Biobanking: The Hidden Infrastructure Behind Precision Medicine

The East Carolina University (ECU) School of Dental Medicine is building its research enterprise.

This spotlight features a saliva Biobank at the ECU School of Dental Medicine as it builds its research enterprise under Dr. Alexandre R. Vieira, DDS, MS, PhD, Dean for Research

Authors: Gerald L. Klein, MD[1]; Freddy Byrth, BS[1]; Michael Fath, PhD[2]; Aida Carfagno, BS[3]; David Weinstein, MD, PhD[4]; Patrick Loebs, MSW, MSH[1]

Affiliation: MedSurgPI[1]; Cavabio Consulting[2]; Cedar and Stone Consulting[3]; David Weinstein Consulting[4]

Technology Innovation Spotlight features a saliva Biobank at the ECU School of Dental Medicine.   Behind nearly every modern biomarker, companion diagnostic, and target-validation program sits an asset that seldom appears in the press release: well-characterized biospecimens, collected under controlled conditions and linked to longitudinal clinical data. Biobanking, the systematic collection, processing, storage, annotation, and distribution of biological specimens and their associated data, has quietly become one of the most consequential enabling technologies in drug, biologic, device, and diagnostic development. What was once thought of as “a freezer in the basement” is now a data-rich, standards-governed, increasingly automated infrastructure layer for precision medicine. Modern biobanks are therefore not only technical infrastructure; they are also trust infrastructure, dependent on transparent consent, privacy protections, and participant confidence that specimens and data will be used responsibly.

THE OPPORTUNITY

Saliva is among the most practical biofluids for population-scale collection. It can be gathered noninvasively, at low cost, and without specialized phlebotomy, and it carries a rich repertoire of analytes, including cells, nucleic acids, extracellular vesicles, metabolites, and proteins. Because oral and systemic health are increasingly understood to be connected, saliva offers a window not only into caries and periodontal disease but also into systemic conditions, with the added advantage of supporting repeated, longitudinal sampling at minimal patient burden.

THE INNOVATION

The center of gravity in biobanking has shifted from the specimen to the specimen plus the data wrapped around it. Three converging developments explain the change.

First, scale. Population-scale biobanks now operate at a size that was impractical a decade ago. The UK Biobank enrolled roughly 500,000 participants with linked genomic, imaging, and health-record data,[1] while the U.S. All of Us Research Program was designed explicitly to build a large, diverse cohort that mirrors the populations medicine actually serves.[2]

Second, data linkage. The research value of a biobank today depends heavily on how richly its specimens connect to electronic health records that can be queried in depth; robust phenotyping, and multi-omic readouts. The combination, not the specimen in isolation, is what enables agnostic and unbiased discovery across thousands of associations among diseases, genes, and exposures.[3]

Third, quality as a discipline. Preanalytical variables such as time to processing, freeze and thaw cycles, fixation, and storage temperature can materially alter the molecular characteristics of a sample and, with it, the validity of any downstream result. Reporting frameworks such as BRISQ (Biospecimen Reporting for Improved Study Quality) were created to make those variables transparent and reproducible,[4] and the international standard ISO 20387 now defines general requirements for biobanking competence and consistency.[5] Alongside scale and linkage, this quality science is what turns a collection of tubes into an extensive and rich research asset.

WHY IT MATTERS

•    Noninvasive, low-cost collection enables large, diverse cohorts and repeat sampling that blood-based biobanks struggle to match.

•    Chart-linked saliva supports biomarker discovery for oral conditions such as caries and periodontitis, as well as for systemic disease through the oral-systemic axis.

•    A newer school building its portfolio can design consent scope, quality systems, and annotation for partnering from the outset rather than retrofitting them later.

•    For sponsors, a well-governed saliva resource offers a practical platform for noninvasive biomarkers and companion-diagnostic work.

Representative large-scale biobanks frequently cited as exemplars:

FEATURED EXAMPLE:

Saliva is among the most practical biofluids for population-scale collection. It can be gathered noninvasively, at low cost, and without specialized phlebotomy, and it carries a rich repertoire of analytes, including cells, nucleic acids, extracellular vesicles, metabolites, and proteins. Because oral and systemic health are increasingly understood to be connected, saliva offers a window not only into caries and periodontal disease but also into systemic conditions, with the added advantage of supporting repeated, longitudinal sampling at minimal patient burden. ECU School of Dental Medicine is building its research enterprise under Dr. Alexandre R. Vieira, DDS, MS, PhD, Dean for Research, a dentist and human molecular geneticist whose work emphasizes characterizing patients’ whole health trajectories rather than studying one disease at a time. At his prior institution, Dr. Vieira established a dental-school registry under which patients entering the building were invited to contribute two things: permission to draw data from their records and a saliva sample. That pairing of biological specimen with chart-linked clinical data is the linkage that gives a modern biobank its translational power, and it is the model now being extended at ECU as the school formalizes a research portfolio supported by its Office of  research facilities, including a Basic Science Laboratory, a Vivarium, and a Clinical Research Center.[1]

Why this matters to sponsors and licensees:

·         Specimen quality is a data-quality problem: undocumented preanalytical variables undermine biomarker and companion-diagnostic claims.

·         Consent scope is a gating factor: commercial and future-use permissions determine whether a collection can support a development program.

·         ISO 20387 accreditation and BRISQ-style reporting are now table stakes in diligence, not nice-to-haves.

Diverse, electronic health record-linked cohorts shorten the path from hypothesis to validated, generalizable evidence.

THE COMMERCIAL AND TRANSLATIONAL OPPORTUNITY

Industry licensees and development partners do not value specimens generically. They value fit-for-purpose specimens. Four attributes drive whether a collection is commercially useful: documented provenance and preanalytical history; the depth and accuracy of clinical annotation; the scope of consent (in particular, whether commercial and future unspecified research use is permitted); and quality accreditation against an industry-recognized standard. Fit for purpose also depends on intended use: a collection that is adequate for exploratory biomarker discovery may not be sufficient for clinical validation, companion diagnostic development, or regulatory submission if chain of custody, preanalytical controls, assay validation, consent scope, or population representativeness are incomplete. A technically impressive collection with ambiguous consent or undocumented handling can be commercially unusable, an avoidable and expensive surprise late in a program.

For institutions that hold biobank assets, including universities, academic medical centers, and federal labs, this creates a real partnering opportunity, provided the asset is positioned in the language sponsors evaluate against. That framing is where many otherwise-strong collections under-realize their value.

