Get Citation. Herson, J. Ounpraseuth, The American Statistician In the first edition of this well-regarded book, the author provided a groundbreaking and definitive guide to best practices in pharmaceutical industry data monitoring committees DMCs. Newly added interim analysis for efficacy and futility section. DMC responsibilities for data quality and fraud detection Fraud Recovery Plan Use of patient reported outcomes of safety Use of meta analysis and data outside the trial New ideas for training and compensation of DMC members Jay Herson is Senior Associate, Biostatistics, Johns Hopkins Bloomberg School of Public Health where he teaches courses on clinical trials and drug development based on his many years experience in clinical trials in academia and the pharmaceutical industry.
View abstract. Instead of targeting the statisticians, the focus should be on those MDs in the medical field. Very often, we have difficulties to find the MDs who can serve on the data monitoring committee, let alone to find the MDs who have prior experience serving in the data monitoring committee. For a large scale clinical trial, there may be several committees: steering committee, event or endpoint adjudication committee, and data monitoring committee.
There is often a shortage of members for these committees. Nowadays, the study protocols are getting more and more complicated.
The DMC committee members may not understand the complexity of the complicated trial design. This is especially true for clinical trials using adaptive design and Bayesian design. Continuing review of such research should not be required because it is unlikely to provide any additional protection to research participants and would merely increase IRB burden. However, because minimal risk research does involve some risk, IRBs may choose to require continuing review when they have concerns.
In these cases, other types of monitoring would be more appropriate, such as assessing investigator compliance with the approved protocol or requiring reporting of protocol changes and unanticipated problems. Recommendation 5.
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Plans and resources for data and safety monitoring within an individual study should be commensurate with the level of risk anticipated for that particular research protocol. Box 5. However, not all research with humans requires this level of intensive monitoring and safety review. Through federal regulations, the government has established a system of protections for research participants that involves requirements for minimizing risk and monitoring the safety of studies that are under way. Seventeen federal agencies and departments adhere to the Common Rule 45 CFR 46, Subpart A , which is a set of identical regulations codified by each agency that applies to human research conducted or sponsored by the agency.
The mechanisms by which oversight is generally conducted are described below. This system of protections, however, applies only to research that is federally funded by an agency that is subject to the Common Rule or that is subject to FDA review and approval. A k clearance, not an approval, is granted for marketing these devices. Medical devices requiring a k clearance rather than a Premarket Approval PMA are typically lower-risk medical devices and devices that are substantially equivalent to devices that have been on the market since pre-amendment devices.
These devices also do not require an investigational device exemption for conducting clinical studies. This regulation consolidates requirements for IRB review and informed consent to participate in human subject research. It applies to any DHHS-funded research conducted on human subjects as well as that funded by 15 other agencies. Both sets of regulations apply when research is FDA-regulated and federally funded wholly or partially.
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In addition to the at least annual reviews mandated by federal regulations, reviews may, if deemed appropriate, also be conducted on a continuous or periodic basis. A committee of scientists, physicians, statisticians, and others that collects and analyzes data during the course of a clinical trial to monitor for adverse effects and other trends such as an indication that one treatment is significantly better than another, particularly when one arm of the trial involves a placebo control that would warrant modification or termination of the trial or notification of subjects about new information that might affect their willingness to continue in the trial.
Federalwide Assurances FWA : Under federal regulations, an approved Assurance of Compliance must be in place for any institution that is engaged in federally funded human subject research. In December , OHRP issued a plan to require each institution engaged in research activities, either on its own or as a subcontractor, to hold its own FWA. A single FWA would cover all research conducted at that institution. A revised version of the FWA was issued in March Good Clinical Practice GCP : A standard established by the International Conference on Harmonisation ICH for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical studies that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of study subjects are protected.
E6 is the relevant guideline. Monitor or Monitoring : The act of overseeing the progress of a clinical study and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and applicable regulatory requirement s. This includes but is not limited to blood products, vaccines, and allergenic extracts. Standard Operating Procedure SOP : A document that specifies all the operational steps, acceptance criteria, personnel responsibilities, and materials required to accomplish a task.
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Other mechanisms and authorities also are in place to monitor and oversee the research enterprise. For example, in the Office of Research Integrity was consolidated within DHHS and charged with overseeing investigator misconduct and prevention activities in DHHS-funded research, except for those investigators that fall under the jurisdiction of FDA. Investigative and oversight units of the Executive Branch and Congress have the authority to oversee various aspects of the research enterprise and report on its status. In addition, agencies that sponsor research reserve the right to revoke, suspend, or terminate funding if the research grantee or contractor is in violation of federal policy.
