Medical Monitor's Essential Role in Clinical Trials

Authors: Gerald L. Klein, MD+; Elizabeth Barabash, PharmD++; Roger E. Morgan, MD+; Gail Brown, MD+; Mark Tulchinskiy, MD+; Freddy Byrth+; Emilia Jones Amawoei, MD+; Pavle Vukojevic, MD+; Shabnam Vaezzadeh, MD+; Katie-Louise Dawson, MD+; Gabriel Cohn, MD+; Stephen Haworth, MD+; Anne Blackwood-Chirchir, MD+; Johannes Wolff, MD+; Angela Overton+++

MedSurgPI+ / PV-R++ / Prevail InfoWorks+++

Abstract Medical Monitors (MMs) play a critical and often underrecognized role in ensuring patient safety, regulatory compliance, and scientific integrity during clinical trials. Particularly in early-stage biotechnology and medical device development, the MM serves as an independent safeguard against bias and unanticipated risks, especially those that other team members may not anticipate. This article outlines the rationale, responsibilities, and operational value of the MM role, emphasizing its function in document review, real-time safety oversight, and regulatory alignment. Through illustrative case studies and current best practices, we argue that the independence and objectivity of the MM is a strategic business necessity not merely a regulatory checkbox.

Introduction In the rapidly evolving landscape of MedTech and biotechnology innovation, clinical trials must balance speed of execution with rigor, safety, and ethical integrity. Emerging companies frequently operate under limited resources and compressed timelines, which may lead them to ignore the critical function of the MM. The MM acts as a dedicated physician or clinical scientist, independent of the study sponsor, to oversee participant safety and trial integrity across all phases of a clinical program.[1] Failure to implement robust and unbiased medical monitoring can result in delayed trial timelines, compromised patient safety, regulatory censure and a loss of public trust, all of which significantly outweigh the cost of proper oversight.[2]

Independence and Objectivity
Independence is a cornerstone of effective medical monitoring. Especially in first-in-human and high-risk vulnerable populations such as pediatric and geriatric participants, the MM provides a crucial check against internal biases and premature conclusions. For early-phase studies, independence also enables separation between trial execution and safety oversight, ensuring a firewall between operations and participant protection.[1]

Key Document Review

Protocol Review

The MM evaluates clinical trial protocols to ensure a justifiable risk-benefit profile, scientific validity, and operational feasibility.[1] This includes confirming adverse event (AE) definitions, minimizing unnecessary procedures, and integrating robust safety monitoring. This review should include a comprehensive evaluation of:

•  Risk-Benefit Justification: Assessing whether the anticipated therapeutic benefit outweighs the potential risks based on the current preclinical and clinical data. This includes evaluating the study design, population characteristics, dose selection, and risk mitigation strategies in parallel.

 •  Scientific Validity: Ensuring the study is designed to answer meaningful clinical questions with relation to the study objective. This includes confirming that endpoints are clinically appropriate, inclusion/exclusion criteria are appropriate, and the statistical analysis plan aligns with the study objectives.

 •  Safety Definitions & Reporting Strategy: Confirming clear definitions for AEs, serious AEs  (SAEs), and other key safety endpoints such as dose-limiting toxicities (DLTs) or adverse events of special interest (AESIs). The MM ensures these are aligned with regulatory guidance (e.g., ICH E2A, FDA safety reporting requirements).

 •  Procedural Burden and Patient-Centricity: Minimizing unnecessary or duplicative assessments (e.g., redundant lab work or imaging) that do not enhance safety or efficacy evaluation, thereby improving subject retention and enrollment feasibility.

 •  Integrated Safety Monitoring Plan: Ensuring that an appropriate medical monitoring strategy is embedded in the protocol, including predefined thresholds for dose interruptions, patient and study stopping rules, unblinding procedures, or Data and Safety Monitoring Board (DSMB) engagement if applicable.

•  Operational Feasibility: Evaluating whether the protocol can be realistically implemented at clinical sites, with considerations for patient population availability, complexity of procedures, visit schedules, and investigational product logistics.