REGULATORY, ETHICAL, AND QUALITY CONSIDERATIONS

Biobanking sits at the intersection of human-subjects protection, privacy law, and quality systems. In the United States, the revised Common Rule introduced provisions for broad consent covering storage, maintenance, and secondary research use of identifiable specimens and data,[1] while HIPAA governs the handling of protected health information. In the EU, GDPR imposes its own constraints on personal-data processing. Specimens used to support regulated product validation, particularly diagnostic and companion-diagnostic validation, additionally invite FDA scrutiny of provenance, characterization, and fitness for the intended use. Layered on top are quality and competence standards (ISO 20387)  and BRISQ recognized biorepository best practices. The practical takeaway: governance and documentation decisions made at the moment of collection determine, years later, whether a specimen can be used at all.

MedSurgPI works at the intersection of clinical development, regulatory strategy, and Translational Medical Affairs, the same intersection where biobank value is won or lost. For institutions and inventors, we translate the science of a collection into the terms industry licensees actually evaluate: provenance, consent scope, fitness for purpose, and the regulatory path the specimens can support. For sponsors, we help define fit-for-purpose specimen and annotation requirements up front, scope consent to the development objective, and avoid the late-stage discovery that a collection cannot support the claim it was meant to enable. Medical Affairs adds particular value by defining the clinically meaningful questions a biobank should answer, identifying KOL and sponsor use cases, shaping evidence‑generation plans, and communicating both the potential and the limitations of the asset transparently.

Practical Pointer

A biobank’s translational ceiling is set at the moment of consent, collections built with commercial and future-use permissions from day one avoid the costly retrofitting that sidelines otherwise strong assets.

[1] Office for Human Research Protections, US Department of Health and Human Services. Federal Policy for the Protection of Human Subjects; Final Rule. Fed Regist. 2017;82(12):7149-7274. Codified at 45 CFR part 46.

[2] East Carolina University School of Dental Medicine. Research. Accessed June 9, 2026. https://dental.ecu.edu/research-department/

[3] Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M, Liu B, Matthews P, Ong G, Pell J, Silman A, Young A, Sprosen T, Peakman T, Collins R. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779. doi:10.1371/journal.pmed.1001779.

[4] All of Us Research Program Investigators. The “All of Us” Research Program. N Engl J Med. 2019;381(7):668-676. doi:10.1056/NEJMsr1809937.

[5] Beesley LJ, Salvatore M, Fritsche LG, Pandit A, Rao A, Brummett C, Willer CJ, Lisabeth LD, Mukherjee B. The emerging landscape of health research based on biobanks linked to electronic health records: existing resources, statistical challenges, and potential opportunities. Stat Med. 2020;39(6):773-800. doi:10.1002/sim.8445.

[6] Moore HM, Kelly AB, Jewell SD, McShane LM, Clark DP, Greenspan R, Hayes DF, Hainaut P, Kim P, Mansfield E, Potapova O, Riegman P, Rubinstein Y, Seijo E, Somiari S, Watson P, Weier HU, Zhu C, Vaught J. Biospecimen reporting for improved study quality (BRISQ). J Proteome Res. 2011;10(8):3429-3438. doi:10.1021/pr200021n.

[7] International Organization for Standardization. ISO 20387:2018. Biotechnology, Biobanking, General Requirements for Biobanking. Geneva, Switzerland: International Organization for Standardization; 2018.

Oral Health: A Missing Piece of Routine Care

From East Carolina School of Dentistry Research Division and MedSurgPI

Authors: Gerald L. Klein, MD1; Alexandre R. Vieira, DDS, MS, PhD2; Stephen Haworth, MB, BS1; Freddy Byrth, BS1; Roger Morgan, MD1; Rob Walsh, MD1; Larry Florin, MBA3

Affiliations: MedSurgPI, LLC1; East Carolina University School of Dental Medicine2; LBF Biopharma Consulting3

Why Primary Care Should Ask, Look, Treat, and Refer

Practical pointer: A one-minute oral-health questionnaire paired with a quick visual check of the mouth helps primary care teams identify pain, infection, cancer warning signs, dry mouth, caries risk, periodontal risk, and lack of dental access. The goal is not to make primary care a dental office; it is to close a common gap by counseling, applying evidence-supported preventive care when appropriate, treating urgent medical consequences, and arranging timely dental referrals.

The mouth is part of the body, but it is often left outside routine medical care. That separation matters. CDC surveillance data show that nearly 21% of U.S. adults aged 20-64 had untreated decay in permanent teeth, with higher burden among people living in poverty, some racial and ethnic groups, (for example, American Indian/Alaska Native, African American and other historically marginalized populations), people with lower educational attainment, and current smokers.[1] Untreated oral disease can produce pain, infection, tooth loss, difficulty eating and speaking, missed school and work, and avoidable emergency visits.[2]

Primary care is uniquely positioned to help. Patients with diabetes, pregnancy, xerostomia, tobacco or alcohol  use, immunosuppression, chronic disease, medication burden, or poor access to dental care are already in our exam rooms. A simple oral-health workflow can be framed as Ask, Look, Decide, Act, and Document/Follow Up - a model described for primary care integration by the National Academy of Medicine and the Oral Health Delivery Framework.[3]

This is a practical clinical screen, not a substitute dental diagnosis. The United States Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against routine primary-care screening or preventive interventions for asymptomatic adults and for children/adolescents aged 5-17. That insufficient “evidence statement” should not be read as a recommendation to ignore the mouth; it means the evidence is incomplete and clinicians should use judgment. However, Rural America has a greater incidence of oral problems and recommends a greater need for this intervention.[4] The stronger primary care role is to identify symptoms and risk, deliver brief prevention, and connect patients to dental care. For children younger than 5 years, the USPSTF specifically recommends fluoride varnish after primary tooth eruption and oral fluoride supplementation from age 6 months when the water supply is fluoride deficient.[5],[6]

A short questionnaire for primary care

Use these questions at annual visits, well-child visits, diabetes visits, pregnancy visits, medication reviews, transitions of care, and visits for pain, fever, swelling, weight loss, or nutrition problems. A positive answer should prompt a brief mouth exam and a clear follow-up plan.

