Journal of Clinical Research Best Practices
Medical Monitoring of Clinical Research Studies
By Gerald L. Klein, Peter C. Johnson, and Roger Morgan
Introduction
The Medical monitor’s (MM’s) primary responsibilities in a clinical trial are to oversee the safety and protection of the research subjects and to provide independent oversight to help ensure the scientific reliability, clinical integrity, and quality of the clinical trial. Although the Food and Drug Administration (FDA) has not spelled out the necessity and role of the medical monitor, MM participation is important for compliance with Good Clinical Practice (GCP) guidelines and MMs almost always play a significant role in multicenter clinical trials.1 The best practices for MMs described in this article can also help study sponsors comply with International Council for Harmonization (ICH) guidelines, Technical Requirements for Pharmaceuticals for Human Use, the United States Code of Federal Regulations (CFR), and FDA regulations and guidances.2
The MM collaborates with the project manager, safety, data management, biostatistics and quality departments, principal and sub-investigators, the site coordinator, the Data & Safety Monitoring Board (DSMB), and any other group that directly or indirectly protects the safety of study participants.
Communications
Prompt and transparent communication is an essential element underlying safety in all human clinical studies.3 The MM should be the point person for medical, scientific and safety questions posed by clinical investigators, their site personnel, and staff at the study sponsor and contract research organization (CRO) involved in the trial. The MM’s contact information should be readily available to investigators and their staff. The MM should be available essentially 24/7 with a back-up MM when the primary MM is not available.
MMs often address significant questions on the following topics:
Documentation
Protocol and investigator brochure
Inclusion criteria
Exclusion criteria
Safety
Patient concerns
Adverse events (AEs)
Serious adverse events (SAEs)
Suspected Unexpected Serious Adverse Reactions (SUSAR)
Pregnancy
Medication errors
Concomitant medications
Laboratory values
Protocol deviations and waivers
Informed consent
Unblinding
Early termination or withdraw of a subject
Protocol-stopping rules
Other topics related to clinical research
DSMB and pharmacovigilance team questions with respect to adverse events
MMs document all relevant communications in the appropriate database. When there are multiple significant errors at an investigational site, the MM may be called into an investigation to determine the cause and whether corrective actions or new training is required.4 In rare cases, the MM, together with the project manager and quality assurance, assesses whether a site must be removed from a study due to safety issues, poor data quality, or violation of GCPs.
Maintain a Question and Answer (Q & A) log. Create anticipated Q & A’s prior to the study and then maintain a log to help provide quick, accurate and consistent answers to repeat questions. The clinical sites should be able to search the log for themselves.
Protocol and Investigator’s Brochure (IB)
The MM may write all or just parts of the protocol and investigator’s brochure. At minimum, the MM should review and approve these documents.5 Since the MM is expert on the protocol and the specific therapeutic indication being studied, the best practice is to involve the MM in training sponsor and/or CRO staff as well as the investigators and their personnel on the protocol and IB.
The MM should ensure that protocol endpoints make medical and scientific sense and are safely achievable. The clinical trial’s expected benefits must outweigh its risks.6 Inclusion and exclusion (I/E) criteria must align with this goal. I/E criteria must prevent the enrollment of subjects who are unlikely to obtain a positive therapeutic clinical endpoint or would be put at unacceptable risk in the study. For instance, a patient with a childhood history of bronchial asthma may not be appropriate to enroll in a clinical trial testing a medication that has properties of beta blockers, which can exacerbate symptoms of asthma.
The MM reviews permitted and prohibited concomitant medications (including over-the- counter drugs, herbs and dietary supplements) for possible interactions with the molecule being studied. The MM also ensures that the protocol does not specify types or numbers of procedures that would pose unnecessary risks for study subjects. The MM may recommend ways mitigate such risks.
The MM ensures that the IB clearly describes non-clinical studies and any adverse events of special interest (AESIs). An example of an AESI would be an abnormal electrocardiogram when all cardiac adverse events are of special interest to the regulatory authorities. All current knowledge about the drug, device or biologic must be clearly spelled out in the IB, not hidden in esoteric study reports.7 It is unfortunate that many investigators do not read the IB in detail. Therefore, the MM should try to convey the important aspects of the pharmacokinetics, pharmacodynamics, metabolism, drug interactions and expected adverse events associated with the study therapy to the investigator and the appropriate staff at the clinical site.
Review and Discussion
The MM reviews each subject’s eligibility data, screening physical examination results, medical history, concomitant medications, and laboratory tests before approving their entry into the study. If the investigator is attempting to enroll unqualified subjects, training may be required. The MM thoroughly discusses non-trivial protocol deviations (PDs), which should be rare, with the investigator, and only the most minor ones should be approved. A major PD may affect subject safety, data integrity, or the integrity of the entire study.8 A dosing error by which a subject received twice the dose of the investigational drug during one dosing interval would be a major deviation. A subject’s labs being a few hours out of the visit window would be a trivial deviation.
If time permits, the investigator should consult with the MM before unblinding a subject so the MM can assess and document the decision. The investigator should also discuss with the MM any early unusual termination or withdrawal of a subject from the study.
