Published in Cureus: The Essential Role of Medical Monitors in Clinical Trials

New in Cureus: we outline how independent Medical Monitors safeguard patient safety, ensure regulatory alignment, and deliver unbiased, real-time oversight from protocol design through signal detection. Drawing on practical duties, escalation pathways, and cautionary case examples (e.g., first-in-human and CAR-T), we argue that medical monitoring is a strategic necessity—not just a compliance checkbox.

Navigating FDA meetings

Authors: Gerald L. Klein, MD+; Melissa Palmer, MD++; Freddy Byrth+; Roger E. Morgan, MD+; Thomas Krol, PharmD+; Seema Kumbhat, MD+++; Eric Hacherl, PhD++++, Shabnam Vaezzadeh, MD+++++

MedSurgPI+ Liver Consulting++ Ganglion Health+++ Smart Bio Works++++ Exquisite Biomedical Consulting+++++

Navigating FDA meetings is central to keeping drug, biologic, and device programs on track. This quick-reference chart highlights each meeting type’s purpose, timelines, and formality levels to help development teams plan more effectively and avoid delays

Transforming Clinical Trials through Remote Patient Monitoring (RPM): Evidence-Based Benefits and Implementation Strategies

Authors and Affiliations: Michael J. Fath, PhD; Gerald L. Klein, MD; Yvonne Elizabeth Otieno: MedSurgPI, Research Triangle Park, NC 27709

Abstract

Background: Clinical trials conducted with traditional methods encounter numerous obstacles, such as problems with patient recruitment and retention, high expenses, and insufficient participant diversity. RPM addresses these clinical trial challenges by combining wireless technology with real-time data collection and minimizing geographic participation barriers.

Objectives: This review examines the effects of wireless RPM technologies on decentralized and hybrid clinical trials. It examines the improvements that RPM can make as well as the regulatory requirements for this type of technology.

Methods: We identified implementation strategies, technological frameworks, and outcomes of RPM in clinical trials found in recent publications and case studies. We identified common challenges in traditional trials and evaluate RPM solutions across diverse therapeutic areas, device types, and implementation contexts using a systematic approach to data extraction, quality assessment, and comparative outcome analysis.

Results: The deployment of RPM systems has yielded substantial benefits, as demonstrated by better participant recruitment and retention rates, increased diversity and data quality, and decreased costs. Case studies demonstrated lower readmission rates, decreased emergency visits, and healthcare costs while achieving better participant compliance. Implemented programs produced diversity improvements between 15 and 28%, maintained participant retention between 85 and 91%, and achieved cost savings of $2,000 to $2,300 per person. The implementation of RPM systems achieved a 60-85% reduction in recall bias and a 60% decrease in manual data entry errors while enhancing data completeness by 40-85% compared to traditional methods.

Conclusion: Remote patient monitoring delivers a practical way of conducting clinical trials that complies with regulatory standards and improves trial efficiency, quality, and participant experience. By implementing RPM technologies, clinical research can achieve a more economical and patient-focused study structure.

Click here to read the full article.

Data and Safety Monitoring Board (DSMB) Best Practices in Clinical Trials

Authors: Gerald L. Klein, MD+; Roger E. Morgan, MD+; Melissa Palmer, MD++; Freddy Byrth+; Wayne Dankner, MD+; Jamie Chang, MD +++; John Hinkle, PhD++++; Jim Sergi+++++

MedSurgPI+ / Liver Consulting LLC++ / Rho +++ / EarlyPhase Sciences Inc+++ / Qnova LifeSciences+++++

Abstract

Data and Safety Monitoring Boards (DSMBs) play a pivotal role in safeguarding participant safety, ensuring data integrity, and upholding scientific validity in clinical trials. Their oversight is especially critical in studies involving higher-risk interventions (e.g., cell-based or gene therapy) or vulnerable populations (e.g., children, pregnant individuals, the very elderly, or those who are terminally ill or cognitively impaired). With rising regulatory expectations and trial complexity, robust DSMB best practices are essential. This article provides a detailed overview of key best practices across DSMB composition, governance, data review and integrity, statistical thresholds, and regulatory compliance, informed by U.S. Federal Drug Administration (FDA), National Institutes of Health (NIH), European Medicines Agency (EMA), and relevant literature.

1. Introduction

A DSMB, also referred to as a Data Monitoring Committee (DMC), is an independent group of experts external from the sponsor and tasked with the ongoing assessment of safety, (sometimes efficacy), and trial conduct in ongoing clinical studies. Their unbiased oversight mitigates ethical, scientific, and regulatory risks, especially in multi-centered or double-blinded randomized trials with investigational products and vulnerable populations (e.g. potentially fragile populations such as children, pregnant women, the very elderly, terminally ill, or of diminished mental capacity) with potential significant risks to the participants or mortality endpoints. Inadequate DSMB governance risks missing safety signals, delaying risk mitigation, and causing noncompliance, ultimately compromising participant welfare and trial validity. This article outlines the best practices that sponsors, Clinical Research Organizations (CROs), and DSMB members should follow to uphold participant safety and trial integrity.

2. Regulatory Background

Several regulatory authorities and professional bodies have issued guidance on DSMB operations:

·         The FDA's Guidance for Clinical Trial Sponsors: Use of Data Monitoring Committees in Clinical Trials (2024) outlines when and how DSMBs should be constituted and managed.

·         The International Council for Harmonisation (ICH) E6(R2) Good Clinical Practice guideline recommends DSMB oversight in studies involving high risk or mortality endpoints. Effective until 22 July 2025.

·         ICH E6(R3) (2023) Guideline for Good Clinical Practice integrates DSMBs into risk-based quality management, emphasizing proactive safety oversight. Effective from 23 July 2025.

·         The NIH mandates DSMBs for Phase 3 trials and other studies with significant safety concerns.

·         The EMA similarly emphasizes DSMBs for adaptive designs and pediatric studies.

 Although the FDA does not mandate DSMBs for all Phase 1 clinical trials, except those that are known to have significant risk to the participants, we suggest their use as a best practice. As first-in-human studies, these trials carry the risk of significant or serious adverse events (SAEs) that may be unknown, significant, or not fully established. Relying on Principal Investigator (PI)-led safety oversight or Data Safety Committees (DSC), often composed of the PI, the medical monitor, and a sponsor-appointed representative, may introduce bias and lacks the independence necessary for objective safety evaluation. A well constituted DSMB can operate at comparable speed, often through emails and enabling timely decisions without added delays. It can convene ad hoc meetings promptly for urgent safety or efficacy concerns.

“FDA strongly recommends establishing a DMC if trial subjects are at risk of serious morbidity or  mortality (e.g., hospitalization, heart attack, stroke, death). In addition to the effects of the subject’s condition, investigational products may cause serious unexpected adverse events—an important reason to consider monitoring interim results using a DMC. In cases where an  assessment of causality can be made on the basis of a single event (e.g., agranulocytosis, Stevens-Johnson syndrome), the sponsor’s internal safety management team or other entity  responsible for reviewing safety data (see section V.E of this guidance) may be able to identify a potential risk and bring it to the attention of the sponsor and regulators. In cases where the event  may be anticipated to occur in the population enrolled in the trial regardless of the intervention  (e.g., myocardial infarctions in an older population) or could be related to other treatments being  administered, the relationship between the investigational product and the adverse events will be less clear. In these cases, it is often critical to conduct an analysis of safety data to determine whether, for investigational drugs, there is a reasonable possibility that the adverse event was  caused by the investigational drug or whether, for investigational devices, it was caused by or  associated with the investigational device.  In such cases, a DMC or another independent entity  should review aggregate safety reports across study arms.”[1]

3. Composition and Independence

DSMBs should be composed of experienced experts who are truly independent from the sponsor. Members must have no financial, scientific, or operational conflicts of interest with the sponsor or investigational product. Conflicts must be disclosed and updated regularly. It’s useful to include at least three voting physicians to ensure the ability to reach a majority decision.

The DSMB Chair should be filled by an individual with extensive experience in both DSMB operations and clinical trial conduct. The Chair is responsible for leading deliberations and serving as the primary liaison with the study sponsor and the CRO. Sponsor preferences for Chair may differ: some want physicians who are board certified in the study’s therapeutic area, while others prefer those specialized in safety monitoring and clinical trial conduct. Ideally, select physicians who possess both safety expertise and clinical trial experience within the relevant therapeutic area but not necessarily formally trained in that area. A statistician with experience in DSMB processes and familiarity with the therapeutic area is essential for many trials, particularly those involving interim analyses to assess whether the study should continue or be stopped for futility.

 4. Charter and Governance

A comprehensive DSMB Charter governs operations and ensures consistency with the protocol. The charter should clearly outline the DSMB’s roles and responsibilities, the frequency, format, and procedures for meetings; data review protocols; statistical methods (e.g., alpha spending functions) and decision-making processes, including voting procedures and criteria for trial modification, pausing, or termination. It should also define rules for data access control for sensitive unblinded data, and establish clear communication pathways with the CRO, sponsor, and regulatory authorities. Additionally, the charter must address succession planning and procedures for member replacement. Provisions for data access should be explicitly stated, including the types of data to be reviewed, timing of data cutoffs, and the handling of revised or updated information. Incorporate these expectations into the charter and DSMB-sponsor-CRO agreements.

5. Data Access and Statistical Reporting

DSMBs require timely access to accurate, relevant data, whether appropriately blinded or unblinded to enable informed decision making. Independent statisticians, separate from the sponsor, should prepare both open-session reports (blinded to preserve integrity) and closed-session reports (unblinded). These reports must include enrollment trends, tolerability assessments, summaries of adverse events (AEs) and SAEs, efficacy endpoints, and any interim analyses aligned with predefined statistical stopping boundaries.

The independent DSMB statistician should develop a dedicated DSMB Statistical Analysis Plan (SAP) that details methods for multiplicity adjustments, sensitivity analyses, and estimand definitions per ICH E9(R1). This statistician will also collaborate with the sponsor’s or CRO’s data management team to create a Data Management Plan (DMP). The DMP should specify the data to be transferred, formatting standards (e.g., Clinical Data Interchange Standards Consortium (CDISC)), validation procedures and delivery timelines (e.g., within 7 days post-data cutoff). All data provided to DSMB members must be timely, usable, and aligned with the board’s review schedule and decision-making requirements.

6.      Safety Monitoring Best Practices

DSMBs should systematically review cumulative safety data, including:

·         AEs, SAEs, deaths, adverse events of special interest (AESIs), laboratory abnormalities, and withdrawals due to an AE.

·         Assessments of causality, using standardized methods where applicable.

·         AE narratives and exposure-adjusted event rates (e.g., events per 100 patient-years) to inform risk-benefit evaluations.

In addition to safety oversight, DSMBs should monitor:

·         Enrollment pace, as it impacts endpoint accrual and trial feasibility.

·         Major protocol violations that could compromise the trial integrity or outcomes measures.

Risk-benefit evaluations should integrate safety findings with emerging efficacy signals.

7. Interim Analyses and Trial Modifications

Interim analyses, if undertaken, must be pre-specified in the protocol and SAP to preserve trial integrity. The DSMB should be empowered to recommend:

·         Trial continuation as planned.

·         Protocol modifications (e.g., sample size adjustment or endpoint refinements).

·         Enrollment pauses for further evaluation.

·         Early termination due to futility, overwhelming efficacy, or safety concerns.

In adaptive designs, implement safeguards, such as independent statistical centers in order to prevent unintentional unblinding and maintain blinding integrity.

8. Confidentiality and Blinding

Strict confidentiality and blinding maintenance are essential to preserve trial integrity and prevent bias. To support this, DSMB meetings typically follow a two-part structure:

·         Open Sessions: Attended by DSMB members, sponsor representatives, and CRO staff. Focused on blinded data presentation, operational updates (e.g., enrollment status, site performance) and logistical matters without revealing treatment allocations.

·         Closed Sessions: Limited to DSMB members, the independent statistician, and an unblinded administrator (if needed). Review unblinded safety and efficacy data, deliberate on sensitive issues, and vote on recommendations, such as:

o   Continuing the trial as planned.

o   Suggesting protocol modifications (e.g., dose adjustments or inclusion criteria changes).

o   Advising on enrollment pause or early termination based on safety concerns, futility, or overwhelming efficacy.

The DSMB may also provide blinded operational feedback to the sponsor to enhance trial conduct without compromising integrity or confidentiality.

9. Meeting Logistics and Documentation

DSMBs should convene at regular intervals, typically every 3 to 6 months, with more frequent meetings for higher-risk studies or when predefined milestones are met (e.g., a predefined percentage of participants complete a set duration on study, as outlined in the protocol or charter).

Meeting Triggers and Frequency:

·         Schedule ad hoc meetings promptly for emerging safety concerns, unexpected AEs or urgent efficacy signals.