The brief mouth look

Use gloves, a light, and a tongue blade. Inspect the lips, buccal mucosa, tongue and floor of mouth, palate, gingiva, teeth, dentures, and visible oropharynx. Note saliva quality, odor, plaque, visible decay, broken teeth, gingival swelling, ulcers, white patches that scrape or do not scrape, red patches, masses, facial swelling, trismus, and ability to swallow. If clinic policy allows photos, obtain consent and include images in the referral. CDC lists oral-cancer symptoms such as nonhealing sores, swelling or unusual bleeding, difficulty breathing/speaking/ chewing/swallowing, and persistent mouth or throat pain; tobacco and alcohol are common risk factors, and HPV is linked to some oropharyngeal cancers.[1]

Preventive and therapeutic actions

Most oral diseases require definitive dental care. Primary care can still reduce harm by triaging urgency, treating medical complications, and making referral specific rather than vague.

Make referral closed-loop, not aspirational

A strong oral-health plan is specific: name the concern, urgency, destination, and follow-up. For example: “localized dental swelling without fever, urgent dental appointment within 48 hours; call if fever, worsening swelling, difficulty swallowing, or breathing symptoms.” Build a dental referral list that includes practices accepting Medicaid, Federally Qualified Health Center (FQHC) dental sites, pediatric dentists, oral surgeons, ENT clinics, pregnancy-capable dental practices, and after-hours emergency pathways. Document the questionnaire response, mouth findings, treatment/counseling, referral, and how the team will confirm completion. Because oral disease contributes to significant productivity and school losses nationally, prevention and care navigation should be considered essential elements of primary care, not add-ons.[1]

Oral cancer:  An estimated 60,500 new cases will be diagnosed in 2026.[2] They are usually diagnosed late; primary care examination may help to modify this current situation.

Bottom line: Primary care should evaluate the mouth because oral problems are common, visible, consequential, and often missed. A short questionnaire, a quick look, brief prevention, targeted therapy, and closed-loop referral can prevent avoidable suffering while respecting the essential role of dental professionals.

[1] Centers for Disease Control and Prevention. Oral Health Facts. May 15, 2024. https://www.cdc.gov/oral-health/data-research/facts-stats/index.html

[2]  CDC, 2024 Oral Health Surveillance Report: Selected Findings; USPSTF, Oral Health in Adults: Screening and Preventive Interventions, 2023.

[3]  National Academy of Medicine, Integration of Oral Health and Primary Care: Communication, Coordination and Referral; Oral Health Delivery Framework: Ask, Look, Decide, Act, Document & Follow-Up.

[4] U.S. Preventive Services Task Force. USPSTF Procedure Manual. 2021. Accessed May 13, 2026. https://www.uspreventiveservicestaskforce.org

[5]  USPSTF, Prevention of Dental Caries in Children Younger Than 5 Years: Screening and Interventions, 2021.

[6]  USPSTF, Oral Health in Adults: Screening and Preventive Interventions, 2023; USPSTF, Oral Health in Children and Adolescents Aged 5 to 17 Years, 2023.

[7]  National Institute of Dental and Craniofacial Research, Dry Mouth.

[8]  American Dental Association, Home Oral Care, updated 2024; American Dental Association, Topical Fluoride Clinical Practice Guideline, 2013.

[9]  CDC, Promoting Oral Health for People With Diabetes, 2024; CDC, Dental Care Is Safe and Important During Pregnancy, 2024.

[10]  CDC, About Oral Cancer, 2024.

[11] American Dental Association, Antibiotics for Dental Pain and Swelling Guideline, 2019; endorsed by the American College of Emergency Physicians.

[12] American Dental Association. Antibiotics for Dental Pain and Swelling Guideline. 2019. https://www.ada.org/resources/research/science/evidence-based-dental-research/antibiotics-for-dental-pain-and-swelling

[13] CDC, Oral Health Facts, 2024.

[14] American Cancer Society. Key Statistics for Oral Cavity and Oropharyngeal Cancers. Updated March 23, 2026.

Medical Monitoring is Critical: The Industry is Ready for a Standard

LinkedIn poll results suggest interest in a “formal certification process”

Authors: Gerald L. Klein, MD[1]; Roger Morgan, MD[1]; Melissa Palmer, MD[2]; Freddy Byrth, BS[1]; Patrick Loebs, MSW, MPH[1]; Stephen Haworth, MB[1]; Emila Jones, MD[3]; Katie Louise Dawson, MD[1]

Affiliations: MedSurgPI[1]; Liver Consulting, LLC[2]; EJ Med Insights[3]

Medical monitoring operates within one of the most consequential intersections in clinical research: participant safety, protocol integrity, regulatory compliance, clinical judgment, and real-time operational decision-making. Yet despite its importance, the role remains inconsistently defined across sponsors, clinical research Organizations (CROs), therapeutic areas, and study phases and types.

For the purposes of this discussion, medical monitoring is defined as medically qualified oversight that supports participant safety, protocol interpretation, participant eligibility, medical-data review, safety surveillance, escalation of emerging risks, and clinical decision support to sponsors, CROs, investigators, and safety governance bodies. 

We recently surveyed the clinical research community in a LinkedIn poll through the following question with one of four possible responses. To ensure the poll reached the appropriate audience, we distributed it specifically within LinkedIn groups composed of clinical research professionals. Although this represents a relatively small sample of the broader clinical trial community, we believe the responses offer a meaningful anecdotal reflection of prevailing community perspectives.

That is a meaningful signal. While the sample size is limited, the results suggest meaningful professional recognition of a growing gap in standardization. The broader conversation is shifting from whether medical monitoring matters to how it should be defined, supported, and documented. It is now a question of whether the industry should define a consistent standard, who performs medical monitoring, what competencies are required, and how readiness is demonstrated.

Why does this question matter now?

Clinical trials are becoming increasingly complex across scientific, operational, and regulatory dimensions. Protocols now frequently incorporate adaptive designs, decentralized elements, biomarker‑defined populations, digital endpoints, real‑world data, sophisticated safety requirements, global execution models, and intricate monitoring or stopping criteria. These factors, combined with substantially higher data volumes, create significant burden for both participants and research sites. Recent analyses from the Tufts Center for the Study of Drug Development (CSDD) and TransCelerate BioPharma both confirm that Phase III pivotal trials now involve far more procedures and data points than in previous decades, underscoring the accelerating complexity of modern clinical research.²

Table 1 summarizes these drivers of complexity and their operational impact on sites and participants.