Data & Safety Monitoring Board (DSMB) or Data Safety Committee (DSC)
If there is a DSMB or DSC, the MM should participate in the blinded section of any meetings to help answer any questions related to adverse events and other potential safety and enrollment issues.9
Adverse Events
One of the most significant MM responsibilities is to work with the investigator to determine the most accurate causality of Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). SUSAR expectedness determinations should be based on the Reference Safety Information section of the IB, or, in studies of marketed drugs, the applicable package insert. Many investigators do not have a good understanding of causality assessment, and poorly defined regulatory terms and examples do not help the situation.10 Following the CIOMS report recommending a binary approach of “related” or “not related” in determining causality simplifies the complex and confusing terminology.11 There is no accepted standard for assigning causality to an SAE, but employing the following Bradford Hill Criteria is an excellent way to determine causality:12,13
1. Strength of Association. A strong association between a treatment and an adverse event indicates causation. For example, each time the drug was given to a subject, it caused vomiting within a predictable time period.
2. Consistency. Established adverse event attributions or previous determinations in similar situations indicate causation.
3. Specificity. An established mechanism of action connecting the treatment and the adverse event indicates causation.
4. Temporality. Exposure to the product must occur before the disease or event, and not after a latency period. However, temporality is not sufficient to establish causation.
5. Biological Gradient. A dose response effect is a strong argument for causation.
6. Plausibility. The causal relationship is biologically plausible.
7. Coherence. The known facts fit the natural history and biology of the disease.
8. Experiment. Epidemiologic studies indicate causation.
9. Analogy. A similar agent causes the same type of AE.
Safety and Pharmacovigilance Reporting
The MM develops or reviews a brief narrative describing each SAE and SUSAR, which should include the following elements:14
Clinical event (postmortem findings if applicable)
Course of event, with temporal relationship to experimental product
Outcome of the event with the nature, severity and intensity
Relationship of the subject’s medical history and concomitant medications to the event
Significant test results or laboratory findings
Therapeutic treatment for the event
Action, if any, taken with regard to experimental product
Causality assessment by investigator and sponsor
Review and analysis of similar events with the experimental product
The MM works with the safety/pharmacovigilance team to code adverse events based on the latest edition of the Medical Dictionary for Pharmaceuticals for Human Use (MedDRA).15 The MM also reviews the coding of concomitant medications using the World Health Organization’s (WHO’s) latest edition of pharmaceutical names (when it is used in the clinical trial). The MM reviews all SAE and SUSAR reports for accuracy and completeness and is the point person to discuss such events with the sites.
Conclusion
Since there are no regulatory guidelines on MM duties, this article has discussed those that are most significant. With the possible exception of the lead principal investigator, the MM should be the person most expert on the medical and scientific aspects of a multicenter study. The principal investigator at each site and the MM, along with DSMB and the institutional review board (IRB), share primary responsibility for the health and safety of study subjects and ensure the validity of the study. They must establish working relationships to ensure that subjects are protected and study data, including SAE and SUSAR reports, are accurate. This profound responsibility means that the MM for a study must have the requisite expertise, personality, dedication and ability to use the processes outlined in this article.
References
Vijayananthan A. et al., “The importance of Good Clinical Practice guidelines and its role in clinical trials.” Biomed Imaging and Intervention Journal, 2008; 1: e5.
E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1) Guidance for Industry, FDA, March 2018.
“FDA Guidance for clinical investigators, sponsors, and IRBS: adverse event reports to IRBs-Improving human subject protection,” FDA, Jan 2009.
Knepper D. et al., ‘Detecting data quality issues in clinical trials: current practices and recommendations,’ Therapeutic Innovation 7 Regulatory Science, 2016; 50:15- 21.
World Health Organization, Guide for writing a Research Protocol for research involving human participation; 2014.
Emanuel E. et al., “What makes clinical research ethical?” JAMA, 2000; 283:2701- 2711.
Fiebig D. et al., “The investigator’s brochure: A multidisciplinary document,” Medical Writing, 2014; 23:96-100
Attachment C: Recommendation on Protocol Deviations, Office of Human Research Protection, HHS.gov.
Calis A. et al., “Understanding the functions and operations of data monitoring committees: survey and focus group findings,” Clinical Trials, 2017:59-66.
Morse M. et al., “Monitoring and ensuring safety during clinical trials,” JAMA. 2001; 285:1201-1205
“Management of Safety Information for clinical trials: Report of CIOMS VI,” 2005.
Federak, K. et al., “Applying the Bradford Hill criteria in 21st century data integration has changed causal inference in molecular epidemiology.,” Emerging Themes in Epidemiology, 2015; 12:14-23
Howick, J., “The evolution of evidence hierarchy: What can Bradford Hill’s guidelines of causation contribute?” Journal for the Royal Society of Medicine, 2009; 102; 2009:186-194
Modified from Ledade, S. et al., “Narrative writing: Effective ways and best practices. Perspectives in Clinical Research,” Perspectives in Clinical Research, 2017; 8:58-62
Brown. E. G., “Using MedDRA: implications for risk management,” Drug Safety. 2004;27(8):591-602
Authors
Gerald L. Klein, MD, is a principal at MedSurgPI. Contact him at 1.919.930.9180 or gklein@medsurgpi.com.
Peter C. Johnson, MD, is president and CEO of Cell X Technologies.
Roger Morgan, MD, is vice president of medical affairs at MedSurgPI, LLC.