 A well-known failure in protocol oversight occurred during the TGN1412 trial conducted by TeGenero AG in 2006. In this first-in-human study, six healthy volunteers experienced cytokine storm and multi-organ failure following the administration of a CD28 super agonist monoclonal antibody.[2] The protocol failed to anticipate human immune responses. This catastrophic event prompted major reforms in Phase 1 safety practices, including enhanced medical monitoring mandates.[3]

Investigator’s Brochure (IB)

The MM ensures that the IB comprehensively presents preclinical and clinical data, translating pharmacologic properties into actionable safety information for investigators.[4] This includes clarifying potential risks, contraindications, AEs, SAEs, and AESIs that may emerge during human exposure. It’s also important to keep the IB updated appropriately.

Medical Monitoring Plan

The Medical Monitoring Plan (MMP) delineates the MM’s responsibilities and formalizes the communication pathways required for effective safety oversight.[5]  The plan would typically specify the following:

·         SAE review within 24 hours (when possible)

·         Assessment of suspected unexpected serious adverse reactions (SUSARs) or Unanticipated Adverse Device Effects (UADEs) as applicable in accordance with regulatory requirements in medical device studies

·         Ongoing support to sites on causality and AE grading

·         Review of safety data, protocol deviations, and eligibility criteria[6]

·         Leadership or participation in committees such as the Safety Monitoring Committee, and the scheduled investigator meetings.

The plan should clearly outline both mandatory and optional responsibilities: This distinction ensures transparency in role expectations, facilitates consistent execution across study sites, and supports compliance with regulatory and Good Clinical Practice (GCP) requirements.

Table: Medical Monitor Specific Duties

Core Duties:

·         Review and comment on the IB and protocol

·         Write the medical monitoring plan

·         Review and approve a safety management plan

·         Review relevant protocol deviations for participant safety and data integrity

·         Review medical history, concomitant medications, vital signs, laboratory data, and physical exams

·         Offer prompt and readily accessible medical support (typically available 24/7 to clinical sites for all protocol-related inquiries, including AEs and investigational product questions)

·         Recommendations on continued participation for high-risk individuals[7]

·         Review SAEs, AEs, and AESIs

o   Causality assessment of AEs and SAEs[8]

·         Escalate potential safety signals or trends to the appropriate governing body such as the sponsor or an oversight committee (e.g., DSMB)

·         Manage relationships with clinical investigators and their site staff

Optional Contributions:

·         Review coding (MedDRA and WHO)

·         Educate both the site and sponsor teams on trial-related medical and safety issues

·         Support site selection or medical feasibility assessments

·         Present safety content at the investigator meetings or at the site initiation visit (SIV) meeting and sponsor meetings

·         If the protocol stipulates, the MM should approve participant eligibility (typically seen in complex oncology studies)

·         Review and comment on DSMB/Safety Review Committee (SRC) charter

Safety Concerns and Escalation

The MM is tasked with identifying and escalating emerging safety concerns. This includes trends in AE events, unexpected toxicities, or deviations that may threaten participant welfare or data validity.[9] The MM may recognize a safety signal and recommend halting enrollment, modifying protocol elements, or convening the DSMB.[10] The MM may support the pharmacovigilance team in identifying safety signals, conducting signal evaluation, investigating the mechanism of toxicity, assessing risk-enhancing variables, and determining appropriate risk mitigation strategies.

A pivotal example is the 2016 Juno Therapeutics JCAR015 trial which was terminated following several patient deaths from cerebral edema in a CAR-T Phase II trial for acute lymphoblastic leukemia.[11] Initial attribution to chemotherapy preconditioning was later questioned. This event underscored the need for signal detection and continuous, independent safety surveillance in high-risk studies involving novel modalities like cell or gene therapies.[12]

Regulatory Alignment and Reporting

Regulatory authorities increasingly emphasize the need for qualified and independent medical oversight. The U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and International Council for Harmonization (ICH) require prompt reporting of SUSARs and stress the value of medical oversight causality assessment and review.[13],[14],[15]

Moreover, having an MM bolsters readiness for inspections and audits by demonstrating a robust pharmacovigilance infrastructure. The MM’s documented reviews, queries, and recommendations form part of the trial’s safety file which is a critical element in regulatory submissions and approval decisions.[16]

Conclusion

The Medical Monitor serves as a linchpin in modern clinical trial safety oversight, especially for small and emerging life sciences firms. Engaging a qualified MM improves safety signal detection, enhances protocol feasibility, and ensures regulatory alignment. As novel technologies continue to enter clinical development, the MM’s function becomes increasingly indispensable. Independent medical monitoring is not a formality; it is a strategic pillar of credible, compliant, and ethical drug and device development. Moreover, the MM plays a critical role in risk mitigation, enabling real-time clinical insight that supports early decision-making and protects patient welfare. By bridging scientific, clinical, and operational domains, the MM contributes directly to trial success, data integrity, and long-term public trust.