At the same time, global regulatory expectations are moving toward risk-based quality management, proportionality, quality by design, and clearer accountability. The new International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6(R3) Good Clinical Practice (GCP) guidance emphasizes flexible, risk-based approaches, quality by design, participant protection, reliability of trial results, and clarified sponsor and investigator responsibilities.³ The FDA’s risk-based monitoring guidance similarly focuses sponsor oversight on the most important aspects of study conduct and reporting to enhance human subject protection and data quality.⁴

In other words, the industry is being asked to become more agile and adopt more risk-based operational strategies, while trials are becoming more medically, operationally, and technologically complex. Medical monitoring expertise is central to that transition to more complex studies and greater safety oversight.

The standardization gap

Current regulations and guidance establish sponsor accountability for appropriate monitoring, safety review, and use of qualified personnel. For example, FDA regulations state that sponsors are responsible for ensuring proper monitoring of investigations, and that sponsors must select monitors qualified by training and experience.⁵ The National Institutes of Health (NIH) policy also recognizes the medical monitor as a possible data and safety monitoring entity and states that monitoring plans should be commensurate with the level of risk, nature and complexity of the research, and population under study.⁶

However, regulators generally do not define a standardized role-specific set of competencies for the modern medical monitor, and current expectations do not translate into a single, industry-wide, regulator-recognized standard. In practice, the role may vary substantially from one organization to another. In some studies, the medical monitor is deeply involved in protocol development, eligibility review, safety surveillance, adverse event assessment, protocol deviation review, medical data review, site escalation, investigator support, and DSMB or safety committee interactions. In others, the role is narrower, reactive, or insufficiently documented.

That variability creates risk. Not necessarily because some medical monitors lack expertise, but because the industry lacks a consistent way to define, verify, and maintain the competencies required for the role. And sometimes medical monitors do lack the necessary expertise.

What the poll tells us

The poll results suggest that the industry supports medical monitor certification. A practical model could include a common baseline certificate, an advanced certificate for high-risk or complex trials, and optional therapeutic-area or modality modules.

The goal should not be to create another administrative hurdle or to imply that certification can replace clinical experience. Poorly designed certification programs would add cost without improving results.  The value of a framework would depend on whether it is practical, case-based, risk-proportionate, and clearly tied to decisions medical monitors make during trial conduct.

What a practical framework could look like

A practical medical monitoring certification framework should be demonstrated around competency, judgment, and risk, not paperwork. A useful model could include three levels:

1. Foundational Medical Monitoring Certification
This would apply to physicians or qualified health-care professionals supporting clinical trials. Core competencies would include GCP, regulatory responsibilities, participant protection, informed consent process, safety surveillance, adverse event assessment, protocol interpretation, medical data review, documentation standards, and clearly defined escalation pathways.

2. Advanced Certification for High-Risk or Complex Trials
This level would be intended for medical monitors supporting studies with elevated medical, operational, or regulatory complexity, including first-in-human trials, complex oncology programs, rare disease studies, gene and cell therapy development, high-risk device investigations, adaptive or platform trial designs, and research involving vulnerable populations. Additional competencies could include dose-escalation governance, monitoring, pausing, and stopping criteria, emerging safety signal management, benefit-risk assessment, DSMB/Data Monitoring Committee (DMC) interface, blinded vs. unblinded safety management processes, and crisis escalation procedures.

3. Therapeutic Area or Modality Modules
Optional specialization modules could further strengthen this framework by addressing therapeutic areas and operational domains where medical monitoring demands distinct expertise such as oncology, immunology, infectious disease, hepatology, neurology/CNS, cardiovascular, endocrinology, dermatology, gastroenterology, rare disease, pediatrics, women’s health, medical devices, digital endpoints, advanced biologics, gene and cell therapies, real world evidence integration, decentralized trials, or advanced therapies. This would preserve flexibility while recognizing that medical monitoring expertise is not interchangeable across all contexts.

To avoid becoming a “check-the-box” exercise, certification should include case-based assessment, continuing education, conflict-of-interest principles, documentation expectations, and periodic renewal. It should also clarify the medical monitor’s relationship matrix regarding trial conduct with the sponsor, investigator, CRO, safety management team, pharmacovigilance function, and independent DMC/DSMB when applicable. FDA’s DMC guidance underscores the importance of determining when independent committees are useful and how their operation should be structured; a medical monitoring framework should complement, not duplicate, that oversight.⁷

To bring this idea to life, Table 2 below shows how certification can stay meaningful, grounded in real‑world case work and clear professional boundaries. It highlights the essential competencies and the relationships that define effective medical monitoring oversight.

Table 2: Medical Monitoring Certification Framework

The right framework would not replace sponsor accountability, therapeutic expertise, clinical judgment, or trial-specific training. It would create a common baseline for what “qualified” means in practice and provide a more transparent way to demonstrate readiness for a role that directly affects participant safety and trial integrity.

A practical and achievable initial step would not need to be a regulator-mandated credential.  Instead, the industry could begin with a voluntary consensus-based competency framework developed collaboratively by key stakeholders including sponsors, CROs, academic clinical trialists, professional societies, experienced medical monitors, patient representatives, and regulatory bodies. Such an approach would allow for scalable standardization while preserving flexibility and stakeholder alignment. An initial pilot program could reasonably focus on high-risk interventional trials, where oversight demands are the greatest, competency gaps may carry the highest consequences, and the potential value of standardized medical monitoring qualifications is most immediately evident.

A call to action

The poll’s message is clear: the clinical research community sees a gap and is ready to discuss solutions.

Moving forward, progress will likely require a collaborative, multi-stakeholder approach. Sponsors, CROs, investigators, regulators, professional societies, academic medical centers, patient representatives, and experienced medical monitors should work together to define a practical competency framework. An initial pilot approach focused on high-risk trials, where the need is most obvious and the value proposition is strongest.

Medical monitoring has evolved well beyond a purely supportive role and now functions as a strategic safeguard for participant safety, protocol integrity, and risk management. As clinical trials continue to increase in complexity, reliance on inconsistent interpretations of this role may no longer be sufficient.

While a formal, risk-based certification framework would not eliminate sponsor accountability, clinical judgment, or trial-specific training, it could represent an important step toward consistency, transparency, and trust.

The question is no longer whether medical monitoring is essential; the question is whether we are ready to define the standard it deserves.

