjects who meet the entry criteria and source documents that are accurate with all fields filled out accordingly. There should be no need to query data and all data should show consistency. A site that is run smoothly will be able to generate reliable data which would allow for valid conclusions to be drawn. As long as these characteristics are met, then they should lead to high quality data with compelling results that can be reproduced. This helps eliminate errors and generate good, usable data. With this in mind, it helps to question any missing information and retrieve records to fill in the blanks. If for some reason there seems to be a great deal of blame shifting, then this might be a sign of hiding delinquency and could be a cause for alarm.
Zagzoug, CRA 209 Monitoring Clinical Research The Consequences of Deficiencies in Investigator Monitoring Considering the causes in which misconduct and divergence from good clinical practice can manifest in research, the clinical research industry cannot be complacent towards these actions. Even with the regulations, policies, and guidelines currently in place to help researchers properly conduct ethical trials, the need for effective monitoring still remains. When a study is infected with problems, its affects become contagious. Deficiencies in monitoring can result in a spiraling downward on a path that only leads to a devastating nightmare for many stakeholders. For starters, the site may be closed down. The clinical investigator would be at risk of expulsion (21 CFR 312.70), being forever listed on the Disqualified or Totally Restricted List of Clinical Investigators (FDA, 2008), otherwise known in the industry as the infamous “black list” (Ginsberg, 2005). In the worst cases of unethical research practice or misconduct, investigators may face legal troubles, heavy fines, or even be sent to prison. As for sponsors, the damage may be irreversible for them as well. The vast amount of time, money, and energy invested in developing a drug and having it tested in a clinical trial goes to waste. They would face a huge loss in finances and be set back several years in the drug development program. Such events would delay the New Drug Application, or NDA process, and ultimately prevent the drug from reaching the market. Indeed, this emphasizes the critical need for effective investigator monitoring and its value in avoiding such severe and serious penalties. Monitoring deficiencies breaks public confidence in the clinical trial process, while raising concerns as to what steps are being taken to uphold effectiveness in trial monitoring. In the recent years, the need to preserve the integrity of clinical research has been apparent now more than ever. The nature of science necessitates that researchers have an obligation to check their data meticulously for thoroughness and accuracy and to draw only valid conclusions from them. Deficiencies in monitoring result in falsification of data, fabricating reports, and allowing bias due to conflict of interest; all of which are a threat to good clinical practices. If these incidences are overlooked, researchers will grow tolerant of such behavior, which would lead to more occurrences of inaccuracy and unethical conduct. The only ethical principle which has made science possible is that the truth shall be told all the time. If we do not penalize false statements made in error, we open up the way, don't you see, for false statements by intention. And of
Zagzoug, CRA 209 Monitoring Clinical Research course a false statement of fact made deliberately, is the most serious crime a scientist can commit. (Snow, 2000, p.74) Conclusion Monitoring a clinical trial is a delicate process that has many potential pitfalls. The entire procedure involves a complete cycle of thought from analyzing the monitoring needs of the study, developing the appropriate method for a monitoring strategy, assessing the potential risks and problems that may arise along the way, implementing and executing the actual monitoring approach, and finally achieving the desired outcome of a study that meets the standards of high quality research as a result of thorough monitoring, ethical practice, and well documented reports of all activities and data. As a final note, it should be taken into consideration that there are many ways to achieve effective monitoring without following the exact format and content presented here. In any case, when monitoring is conducted properly, it can effectively streamline the course of drug development to a smooth, efficient and relatively economical process. Ultimately, proper planning before execution is the key. Planning at the outset, with the end goal constantly in sharp focus, is the most efficient way to ensure clinical success and advance the standard of medical care.
Zagzoug, CRA 209 Monitoring Clinical Research References Ginsberg, D. (2005). Becoming a Successful Clinical Research Investigator. Boston, MA: CenterWatch. Martinson, B. C., Anderson, M. S., & De Vries, R. G. (2006). Scientists’ perceptions of organizational justice and self reported misbehaviors. Journal of Empirical Research on Human Research Ethics, 1(1), 51-66. International Conference on Harmonization [ICH]. (1996, April). Guidance for Industry: E6 Good Clinical Practice. Retrieved July 13, 2008 from http://www.ich.org/LOB/media/MEDIA482.pdf U.S. Code of Federal Regulations Title 21 Part 50 Section 1 (CFR). (2007). Protection of Human Subjects. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=50&showFR=1 U.S. Code of Federal Regulations Title 21 Part 50 Section 20 (CFR). (2007). General Requirements for Informed Consent. Retrieved July 14, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=50.20 U.S. Code of Federal Regulations Title 21 Part 50 Section 27 (CFR). (2007). Documentation of Informed Consent. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=50.27 U.S. Code of Federal Regulations Title 21 Part 54 Section 4 (CFR). (2007). Certification and disclosure requirements. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=54.4
Zagzoug, CRA 209 Monitoring Clinical Research U.S. Code of Federal Regulations Title 21 Part 312 Section 3 (CFR). (2007). Investigational New Drug Application – Definitions and interpretations. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.3 U.S. Code of Federal Regulations Title 21 Part 312 Section 32 (CFR). (2007). IND safety reports. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.32 U.S. Code of Federal Regulations Title 21 Part 312 Section 53 (CFR). (2007). Selecting investigators and monitors. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.53 U.S. Code of Federal Regulations Title 21 Part 312 Section 60 (CFR). (2007). General responsibilities of investigator. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.60 U.S. Code of Federal Regulations Title 21 Part 312 Section 62 (CFR). (2007). Investigator recordkeeping and record retention. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.62 U.S. Code of Federal Regulations Title 21 Part 312 Section 64 (CFR). (2007). Investigator reports. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.64 U.S. Code of Federal Regulations Title 21 Part 312 Section 68 (CFR). (2007). Inspection of investigator’s records and reports. Retrieved July 13, 2008 from http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.68 U.S. Code of Federal Regulations Title 21 Part 312 Section 69 (CFR). (2007). Handling of controlled substances. Retrieved July 13, 2008 from
Zagzoug, CRA 209 Monitoring Clinical Research http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.69 U.S. Code of Federal Regulations Title 21 Part 312 Section 70 (CFR). (2007). Disqualification of a clinical investigator. Retrieved July 13, 2008 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=312.70 U.S. Food & Drug dministration. (2008). Disqualified or Totally Restricted List for Clinical Investigators. Retrieved July 13, 2008 from http://www.fda.gov/ora/compliance_ref/bimo/disqlist.htm U.S. Food & Drug Administration. (2007, April). Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting – Improving Human Subject Protection. Retrieved July 13, 2008 from http://www.fda.gov/CbER/gdlns/advreport.pdf U.S. Food and Drug Administration. (2006, March). Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. Retrieved July 13, 2008 from http://www.fda.gov/CbER/gdlns/clintrialdmc.pdf U.S. Food & Drug Administration. (1998). Guidance for the Monitoring of Clinical Investigations. Retrieved July 13, 2008 from http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html Woodin, K. E., & Schneider, J. C. (2003). The CRA’s Guide to Monitoring Clinical Research. Boston, MA: CenterWatch.
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