References

[1] S Food and Drug Administration. Oversight of clinical investigations—A risk-based approach to monitoring. Silver Spring, MD: FDA; August 2013. Accessed June 23, 2025. https://www.fda.gov/media/116754/download

[2] S Food and Drug Administration. Oversight of clinical investigations—A risk-based approach to monitoring. Silver Spring, MD: FDA; August 2013. Accessed June 23, 2025. https://www.fda.gov/media/116754/download

[3] Klein, G. L., & Johnson, P. C., and Morgan R. (2021). Medical Monitoring of Clinical Research Studies. Journal of Clinical Research Best Practices. 2021;17(1).

[4]Klein GL, and Morgan R.Potential Errors and Corrections in Early Phase Drug Development, Clin Trial Pract Open J. 2022. 5(1): 1-5. doi:10.17140/CTPOJ-5-124

[5] Suntharalingam, G., et al. Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412, New England Journal of Medicine. 2006;355(10): 1018–1028.

[6] Attarwala H. TGN1412: From Discovery to Disaster. J Young Pharm. 2010 Jul;2(3):332-6.  doi:10.4103/0975-1483.66810

[7] European Medicines Agency. Guideline for Good Clinical Practice E6(R2): Integrated Addendum to ICH E6(R1). EMA/CHMP/ICH/135/1995; EMA/CHMP/ICH/489227/2013. London: EMA; 2016.  https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e6-r2-guideline-good-clinical-practice-step-5_en.pdf

[8] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH guideline for good clinical practice E6(R3). 2023. https://database.ich.org/sites/default/files/E6_R3_Guideline_2023.pdf

[9] National Institute of Arthritis and Musculoskeletal and Skin Diseases. Reporting to the safety officer. Updated 2023.  https://www.niams.nih.gov/grants-funding/conducting-clinical-research/trial-policies-guidelines-templates/data-safety-monitoring-guidelines-policies/reporting-safety-officer#topic-2

[10] National Institutes of Health. Policies and guidelines for the inclusion of individuals in clinical research. Updated 2020. https://grants.nih.gov/policy/inclusion.htm

[11] Klein GL. How to More Objectively Assess Adverse Event Causality in a Clinical Trial, SOCRA Source, August 2024; pp. 79-84.

[12] Singh, D., et al. (2015). Strategies for Signal Detection in Early Clinical Development. Drug Safety, 38(2), 123–132. doi:10.1007/s40264-014-0252-4.

[13] Buchanan J and Mengchun L, Important Considerations for Signal Detection and Evaluation. Therapeutic Innovation and Regulatory Science. 2023: doi:10.1007/s43441-023-00525-7.

[14] CAR-T therapy trial halted due to patient deaths. ASH Clin News. 2016. Accessed June 23, 2025. https://ashpublications.org/ashclinicalnews/news/2779/CAR-T-Therapy-Trial-Halted-Due-to-Patient-Deaths

[15] Lu L, Xie M, Yang B, Zhao WB, Cao J. Enhancing the safety of CAR-T cell therapy: Synthetic genetic switch for spatiotemporal control. Sci Adv. 2024 Feb 23;10(8):eadj6251. doi: 10.1126/sciadv.adj6251. Epub 2024 Feb 23. PMID: 38394207; PMCID: PMC10889354.c

[16] European Medicines Agency. Module VI – Management and Reporting of Adverse Reactions to Medicinal Products. Rev. 2, 2017.

[17] FDA Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. December 2012. U.S. Department of Health and Human Services, Food and Drug Administration.

[18] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. October 1994.

[19] U.S. Department of Health and Human Services, Office for Human Research Protections. Institutional Responsibilities for Clinical Trial Oversight. 2021.