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

Mesa Science Associates and MedSurgPI announce a partnership

Mesa Science Associates, Inc. (MSA) and MedSurgPI, LLC have announced a partnership between their two companies, which will expand and consolidate the offerings of both to the pharmaceutical and bio-pharmaceutical research and development communities, offering a single source for services of particular importance to small and mid-sized biotech firms.

MSA is located in the Frederick Innovative Technology Center in Frederick, MD and specializes in drug-delivery development and clinical study design and operations. Its services include: consulting and management in the broad areas of Active Pharmaceutical Ingredient (API) sourcing; expertise in chemistry manufacturing and control; in vivo and in vitro pre-clinical and clinical-trial support services; and expertise in consulting on drug-delivery devices.

MedSurgPI is located in Research Triangle Park, NC and provides medical consulting for product development and medical affairs. Its suite of services includes: medical oversight for clinical studies; clinical strategy; medical monitoring; DSMB and SRC services; medical affairs; journal articles; fractional Chief Medical Officer services; and medical input for promotional (LMR) review.

Commenting on the partnership, Michael Mesa, MSA’s president, had this to say, “We look forward to working closely with MedSurgPI to bring a wider array of pharmaceutical development services to our clients.” Both companies believe their coordinated efforts will offer clients a powerful set of research guidance and management tools, beginning with preclinical studies and running all the way through FDA filings and post-marketing medical affairs. Dr. Gerald L. Klein, Principal of MedSurgPI said this about the partnership, “This collaboration with Mesa Science Associates will enhance our capacity to deliver robust preclinical and scientific consulting services to our clients.”

The services these two companies are bringing together are especially important for startup biotech companies, which don’t necessarily have the size and staffing to internalize such disparate capabilities under one roof. Small to mid-sized companies will now be able to access them from a single source, which will be a benefit to them and reassuring to their investors, which can range from private equity, to venture capital, to angel investors, and family funds.

About Mesa Science Associates, Inc.

Mesa Science Associates (MSA) is a veteran-owned small business located in the Frederick Innovative Technology Center Inc. (FITCI), located at 321 Ballenger Center Drive in Frederick, MD. MSA provides a comprehensive array of pharmaceutical development solutions to the research community, including the federal government. From product development planning to NDA or BLA submission, MSA’s flexible service model leverages a network of highly skilled research and research support professionals from across the U.S. to consult with laboratory specialists on: pharmacology; preclinical drug evaluation; clinical studies; CMC development; drug delivery systems; and regulatory consulting throughout the drug-approval process.

 About MedSurgPI, LLC

MedSurgPI is a pharmaceutical physician consulting company based out of Research Triangle Park in North Carolina. MedSurgPI provides medical expertise for clinical strategy, protocol review and development, FDA meetings, investigator meetings, and more. It also provides fractional (functional) medical services, including Chief Medical Officer, Medical Monitor, and Medical Director. MedSurgPI’s medical affairs capabilities includes medical communications, LMR review, KOL selection and management, and continuing medical education. MedSurgPI also offers comprehensive DSMB services, bringing together an elite team of experienced physician specialists, statisticians, and pharmacokinetic experts dedicated to serving as your DSMB. 

Practical Pointers for Product Development and Medical Affairs / July 2024

Written by: Gerald L. Klein, MD; Roger E. Morgan, MD; Shabnam Vaezzadeh, MD; Burak Pakkal, MD; Michael Fath, PhD; Larry Florin, MBA

Product Development

• Developing a Diversity Action Plan: The FDA now requires sponsors to submit Diversity Action Plans for certain clinical studies. These plans should outline the sponsor’s goals for enrolling participants from underrepresented populations, including specific targets for age, ethnicity, sex, and race. The plan should also describe the strategies and methods the sponsor will use to achieve these goals.[1]

• Informed Consent Form Design: The importance of ensuring that your IRB is following the recent regulations, ethics, and patient protection policies is tantamount to conducting good clinical trials.[2] In June 2024, the FDAs issuance of a 483 highlighting issues with informed consent at a leading US research institution was one among several noted failures:

  • Failure to ensure that information given to subjects as part of informed consent is in accordance with 21 CFR 50.25 [21 CFR § 56.109(b)]:

    • Failure to disclose appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject, as required by 21 CFR 50.25(a)(4).