Disclaimer: This issue references an informal poll conducted on LinkedIn.  LinkedIn did not sponsor, endorse, or participate in the poll.  Content is for general informational purposes only.

Free Cash Flow: What It Is and Why It Matters for Biotech and Other Startups

Authors: Gerald L. Klein, MD1 and Alex Walden, MBA1; Larry Florin, MBA2; Rob Walsh, MD1

Affiliations: MedSurgPI, LLC1; LBF BioPharma Consulting2

For early-stage companies, cash is not just a balance sheet line. It is time, leverage, and strategic optionality. It pays clinical trial invoices, keeps the team moving, and gives leadership room to make decisions before the market makes them instead. Profit on paper does not pay salaries, CRO invoices, regulatory consultants, server bills, or vendors. Free cash flow does.

Free cash flow, often abbreviated FCF, is one of the clearest measures of whether a business is generating more cash than it consumes. It cuts through accounting noise and focuses on the practical question every founder, board member, investor, and operating team eventually has to answer: after running the business and funding required investment, how much cash is actually left?

The standard formula is simple:

FCF = Cash Flow from Operations - Capital Expenditures

Cash flow from operations starts with net income and adjusts for non-cash items and working-capital changes. Capital expenditures (CapEx) include spending on equipment, facilities, laboratory infrastructure, manufacturing assets, technology systems, and capitalized software. Subtracting CapEx gives leadership a more realistic picture of available cash.

Many startups report negative FCF for years. That is not automatically bad. A biotech company advancing a promising therapeutic, device, diagnostic, or platform may appropriately consume cash before revenue begins. The real issue is whether negative FCF is intentional, milestone-driven, and adequately funded.

Why FCF matters more than “profit on paper”

Traditional profitability metrics can be useful, but they often miss what matters most in early-stage companies. Net income may include accounting treatments that do not reflect immediate cash movement. Earnings Before Interest, Taxes, Depreciation, and Amortization (EBITDA) can make a company look stronger by excluding items that still affect cash needs. Revenue growth can look impressive while the underlying business still consumes cash.

FCF brings the conversation back to operating reality. It asks whether the company has enough cash to execute the plan, reach the next milestone, and preserve negotiating power.

1. FCF defines runway

Runway is one of the most important numbers in any startup boardroom. A company with $36 million in cash and a monthly cash burn of $3 million has approximately 12 months of runway. That number drives hiring plans, trial design, vendor negotiations, fundraising timing, partnership outreach, and whether a company can wait for stronger data before raising capital.

In biotech and medtech, runway should not be modeled as one flat average. Cash burn changes by development stage. Preclinical work may be modest. Phase 1 and phase 2 trials increase costs through sites, monitoring, data management, safety oversight, and Clinical Research Organization (CRO) support. Phase 3 trials, manufacturing scale-up, regulatory filings, and launch preparation can change the cash profile dramatically. The organization’s Financial Planning and Analysis (FP&A) function needs to consider the timing of the future cash outflows and inflows (milestone payments). To the above example, that might mean a company with $36 million in cash may only have 9 months left because of known payments.  Conversely, said company may hit a milestone in seven months and end up with an additional 18 months of cash. 

2. FCF exposes the real cost of growth

Growth is attractive only when it is financially sustainable. A Software as a Service (SaaS) company can grow revenue while spending aggressively on customer acquisition. A medtech company can expand evidence generation while absorbing device manufacturing, quality-systems, and regulatory costs. A biotech company can advance a pipeline while committing to expensive clinical, chemical, manufacturing, and controls (CMC), pharmacovigilance, and medical affairs work.

FCF forces leadership to connect scientific and commercial progress with financial reality. A milestone is not only a scientific event. It is also a cash event. The question is not just, “Can we get to the readout?” It is, “Can we get to the readout with enough cash and credibility to act on the result?”

3. FCF is the language of capital

Investors do not fund narratives alone. They fund risk reduction, value creation, and credible use of proceeds. Venture investors, crossover funds, strategic partners, lenders, and acquirers all want to understand how cash will be deployed and what milestone changes the company’s financing profile.

For biotech companies, this often means modeling cash burn through commercialization.  While accomplishing the next milestone will be the priority of the organization, losing track of the long FCF projection can become detrimental.  Not properly forecasting FCF is inefficient in the best of cases. Biotech history is filled with companies that advanced promising science but exhausted available capital before development milestones could create financing leverage. In many cases, the constraint to success was not scientific viability alone, but the inability to sustain free cash flow through increasingly expensive stages of development. 

A management team that understands FCF can explain which expenditures are milestone-critical, which are discretionary, which can be delayed, and which create leverage in financing or partnering discussions. That clarity can improve fundraising conversations and reduce surprises.

4. FCF signals operating discipline

In strong capital markets, inefficient spending can hide behind optimism. In tighter markets, it becomes visible quickly. Boards and investors scrutinize burn, hiring, vendor commitments, consulting spend, and capital expenditures. Managing FCF well means aligning spend with value creation.  Periodically reviewing the assumptions surrounding the FCF projection is prudent. This process may highlight changes in the assumptions or the market or both.  In that case, the company will have plenty of time to take corrective actions. Those actions may include finding a development partner at favorable terms. 

That may include negotiating better supplier terms, sequencing trials intelligently, avoiding premature fixed costs, using fractional leadership, reassessing non-core programs, and timing CapEx around milestones.

The MedSurgPI Business & Financial Insights Lens

Biotech FCF requires a specialized view. R&D is often the dominant cash outflow. Clinical trials, CRO contracts, medical monitoring, safety oversight, manufacturing, regulatory preparation, scientific communications, and medical affairs support may appear as operating expenses, but they behave like strategic investments.

One-time inflows can also distort the picture. Licensing fees, grants, partnership payments, and milestone receipts may create a positive FCF quarter while the underlying business still burns cash. That is why leadership should separate recurring operating cash flow from one-time inflows and maintain a clear “core burn” view.

A practical approach is to forecast FCF by milestone: preclinical package, IND submission, phase 1 completion, proof-of-concept readout, pivotal planning, approval, and launch preparation. Each stage should have its own assumptions, risk points, financing requirements, and decision gates. A seasoned CFO will consider all the events and their likelihood and develop a cash projection. 

The bottom line

Free cash flow is not a finance-department exercise or a year-end cleanup metric. It is the operational heartbeat of a startup. For biotech, medtech, and other innovation-driven companies, it determines how long the company can pursue its mission, how much flexibility management has, and whether the next strategic decision is made by the company or imposed by the market.