·         In early-phase trials (e.g., Phase 1 dose-escalation), hold expedited reviews to evaluate safety data and decide on dose progression or modifications.

Session Structure:

Provide all relevant meeting materials (e.g., reports, and data summaries) to members 5 to 10 days in advance to allow for thorough preparation. Document the meeting comprehensively in minutes, including attendees, data reviewed, decisions reached, rationale, and any dissenting opinions, in order to promote transparency and regulatory compliance.

10. Sponsor Responsibilities

Sponsors bear primary responsibility for supporting DSMB operations while upholding independence to ensure unbiased oversight. Key obligations include:

·         Provide clean, accurate, and timely data through validated systems, with predefined cutoffs and formats aligned with the DSMB charter and DMP.

·         Offer statistical support via independent experts (e.g., for generating blinded/unblinded reports) and logistical resources, such as secure platforms for data sharing and meeting facilitation.

·         Respect DSMB independence by avoiding any attempts to influence deliberations, access unblinded data prematurely, or override recommendations.

Any sponsor resistance, interference, or undue influence risks jeopardizing DSMB validity, potentially leading to biased outcomes, regulatory non-compliance, delayed risk mitigation, and compromised participant safety.

11. Challenges and Pitfalls

DSMB operations face several common challenges that, if unaddressed, can compromise participant safety, trial integrity, and regulatory compliance. Key pitfalls include:

·         Conflicted Members: Failing to identify or manage financial, scientific, or operational conflicts of interest can bias deliberations; require annual disclosures and independent vetting per FDA guidance to maintain objectivity.

·         Ambiguous Charters: Vague roles, responsibilities, or decision criteria which can lead to inconsistent oversight; develop charters with explicit provisions for meetings, data reviews, and escalation pathways, aligned with the protocol.

·         Delayed Data Access: Untimely or incomplete data hinders informed decisions and risks missing safety signals; establish strict timelines for data management to facilitate prompt transfers and analyses.

·         Sponsor Resistance or Influence: Attempts to sway DSMB recommendations undermine independence; enforce clear boundaries in charter and agreements.

·         Inadequate Documentation: Poor meeting minutes or records invite scrutiny during audits; ensure comprehensive logging of attendees, discussions, decisions, and dissents to support transparency and adherence.

·         Lack of calling for ad hoc DSMB meetings when needed to examine potential or important safety events.

Additionally, unclear interim analysis plans can inflate error rates or cause unintentional unblinding; pre-specify methods (e.g., stopping boundaries) to preserve statistical validity and trial integrity.

12. Future Directions

Emerging innovations in DSMB operations can enhance efficiency, inclusivity, and adaptability in clinical trials. Key future directions include:

·         Bayesian monitoring: Incorporate Bayesian statistical approaches for flexible interim analyses and adaptive decision-making, allowing real-time incorporation of prior data to optimize trial efficiency and safety oversight.

·         DSMBs for decentralized trials: Tailor DSMB processes to support decentralized clinical trials (DCTs), including remote data reviews and hybrid monitoring to accommodate virtual elements while maintaining rigorous safety evaluations.

·         Increased diversity in board composition: Promote greater diversity (e.g., in expertise, demographics, and perspectives) among DSMB members to improve equitable risk assessments and address biases in trial data interpretation.

·         AI assistance: Leverage artificial intelligence for data pattern recognition and preliminary signal detection but ensure human judgment oversees final decisions to uphold ethical and regulatory standards.

·         Program-level DSMBs: For resource-constrained sponsors, establish a single DSMB across multiple studies in a program; empower it via the charter and agreements to adjust monitoring scope (e.g., more intensive for high-risk trials) for cost-effective, consistent oversight.

Conclusion

DSMBs are essential for protecting participant safety, upholding scientific rigor, and achieving regulatory compliance in clinical trials. Adhering to the best practices detailed in this article, which include multidisciplinary composition, clear governance, systematic data reviews, safety monitoring and adaptive decision-making enables sponsors, CROs, and DSMB members to conduct ethical, efficient, and successful trials. This approach supports the advancement of innovative therapies while effectively mitigating risks.

References

1.       International Council for Harmonization (ICH). E6(R3) Good Clinical Practice: Integrated Addendum to ICH E6(R1). November 2023.

2.       National Institutes of Health. NIH Policy for Data and Safety Monitoring. June 1998.

3.       European Medicines Agency. Reflection Paper on Risk-Based Quality Management in Clinical Trials. November 2013.

4.       Meinert CL. Clinical Trials: Design, Conduct, and Analysis. Oxford University Press; 2012.

5.       Ellenberg SS, Fleming TR, DeMets DL. Data Monitoring Committees in Clinical Trials: A Practical Perspective. Wiley; 2002.

6.       Calis KA, Archdeacon P, West S. Data monitoring committee practices and recommendations. Clin Trials. 2017;14(6):607–614.

7.       Proschan MA, Lan KKG, Wittes JT. Statistical Monitoring of Clinical Trials: A Unified Approach. Springer; 2006.

8.       Temple R. Safety Assessment During Drug Development. Clin Pharmacol Ther. 2002;71(3):174–181.

9.       Rockhold F, Krall RL. Risk-Benefit Analysis in Clinical Trials: Best Practices. JAMA. 2020;324(1):13–14.

10.   U.S. Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics: Guidance for Industry. November 2019.

11.   EMA. Guideline on Data Monitoring Committees. EMEA/CHMP/EWP/5872/03 Rev. 1. 2005.

12.   Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5(1):27–36.

13.   van der Maas, NG, Versluis, J., Nasserinejad, K. et al. Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial. Blood Cancer J. 14, 56 (2024).

14.   U.S. Food and Drug Administration. Guidance for Conducting Clinical Trials With Decentralized Elements, September 2024

15.   Bunning BJ, Hedlin H, Chen JH, Ciolino JD, Ferstad JO, Fox E, Garcia A, Go A, Johari R, Lee J, Maahs DM, Mahaffey KW, Opsahl-Ong K, Perez M, Rochford K, Scheinker D, Spratt H, Turakhia MP, Desai M. The evolving role of data & safety monitoring boards for real-world clinical trials. J Clin Transl Sci. 2023 Aug 2;7(1):e179.

16.   U.S. Food and Drug Administration. DRAFT Guidance on Use of Data Monitoring Committees in Clinical Trials, February 2024 

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.

Practical Pointers for Product Development and Medical Affairs / July 2025

Authors: Gerald L. Klein, MD+; Roger E. Morgan, MD+; Freddy Byrth+; Melissa Palmer, MD++; Seema Kumbhat, MD+++ Michael Fath, PhD++++; Thomas Krol, PharmD+; Gail Brown+, MD; Stephen Haworth, MD+

MedSurgPI+ / Liver Consulting LLC++ / Ganglion Health+++ / Cavabio Consulting LLC++++

Product Development

FDA Guidance for New Antibacterial Treatment

●        The development of new antibacterial treatments has been challenging, and relatively few companies are actively working in this area. To support the development of these vital drugs, the FDA has released a new guidance document titled: Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases- Questions and Answers.

 “Given the urgent need for development of new antibacterial drugs to treat serious bacterial diseases, FDA intends to apply appropriate regulatory flexibility with regard to meeting the requirements for substantial evidence of effectiveness in such situations, as stated in 21 CFR part 312, subpart E (Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses): [1] 

The Food and Drug Administration (FDA) has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated and the availability of treatment options.[2]”

●        The use of the FDA 510 Pathway is sometimes problematic when selecting a predicate device, especially if the device is to be used in a different organ. The proposed device must have the same intended use, technological characteristics, performance testing, labeling (must not introduce new intended uses or misleading claims), and must not raise new safety or effectiveness questions as the predicate device.[3]   o An experienced consultant who understands the detailed regulations and has knowledge in dealing with the device division of the FDA is highly effective in navigating the regulatory approval process. Examples of such companies are Facet Life Sciences (Wayne, PA), regulanet® (Germany), QNova Life Sciences (Columbia, MD) and MedSurgPI (Research Triangle Park, NC). 

Assessing Causality for SAEs

● Occam’s Razor is a problem-solving principle that states the simplest explanation for a phenomenon is usually the correct one. Applying this principle when assessing causality for a serious adverse event in complex oncology or cell and gene therapy trials, particularly those involving multiple concomitant therapies (chemotherapies, hormone therapy, checkpoint inhibitors) alongside investigational products, it is prudent to prioritize the most plausible causative agents with known associations to the event. If causality relationships remain undefined after the more plausible relationships have been explored without yielding a determination, wider exploration is warranted. Speculative attribution to products lacking supporting evidence from preclinical, clinical, or real-world data should be avoided.[4] 

Medical Affairs

AI for Real World Evidence

● Artificial Intelligence (AI) is being employed more and more to gather and analyze real-world data and registry data to create real-world evidence.[5] Together with clinical trial results, AI can help identify gaps in existing evidence and prioritize research questions that support new evidence-generation opportunities. These insights can be produced more efficiently and cost-effectively versus when traditional manual approaches are used alone.[6]  

 Post-Marketing Safety Data  

● Medical Affairs teams can be instrumental in obtaining important post-marketing safety data. They may discover evidence of unreported adverse events in the following:

o Scientific exchanges with clinicians and their staff[7]   o Literature reviews o Webinars o Panel discussions o Conference attendance o Registries o Real-world data o Post-marketing studies.[8]  

 The number of adverse events, by type/category as well as the overall volume, which occur after a product is launched, is known to be significantly under-reported. The use of medical record data mining coupled with medical affairs directed AI analysis of the medical literature can significantly improve the detection of unreported serious adverse drug reactions.[9]

 Ideas for Medical Journals 

● Medical journals are continually evolving in their content, coverage, and influence on healthcare. We believe that their contributions could be further enhanced by incorporating new dimensions into their offerings. The following are seven suggestions to increase the relevance and utility of medical journals in today’s healthcare landscape:

1.       Encourage greater interactivity by publishing moderated comment sections on important issues. For example, the distinction between antihypertensive drugs found to be efficacious in controlled trials versus those proven to be more effective in real-world settings. 

2.       Articles discussing diagnostic innovations, emerging therapeutic trends, and results from early-phase studies.

3.       Nutritional aspects of the treatment plan such as improving the nutritional status of oncology patients before and during therapy.

4.       Practical diagnostic and therapeutic paradigms, such as the use of remote patient monitoring (RPM) and telehealth, to prevent severe respiratory exacerbations that may otherwise require emergency department visits or hospitalization.

5.       Publication of medical tips or practical pointers to improve patient care. For example, “Allergy Tips of the Month” was successfully published in the now-defunct journal Immunology and Allergy Practice. Similar tips are published today in the American Academy of Allergy, Asthma & Immunology (AAAAI) journal. These brief, actionable insights provide readers with practical ideas that can be readily applied in clinical practice. 

6.       Journals should encourage more people to contribute articles, case histories, case series, reviews, etc. by offering shorter review timelines and reduced publication fees. More professionals across healthcare should be encouraged to write, read, and review scientific articles, thereby expanding the impact and utility of medical journals.

7.       The lack of negative results in the scientific literature can create a biased view of the scientific landscape. This can potentially lead to flawed conclusions and to others repeating a clinical study, which can actually harm patients, or not help them. Journal editors need to encourage and publish negative results. 

8.       Finally, patient advocates and advocacy groups should be invited to participate or submit publications or author editorials to provide the patient’s perspective.

[1] Rachel Knevel, Katherine P Liao, From real-world electronic health record data to real-world results using artificial intelligence, Annals of the Rheumatic Diseases, Volume 82, Issue 3, 2023, Pages 306-311, https://doi.org/10.1136/ard-2022-222626.

[2] Zhaoyi Chen, Xiong Liu, William Hogan, Elizabeth Shenkman, Jiang Bian, Applications of artificial intelligence in drug development using real-world data, Drug Discovery Today, Volume 26, Issue 5,2021, Pages 1256-1264,https://doi.org/10.1016/j.drudis.2020.12.013.

[3] Furtner D, Shinde SP, Singh M, Wong CH, Setia S. Digital Transformation in Medical Affairs Sparked by the Pandemic: Insights and Learnings from COVID-19 Era and Beyond. Pharmaceut Med. 2022 Feb;36(1):1-10. doi: 10.1007/s40290-021-00412-w.

[4] Alomar M, Tawfiq AM, Hassan N, Palaian S. Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: current status, challenges and the future. Ther Adv Drug Saf. 2020 Aug 10;11:2042098620938595. doi: 10.1177/2042098620938595.

[5] Ventola CL. Big Data and Pharmacovigilance: Data Mining for Adverse Drug Events and Interactions. P T. 2018 Jun;43(6):340-351.