    • Failure to provide an explanation as to whether any compensation is available if injury occurs and, if so, what it consists of, or where further information may be obtained as required by 21 CFR 50.25(a)(6).

    • Failure for a statement that notes the possibility that the FDA may inspect the records, as required by 21 CFR 50.25(a)(5).

  • This is a wakeup call for all IRBs, research institutions, sponsors, and CROs, to ensure that the IRB is doing their job properly.

• The new FDA guidance on Use Related Risk Analysis (URRA) is now required for device drug combination, and also to determine if human factors (HF) data will be required to support an NDA or BLA.[3] This plan should include the following:

  • A comprehensive list of all tasks required for the use of the product

  • The potential use errors and harms that may occur with those tasks

  • A determination whether each task is a critical task

  • Risk controls employed in the user interface designed to mitigate use errors

  • Evaluation methods that have been used (or will be used) to evaluate the effectiveness of the risk controls

Medical Affairs

• Enhancing Patient-Centric Medical Communication: In today’s information-saturated environment, delivering effective patient-centric medical communication is more crucial than ever. The influx of information, much of it potentially false or misleading, can dilute essential messages from drug manufacturers and distributors. To counter this, medical communication professionals must craft messages that are creative and impactful, helping to overcome any negative attitudes towards pharmaceutical discussions. To achieve this, communication materials should include the following key elements:

  • Clear and accessible language:

    • Avoid using jargon and technical terminology.

    • Ensure the language is simple and easy to understand for all audiences.

  • Conciseness and precision:

    • Present information in a clear, concise manner.

    • Keep messages focused to prevent overwhelming the audience.

  • Factual and substantiated content:

    • Ensure all statements are based on verified data and research.

    • Provide references to credible sources to enhance trust and reliability.

  • Enhanced visualization:

    • Utilize appropriate drawings, photos, tables, and figures to illustrate key points.

    • Visual aids significantly improve comprehension and retention.

  • Resources for further information:

    • Offer additional resources and follow-up options for those seeking more details.

    • Include links to reputable websites, support groups, and detailed guides.

  • Leveraging artificial intelligence (AI):

    • Use AI to develop engaging multimedia programs that capture the attention of younger and broader audiences.

    • AI can create dynamic platforms that simplify understanding of disease processes and therapeutic approaches.

• The use of AI may assist in the development of multimedia programs that capture the attention of a younger and/or a wider audience. This can provide a dynamic platform to address the better understanding of disease processes and your therapeutic approach. The benefits and adverse effects of your product(s) should be clearly articulated in an easy to understand manner.

• Maximize the Effectiveness of Medical Science Liaisons (MSLs). In order to fully utilize your MSL team, consider implementing a creative approach with the following strategies:

  • Advanced training: Provide comprehensive and ongoing training programs to keep MSLs updated on the latest medical and scientific developments.

  • Mentoring programs: Pair less experienced MSLs with seasoned mentors to foster professional growth and knowledge sharing.

  • Unique challenges: Offer opportunities that encourage MSLs to develop innovative solutions and think outside the box.

  • Innovative technology: Equip MSLs with cutting-edge tools and technologies to enhance their efficiency and effectiveness in the field.

  • Individual techniques: Encourage MSLs to develop and utilize their unique approaches and techniques tailored to their strengths and preferences.

  • Flexible work schedules: Allow flexibility in work schedules to accommodate personal and professional needs, promoting a healthy work-life balance.