Companies that master FCF can choose when to raise, when to partner, when to expand, and when to conserve. Companies that do not often discover too late that progress without cash discipline is not enough and potentially fatal to the organization.  A start-up biotech CFO will have a good handle on the assumptions surrounding the FCF and most importantly, will track changes to those assumptions. 

MedSurgPI Business & Financial Insights will continue to explore practical financial, operational, and development topics that help founders, boards, investors, and clinical leaders make better decisions in capital-constrained environments.

Disclaimer: This article is for educational and informational purposes only and does not constitute financial, investment, accounting, tax, legal, regulatory, or medical advice. Readers should consult appropriate professional advisors before making business, financial, investment, or regulatory decisions.

Translational Medical Affairs (TMA): A New Operating Model Bridging Preclinical Science, Clinical Development, and Real-World Impact

Authors: Gerald L. Klein, MD; Patrick Loebs; Freddy Byrth; Lee Schacter, PhD, MD; Michael Fath, PhD

Introduction

Medical Affairs (MA) is undergoing a fundamental transformation. Historically positioned as a late-stage, support-oriented function focused on scientific exchange and data dissemination, MA is now expected to play a far more strategic role in evidence generation and decision-making.

The drivers are clear:

●        Increasing regulatory complexity

●        Growing reliance on real-world evidence (RWE)

●        Heightened expectations from payers and Health Technology Assessment ( HTA) bodies

●        Persistent evidence gaps at launch

●        Rapid integration of AI and advanced analytics 

Traditional MA models—largely reactive and downstream—are no longer sufficient. A new model is emerging: Translational Medical Affairs (TMA).

What Is Translational Medical Affairs?

Unlike traditional MA inclusion strategies, in which MA is engaged late in the development cycle, TMA refers to a clinical development operating model where MA is embedded from the earliest stages of development as an integrated, lifecycle-spanning part of the interdisciplinary development team that augments the connections across preclinical development, clinical trial design and execution, real-world evidence generation, market access and payer strategy.

Why Preclinical Integration Is Critical

The most important decisions in drug development occur before the first patient is enrolled, including mechanism of action (MoA) selection, translational biomarker strategy, patient population definition, and early safety characterization.

Another critical consideration, particularly in therapeutic areas with a high density of active development programs, is the availability of patients for clinical trials. This includes not only the size of the addressable patient population, but also the number of ongoing and anticipated studies that may compete for the same patients, potentially impacting feasibility, enrollment timelines, and overall trial success.

In addition, early clinician input is essential in shaping study design and protocol execution, including inclusion and exclusion criteria and overall operational feasibility in real-world clinical settings.

TMA embeds Medical Affairs early, enabling validation of clinical relevance, alignment with ICH E8(R1) fit-for-purpose study design, anticipation of payer evidence needs, and identification of evidence gaps before costly Phase 1/2 trials.

Regulatory Alignment: A Key Driver

TMA aligns with evolving global regulatory expectations:

●        ICH E6(R3) – Quality by Design and proactive risk management

●        ICH E8(R1) – Fit-for-purpose study design aligned with stakeholder needs

●        FDA Real-World Evidence Framework

●        FDA Project Optimus

●        FDA Artificial Intelligence/Machine Learning (AI/ML) guidance (January 2025

●        EMA Artificial Intelligence Workplan (2023–2028)

These frameworks reinforce that evidence must be prospectively aligned with decisions—not retrospectively adapted.

Operationalizing Translational Medical Affairs

●        Embed MA in preclinical development (Target Product Profile (TPP), biomarkers, MoA relevance)

The target product profile should be tightly linked to the overall clinical development plan, with periodic cross-functional clinical review to ensure continued alignment with emerging data, regulatory expectations, and strategic objectives.

●        Develop a lifecycle evidence plan (regulatory, clinical, payer, RWE)

This lifecycle evidence plan should not function as a standalone document, but rather as an integrated component of the broader Clinical Development Plan, ensuring that evidence generation is coordinated, continuously updated, and aligned with key development and decision milestones.

●        Integrate real-world evidence early (feasibility, endpoints, external validity)

Evolve MSLs into insight generators and evidence strategists

Strategic Value of TMA

●        Higher probability of technical and regulatory success (PTRS)

●        Reduced late-stage development risk

●        Stronger payer positioning

●        Faster clinical adoption

●        More efficient resource utilization

●        Generation of clinically meaningful insights to inform early prediction of risk-benefit profiles and logistical burden for both patients and clinical practice settings, including feasibility within routine care workflows.

The TMA Lifecycle Model

Preclinical → Clinical Development → Real-World Evidence → Market Access → Feedback to Development (continuous loop with bidirectional insight flow).

Conclusion

Translational Medical Affairs is a redefinition of the usual Medical Affairs function/construct. By integrating preclinical insight, clinical development, and real-world evidence, and the integration of artificial intelligence models and model development, TMA positions Medical Affairs as a strategic driver of development success, regulatory alignment, and clinical impact.

References

1. International Council for Harmonisation (ICH). E6(R3) Good Clinical Practice. 2025.

2. International Council for Harmonisation (ICH). E8(R1) General Considerations for Clinical Studies. 2021.

3. U.S. Food and Drug Administration. Framework for FDA’s Real-World Evidence Program. 2018.

4. U.S. Food and Drug Administration. Project Optimus. 2023.

5. European Medicines Agency. Artificial Intelligence Workplan 2023–2028.

6. U.S. Food and Drug Administration. Artificial Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions: Lifecycle Management and Marketing Submission Recommendations. Published January 2025.

7. U.S. Food and Drug Administration, Health Canada, Medicines and Healthcare products Regulatory Agency. Good Machine Learning Practice for Medical Device Development: Guiding Principles. Published 2021.

8. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence—what is it and what can it tell us? N Engl J Med. 2016;375(23):2293-2297.

9. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273-286.

10. Drummond MF, Schwartz JS, Jönsson B, et al. Key principles for the improved conduct of health technology assessments for resource allocation decisions. Nat Rev Drug Discov. 2008;7(3):255-263.

The Target Product Profile and the Development Plan - Inextricably Intertwined

Authors: Lee Schacter, PhD, MD and Gerald L. Klein, MD

The development of a new chemical entity is guided by two documents; the Target Product Profile and the Development Plan. The first is a wish list, the second, a road map to those wishes and the pot of gold that awaits if they are achieved.