[6] Klein G, Barabash E, Morgan R, et al. Medical Monitor’s Essential Role in Clinical Trials. SSRN. Published July 1, 2025. Accessed August 1, 2025. https://ssrn.com/abstract=5336047

[7] U.S. Food and Drug Administration. Search FDA guidance documents. Accessed July 30, 2025. Available from: https://www.fda.gov/regulatoryinformation/search-fdaguidance-documents

[8] U.S. Food and Drug Administration. Code of Federal Regulations. Title 21, Section 312.80. Drugs intended to treat life-threatening and severelydebilitating illnesses. Silver Spring, MD: FDA. Updated [access date]. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapterD/part-312/subpart-E/section-312.80

[9] U.S. Food and Drug Administration. Code of Federal Regulations. Title 21, Section 807.100. Premarket notification. Silver Spring, MD: FDA. Updated [access date]. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-807/subpart-E/section-807.100

Practical Pointers for Medical Affairs / June 2025

Authors:  Gerald L. Klein, MD; Roger E. Morgan, MD; Johannes Wolff, MD; Freddy Byrth; Marion Stamp-Cole; Melissa Palmer, MD

bridging innovation and practical application

As treatment regimens for both surgical and medical interventions grow increasingly complex, there is heightened need for focused medical affairs efforts to deliver thorough training and guidance to healthcare providers. Innovations in therapy often come with intricate dosing algorithms, novel mechanisms of action, and sophisticated delivery systems, all of which require clear, accessible, and evidence-based communication from medical teams. Practical aspects such as patient selection, dosage, safety, and tolerability should be clearly and concisely defined. Most devices require a human factors validation study, particularly those intended for patient self-use or in high-stakes clinical environments.

RWE Growth and Alignment

There has been a significant increase in the number of real-world evidence-based studies and their significance in both medical affairs and in product development. For example, PubMedindexed real-world evidence (RWE) publications nearly tripled between 2016 - 2018, rising from 326 to over 930 studies.[1] To foster better communication around this evolving body of work, the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have developed a standardized glossary of terms specific to real-world data (RWD) and RWE.[2] Adoption of these terms helps ensure consistent interpretation, improves stakeholder communication, and supports regulatory alignment when using RWE in product development and labeling strategies.

Post-Launch Insights that matter

Launching a new product is a tremendous undertaking and also presents a valuable opportunity to gather timely, real-world insights through what we refer to as post-launch data capture. There is generally increased interest and excitement about a new product and early adapters are keen to try this, so it is an ideal time to capture important medical affairs information.

• This is the time to query patients, healthcare providers (HCPs) and pharmacists on the following:

  • How well is the product understood: This gauges the depth of knowledge and clarity around the product’s mechanism of action, indication, administration route and monitoring requirements. Misunderstandings may lead to suboptimal use or hesitancy in adoption and the feedback helps inform targeted educational intervention.

  • Is it appropriately prescribed and dosed: This evaluates whether prescribers are using the product in accordance with the approved label, real-world best practices, and any clinical guidelines. Dosing errors or off-label trends may indicate gaps in education or highlight the need for label refinement or further clinical clarification.

  • Product effectiveness: This assesses whether the clinical benefits observed in  trials are being replicated in routine clinical practice. Factors such as adherence, comorbidities, and healthcare access may influence this and require RWE follow-up.

  • Perceived product value: Assess the economic and therapeutic value as perceived by both patients and HCPs.  Are the benefits seen as commensurate with the cost, burden of use, or any associated monitoring requirements?  This is critical for market access, payer discussions, and retention. ▪ Willingness for HCPs to prescribe the product:  Investigating barriers that may hinder prescribing behavior (clinical, logistical, financial or psychological). Even highly efficacious products may struggle if providers lack confidence or clarity in how or when to use them.

  • Willingness for patients to use the product: Examining patient acceptance, particularly around tolerability, ease of use, and alignment with lifestyle may lead to the understanding of cultural, social, or health literacy factors that shape decision-making.

  • Additional side effects: Examining emerging safety signals or tolerability concerns that may not have been apparent in the controlled environment of clinical trials which may include mild but impactful events that affect adherence and satisfaction.

  • Additional benefits: Possibly identifying positive secondary outcomes or “halo” effects that weren’t the primary focus of trials but are meaningful to patients or providers. These may include improvements in energy, mood, or comorbidity control and can become valuable talking points in peer-to-peer education and lifecycle management.

References

1. Makady A, de Boer A, Hillege H, Klungel O, Goettsch W. What is real‑world data? A review of definitions based on literature and stakeholder interviews. Value Health. 2017;20(7):858‑865. doi:10.1016/j.jval.2017.03.008.

2. Rivera DR, Cutler TL, McShane L, et al. Modernizing Research and Evidence Consensus Definitions: A Food and Drug Administration–National Institutes of Health Collaboration. JAMA Netw Open. 2025;8(6):e2516674. doi:10.1001/jamanetworkopen.2025.16674.

Practical Pointers for Product Development / June 2025

Authors:  Gerald L. Klein, MD; Roger E. Morgan, MD; Johannes Wolff, MD; Freddy Byrth; Marion Stamp-Cole; Melissa Palmer, MD

Developing Drugs for Obesity and Weight loss

• The general recommendation for a sample size to assess the safety of a weight-reduction drug is 3,000 subjects randomized to the investigational drug within the to-be-recommended dosage range and no fewer than 1,500 subjects randomized to placebo for at least one year of treatment at the maintenance dosage. Sponsors developing multiple dosing regimens should consider a randomization scheme that assigns more subjects to higher doses and are encouraged to discuss the overall size of the safety database with the Agency at or before the end of Phase 2.[1] In addition to these safety considerations, sponsors should align with FDA guidance recommending at least one unsuccessful attempt at lifestyle modification (e.g., diet and exercise) prior to enrollment and should consider removing the ≥5% long-term weight loss requirement as a singular efficacy benchmark. Inclusion of electronic Clinical Outcome Assessments (eCOA) and validated Quality of life (QOL) measures as secondary endpoints is also advised to support potential labeling claims. Furthermore, sponsors are encouraged to propose a pediatric sub-study to address the pressing issue of childhood obesity and explore opportunities for pediatric exclusivity through regulatory pathways that may support patent extension.[2]

• The recommended sample size will provide 80% power to detect, with 95% confidence, an approximately 50% increase in the incidence of an adverse event that occurs at a rate of 3% in the placebo group (i.e. 4.5% vs. 3%).

• This sample size would also allow for efficacy and safety analyses to be conducted within important subgroups such as age, sex, race, ethnicity, and baseline BMI, provided that a sufficient number are enrolled in each of these groups.

For all products

• We recommend strategic refinement to the traditional FDA requirement of two well-controlled Phase 3 clinical trials. Specifically, we propose a hybrid development and approval model designed to maintain scientific rigor while enhancing speed to market and real-world relevance demonstrating robust and statistically significant results. Notably, the FDA has previously granted approval based on a single pivotal study in certain high-need indications, such as Elzonris, approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN) based on a single Phase 2 trial of 94 patients, and Lumoxiti, approved for relapsed/refractory hairy cell leukemia based on a single-arm, open label Phase 3 trial of 80 patients.[3] These examples demonstrate that regulatory flexibility exists when the benefit-risk profile is compelling. We suggest the following approach:

  • Primary Pivotal Trial: Conduct one well-controlled Phase 3 trial demonstrating statistically robust efficacy, safety and tolerability under traditional randomized, controlled conditions. This trial would serve as the primary basis for conditional approval.

  • Conditional Approval Linked to real-World Validation: Upon successful completion of the pivotal trial, conditional approval would be granted with a clear commitment to complete a second Phase 3 trial within a defined timeframe. This second trial would be designed to:

    • Incorporate real-world evidence (RWE) methodologies (e.g., pragmatic design, broader inclusion criteria, decentralized elements).

    • Provide confirmatory data on effectiveness, safety, and tolerability in routine clinical practice.

    • Serve as a tool for refining labeling, guiding post-marketing surveillance, and supporting payer decisions.

This two-step model offers several advantages:

• Accelerates access to promising therapies for patients in need.

• Incentivizes real-world accountability through mandatory confirmatory RWE trials.

• Mitigates risk by anchoring initial approval to high-quality evidence while ensuring continued scrutiny.

• Aligns with FDAs evolving openness to RWE and flexible development frameworks (e.g., as reflected in 21st Century Cures Act and FDAs guidance). This approach has the potential to accelerate approvals, prevent the approval of ineffectual medications and provide greater safety and tolerability of actual real-world events.[4]

planned protocol deviations

Planned protocol deviations should be avoided in clinical trials to maintain scientific integrity and regulatory compliance. However, in certain complex settings, such as oncology or cell and gene therapy trials, predefined deviations may be necessary due to the individualized nature of treatment or logistical constraints. In such cases, advanced Institutional Review Board (IRB) approval must be obtained, and the rational clearly documented on the protocol or amendment to ensure ethical oversight and participant safety.[5]

References:

1. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs

2. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-regulatoryconsiderations-complying-pediatric-research-equity-act-and?utm

3. U.S. Food and Drug Administration. Drug Trial Snapshot: ELZONRIS. FDA website. Published December 21, 2018. Accessed July 2, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-elzonris

4. Burns L, Roux NL, Kalesnik-Orszulak R, Christian J, Hukkelhoven M, Rockhold F, Khozin S, O’Donnell J. Real-world evidence for regulatory decision-making guidance from around the world. Clinical Therapeutics. 2022;44(3):420-437. doi:10.1016/j.clinthera.2021.12.013.

5. U.S. Food and Drug Administration. Protocol Deviations – A Regulatory Perspective: Draft Guidance for Industry. Silver Spring, MD: FDA; April 2024. Available at: https://www.fda.gov/media/184745/download.

Unlocking Efficiency and Expertise: The Strategic Value of Fractional Service Providers in Drug Development and Medical Affairs

Executive Summary

In today’s dynamic and capital-constrained biotech environment, early-stage companies must balance scientific innovation with lean operations. Leveraging fractional service providers (FSPs)—highly experienced professionals or firms that provide part-time, on-demand support—has become an increasingly popular and effective strategy. This white paper outlines the strategic advantages of using FSPs in drug development and medical affairs, including cost savings, access to Subject Matter Experts (SMEs), scalability, and accelerated timelines.

Introduction

Drug development is inherently complex and resource-intensive, requiring coordinated, cross-functional expertise across multiple domains – including regulatory science, clinical operations, pharmacovigilance, Health Economics and Outcomes Research (HEOR), manufacturing, medical affairs, scientific communications, and field-based medical liaisons. Similarly, medical affairs plays a vital role in bridging scientific knowledge and stakeholder engagement. However, building full-time internal teams for each function is often impractical for startups and small biotech firms. Fractional service providers offer a flexible, high-impact alternative.

Key Benefits of Fractional Service Providers

1. Cost Efficiency Without Compromising Quality

• Reduced Overhead: Eliminate long-term employment costs, benefits, and infrastructure burdens. For many small companies developing a single investigational product, hiring a full-time expert may be unnecessary and inefficient—both financially and operationally. Moreover, top-tier professionals may be disinclined to accept full-time roles that lack sufficient workload or long-term engagement.

• Predictable Budgeting: FSPs typically work on defined scopes or hourly retainers, allowing tighter financial control.

• High Value: Gain access to SMEs with industry experience that would be cost-prohibitive to hire full-time.

2. Access to Senior-Level Expertise

• FSPs can bring decades of experience from large biopharma, regulatory agencies, and successful startups.

• Strategic Insights

• Preclinical planning and execution

• Regulatory strategy and submissions

• Clinical operations

• Reimbursement execution (Health Economics and Outcomes Research)

• Payer Value Proposition

• Economic models

• Pre-approval communication and negotiation with Health Technology Assessment (HTA) bodies

• While Quality of Life (QoL) metrics are rarely the primary drivers of reimbursement decisions, patient-reported outcomes (PROs) collected during clinical trials play a crucial role. These data inform long-term cost-effectiveness and utility models and are frequently evaluated by Health Technology Assessment (HTA) bodies to guide pricing and market access decisions.

• Payer Value Dossier

• Real-World Evidence (RWE) planning, execution and scientific communication

• Post-approval studies to inform and secure payer contractual agreements

3. Speed and Agility

• Rapid onboarding of fractional experts accelerates early-stage milestones.

• FSPs are project-focused and delivery-oriented, enabling faster document turnaround, strategic decisions, and agency responses.

• Minimizes internal delays caused by hiring gaps or capability bottlenecks.

4. Scalable Support Across Development Milestones

• Support can evolve across the product lifecycle:

• Preclinical/IND: Regulatory planning, toxicology review, Chemistry, Manufacturing, and Controls (CMC) input, and RWE to inform clinical trial design.

• Clinical Phase I–III: Protocol development (including incorporation of patient reported outcomes), medical monitoring, Data and Safety Monitoring Board (DSMB) engagement and RWE (market mapping, burden/cost of illness studies to support unmet medical need and inform economic models.

• Post-Approval: RWE generation, scientific publications, launch support.