  • Scientific stimulation: Provide continuous scientific stimulation through access to the latest research, conferences, and collaborative opportunities.

  • Competitive compensation: Ensure competitive compensation packages with incentive opportunities to attract and retain top talent in the industry.

By focusing on these elements, medical communication professionals can create impactful and trustworthy messages that resonate with patients while also empowering MSL teams to excel in their roles.

[1]https://www.fda.gov/news-events/press-announcements/fda-guidance-provides-new-details-diversity-action-plans-required-certain-clinical-studies.

[2]Rogers, C.A., Ahearn, J.D. & Bartlett, M.G. Data Integrity in the Pharmaceutical Industry: Analysis of Inspections and Warning Letters Issued by the Bioresearch Monitoring Program Between Fiscal Years 2007–2018. Ther Innov Regul Sci 54, 1123–1133 (2020).

[3]https://www.fda.gov/regulatory-information/search-fda-guidance-documents/purpose-and-content-use-related-risk-analyses-drugs-biological-products-and-combination-products.

Practical Pointers for Product Development and Medical Affairs / June 2024

Written by: Gerald L. Klein, MD; Roger E. Morgan, MD; Michael Fath, PhD; Larry Florin, MBA

Product Development

• The FDA has just issued a new guidance document June 2024: Diabetic Foot Infections: Developing Drugs for Treatment.[1] This guidance provides important trial design such as emphasizing the importance of including subjects with diverse foot ulcer depths and area of involvement. The guidance considers surgical debridement after 48 hours as a criterion for treatment failure.

• The importance of using a placebo in Phase I clinical trials is particularly crucial when testing medication on patients with disorders known to exhibit a significant nocebo and placebo effect. The nocebo effect results from the negative anticipations, beliefs, expectations, or previous experiences that study participants have toward the medication that they will be administered.[2] This effect in clinical trials may not always be recognized but may distort the results, leading to increased withdrawal of participants, and complicate interpretation of the data.[3]

• When is an AE resolved so that it no longer has to be followed by the Principal Investigator (PI)?[4] This is usually straight forward such as when an infection that was treated with an antibiotic resolves. However, in certain chronic conditions this decision point may be difficult to ascertain. Some protocols state that when the condition returns to baseline the event is resolved. Not all conditions will return to baseline. Other studies state that if it is a chronic condition that has stabilized, it should be considered resolved. However, if it has not stabilized and/or requires long-term treatment, such as an aggressive cancer (and the protocol does not cover this), we suggest that it be listed as resolving and only followed until the study ends. For SAEs, the protocol should include specific language that outlines the duration of follow-up required after a patient has discontinued participation in the study.

Medical Affairs

• It may be difficult to present evidence demonstrating the effectiveness of one pharmaceutical product over another marketed therapy. Meta analysis has been frequently used for such proof, but these have multiple drawbacks and may not be readily accepted by healthcare providers. The use of real world data and clinical studies may help solve this problem.[5]

• The more rapid adapatation to the use of plain langauge can go a long way in getting your message out to the public and even to some health care providers. Just because pharmaceutical diagnostics and therapeutics may be complicated, it does not mean that your language has to be written in more difficult to understand jargon.[6] An improved communication methodology can significantly enhance the value and impact of your messaging.

• Although there has been a significant increase in the use of omnichannel digital marketing in medical affairs, direct person-to-person contact should not be overlooked. A medical liaison who has established respect, trust, and likeability will magnify the effectiveness of a personal digital campaign sent from that same individual.[7]

Practical Pointers for Product Development and Medical Affairs / May 2023

Written by: Gerald L. Klein, MD; Roger E. Morgan, MD; Shabnam Vaezzadeh, MD; Burak Pakkal, MD and Michael Fath, PhD

Product Development

• Academic Innovation Centers can serve as pivotal hubs in the context of product development. These hubs can be a focal point in the development of entrepreneurial centers. The ideal center combines diverse university schools of science, nursing, engineering, dental, pharmacology, and dentistry medicine along with a business school. If they can break down the myriad of academic political walls and combine forces with regional governments, state governments, and industry, they can develop a scientific and economic powerhouse. Tremendous centers of innovation and entrepreneurship have been established in the Boston, San Francisco, San Diego, NJ/NY Corridor, and in Research Triangle Park, North Carolina. Academic leadership should proactively enhance the effectiveness of their innovation centers in order to be more effective.