 Whether it is a new compound “tossed over the fence” from discovery to clinical in Big Pharma or the precious creation of a biotechnology company, the challenge for the clinical group is to turn a chemical entity into a marketable product. 

 Step one is the wish list. If the new compound, which we will call FRED, works as well as possible based on preclinical models, what is the ideal labeled indication for use that can be approved? For example, if FRED has been designed to treat rheumatoid arthritis, the dream label could read “FRED is indicated for the initial treatment of rheumatoid arthritis in adult and pediatric patients.” But not all dreams come true and sometimes it is necessary to accept a second or third place finish such as “FRED is approved for the treatment of rheumatoid arthritis in adults after the failure of initial therapy” or even worse; “FRED is approved for the treatment of adults with rheumatoid arthritis refractory to all other available modalities.” 

Now the “game is afoot.” Will management be flexible with the label? Is the worst possible label acceptable to management? Will it represent an adequate return on investment to justify further development?  What if the worst possible label is first to market for a new class of agents and there is an opportunity to expand the label? What  compounds, if any, with the same mechanism of action are in development, and at what stage? How will FRED be positioned? What will be its therapeutic niche? Will it be first-in-class agent, the best-in-class among similar compounds, or  a me-too product, perhaps differentiated only by a more favorable pharmacokinetic profile that supports a lower price point? All these factors and more (Table 1) have to be considered in the Target Product Profile.

Table 1

Considerations for the Target Product Profile

• Expected clinical activity

• Therapeutic needs (current and projected) the product can address

• Comparisons to existing agents; strengths, weaknesses, opportunities, and threats (SWOT analysis)

• Route of delivery vs. existing agents

• Cost of goods

• Overall competitive environment including marketed products and those in development

The Development Plan takes the Target Product Profile for FRED and creates a path to making dreams come true. This plan is based on the science behind the new agent, the treatment options currently available for the target disease, along with those in development, and the projected cost of development. The Development Plan should represent the “value proposition” for FRED.  While it aims to account for both the current and future competitive environment for FRED, it must remain a living document, modified as new data for both FRED and for other agents, both approved and in development, become available.

 A major consideration is cost and time in development. New drug development spending is stratospheric. A recent paper[1] concludes “that the median… total R&D expense, reflecting all clinical trials and including adjustments for inflation, capitalization, and discontinued products, was approximately …. $708 million” in 2019. They also note that “…costs captured by patient-months comprise most total … R&D spending….”  Similar findings were reported elsewhere, estimating that “the mean cost of the clinical phase per drug candidate was $117.4 million”, with approximately  $27 million for phase 1, $34 million for phase 2, and $38 million for phase 3.[2]

 Faced with these costs and the success rate of new compounds (approximately 10-20%)[3,4] the development plan has to be focused on the rapid efficient evaluation of any new compound. This requires carefully crafted go/no go criteria at each stage of clinical trials along with timelines that are aggressive but achievable. The endpoints must also be chosen to support the earliest possible registration.

Critical elements therefore include:

• Define the regulatory strategy for the US, EU, and other territories

          o   Determine if the compound will be developed as a first-in-class, best-in-class, or “me too” agent and where it will fit in the treatment paradigm                  of the target disease

•  Meet with regulatory authorities to discuss the proposed development and registration strategy, obtain feedback on the registration pathway,         and align the clinical and nonclinical development program with regulatory requirements and expectations. Define the data needed for go/no go      decisions for each stage of development (phases 1-3).

          o   In a competitive environment for patients and investigators, design studies need to be attractive to both by minimizing patient and site                              burden, and by  keeping protocols  focused and as simple as possible.

• Avoid scientific side shows or academic curiosities that are of interest but not on the critical path to regulatory approval while collecting essential data for next generation drugs.

• Track therapeutic landscape in the target disease including compounds in development and emerging relevant science.

———————————————————————

[1] Mulcahy AW, et al. Use of Clinical Trial Characteristics to Estimate Costs of New Drug Development. JAMA Network Open. 2025;8:e24533275. doi:10.1001/jamanetworkopen.2024.53275

[2] Setkaya A, et al. Costs of drug development and research and development intensity in the US, 2000–2018. JAMA Network Open. 2024;7:e2415445. doi:10.1001/jamanetworkopen.2024.15445

[3] Yamaguchi S, et al. Success rates of new compound development. Clin Transl Sci. 2021;14(3):1113-1122. doi:10.1111/cts.12978

[4] Duxin S, et. al. Why 90% of clinical drug development fails and how to improve it? Acta Pharma Sin B 2022; 12(7): 3039-3062

Contract Research Organizations - Trust but Verify

Authors: Lee Schacter, PhD, MD; Gerald L. Klein, MD

A recent news article published in Science[1] highlights disturbing incidences of apparent maleficence by Clinical Research Organizations (CROs) in South Florida. The article stated that the biotech T3D Therapeutics found data generated by a CRO from an Alzheimer’s trial to be “medically impossible”. Issues ranged from treatment of patients without evidence of the disease to levels of the test agent in patients receiving placebo and led to the write off of a $35 million study. Challenging for any company but especially for a startup.

Other companies have been burned by CROs conducting Alzheimer’s trials including Annovis Bio and BioVie according to the article, again with the enrollment of inappropriate patients or brain scans that were copied and pasted. Big Pharma is not immune to the issue. Bristol-Myers Squibb was burnt by irregularities leading to exclusion of data in a trial of Cobenfy and needs to replace subjects. A study by Eli Lily may also be affected.

Malfeasance by CROs happens and sponsors must be careful not only in their choice of CRO but should have their studies monitored independently and often. It is not a good practice to give your clinical trial to a CRO and not be involved until it is completed. Independent consultants to help with the in-house medical and clinical operations is a cost-effective way to protect the study and the company. Reviews need to be unblinded and detailed, conducted by experienced individuals able to spot irregularities as they occur and recommend corrective action. If a CRO is also responsible for any critical elements such as the development plan, study design, statistical plan, electronic medical record creation, and maintenance; these too need to be carefully reviewed by outside experts, especially for a small company to assure they will meet the sponsor’s requirements and the regulators’ needs. The extra expense of these activities is more than justified by the risk of misconduct or suboptimal performance by the CRO.

Bottom line: when a CRO manages a trial, sponsors should trust—but always verify.