• The ability to increase or reduce engagement based on funding cycles or pipeline progress.

5. Strategic Partnership Without Organizational Bloat

• FSPs often act as embedded team members while maintaining independent objectivity.

• Allows startups to "punch above their weight" in meetings with FDA, European Medicines Agency (EMA), payers, and investors.

• Fosters knowledge transfer and capacity building for in-house teams.

  Use Cases in Drug Development and Medical Affairs

Phase and Example FSP Roles:

Pre-IND: Regulatory strategist, preclinical toxicologist, CMC advisor, epidemiologist

Phase I/II: Medical monitor, clinical operations advisor, statistician, protocol medical writer, HEOR consultant

Phase III: Safety surveillance, medical publication professional, payer strategist, HEOR consultant, epidemiologist

Post-Approval: HEOR consultant, medical science liaison trainer, advisory board moderator, epidemiologist

Real-World Example

A virtual oncology biotech engaged a fractional Chief Medical Officer (fCMO) and medical monitor from MedSurgPI. Over six months, they:

• Finalized an IND with FDA-ready protocols,

• Set up medical review procedures for a First in Human (FIH) trial,

• Initiated early scientific engagement with KOLs across US and EU.

The company saved over $500,000 compared to hiring a full-time team and moved from candidate nomination to IND submission in just nine months.

Conclusion

Fractional service providers are not just a stopgap—they are a strategic solution for modern drug developers seeking flexibility, efficiency, and deep expertise without the cost and complexity of traditional hiring. Especially in medical affairs and development functions, FSPs offer a high-value way to accelerate innovation while maintaining lean operations.

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About MedSurgPI                                              

MedSurgPI provides fractional medical monitoring, regulatory, and medical affairs to biotech and medtech innovators. Our network of seasoned professionals supports companies from preclinical planning through to market launch.

 info@medsurgpi.com

About Star Biopharma Consulting

Star Biopharma Consulting provides fractional support for HEOR consultants, epidemiologists, medical directors, economists, data scientists, and medical writers. Our specialties include Real-world Evidence Generation, Economic Modeling, Evidence Synthesis, Scientific Communications, Post-Authorization Commitments, Patient-focused Research, HTA Preparedness, and Market Access Support.

 📧 info@starbiopharmaconsulting.com

🌐 www.starbiopharmaconsulting.com

Pre-Clinical Checklist for IND Submissions

Before your initial submission with the FDA,

check with us

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        Pre-Clinical Checklist for IND Submission

General Planning

·         Proposed Route of Administration

·         Target Indication

·         Define drug development goals and regulatory strategy

·         Determine target indication(s)

·         Identify the regulatory pathway (e.g., 505(b)(1), 505(b)(2))

·         Confirm if a Pre-IND meeting is needed

·         Develop a list of specific questions for FDA (clinical, CMC, nonclinical)

·         Prepare timeline for IND-enabling activities

Drug Substance & Product (CMC – Chemistry, Manufacturing, and Controls)

·         Proposed Route of Administration

·         Target Indication

·         Stability Studies

·         Drug substance information (source, synthesis, characterization)

·         Drug product formulation details

·         Manufacturing process description and controls

·         Stability data and proposed storage conditions

·         Analytical method development and validation

·         Packaging and labeling overview

Nonclinical/Preclinical Studies

·         Proposed Route of Administration

·         Target Indication

·         Stability Studies

·         Summary of completed pharmacology/toxicology studies

·         Summary of ongoing or planned IND-enabling toxicology studies

·         Justification for proposed first-in-human (FIH) dose

·         Species selection rationale and relevance to humans

·         GLP compliance documentation (if available)

Clinical Plan

·         Proposed Route of Administration

·         Target Indication

·         Stability Studies

·         Draft protocol for Phase 1 study (or Phase 0, if applicable)

·         Clinical trial objectives and design

·         Inclusion/exclusion criteria

·         Safety monitoring plan

·         Risk mitigation strategies

·         Informed consent process summary

Regulatory Documentation

·         Proposed Route of Administration

·         Target Indication

·         Stability Studies

·         Request for Pre-IND meeting (if applicable)

·         Proposed questions for the FDA

·         Pre-IND briefing document draft

·         Investigator’s Brochure (if available)

·         IND application planning and structure (Module 1-5 format)

·         Review of relevant guidance documents

Operational Readiness

·         Identify CROs, CMOs, and other partners

·         Develop timelines and resource plans

·         Ensure team roles and responsibilities are defined

·         Intellectual property status reviewed

·         Regulatory consulting company

·         Pre-clinical animal testing facility

Practical Pointers for Product Development and Medical Affairs / May 2025

Authors: Gerald L. Klein, MD; Roger E. Morgan, MD; Emilia Jones Amaowei, MD; Michael Fath, PhD; Freddy Byrth

Product Development

●       Choosing the right contract manufacturer is critical for a biotech company to successfully bring new products to market. They must be able to provide a high-quality product on time, without unexpected cost increases and minimal delays.

o   Small companies should understand that a poor choice can ruin or significantly delay company efforts. Engaging a specialized consultant with expertise in the specific type of manufacturing needed is often a crucial component of the team.

o   Consideration should also be given to confirming the contract manufacturer has a back-up location for providing medication, in the event the primary facility becomes inoperable due to a catastrophic incident.

o   The manufacturer should have a strong record of compliance with FDA, European Medicines Agency (EMA), and other regulatory bodies, supported by extensive quality systems (e.g., Good Manufacturing Practice) (GMP) certification, validated processes, audit readiness).

●       AI may be a useful tool, but its outputs must be thoroughly reviewed. Some platforms have been known to generate inaccurate or even fictitious information (termed hallucinations). For example, when asked to supply scholarly references for a publication, some AI tools generate fabricated citations.

●       One potential FDA reform that could significantly reduce the time and cost of pharmaceutical product development is the formal acceptance of approval based on a single, well-designed Phase 3 efficacy trial—on the condition that a confirmatory post-marketing effectiveness study, capable of generating statistically robust results, is conducted within a predefined timeframe. This approach would not only accelerate initial market access but also provide real-world evidence of the product’s pharmacoeconomic value. Failure to complete the post-marketing study as agreed would trigger automatic market withdrawal. While it is sometimes possible to negotiate approval based on a single Phase 3 trial under current regulations, formalizing this as a consistent regulatory pathway would eliminate the default expectation for two pivotal trials in most cases.

Medical Affairs

●       It appears that when major journals publish articles on the results of drug clinical trials, they sometimes omit significant safety information.

o   An article may compare the number of serious adverse events (SAEs) and adverse events (AEs) in both the placebo and investigational product groups but fail to specify which events were related to the active product. This omission is especially disconcerting as it may obscure the complete safety profile of the active product. This omission makes it difficult to assess the actual risk-to-benefit ratio.

o   To enhance transparency without shifting focus from efficacy, journals should require brief, clear attribution of AEs or SAEs to the investigational product. This simple step strengthens credibility and ensures readers understand a more complete safety profile.

 ●       When developing consumer information, it is critical to present accurate details without sugarcoating or concealing a product’s disadvantages. Although it is appropriate to emphasize the benefits of its use, the total story should be clearly articulated. Failure to do so may result in regulatory issues which may undermine trust with both healthcare professionals and the general public.

 ●       Optimizing the Medical Affairs Role in Real-World Evidence Generation:  Medical Affairs is essential in developing real-world evidence to complement data from controlled clinical trials and support the broader understanding of a product’s value and use.

o    Stakeholder Engagement: Collaborates with healthcare professionals, payers, and patient advocacy groups to gather post-market insights.

o    Real-World Insights: Tracks safety signals, uncovers new therapeutic benefits, and observes usage patterns across diverse populations.

o    Data Utilization: Leverages real-world data sources such as electronic health records (EHRs), patient registries, and claims databases.

o    Evidence Generation: Produces data that informs medical decision-making and supports peer-reviewed publications.

o    Payer Communication: Provides critical input for pharmacoeconomic discussions and value-based reimbursement strategies.

April 2025: Practical Pointers for Product Development and Medical Affairs

Authors: Gerald L. Klein, MD; Roger E. Morgan, MD; Shabnam Vaezzadeh, MD; Michael Fath, PhD; Niti Goel, MD; Freddy Byrth; Emilia Jones Amaowei, MD

Clinical Development and Operations

●    Logistics is of increased importance when conducting complicated cell and gene therapy, immunotherapies, or oncology clinical trials. The therapies mentioned above often require complex cold-chain management, strict vein-to-vein time windows (the total time when cells are collected from the patient’s vein to when the engineered cells are infused back into the patient’s vein, typically within 2-4 weeks), real-time biomarker monitoring, and specialized personnel or equipment. Logistical inefficiencies can compromise the viability of autologous cell products or delay dose administration, negatively affecting both safety and efficacy outcomes.[1] Poor logistics may lead to missed dosing or testing, resulting in frustration not only among participants but also at clinical sites. Over time, these challenges can contribute to reduced study retention, strained site relationships, and compromised data quality.

●    Participant concierge transportation may foster enrollment and retention, especially in rare diseases. In both rare disease trials and studies of longer duration and greater complexity, patient  populations are often geographically dispersed and may have limited mobility due to complex health needs. Providing travel support–such as concierge services, lodging assistance, and reimbursement–can significantly improve both recruitment and adherence[2] to study protocols. This is especially critical in decentralized trial models, where on-site visits are minimized but not entirely eliminated. In such cases, the integration of remote patient monitoring systems can help address logistical challenges and maintain study engagement. It may also be useful for protocol planners and writers to adopt a multifaceted approach, rather than thinking in terms of “this and that” (e.g., either travel support or remote monitoring). Instead, a “this and that” strategy–combining travel support with decentralized solutions–may better support participants’ needs and improve trial outcomes. Importantly, these strategies are not limited to rare disease trials; they can also enhance the success of studies with longer durations or complex treatment regimens by reducing participant burden and supporting higher retention rates.

●    Vast differences may exist between effectiveness of a treatment vs its efficacy. While efficacy studies have their own merit, primarily serving regulatory approval processes, effectiveness studies play an important role. Efficacy is measured under ideal, controlled conditions (e.g., randomized controlled trials), whereas effectiveness evaluates real-world performance. The general patient population is often excluded from efficacy studies due to strict inclusion and exclusion criteria, making it challenging to extrapolate their results[3] to everyday clinical practice. As a result, vast differences may exist between a treatment’s efficacy and its real-world effectiveness. Many interventions demonstrate high efficacy but fall short in effectiveness due to factors such as patient heterogeneity, variability in adherence, and system barriers within actual healthcare settings. Real-world studies that demonstrate therapeutic effectiveness can strengthen clinical decision-making, support reimbursement efforts, and lead to more efficient and patient-centered product development.   

● Expensive protein manufacturing can be improved with the use of AI. AI models are increasingly used to optimize codon selection, expression vectors, and fermentation parameters, substantially improving yield and purity in protein biologics. Various startups use generative biology platforms to engineer custom proteins as well as closed-loop optimization.

Medical Affairs

●    Marketing and commercial key points should be planned from Phase 1 clinical trials. Early involvement of commercial and medical affairs teams in developing the Clinical Development Plan (CDP) can help shape value propositions,[4]health economics outcomes, and Key Opinion Leader (KOL) engagement strategies. Defining market access, pricing sensitivities, and differentiation points during Phase 2 and then Phase 3 studies supports faster launch readiness and payer negotiation. Collaboration with regulatory affairs at this stage also helps to ensure alignment with clinical endpoints to anticipated label claims and global submission requirements. Establishing a medical communication plan early-particularly for congresses and other medical meetings-can be highly beneficial, as data or case histories from early studies may provide valuable content for effective medical communications, including white papers, slide decks, and journal articles. In addition, early planning for real-world evidence generation and post marketing commitments can further strengthen the product's long-term positioning and support its value story across diverse markets. 

●    AI can help speed up medical communication. AI is transforming medical communication by rapidly generating and summarizing scientific publications, MSL briefings, and standard medical responses with greater consistency and compliance.[5] Natural Language Processing (NLP)-powered tools enable real-time resolution of HCP and field queries through intelligent chatbots and enhanced search capabilities. Machine learning analyzes field insights and literature to identify educational gaps, monitor sentiment shifts, and inform medical strategy. AI also supports internal alignment by generating cross-functional updates and assisting with compliant medical writing. Finally, it personalizes communication through auto-generated slide decks and regionally adapted messaging tailored to stakeholder needs. 

●    Establishing common goals with patient advocacy groups. Collaborating with advocacy groups helps to ensure that clinical endpoints, communication, and access strategies reflect patient-centered priorities. Such partnerships can also aid communication, awareness, and recruitment efforts. They enhance trial design, build trust with key stakeholders,[6] and foster co-created education content-contributions that are particularly vital in complex therapeutic areas such as oncology, immunology, neurology, and rare diseases.