• Efficient clinical trial enrollment is a critical factor in successful product development. Poor patient enrollment into clinical trials is one of the main reasons for study failure. This is an expensive, time-consuming process. One way that may aid this process is to use Artificial Intelligence (AI) to help with enrollment. There are many AI systems available to achieve this critical goal. Some examples include:

  • IBM Watson Health: Uses machine learning and Natural Language Processing (NLP) to analyze medical records and identify eligible patients for clinical trials. Provides predictive analytics for patient recruitment and engagement.

  • Deep 6 AI: Leverages AI to match patients to clinical trials by analyzing structured and unstructured data from electronic health records. Focuses on speed and accuracy in patient identification.

  • TriNetX: A global health research network that uses real-time access to HER data to identify eligible patients for clinical trials. Offers analytics and patient recruitment solutions.

  • Antidote: Utilizes AI to connect patients with relevant clinical trials. Uses advanced search algorithms to match patient profiles with trial eligibility criteria.

  • CureMetrix: Employs AI to enhance patient identification and engagement through medical imaging analysis and predictive analytics. Helps improve the accuracy of patient matching and recruitment.

  • Clinical AI: Uses AI to streamline the clinical trial process, from patient recruitment to data analysis. Focuses on automating trial management and enhancing patient engagement through AI-driven insights.

• Include clinical research training for students in health care related programs. Providing proper training for students in medical, nursing, PA, PharmD, and other health care related programs can contribute significantly to product development. We believe that it is important to teach the basic elements of clinical research to all health care students in order to instill the following virtues:

  • Increase their scientific curiosity

  • Enhance their ability to understand the scientific literature

    • Increase their capability to analyze pharmaceutical product effectiveness and adverse effects.

  • Improve their interpretation of clinical trials

  • Be able to apply scientific literature to clinical pracctice

  • Increase the likelihood that students will engage in conducting clinical research and publication

Medical Affairs

• Webinars serve as a powerful way to get your message out. In order for this to be successful, the target audience must be persuaded to watch this event in either real time or at a later date. This can be enhanced by the following:

  • Selecting appropriate speakers

  • Timing of the event

  • Cutting edge or important subject matter

  • Promotional campaign to attract an audience

• Strategy: One key strategy in product promotion is to identify a medical need. This could be:

  • Specific populations: consider unique patient groups (e.g., pediatric, geriatric or rare diseases) that require tailored solutions.

  • Intolerant patients: highlight cases where patients cannot tolerate existing therapies. Position your product as an alternative.

  • Niche Situations: Explore scenarios where your product fills a gap. Initiate communication with key opinion leaders (KOLs) and other healthcare providers.

• Cost-effective data generation using surveys and small studies: The use of surveys and small studies are a cost-effective way to produce data for poster sessions at scientific conferences. This data can be published in a brief publication, and then followed up with subsequent studies and publications. It may be a way to initiate a marketing campaign when you are faced with a low budget.