These activities at the federal level provide an overarching system of protections that are operationalized, implemented, and responded to by research institutions and programs. A central role of these agencies is the provision of monitoring and oversight. However, the two leading agencies responsible for regulating the bulk of human research in the United States— the DHHS OHRP and FDA—should do more to harmonize regulatory requirements in these areas; share the results and findings of oversight activities; and provide useful guidance for investigators, research institutions, and HRPPPs to facilitate the enhancement of protection functions.
DHHS is the federal agency in which the bulk of clinical research and its oversight occurs. Thus, OHRP monitors compliance with regulations that specifically address IRBs, informed consent, vulnerable populations, and other issues directly related to the protection of participants as addressed in the federal regulations. OHRP operates on a system of Written Assurances of Compliance, in which the institution assures its compliance with the regulations.
Although ensuring compliance through monitoring and site visits is essential to maintaining the integrity of the system, to maximize its impact, OHRP should expend more resources on facilitating the work of protection programs to meet compliance goals. One way to do so is through informing the research organization of the outcome of its compliance assessment and by more proactively assisting programs in meeting regulatory requirements. DHHS should provide additional resources to OHRP to build its capacity to develop useful guidance and facilitate educational and problem-solving activities to better complement its regulatory compliance mandate.
This language can be reviewed at ohrp. Included within the count of Determination Letters are instances in which a single institution received multiple letters. OHRP maintains determination letters from July forward at ohrp. For more information, see www.
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Friends Research Institute has also instituted an award for research ethics. In addition, OHRP should continue to advance its activities to emphasize an oversight system based on routine surveillance and proactive performance improvement see, for example, Recommendation 3. The federal regulations at 45 CFR The conduct and adequacy of such reviews have been considered erratic and ineffective for some time.
A study of 61 institutions conducted for the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research National Commission found that half of the IRBs seldom or never reviewed interim reports from investigators Cooke and Tannenbaum, The National Commission recommended, at a minimum, annual continuing review for research studies involving more than minimal risk or vulnerable populations Likewise, monitoring reports prepared by or for sponsors that identify serious violations should be submitted to the principal investigator and the designated Institutional Review Board of record.
In multicenter trials, these reports should be submitted to the central Research ERB, if applicable. All such communications should occur in a prompt and timely fashion. The most extensive system of data and safety monitoring exists in the area of clinical trials subject to FDA review and approval. FDA does not have the resources to inspect every investigator and thus is more likely to focus inspections on those entities that enroll large numbers of participants.
Foreign as well as U. The Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act 7 promulgated new regulations to improve protections for persons involved in clinical research investigations. In addition to proving efficacy, sponsors were expected to monitor the progress of studies, and investigators were required to maintain case histories for enrolled participants that included reports of serious adverse events.
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In , a distinct oversight unit within FDA was formed to provide ongoing surveillance of clinical research investigations. The Bioresearch Monitoring Program audited the activities of clinical investigators, monitors, sponsors, and nonclinical animal laboratories. It was intended to ensure the quality and integrity of data submitted to FDA for regulatory decisions, as well as to protect research participants.
Thus, FDA inspects data to ensure their validity in support of an application, as well as the protec-. Federal Food, Drug, and Cosmetic Act of From June through January , FDA performed 3, onsite inspections and discovered that 56 percent of these sites had problems with consent forms. Other deficiencies included the following: 29 percent of the sites had not adhered strictly to the protocols; 23 percent kept poor records; 22 percent were unable to properly account for the drugs they had dispensed; 12 percent had problems with their IRBs; and 3 percent were missing a significant number of their records.
Still, during this same interval, extremely serious problems—including those that led to barring of investigators from conducting clinical studies—had decreased from 11 percent of total trials to 5 percent Cohen, Figure 5. The data reflect clinical investigator inspection files that are closed with a final classification by FDA. FDA may also audit the IRB of record for an inspected study, as well as investigate consumer complaints or reports from whistleblowers. If FDA finds that an investigator is noncompliant, he or she can be disqualified from future studies.
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FDA inspections of clinical investigators generally are conducted after the trial is completed and a new drug application has been submitted for review Box 5. NBAC has noted that. Most FDA inspections of investigators are conducted after the trial is complete. Thus, any detected violations of regulations to protect research participants are found after the point when participants in the particular trial could have received adequate protection. However, the inspections are helpful in improving compliance of investigators and, therefore, protection of participants in future research b, p.
However, a significant gap in this oversight exists in situations in which a sponsor elects not to submit an application to FDA [NDA, PMA, BLA, PLA, and k ] due to the toxicity or ineffectiveness of the candidate compound or medical device, because the termination of a trial before the submission of an application for approval will eliminate the trigger for an FDA inspection.
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