Footnotes:

[1] Abou-El-Enein M, Hey SP, Leferman L. "The critical role of logistics in the success of cell and gene therapies." Nature Biotechnology. 2021;39(9):1057–1059.

[2] Esmail LC et al. "Improving patient access and engagement in clinical trials through concierge services." Therapeutic Innovation & Regulatory Science. 2022;56(4):556-562.

[3] Gartlehner G et al. "What is the difference between efficacy and effectiveness?" Agency for Healthcare Research and Quality (AHRQ). 2006.

[4] Le Meur N, et al. "Bridging clinical development and commercial strategy: The evolving role of medical affairs." Pharmaceutical Medicine. 2021;35(5):287–296.

[5] Zhang Y et al. "Using NLP for automated generation of medical communications." Journal of Medical Systems. 2021;45:92.

[6] Wicks P et al. "Patient advocacy groups: Partners in health research and drug development." Health Affairs. 2018;37(3):475-480.

References:

1.       Abou-El-Enein M, Hey SP, Leferman L. "The critical role of logistics in the success of cell and gene therapies." Nature Biotechnology. 2021;39(9):1057–1059. 

2.       Anderson M et al. "Engaging patients in rare disease research through advocacy partnerships." Orphanet Journal of Rare Diseases. 2020;15:156. 

3.       Brolund A et al. "Chatbots and AI in medical affairs: potential and pitfalls." Frontiers in Pharmacology. 2023;14:1230874.

4.       Daly B, Brawley OW, Gospodarowicz MK, et al. Remote Monitoring and Data Collection for Decentralized Clinical Trials. JAMA Netw Open. 2024;7(4).

5.       Esmail LC et al. "Improving patient access and engagement in clinical trials through concierge services." Therapeutic Innovation & Regulatory Science. 2022;56(4):556-562.

6.       Getz KA. "Patient recruitment and retention in rare disease trials." Applied Clinical Trials. 2020. 

7.       Gartlehner G et al. "What is the difference between efficacy and effectiveness?" Agency for Healthcare Research and Quality (AHRQ). 2006. 

8.       Le Meur N, et al. "Bridging clinical development and commercial strategy: The evolving role of medical affairs." Pharmaceutical Medicine. 2021;35(5):287–296.

9.       Makady A et al. "What is real-world data? A review of definitions based on literature and stakeholder interviews." Value in Health. 2017;20(7):858-865.

10.    Marks P. "The future of cell and gene therapies: logistics and regulatory convergence." FDA CBER Keynote Address. 2023. 

11.    Wicks P et al. "Patient advocacy groups: Partners in health research and drug development." Health Affairs. 2018;37(3):475-480.

12.    Zhang Y et al. "Using NLP for automated generation of medical communications." Journal of Medical Systems. 2021;45:92.

Practical Pointers for March 2025

Authors: Gerald L. Klein, MD*; Roger E. Morgan*, MD; Angela Overton, MSc**; Mark Tulchinskiy, MD*; Johannes Wolff*, MD/PhD*; Freddy Byrth*; Marion Stamp-Cole*

MedSurgPI* Prevail InfoWorks, Inc.**

Why is it so important to determine the relationship of a Serious Adverse Event (SAE) or Adverse Event (AE) to the investigational product (IP)?

• Consequences of incorrectly attributing causality to the Investigational Product (IP) despite a lack of reasonable evidence linking the drug to the adverse event:

  • May prevent product approval due to significant SAEs or the quantity of AEs and SAEs.

  • May impact the product label, reduce medication adoption by prescribers.

  • May impose unnecessary burden on patients and health care providers (HCPs) by means of FDA mandating REMS (Risk Evaluation and Mitigation Strategy.

• Consequences of assigning unrelated causality to the IP when there is evidence of relatedness:

  • Unsafe drug may be approved.

  • A drug could receive approval with faulty/misleading information regarding the balance of safety and efficacy.

  • Safety drug-use mitigation strategies may not be considered and implemented.

  • It can cause unnecessary patient harm.

  • The development of supportive care guidelines may be inaccurate.

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What does it mean that an SAE or AE is possibly related?

• Just because there is a temporal relationship between AE/SAE and the drug, there could still be a critical judgment for reasonable possibility. The Principal Investigator (PI) should not blindly follow the ancient Greek maxima “Post hoc ergo proper hoc”, that means “after this therefore because of this”. Instead, the PI should consider these factors when evaluating AE causality:

  • Associations and Sources

    • Consider whether the event is associated with the IP or a concomitant medication, intercurrent disorder, disease progression, or comorbidity.

    • Rely on the Investigator’s Brochure (IB), preclinical research, medical literature on the studied product, and similar drugs for essential information.

  • Modifying Factors

    • Overdose and incorrect administration (for example, the wrong frequency or route) can impact AEs.

    • Assess drug interactions that may increase toxicity.

    • Be aware of subjects inadvertently taking excluded drugs, herbs, or supplements during the trial.

    • Significant changes in diet or nutritional status may also be a factor.

    • Modification of psychological status may become a stimulating factor.

  • Patient History

    • Differentiate between exacerbations of past medical history and comorbidities and new AEs.

    • Consider symptoms occurring before exposure to the IP.

      For an explanation of the standard WHO causality classification system, please follow this link.

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Causality Factors to Consider

• Has there been a dechallenge/rechallenge of the product?

• Biological gradient criterion states that a dose-response effect is a strong argument for causation. If a subject received 5mg of a drug and had a mild headache, and the headache increased when the dose increased, there is a dose-response effect. Similarly, aggregate data, occurrence percentages, and dosage can be correlated.

• Plausibility: the causal relationship between the AE and the IP must be biologically possible and logical. For example, if a subject receives a new type of aspirin formulation and their blood pressure (BP) increased, it is not plausible that the BP change is related to the aspirin.

• Coherence refers to assessing whether the facts align with the natural history and biology of the disease. The data may support an extension or exacerbation of the disease, which is frequently seen in oncology studies.

  • Example: In metastatic breast cancer, a patient develops anemia, which is known to occur in this disorder.

• Have experimental epidemiologic or other objective (preclinical or clinical) studies demonstrated similar causality?

• Does an analogy exist, meaning a similar drug has caused the same type of AE under comparable circumstances? This is frequently seen as a class effect in similar drugs. For example, beta blockers may cause bradycardia.

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When is a laboratory test result an AE?

• Many protocols state that a laboratory result is an AE if it is clinically significant in the investigator’s opinion. This frequently causes confusion.

  • A good rule of thumb: if the test results prompt further diagnostic studies (excluding repeats for confirmation) or leads to therapeutic action. If either occurs the laboratory results may be considered clinically significant.

Overlooked reasons which qualify as an SAE

• A persistent or significant incapacity.

• Substantial disruption of the ability to conduct normal life functions. [1]

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References

1. Council for International Organizations of Medical Sciences (CIOMS). Guidelines for preparing core clinical-safety information on drugs: report of CIOMS Working Groups III and V. Geneva, Switzerland: CIOMS; 1999.

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

3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther.1981;30(2):239-245.

4. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

5. Shimonovich, M., Pearce, A., Thomson, H. et al. Assessing causality in epidemiology: revisiting Bradford Hill to incorporate developments in causal thinking. Eur J Epidemiol 36, 873-887 (2021). https://doi.org/10.1007/s10654-020-00703-7.

6. The Use of the WHO-UMC system or standardized case for standardised case causality assessment. https://www.who.int/docs/default-source/medicines/pharmacovigilance/whocausality-assessment.pdf.

7. U.S. Food and Drug Administration (FDA). Guidance for Industry: Clinical Laboratory Studies for Regulatory Submissions. Silver Spring, MD: FDA; 2018

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[1] https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-reporting-safety-reports

Latin America as Part of Rare Disease and Oncology Drug Development

Contributors: Sara Tylosky, CEO/Farmacon Global; Luis Squiquera, MD, CMO/Farmacon Global; Gerald L. Klein, MD, Principal at MedSurgPI, LLC and Roger E. Morgan, MD, Vice President, Medical Affairs at MedSurgPI, LLC

Introduction

Rare disease and oncology research represent some of the most challenging yet rewarding areas in clinical development. With over 700 rare disease therapies in development and thousands of oncology trials underway globally, the race to bring innovative treatments to patients is intensifying. Despite these advances, drug and treatment development in these fields face significant obstacles, ranging from protocol design to patient recruitment. This paper examines these challenges and offers strategic solutions for investors and biotech companies aiming to accelerate clinical trial success and reduce development costs.

Challenges in Rare Disease and Oncology Drug Development

Developing Practical Protocols with Robust Statistical Support

Protocols for rare disease and oncology trials must balance scientific rigor with real-world feasibility. Rare disease trials, in particular, face the challenge of small patient populations, complicating statistical power and endpoint selection. These constraints necessitate advanced statistical methodologies, such as linkage analysis, transmission disequilibrium tests, and rare-variant association studies, supported by cost-effective sequencing and genotyping platforms. Additionally, national-scale electronic health records (EHRs) provide invaluable data for estimating prevalence and clinical characteristics (Abdala, 2023). 

Streamlining Inclusion and Exclusion Criteria

Overly complex or restrictive eligibility criteria can hinder patient recruitment and trial efficiency. Pragmatic, well-defined inclusion and exclusion steps are essential for maintaining regulatory compliance while ensuring a broad patient participation.

Engaging Key Opinion Leaders (KOLs)

Involving experienced KOLs enhances protocol design and ensures clinical applicability. We have identified and engaged key Latin American KOLs so that we save significant time and resources in selecting clinical sites. 

Selecting Optimal Trial Sites

Choosing trial sites with limited patient pools or inadequate infrastructure can lead to costly delays. Our unique expertise and strong relationships enable strategic site selection, guided by demographic and epidemiological data, to drive trial success.

Partnering with Patient Advocacy Groups (PAGs)

PAGs play a critical role in connecting researchers with patient communities, enhancing recruitment and retention. Building effective partnerships requires significant time and effort to establish culturally sensitive relationships and these dedicated resources.

Ensuring Quality and Compliance Among Principal Investigators (PIs)

Quality regulatory compliance is vital for trial integrity. PIs must be well-versed in Good Clinical Practice (GCP) guidelines to mitigate risks and enhance data reliability. This necessitates a collaborative partnership and ongoing quality improvement with trial sites to uphold data integrity and ensure the highest standards of excellence.

Comprehensive Training for Trial Staff

We ensure comprehensive training to decrease the potential of protocol deviations and data integrity concerns, including audit preparation for sites. Standardized training programs ensure consistency and adherence to best practices.

Solutions for Success in Rare Disease and Oncology Trials

Strategic Regulatory Support

Engaging experienced regulatory teams facilitates navigation through complex global frameworks, ensuring adherence to stringent approval processes.

Expanding Trials into Emerging Markets

Latin America has become a key destination for clinical trials due to multiple advantages:

●        Large Treatment-Naïve Population:  With a population of 664 million, the region offers a substantial pool of treatment-naïve patients who may meet eligibility requirements for oncology and rare disease studies.

●        Cost Advantage:  Clinical trials in Latin American can be 30-40% less expensive than those conducted in the U.S. or Europe, making it a financially viable option.

●        Availability of Experienced Investigators and High-Quality Research Sites: Rather than focusing solely on real-world data, Latin America benefits from a strong network of experienced principal investigators and high-quality research sites capable of efficiently conducting trials.

●        Lower Competition for Clinical Trials: Unlike North America and Europe, Latin America has fewer competitive trials, allowing for faster patient recruitment and higher enrollment rates.

●        Diverse Representation:  The region’s diverse ethnic mix has a significant Latino/Hispanic population, and in places like Brazil and Colombia also includes African descent, which enhances inclusivity and representativeness in clinical trials.

●        Regulatory Expertise: Regulatory timelines have significantly improved in Brazil, Mexico, and Argentina. With our expert guidance, we ensure a seamless and efficient regulatory approval and drug importation process, helping you stay on track and accelerate your clinical trial progress.

Collaborating with Leading Experts

Engaging KOLs in rare diseases and oncology helps refine protocol design and improve recruitment strategies. Early expert involvement ensures trials align with real-world patient needs and regulatory expectations.

Comprehensive Training Initiatives

Providing targeted training for PIs, site staff, and monitors enhances protocol adherence and regulatory compliance, reducing risks and optimizing efficiency.

Optimized Site Selection

Leveraging local expertise and networks in Latin America allows sponsors to identify sites with strong infrastructure and access to large patient populations.

Strengthening Partnerships with PAGs

Collaborating with PAGs ensures patient-centric trials, boosting recruitment and retention while refining research methodologies based on patient experiences.

Conclusion

Rare disease and oncology clinical trials are essential for advancing medical innovation. However, these trials require tailored strategies to overcome challenges related to protocol design, patient recruitment, and regulatory compliance. By leveraging emerging markets, engaging key experts, and fostering strong patient advocacy partnerships, biotechs and investors can reduce costs, accelerate timelines, and enhance trial outcomes.