Practical Pointers for Drug Development and Medical Affairs

Written by: Gerald L. Klein, MD; Roger E. Morgan, MD; Shabnam Vaezzadeh, MD; Renu Jain, PhD; Pavle Vukojevic, MD; Burak Pakkal, MD; Michael Fath, PhD; Larry Florin, MBA; Victoria Manax, MD; L. Allen Kindman, MD

Drug, Device, and Diagnostic Development

• It is extremely difficult to demonstrate statistical significance and efficacy in clinical trials. The placebo and nocebo effects, which appear to be increasing in randomized clinical trials, begin to account for some of these difficulties.[1] Caliskan et al. state, “Placebo effects can enhance the efficacy of a treatment through positive treatment expectations, wherby nocebo effects can induce side effects or abolish the treatment effect through negative treatment expectations. Addressing and optimizing patient’s expectations as well as previous experiences about a treatment could improve patient’s adherence and compliance to a therapy.”[2]

  • By providing clear and unbiased information, it may be possible to limit the negative impacts of both the placebo and nocebo effects. A centrally supplied video informing patients of the positive and negative aspects of the test product and clear outline of the study may help decrease this problem; this process would allow for more effective patient treatment in the future.

• The FDA’s New Key Information Section for Informed Consent Forms (ICFs) recommends that the most important information be presented in the beginning of the form in a key information section.[3] The agency recommends that key information be presented in a bubble format. The FDA provides examples as shown in Appendix A.

• Similar to the role filled by all Data and Safety Monitoring Board (DSMB) members, we strongly recommend that all clinical trials employ an independent medical monitor. A medical monitor that has direct ivolvement in the study or any other conflict of interest, including but not limited to, financial, proprietary, or professional interests, via the sponsor has built in bias.[4] For example, one NIH division recommends that an independent physician safety monitor be used in clinical trials.[5] Implementing unbiased reviews can elevate the quality benchmarks for clinical trials, product development, and the overall industry.

  Medical Affairs

• Establishing and running a medical affairs organization can be a significant financial burden on small commercial pharma and biotech companies. The use of a lower cost program that provides strategic goals can ease the financial burden on smaller commercial enterprises. This practice supplements the marketing and sales plan until more economic resources are available for growth. The following are examples of such activities:

  • Targeted communication plan - publishing in less expensive open access journals and then promoting them on social media offers a realistic alternative to high-cost publication and advertisements.

  • Case histories, series, and review articles - these forms of publication support your product in medical literature and help to drive conversation and traffic surrounding the product.

  • Low-cost clinical studies - studies including quality of life, real world data, and registries may be of value to smaller medical affairs programs.

• The use of a limited number of medical liaisons that can be used to target key opinion leaders (KOLs) that are interested in the product and active in the community. KOLs must be interested in supporting the product with papers, presentations, and other scientific activities.

  • Your medical affairs small program can also focus on less expensive clinical studies such as quality of life, real world data, and registries.

• The use of fractional medical affairs members as opposed to full time employees can provide an experienced staff at a fraction of the cost.

Appendix A

[1] Vase, Lene. "Can insights from placebo and nocebo mechanisms studies improve the randomized controlled trial?" Scandinavian Journal of Pain, vol. 20, no. 3, 2020, pp. 451-467. https://doi.org/10.1515/sjpain-2019-0183

[2]  Caliskan, Elif Buse*; Bingel, Ulrike; Kunkel, Angelika. Translating knowledge on placebo and nocebo effects into clinical practice. PAIN Reports 9(2):p e1142, April 2024. | DOI: 10.1097/PR9.0000000000001142

[3] https://www.fda.gov/media/176663/download

[4]  https://www.nidcr.nih.gov/research/human-subjects-research/independent-safety-monitor-guidelines

MedSurgPI announces the publication of Practical Pointers for Drug Development and Medical Affairs in Clinical Trials and Practice Open Journal

Written by Gerald L. Klein, MD; Roger E. Morgan, MD/ Shabnam Vaezzadeh, MD; Burak Pakkal, MD; Pavle Yukojevic, PhD

MedSurgPI is thrilled to announce the publication of Practical Pointers for Drug Development and Medical Affairs in Clinical Trials and Practice Open Journal.  In this publication, we delve into essential insights, best practices, and practical tips for navigating the landscape of drug development and medical affairs within clinical trials and practice.  Click here to access this article.