[1] Kaiser J. Alzheimer’s drug developers accuse clinical trial sites of faking data. Science. 2026;371(6524):112–115. Published January 8, 2026. doi:10.1126/science.adkXXXX

Expanding Rural Healthcare Access with Remote Patient Monitoring (RPM)

 Leveraging New Federal and HRSA Grants for Rural Health Innovation

 New Federal Opportunity:

• The $50 billion Federal Rural Health Fund (2026–2030) and HRSA’s Outreach Program provide unprecedented funding to strengthen rural health systems.

• Grants will support innovative approaches to expand access, reduce costs, and improve patient outcomes.

Why Remote Patient Monitoring (RPM)?

• RPM uses connected devices (BP cuffs, weight scales, pulse oximeters, glucometers, etc.) to continuously collect patient data and securely transmit it to providers.

Proven Benefits for Rural Communities:

• Improved Outcomes: Up to 40% fewer readmissions; 50% fewer ER visits.

• Expanded Access & Diversity: 15–28% increase in participation from underserved rural populations.

• Retention & Compliance: 85–91% retention and 82–89% adherence rates.

• Cost Savings: $2,000–$2,300 saved per patient on average.

• Data Quality: 60–85% reduction in recall bias; up to 85% improvement in data completeness.

Why Act Now?

• Rural health providers are uniquely positioned to leverage these grants.

• RPM aligns with federal priorities for diversity, equity, and patient-centered care.

• Early adopters gain long-term sustainability and efficiency advantages.

How MedSurgPI Can Help:

• Grant Alignment: Guidance on tailoring proposals to meet CMS and HRSA requirements.

• Implementation: Evidence-based strategies for selecting devices, training staff, and integrating RPM into existing systems.

• Sustainability: Proven models to ensure cost-effectiveness and compliance.

📞 Contact us today to learn how your department can leverage new funding to bring advanced care directly into rural homes.

MedSurgPI – Research Triangle Park, NC
Gerald Klein, MD: gklein@medsurgpi.com

Michael J. Fath, PhD: michaelfath@cavabio.com
www.medsurgpi.com

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

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

Abstract

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

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

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

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

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

Click here to read the full article.

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

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

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

Abstract

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

1. Introduction

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

2. Regulatory Background

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

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

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

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

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

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

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

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

3. Composition and Independence

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

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

 4. Charter and Governance

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

5. Data Access and Statistical Reporting

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

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

6.      Safety Monitoring Best Practices

DSMBs should systematically review cumulative safety data, including:

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

·         Assessments of causality, using standardized methods where applicable.

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

In addition to safety oversight, DSMBs should monitor:

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

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

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

7. Interim Analyses and Trial Modifications

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

·         Trial continuation as planned.

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

·         Enrollment pauses for further evaluation.

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

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

8. Confidentiality and Blinding

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

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

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

o   Continuing the trial as planned.

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

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

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

9. Meeting Logistics and Documentation

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

Meeting Triggers and Frequency:

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

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

Session Structure:

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

10. Sponsor Responsibilities

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

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

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

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

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

11. Challenges and Pitfalls

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

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

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

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

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

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

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

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

12. Future Directions

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

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

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

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

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

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

Conclusion

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Medical Monitor's Essential Role in Clinical Trials

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

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

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

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

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

Key Document Review

Protocol Review

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

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

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

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

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

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

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

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

Investigator’s Brochure (IB)

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

Medical Monitoring Plan

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

·         SAE review within 24 hours (when possible)

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

·         Ongoing support to sites on causality and AE grading

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

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

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

Table: Medical Monitor Specific Duties

Core Duties:

·         Review and comment on the IB and protocol

·         Write the medical monitoring plan

·         Review and approve a safety management plan

·         Review relevant protocol deviations for participant safety and data integrity

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

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

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

·         Review SAEs, AEs, and AESIs

o   Causality assessment of AEs and SAEs[8]

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

·         Manage relationships with clinical investigators and their site staff

Optional Contributions:

·         Review coding (MedDRA and WHO)

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

·         Support site selection or medical feasibility assessments

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

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

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

Safety Concerns and Escalation

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

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

Regulatory Alignment and Reporting

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

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

Conclusion

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

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. 

The AI Revolution in Pharma: Remaking Medical Affairs, One Insight at a Time

MedSurgPI, LLC is pleased to introduce the AI Revolution in Pharma: Remaking Medical Affairs, One Insight at a Time.  This document highlights the role of AI, not just as an automation tool but as a game-changer for medical affairs and stakeholder engagement.  Join us as we explore the evolving landscape of AI, promising a new era of innovation and strategic partnership.

By Michael Fath, PhD1,2; Gerald L. Klein, MD2; L. Allen Kindman, MD2; Larry Florin, MBA2; Victoria Manax, MD2; Shabnam Vaezzadeh, MD2

1Cavabio Consulting, LLC, 2MedSurgPI, LLC

Safety and Pharmacovigilance Tips

These Safety and Pharmacovigilance tips are aimed at improving the understanding of this area of clinical drug and device development. For example, clinical sites are frequently confused about the nuances of adverse event reporting, assessing causality, or the use of proper safety terminology. In addition, some sponsors may not be using the appropriate type of committee to oversee the safety of their clinical trial. See below for the first tip in this series and feel free to reach out to us with any questions: info@medsurgpi.com.

Clinical Investigators and their sites should establish a systematic way of assessing causality when adverse events and serious adverse events occur. The Bradford Hill criteria are an established practical way of determining these events[1]:

1. Strength of Association: a strong association between a treatment and an adverse event indicates causation. For example, each time the drug was given to a subject, it caused vomiting within a predictable time period.

2. Consistency: Established adverse event attributions or previous determinations in similar situations indicate causation.

3. Specificity. An established mechanism of action connecting the treatment and the adverse event indicates causation.

4. Temporality: exposure to the product must occur before the disease or event, and not after a latency period. However, temporality is not sufficient to establish causation.

5. Biological Gradient: a dose response effect is a strong argument for causation.

6. Plausibility: the causal relationship is biologically plausible.

7. Coherence: the known facts fit the natural history and biology of the disease.

8. Experiment: Epidemiologic studies indicate causation.

9. Analogy: a similar agent causes the same type of AE.

[1] Klein, G., Johnson, P. and Morgan R., Medical Monitoring of Clinical Research Studies. J. Clin. Res. Best Practices. 2021: Vol 17 (1)