MedSurgPI, LLC offers expert fractional Chief Medical Officers worldwide, providing strategic medical consulting in development, safety, and medical monitoring. www.medsurgpi.com.

Farmacon Global provides integrated solutions to navigate these complexities. From optimizing site selection and regulatory strategies to engaging stakeholders and advocacy groups, our expertise empowers clinical research teams to advance breakthrough treatments efficiently.

References

bioaccess®. Why Latin America demographics benefit clinical trials. Retrieved from https://www.bioaccessla.com/blog/why-latam-demographics-benefit-clinical-trials.

Abdala, M. July 2023. Strategies to achieve greater competitiveness for clinical trials in Latin America. DIA Global Forum. Retrieved fromhttps://globalforum.diaglobal.org/issue/july-2023/strategies-to-achieve-greater-competitiveness-for-clinical-trials-in-latin-america/

An Introduction to Preclinical Pharmacology: A Mesa Science and MedSurgPI White Paper

Preclinical Studies Required for Obtaining FDA IND Approval

Authors from Mesa Science Associates: Kaitlyn Wylie, Kenneth Dretchen

Authors from MedSurgPI: Gerald Klein, Roger Morgan, Lee Schacter, Freddy Byrd, Devsmita Das

Introduction

The FDA issuance of an Investigational New Drug (IND) application is dependent upon the successful completion of multiple preclinical studies including both pharmacology and toxicology evaluations. These studies consist of pharmacodynamic, pharmacokinetic, and toxicology studies that should be completed prior to submission and other additional required studies after initial FDA discussions. 

Pharmacology 

·         Pharmacodynamics

Pharmacodynamic studies  are investigations that describe and confirm the basic mechanism of action of a new drug candidate.  These involve either or both in vivo or in vitro experiments. It is essential that the physiological response generated by the chemical entity can be measured with high precision and remains stable during the course of the experiment in in vivo studies.  This includes heart rate, blood pressure, cardiac contractility, respiration rate, tidal volume, gastrointestinal motility, skeletal muscle contracture and urinary outflow.  A dose/response or a dose/escalation study which measures the quantity of the drug received versus the initiated response should be undertaken. For example, an agonist will produce a standard S-shaped curve when comparing increasing doses to increasing responses including a threshold point, a rising phase, and a celling.

The other graphical evaluation that is useful in determining the duration of action is referred to as a time-action curve that compares the response obtained over time following the administration of a fixed dose of a drug. Increasing doses of the drug should generate parallel curves until the maximum response is obtained. Additional information that can be obtained are an estimate of the duration of the drug and inferences regarding any overt adverse events. 

If at all possible, in vitro confirmation of the site and mechanism of action would be invaluable (Moctezuma-Ramirez et. al 2023). 

·         Pharmacokinetics (PK)

These experiments characterize the absorption, distribution, metabolism, and excretion (ADME) of the chemical entity. The administration of the drug in these experiments should mimic the intended route for human use. Since most drugs are either weak acids or weak bases, the PK is critically important to determine the degree of ionization which contributes to the drug’s ability to cross lipid membranes. Orally administrated drugs that are acidic would be preferentially absorbed in the stomach whereas those drugs that are basic would be preferentially absorbed in the small intestine. When considering the parenteral administration of drugs, it is imperative to use the correct length/caliber of needle to ensure the drug is in the intended compartment.  Regarding a drug’s distribution, calculating the Volume of Distribution (VD) will indicate if the drug is confined to the plasma, the extracellular space, or the intracellular space (total body of water). Most drugs are metabolized in the liver by first order elimination kinetics. An estimate of metabolism can be obtained by calculating the Elimination Constant (Ke). 

The gold standard of pharmacokinetic testing is the administration of a fixed dose of a drug and the measurements of the resultant plasma levels. The three critical parameters are the Maximum Concentration (Cmax), Time to Maximum Concentration (Tmax) and Area Under the Curve (AUC), which allows assessment of the amount of drug delivered to the bloodstream over time. The graphical representation of the plasma levels over time allows for the calculation of the half-life (T1/2). If a drug is administered by any route other than intravenously, the Bioavailability (F) should be calculated. Bioavailability assesses how much of an orally administered drug is absorbed into the blood. This is defined as the AUC obtained by the intended route of administration (typically oral), divided by AUC of the intravenously administered drug. This is also essential for topical drugs, to determine if significant amounts of the drug reach the systemic circulation and depends on whether the drug was intended for local use, or systemic effects. 

Toxicology 

These experiments are designed to evaluate higher doses of the drug in order to determine the incidence of adverse side effects. One of the most important of these tests is the No Observed Adverse Effects Level (NOAEL) which represents the highest dose prior to the appearance of an adverse effect. The safety of a drug can also be obtained by calculating the Therapeutic Index (TI). This is the ratio of the dose that is lethal to fifty percent of animals tested (LD50), divided by the dose that is effective in fifty percent of the animals (ED50). It should be noted that standard toxicology testing involves both histologic and pathologic examination of all organ systems.

It is recommended that in preparation for the initial meeting with the FDA a dose range finding study in two animal species should be conducted, one in a rodent model and the other in a larger animal species with the drug administered in the intended route of administration. Evaluations which will include clinical pathology, ocular examinations, EKG, toxicokinetic assessments, necropsy and histopathology. A toxicokinetic evaluation (similar to a pharmacokinetic study) should be conducted. Clinical pathology should include hematology, coagulation, clinical chemistry assessment and urinalysis in addition to histopathology. The duration of the study will be dependent on whether the drug is intended for a single or multiple dose administration. Another required test is the AMES study which employs a bacterial reverse mutation assay, to assess the potential of a chemical to cause DNA mutations. Another recommended test is the in vitro micronucleus assay in TK6 cells which is used to evaluate the genotoxicity of the chemical agent. The hERG study is also used to monitor dysfunction of potassium channels which could lead to prolongation of the QT segment on EKG, which can result in sudden death from arrhythmia. 

Additional studies will be required following the initial meeting with FDA. These consist of  toxicity screening in two species of animals, , conducted under Good Laboratory Practice (GLP) conditions using Good Manufacturing Practice (GMP) grade material of the drug substance. Conducting studies by GLP/GMP international standards requires a higher level of quality control than other studies. These studies will be of a longer duration than those previously described.  In addition, studies will be required to assess the safety of the drug on the cardiovascular, respiratory and central nervous system. 

Ensuring a Successful Study Outcome  

·         Protocol

One of the most important aspects is the generation of a comprehensive protocol prior to beginning the study. It is critical that the hypothesis is clear and that the experiments are sufficiently designed to either prove or disprove the hypothesis (Huang, W., et. 2020). No detail should be overlooked, including every component of a drug solution. All details such as the ambient temperature, humidity and lighting need to be recorded. 

·         Animal Model

The animal models selected for the study should be based upon the known comparability of the physiologic responses to the effects observed in humans. For example, studies evaluating the cardiovascular system are often done using pigs since the cardiac anatomy and physiology is comparable to humans (Moctezuma-Ramirez et. al 2023). Although rodents are predominantly used for initial screening of new drugs, there are large differences in the physiology of many organ systems between the two species. 

·         Animal Housing and Welfare

A high degree of non-reproducibility of experimental results between two different laboratories can often be attributed to differences in animal housing and the handling of the animals during acclimation prior to conducting the experiments. The quality of the animal care and use program and in life portion of the study contributes in large measure to the overall quality of an animal experiment (Everitt 2015). From the time of the animal’s arrival at the facility, actions must be put in place to properly prepare the animal for the study during this time, that animal’s baseline vitals and general condition can be assessed (Moctezuma-Ramirez et. al 2023). 

·         Statistical analysis

A critical aspect is the adequacy of the sample size (Lazic et. al 2018). The use of an inadequate number of animals might fail to detect a significant difference due to factors such as minimizing animal to animal variability (Bonapersona et al., 2019; Carneiro et al., 2018; Howells et al., 2014). It is often advisable to calculate power and sample size which is based upon known variability and  probability. One way to increase external validity is to conduct identical studies at multiple sites, emulating an approach already applied in clinical trials (Dechartres et al., 2011; Friedman et al., 2015). Randomization and blinding should also be used in the allocation and administration, respectively, of the new treatment in order to reduce bias in the study and increase the validity of the results (Aban and George 2015). Most of these studies involve administering both drug and placebo to animals, so one may determine what the background incidence of findings are in untreated animals. 

·         GMP Drug Substance and GLP Requirements

It is acceptable to use non-GMP grade material under non-GLP conditions for the initial experiments that confirm the site and mechanism of action as well as the preliminary dose-response and ADME (absorption, distribution, metabolism, and excretion) experiments.  However, all of the pharmacokinetic experiments that calculate the Cmax, Tmax and AUC should be done under GLP conditions. The requirements of a GLP study are much more rigorous than those of non-validated exploratory studies because in GLP studies, the researchers are held accountable for the reliability, reproducibility, and validity of their study techniques, quality control features, and results (Moctezuma-Ramirez et. al 2023). Finally, all of the experiments required for FDA approval of an IND required the use of a GMP drug substance with experiments conducted under GLP conditions. Companies should understand the importance and requirements for GLP/GMP studies.  These studies are more expensive but can result in delay of acceptance of an IND for human study initiation of the package of preclinical studies if it does not meet regulatory requirements. 

Note: This is an abridged version of the white paper.  The full-length version is available on the Mesa Science Associates, Inc. website:  https://www.mesascience.com/ 

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References

Aban, I. B., & George, B. (2015). Statistical considerations for preclinical studies. Experimental neurology, 270, 82–87. https://doi.org/10.1016/j.expneurol.2015.02.024

Bate ST, Clark RA. The Design and Statistical Analysis of Animal Experiments. Cambridge University Press; 2014. 

Bonapersona, V., Hoijtink, H., RELACS, Sarabdjitsingh, R. A., & Joëls, M. (2019). RePAIR: a power solution to animal experimentation. bioRxiv, 864652. 

Carneiro, C. F. D., Moulin, T. C., Macleod, M. R., & Amaral, O. B. (2018). Effect size and statistical power in the rodent fear conditioning literature - A systematic review. PloS one, 13(4), e0196258. 

Charmaine J.M. Lim, Sanna K. Janhunen, Gernot Riedel. Reproducibility in Preclinical in Vivo Research: Statistical Inferences. J. Integr. Neurosci. 2024, 23(2), 30. https://doi.org/10.31083/j.jin2302030 

Dechartres, A., Boutron, I., Trinquart, L., Charles, P., & Ravaud, P. (2011). Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study. Annals of internal medicine, 155(1), 39–51. https://doi.org/10.7326/0003-4819-155-1-201107050-00006 

Everitt J. I. (2015). The future of preclinical animal models in pharmaceutical discovery and development: a need to bring in cerebro to the in vivo discussions. Toxicologic pathology, 43(1), 70–77. https://doi.org/10.1177/0192623314555162 

Friedman, L. M., Furberg, C. D., DeMets, D. L., Reboussin, D. M., & Granger, C. B. (2015). Fundamentals of clinical trials. springer. 

Henderson, V. C., Kimmelman, J., Fergusson, D., Grimshaw, J. M., & Hackam, D. G. (2013). Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS medicine, 10(7), e1001489. https://doi.org/10.1371/journal.pmed.1001489 

Howells, D. W., Sena, E. S., & Macleod, M. R. (2014). Bringing rigour to translational medicine. Nature reviews. Neurology, 10(1), 37–43. https://doi.org/10.1038/nrneurol.2013.232 

Huang, W., Percie du Sert, N., Vollert, J., & Rice, A. S. C. (2020). General Principles of Preclinical Study Design. Handbook of experimental pharmacology, 257, 55–69. https://doi.org/10.1007/164_2019_277 

Kilkenny, C., Parsons, N., Kadyszewski, E., Festing, M. F., Cuthill, I. C., Fry, D., Hutton, J., & Altman, D. G. (2009). Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PloS one, 4(11), e7824. https://doi.org/10.1371/journal.pone.0007824 

Laajala, T. D., Jumppanen, M., Huhtaniemi, R., Fey, V., Kaur, A., Knuuttila, M., Aho, E., Oksala, R., Westermarck, J., Mäkelä, S., Poutanen, M., & Aittokallio, T. (2016). Optimized design and analysis of preclinical intervention studies in vivo. Scientific reports, 6, 30723. https://doi.org/10.1038/srep30723 

Landis, S. C., Amara, S. G., Asadullah, K., Austin, C. P., Blumenstein, R., Bradley, E. W., Crystal, R. G., Darnell, R. B., Ferrante, R. J., Fillit, H., Finkelstein, R., Fisher, M., Gendelman, H. E., Golub, R. M., Goudreau, J. L., Gross, R. A., Gubitz, A. K., Hesterlee, S. E., Howells, D. W., Huguenard, J., … Silberberg, S. D. (2012). A call for transparent reporting to optimize the predictive value of preclinical research. Nature, 490(7419), 187–191. https://doi.org/10.1038/nature11556 

Lazic, S. E., Clarke-Williams, C. J., & Munafò, M. R. (2018). What exactly is 'N' in cell culture and animal experiments? PLoS biology, 16(4), e2005282. https://doi.org/10.1371/journal.pbio.2005282 

Moctezuma-Ramirez, A.; Dworaczyk, D.; Whitehorn, J.; Li, K.; Cardoso, C.d.O.; Elgalad, A. Designing an In Vivo Preclinical Research Study. Surgeries 2023, 4, 544–555. https://doi.org/10.3390/ surgeries4040053 

Perrin S. (2014). Preclinical research: Make mouse studies work. Nature, 507(7493), 423–425. https://doi.org/10.1038/507423a 

Pound, P., & Ritskes-Hoitinga, M. (2018). Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. Journal of translational medicine, 16(1), 304. https://doi.org/10.1186/s12967-018-1678-1 

Warner DS, James ML, Laskowitz DT, Wijdicks EF. Translational Research in Acute Central Nervous System Injury: Lessons Learned and the Future. JAMA Neurol. 2014;71(10):1311–1318. doi:10.1001/jamaneurol.2014.1238.

Top 10 Benefits of Remote Patient Monitoring for Rural Health

Authors: Michael Fath, PhD; Gerald L. Klein, MD: Sukhwant Khanuja, PhD; Roger E. Morgan, MD

Introduction: Rural communities across the U.S. face unique healthcare challenges, including provider shortages, long travel distances to medical facilities, limited access to specialists, and economic challenges. Remote Patient Monitoring (RPM) offers a transformative solution by enabling real-time tracking of patient health from a distance, reducing barriers to care and improving health outcomes. The advent of wireless technology has revolutionized healthcare delivery, particularly for underserved rural populations. Here, we explore the Top 10 Benefits of RPM for Rural Healthcare and how RPM enhances patient care, provider efficiency, and overall healthcare system sustainability.[1]

1. Expands Access to Care

The Challenge: Many rural areas have a limited number of primary care providers and even fewer specialists, requiring patients to travel long distances for routine and urgent medical care.

The RPM Advantage:

• Enables continuous monitoring of patients from their homes, reducing unnecessary travel

• Provides access to remote consultations with specialists via integrated telemedicine platforms

• Addresses chronic disease management without requiring frequent in-person visits

Key Insight: RPM bridges the gap in healthcare access for rural populations by making high-quality care available, regardless of location.[2] Studies show that RPM can extend healthcare services to previously unreachable populations, with up to 87% of rural patients reporting improved access to care.[3]

2. Reduces Hospital Readmissions

The Challenge: Rural hospitals often struggle with high readmission rates due to limited outpatient follow-up care and monitoring.

The RPM Advantage:

• Early detection of deteriorating conditions allows for timely interventions

• Reduces unnecessary ER visits and hospital admissions through proactive care management

• Provides real-time alerts to healthcare providers, allowing improved medication adherence as well as for quick provider responses

Key Insight: Studies have shown that RPM interventions can reduce hospital readmissions by 23% through continuous monitoring and early intervention.[4]

3. Improves Chronic Disease Management

The Challenge: Rural areas have higher rates of chronic conditions such as diabetes, hypertension, and heart disease,[5] yet fewer specialists to manage them.

The RPM Advantage:

• Enables daily tracking of key health metrics (e.g., blood pressure, glucose levels, oxygen saturation)

• Provides real-time data to healthcare providers, allowing for individualized treatment adjustments

• Enhances patient self-management through automated reminders and educational tools

Key Insight: RPM facilitates continuous monitoring and management of chronic diseases, leading to improved patient outcomes. A study by Lee et al. demonstrated significant improvements in blood pressure control using remote monitoring despite disruptions in traditional care.[6]

4. Addresses Rural Healthcare Workforce Shortages

The Challenge: Rural hospitals and clinics often struggle with staffing shortages, limiting access to timely care.

The RPM Advantage:

• Reduces the burden on rural healthcare staff by enabling remote monitoring and triage

• Allows nurses and physicians to manage a larger patient population with fewer in-person visits

• Helps mitigate burnout among rural healthcare workers by streamlining routine monitoring tasks

Key Insight: RPM optimizes provider time and extends healthcare resources to underserved areas. Studies indicate that RPM can increase provider efficiency by up to 30% by reducing unnecessary visits and administrative burden.[7]

5. Enhances Emergency Response and Prevents Crisis Situations

The Challenge: Rural patients experiencing acute medical events often face delayed emergency response times due to long distances to hospitals.

The RPM Advantage:

• Provides continuous tracking of vital signs, identifying early warning signs of health deterioration

• Alerts healthcare providers and caregivers immediately if critical thresholds are crossed

• Supports rapid decision-making, enabling earlier interventions before a crisis occurs

Key Insight: Early detection of worsening conditions through RPM reduces emergency transports and improves survival rates. Data shows that RPM can decrease emergency department visits by up to 25% among rural patients with chronic conditions.[8]

6. Supports Aging in Place for Rural Seniors

The Challenge: Rural seniors often lack nearby family members or healthcare providers to assist with daily medical needs.

The RPM Advantage:

• Enables independent living by offering continuous health monitoring without requiring frequent clinic visits

• Connects patients with healthcare professionals and family caregivers for real-time support

• Helps detect early signs of frailty, falls, or cognitive decline

Key Insight: RPM allows rural seniors to remain in their homes longer while maintaining access to high-quality healthcare. Studies report that 94% of seniors using RPM feel more secure in their homes and experience improved quality of life.[9]

7. Reduces Healthcare Costs for Patients and Providers

The Challenge: Healthcare costs are often higher in rural areas due to travel expenses, limited provider availability, and hospital dependence for non-emergency care.

The RPM Advantage:

• Reduces the need for frequent travel to healthcare facilities

• Prevents costly emergency department and hospital visits enabling early intervention and preventative care

• Helps rural hospitals optimize resource utilization and focus on high-acuity cases

Key Insight: RPM has been associated with reduced healthcare utilization and costs. Research from the Tufts Center for the Study of Drug Development found that remote monitoring initiatives can yield a seven-fold return on investment through reduced clinical visits and improved efficiency.[10]

8. Strengthens Rural Health Infrastructure and Telemedicine Integration

The Challenge: Rural healthcare networks struggle with fragmented care and inconsistent access to specialists.

The RPM Advantage:

• Integrates with telemedicine platforms for seamless remote consultations

• Facilitates data sharing between rural clinics and urban medical centers

• Enhances care coordination by providing continuous health data to multiple providers

Key Insight: RPM strengthens rural healthcare infrastructure, enabling comprehensive, connected care. Healthcare systems implementing integrated RPM-telemedicine platforms report up to 40% improvement in care coordination metrics.[11]

9. Improves Maternal and Prenatal Care in Underserved Regions

The Challenge: Rural areas have higher maternal mortality rates and fewer obstetric providers, putting expectant mothers at risk.

The RPM Advantage:

• Allows remote monitoring of blood pressure, weight, and fetal heart rate for high-risk pregnancies

• Provides real-time alerts for conditions such as pre-eclampsia or gestational diabetes

• Enables virtual prenatal visits, reducing travel burdens for rural mothers

Key Insight: RPM has been shown to reduce complications and improve outcomes for rural maternity care. Studies demonstrate a 30% reduction in pregnancy-related complications when RPM is implemented for high-risk pregnancies in rural settings.[12]

10. Enhances Mental Health Care Access for Rural Communities

The Challenge: Rural areas face a severe shortage of mental health providers, with long wait times for psychiatric care.

The RPM Advantage:

• Enables remote mood tracking and symptom monitoring for mental health conditions

• Facilitates virtual counseling and medication management via telepsychiatry

• Provides real-time support and intervention for crisis situations

Key Insight: RPM expands access to mental health care, addressing a critical gap in rural communities. Implementation of RPM for mental health services has shown up to 60% improvement in treatment adherence and symptom management.[13]

Conclusion

Remote Patient Monitoring is a game-changer for rural healthcare, providing solutions to access barriers, provider shortages, chronic disease management, and emergency response. As technology advances and healthcare policies increasingly support RPM adoption, its role in improving rural health outcomes will only grow stronger. The FDA has recognized the value of remote monitoring technologies in extending healthcare access to underserved populations, particularly those with rare diseases or mobility challenges.[14]

Healthcare providers serving rural communities should consider implementing RPM as a cost-effective strategy to expand their reach, improve patient outcomes, and strengthen rural healthcare infrastructure.

References

[1] Apostolaros M, Babaian D, Corneli A, et al. Legal, Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations from the Clinical Trials Transformation Initiative. Ther Innov Regul Sci. 2020;54:779-787.

[2] Rural Health Information Hub. The use of Remote Patient Monitoring for Rural Communities. https://www.ruralhealthinfo.org/rural-monitor/remote-patient-monitoring.

[3] Sharma NS. Patient centric approach for clinical trials: Current trend and new opportunities. Perspect Clin Res. 2015;6(3):134-138.

[4] Healthcare IT News. How RPM can solve many patient and provider problems in rural areas. https://www.healthcareitnews.com/news/how-rpm-can-solve-many-patient-and-provider-problems-rural-areas.

[5] Aggarwal R, Chiu N, Loccoh EC, Kazi DS, Yeh RW, Wadhera RK. Rural-Urban Disparities: Diabetes, Hypertension, Heart Disease, and Stroke Mortality Among Black and White Adults, 1999-2018. J Am Coll Cardiol. 2021 Mar 23;77(11):1480-1481.

[6] Lee SG, Blood AJ, Cannon CP, et al. Remote Cardiovascular Hypertension Program Enhanced Blood Pressure Control During the COVID-19 Pandemic. J Am Heart Assoc. 2023;12(6). https://www.ahajournals.org/doi/10.1161/JAHA.122.027296

[7] De Jong A, van Rijssel T, Zuidgeest M, et al. Opportunities and Challenges for Decentralized Clinical Trials: European Regulators' Perspective. Clin Pharm & Ther. 2022;111:344-352.

[8] Hanley DF, Bernard GR, Wilkins CH, et al. Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned. Journal of Clinical and Translational Science. 2023;7(1):e170.

[1] Tran VT, Nguyen VT, Ravaud P, Young B, Boutron I. Patients' Perspectives on Transforming Clinical Trial Participation: Large Online Vignette-based Survey. J Med Internet Res. 2022;24(2):e29691.

[9] DiMasi JA, Smith Z, Oakley-Girvan I, et al. Assessing the Financial Value of Decentralized Clinical Trials. Ther Innov Regul Sci. 2023;57(2):209-219.

[10] Stergiopoulas S, Tenaerts P, Brown CA, et al. Cost drivers of a hospital acquired bacterial pneumonia and ventilator associated bacterial pneumonia (HABP/VABP) phase three clinical trials. Clin Infect Dis. 2018;66(1):72–80.

[11] Centers for Medicare & Medicaid Services. Maternal Health Initiatives. https://www.cms.gov/About-CMS/Agency-Information/OMH/equity-initiatives/rural-health/maternal-health-initiatives

[12] Substance Abuse and Mental Health Services Administration. The Use of Telehealth for the Delivery of Behavioral Health in Rural Communities. https://www.samhsa.gov/sites/default/files/telehealth-delivery-behavioral-health-rural.pdf

[14] FDA. FDA Takes Additional Steps to Advance Decentralized Clinical Trials. https://www.fda.gov/news-events/press-announcements/fda-takes-additional-steps-advance-decentralized-clinical-trials

Practical Pointers for February 2025: Asymmetric Weight Distribution: Using the Carematix Scale in Clinical Practice

Authors: Michael Fath, PhD; Gerald L. Klein, MD; Roger E. Morgan, MD

WHAT IS ASYMMETRIC WEIGHT DISTRIBUTION?

When patients favor one side of their body over the other while standing or walking, they're exhibiting asymmetric weight distribution (AWD). This common finding accompanies numerous neurological conditions and can significantly impact mobility, balance, and fall risk.

While we've traditionally relied on expensive force platforms or pressure mats to quantify AWD, a new patented weight scale by Carematix offers a practical alternative that doesn't require a trip to the gait lab.  MedSurgPI is partnering with Carematix to bring this innovation to clinicians across the US.

The Carematix Advantage

The Carematix scale measures weight-bearing through each limb in real-time, providing immediate feedback on asymmetry. Unlike bulky force platforms, it’s portable, affordable, and interfaces with most Electronic Medical Record (EMR) systems.[1]

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Condition-Specific Applications

Stroke:

• What we See: Post-stroke patients typically bear 60-80% of their weight on the unaffected side.[2]

• Why it Matters: Persistent AWD correlates with slower walking speeds, reduced community mobility, and increased fall risk.[3]

• How We Use It:

  • Baseline AWD measurements help quantify impairment severity

  • Weekly measurements track improvement during rehab

  • Patients use visual feedback during weight-shifting exercises

    • Remote monitoring between visits catches regression early[4]

Clinical Nugget: A 10% improvement in weight symmetry often translates to significant functional gains in stair navigation.[6]

Parkinson’s Disease

• What We See: Subtle AWD often appears years before clinical diagnosis.[6]

• Why It Matters: Worsening asymmetry may signal medication wearing off or disease progression.

• How We Use It:

  • Track responses to levodopa throughout the day

  • Guide DBS programming by measuring immediate effects on symmetry

  • Identify fall risk before clinical observation catches it[7]

Clinical Nugget: We’ve found that AWD measurements better predict freezing of gait than standard clinical scales.[8]

Cerebral Palsy

• What We See: Children with CP often develop compensatory patterns that create longstanding AWD.

• How We Use It

  • Guide orthotic adjustments in real-time

  • Measure immediate effects of spasticity interventions

  • Track post-surgical weight-bearing patterns[9]

  • Provide objective feedback during therapy sessions

Clinical Nugget: For pediatric patients, turning AWD measurement into a game (“balance the scale!”) significantly improves engagement.

Neuromuscular Disorders

• What We See: Progressive conditions like ALS and MS show evolving patterns of asymmetry.

• Why It Matters: Changes in AWD often precede functional decline.

• How We Use It:

  • Track disease progression between clinic visits

  • Guide assistive device selection and adjustment

  • Inform home modification recommendations[10]

  Clinical Nugget: Weekly AWD tracking has helped us identify MS exacerbations an average of 10 days earlier than patient self-report.[11]

Incorporating Into Your Practice

Getting Started

1. Establish your patient’s baseline AWD during initial evaluation

2. Document the percentage of weight bornre on each side

3. Set symmetry targets based on diagnosis and functional goals

4. Re-measure at each visit to track progress

Reimbursement Tips

• AWD measurement is billable under CPT97750 (Physical Performance Test)

• Remote monitoring qualifies for RPM codes 99453, 99454, and 99457

• Document medical necessity by connecting AWD to fall risk or functional limitation

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Practical Case Example:

Patient: 68-year-old male, 4 weeks post-stroke

Initial AWD: 75% on right (unaffected side)

Intervention: Twice-weekly PT with Carematix feedback during standing exercises + home program with portable scale

8-Week Result: Improved to 57% weight on right side; 10-meter walk speed increased from 0.5 to 0.8 m/s.[12]

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Bottom Line: The Carematix scale turns the abstract concept of “weight-bearing symmetry” into an objective, measurable target for both clinicians and patients. It’s a practical tool that delivers relevant data without breaking your budget or workflow.

Have you incorporated AWD measurement into your practice? Share your experience with us at info@medsurgpi.com

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References

[1] Winter DA, et al. (2005). Biomechanics and Motor Control of Human Movement. Wiley.

[2] Patterson KK, et al. (2010). "Gait asymmetry in stroke: Determinants and implications for rehabilitation." Neurorehabilitation and Neural Repair, 24(8), 728-735.

[3] Mancini M, et al. (2018). “Mobility and balance in Parkinson’s disease: A review. “Movement Disorders, 33(5), 24-38.

[4] Wang J, et al. (2015). “Remote monitoring in stroke rehabilitation.” Stroke Rehabilitation and Recovery, 10(4), 247-253.

[5] Laufer Y, et al. (2003). “The effects of balance training on gait symmetry in stroke patients.” Clinical Rehabilitation, 17(5), 478-489.

[6] Palmisano C, et al. (2020). “Gait asymmetry in Parkinson’s disease.” Frontiers in Neurology, 11, 585.

[7] Ashburn A, et al. (2001). “Postural instability and fall risk in Parkinson’s disease.” Movement Disorders, 16(5), 946-952.

[8] Mancini M, et al. (2012). “Longitudinal assessment of balance and gait in Parkinson’s disease.” Journal of Neurology, 259(7), 1337-1346.

[9] Tedroff K, et al. (2011) “Surgical outcomes and balance in children with cerebral palsy.” Journal of Pediatric Orthopedics 31(8), 853-859.

[10] DiFabio RP. (1995). “Balance measurement in the elderly and in individuals with neuromuscular deficits.” Physical Therapy, 75(6), 475-491.

[11] Sosnoff JJ, et al. (2011) “Mobility in multiple sclerosis: Relationship between AWD and fall risk.” Neurorehabilitation and Neural Repair, 25(8), 735-742.

[12] Lee MJ, et al. (215). “Asymmetrical weight bearing as a marker of functional recovery following stroke.” Journal of Rehabilitation Medicine, 47(4), 373-389.

MedSurgPI DSMB Capabilities

What We Provide: An experienced team of experts who have served on numerous data safety monitoring boards, safety review committees, adjudication boards, and are seasoned medical monitors.  This includes the physician chairperson, physicians, and administrator.

Our Approach:

• Identifying Medical Needs: The MedSurgPI Team of physicians can cover nearly all indications.

• Addressing Key Questions: Our team of physicians have the regulatory, safety, and scientific understanding of your protocol.

• The Chairperson: Our experienced physicians have served as chairpersons in multiple studies.

Understanding the Safety and Regulatory Pathway

• The safety and regulatory landscape can either accelerate or derail your timelines. Proactively engaging with regulatory bodies and leveraging existing frameworks ensures smoother progression.

• Key Considerations:

  • Do novel therapies require a customized safety and regulatory DSMB strategy?

  • Developing the DSMB Charter:

    • Assess the successes and challenges of similar products.

    • Design a tailored approach to align with your specific safety profile.

Ensuring Alignment and Effective Oversight (key elements)

• Addressing the Protocol and Investigator Brochure: ensure the DSMB charter aligns seamlessly with these critical documents.

• Biostatistician: Who will understand how to examine interim analysis.

• Administration: Ensure a seamless meeting process with an experienced administrator to manage logistics, oversee document disposal, and accurately record meeting minutes.

Key Considerations for Successful Pharmaceutical Product Development

Introduction

Developing a new medical product is no small feat—it’s a balancing act that requires sharp focus, strategic thinking, and adaptability. From identifying unmet medical needs to navigating operational, regulatory, and reimbursement challenges, the process often feels overwhelming. When executed effectively, however, the impact on patient wellbeing and providers is transformative. This issue of Practical Pointers outlines essential strategies to advance a product from concept to clinic and ultimately to the patients who need it.

1. The Pillars of Pharmaceutical Product Development

A. Identifying the Medical Need: Understanding why your product is essential is the cornerstone of success. A well-defined unmet clinical need is critical to securing success as well as guiding development decisions.

• Key Questions to Address:

  • What are the current gaps in treatment?

  • How does the existing standard of care fall short?

  • What do patients and providers identify as unmet needs?

• Common Drivers of Unmet Need:

  • Lack of Effective Treatments: Rare diseases, advanced-stage cancers, and multiple drug-resistant infections often lack sufficient therapeutic options.

  • Tolerability Issues: Treatments like chemotherapy, opioids, immunotherapies or immunosuppressants impose significant side effects.

  • Emerging Science: Innovations in precision medicine, cell therapy, and AI-assisted drug design create opportunities to address previously untreatable conditions.

B. Understanding the Regulatory Pathway: The regulatory landscape can either accelerate or derail your timelines. Proactively engaging with regulatory bodies and leveraging existing frameworks ensures smoother progression.

• Key Considerations:

  • Are there established accelerated regulatory pathways such as Fast Track or PRIME designations for your product?

  • Do/should novel therapies require a customized regulatory strategy?

  • Do you qualify for orphan disease recognition?

• Best Practices:

  • Analyze the success and shortfalls of similar products

  • Schedule pre-IND meetings and regular interaction with various regulators (FDA, EMA, etc.) to clarify expectations and address gaps.

  • Explore expedited pathways, such as Breakthrough Therapy designation or Orphan Drug status.

C. Addressing Preclinical and Clinical Operational Hurdles: Operational efficiency can make or break clinical trial success. From preclinical planning to patient recruitment, strategic management is key.

• Preclinical Essentials

  • Collaborate with experienced consultants.

  • Identify cost-effective manufacturing partners.

  • Select appropriate animal models as well as testing facilities.

  • The use of appropriate biomarkers to assist in the following:

    • Enrich enrollment

    • Accelerate the clinical trial

• Clinical Challenges and Solutions:

  • Patient Recruitment: Leverage advocacy groups, patient registries, and decentralized trial methods to access rare populations. Sites over-estimate how many patients/subjects they can recruit. Incorporating AI into the workflow for accessing Electronic Medical Record (EMR) data will increase the accuracy of site estimates.

  • Cost and Timelines: Adopt virtual trials and lean monitoring to optimize resources. Adopting Risk-Based Quality Monitoring involves identifying critical data points and accepting that some less critical data may be missed, which is an acceptable trade-off for efficiency and focus. Regulatory agencies are encouraging this, but they must be in alignment with the plan.

  • Technology: May enhance clinical trials with greater patient accessibility, accuracy and efficiency.

    • Decentralized trials: Leverage innovations such as remote patient monitoring and telehealth to enable trials beyond traditional clinical settings.

    • Fostering diversity: These advancements can boost patient enrollment and expand diversity in trial populations.

    • Real-Time Data Collection: Tools like eConsent, blockchain, and AI-driven analytics streamline processes, enabling faster and more reliable data collections.

    • Cost-effective development: These technologies support more efficient and cost-effective drug and device development.

D. Navigating the Reimbursement Pathway: Even the most innovative therapies must demonstrate value to ensure accessibility. Early integration of pharmacoeconomic principles is vital.

• Key Elements:

  • Incorporate health economics (e.g., Cost-effectiveness, Quality Adjusted Life Year (QALY) metrics) into Phase 3 trials.

  • Use real-world evidence (RWE) to validate clinical outcomes.

• Case Example: High-cost therapies like Zolgensma have pioneered outcomes-based reimbursement models to achieve payer acceptance.

2. Proper Delegation and Documentation: Clear delegation and meticulous documentation are essential to maintain compliance and streamline operations.

• Best Practices:

  • Assign clear roles for informed consent, eligibility checks, and data collection.

  • Maintain updated delegation logs and implement standard operating procedures (SOPs).

  • Foster strong site relationships through consistent personal communication and training.

  • The use of technology at the site may also significantly reduce bottlenecks in streamlining data collection, reporting, and enhance patient recruitment.

3. Managing Adverse Events in Complex Trials: Adverse event management becomes more challenging with complex therapies such as oncology drugs or gene therapies.

• Strategies:

  • Use causality assessment tools such as the Bradford Hill Criteria or the Naranjo scale.

  • Develop robust escalation and adjudication pathways.

  • Implement independent committees for unbiased assessments such as a Data and Safety Monitoring Board (DSMB) and the Safety Review Committee (SRC).

  • To objectively evaluate severity, the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI_CTCAE) should be used.

• Evaluation Framework:

  • Examine timing between drug administration and adverse events.

  • Consider external factors (e.g., co-medications, underlying conditions).

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Wrapping it up:

Drug development is a multifaceted endeavor, but a clear strategy can transform complexity into success. By focusing on unmet medical needs, regulatory navigation, operational efficiency, and market access, companies can ensure their innovations reach the patients who need them most.

At MedSurgPI, we specialize in overcoming these challenges. Whether you are seeking guidance on regulatory strategy, clinical trial optimization, or market readiness, we’re here to partner with you. Let’s collaborate to bring your vision to life.

Top 10 Benefits of Remote Patient Monitoring for Clinical Trials

Written by: Gerald L. Klein, MD* Michael Fath, PhD* Sukhwant Khanuja, PhD** Roger E. Morgan, MD* MedSurgPI* Carematix Inc**

Introduction

The advent of wireless technology has revolutionized many sectors of healthcare, especially clinical trials and the medical assessment of homebound geriatric patients.  Wireless remote patient monitoring (RPM) can enhance the efficiency and effectiveness of decentralized and patient-centric clinical trials. Decentralized clinical trials (DCTs) are studies that are not limited to a geographical region but are conducted through the use of local investigators with telemedicine and remote patient monitoring.[1] RPM allows the expansion of these studies into more remote and diversified populations that are notoriously underrepresented.  The FDA has released guidance documents on the conduct of decentralized clinical trials.[2] Clinical research organizations (CROs)  now take advantage of both the use of decentralized and hybrid clinical studies which uses a combination of the two. Here, we explore how wireless RPM can improve clinical studies. View the entire article here

[1] Apostolaros M. Babaian D. Corneli Al et al. Legal Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations From the Clinical Trials Transformation Initiative. Ther Innov Regul Sci 54, 2020: 779-787.

[2] https://www.fda.gov/media/167696/download