Practical Pointers for March 2025

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

MedSurgPI* Prevail InfoWorks, Inc.**

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

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

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

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

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

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

  • Unsafe drug may be approved.

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

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

  • It can cause unnecessary patient harm.

  • The development of supportive care guidelines may be inaccurate.

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

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

  • Associations and Sources

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

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

  • Modifying Factors

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

    • Assess drug interactions that may increase toxicity.

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

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

    • Modification of psychological status may become a stimulating factor.

  • Patient History

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

    • Consider symptoms occurring before exposure to the IP.

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

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Causality Factors to Consider

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

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

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

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

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

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

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

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When is a laboratory test result an AE?

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

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

Overlooked reasons which qualify as an SAE

• A persistent or significant incapacity.

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

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References

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

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

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

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

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

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

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

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

Latin America as Part of Rare Disease and Oncology Drug Development

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

Introduction

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

Challenges in Rare Disease and Oncology Drug Development

Developing Practical Protocols with Robust Statistical Support

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

Streamlining Inclusion and Exclusion Criteria

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

Engaging Key Opinion Leaders (KOLs)

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

Selecting Optimal Trial Sites

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

Partnering with Patient Advocacy Groups (PAGs)

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

Ensuring Quality and Compliance Among Principal Investigators (PIs)

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

Comprehensive Training for Trial Staff

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

Solutions for Success in Rare Disease and Oncology Trials

Strategic Regulatory Support

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

Expanding Trials into Emerging Markets

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

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

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

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

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

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

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

Collaborating with Leading Experts

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

Comprehensive Training Initiatives

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

Optimized Site Selection

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

Strengthening Partnerships with PAGs

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

Conclusion

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

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

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

References

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

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

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

Preclinical Studies Required for Obtaining FDA IND Approval

Authors from Mesa Science Associates: Kaitlyn Wylie, Kenneth Dretchen

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

Introduction

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

Pharmacology 

·         Pharmacodynamics

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

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

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

·         Pharmacokinetics (PK)

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

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

Toxicology 

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

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

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

Ensuring a Successful Study Outcome  

·         Protocol

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

·         Animal Model

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

·         Animal Housing and Welfare

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

·         Statistical analysis

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

·         GMP Drug Substance and GLP Requirements

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

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

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References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Top 10 Benefits of Remote Patient Monitoring for Rural Health

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

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

1. Expands Access to Care

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

The RPM Advantage:

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

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

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

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

2. Reduces Hospital Readmissions

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

The RPM Advantage:

• Early detection of deteriorating conditions allows for timely interventions

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

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

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

3. Improves Chronic Disease Management

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

The RPM Advantage:

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

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

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

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

4. Addresses Rural Healthcare Workforce Shortages

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

The RPM Advantage:

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

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

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

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

5. Enhances Emergency Response and Prevents Crisis Situations

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

The RPM Advantage:

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

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

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

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

6. Supports Aging in Place for Rural Seniors

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

The RPM Advantage:

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

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

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

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

7. Reduces Healthcare Costs for Patients and Providers

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

The RPM Advantage:

• Reduces the need for frequent travel to healthcare facilities

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

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

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

8. Strengthens Rural Health Infrastructure and Telemedicine Integration

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

The RPM Advantage:

• Integrates with telemedicine platforms for seamless remote consultations

• Facilitates data sharing between rural clinics and urban medical centers

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

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

9. Improves Maternal and Prenatal Care in Underserved Regions

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

The RPM Advantage:

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

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

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

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

10. Enhances Mental Health Care Access for Rural Communities

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

The RPM Advantage:

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

• Facilitates virtual counseling and medication management via telepsychiatry

• Provides real-time support and intervention for crisis situations

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

Conclusion

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

WHAT IS ASYMMETRIC WEIGHT DISTRIBUTION?

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

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

The Carematix Advantage

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

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Condition-Specific Applications

Stroke:

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

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

• How We Use It:

  • Baseline AWD measurements help quantify impairment severity

  • Weekly measurements track improvement during rehab

  • Patients use visual feedback during weight-shifting exercises

    • Remote monitoring between visits catches regression early[4]

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

Parkinson’s Disease

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

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

• How We Use It:

  • Track responses to levodopa throughout the day

  • Guide DBS programming by measuring immediate effects on symmetry

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

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

Cerebral Palsy

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

• How We Use It

  • Guide orthotic adjustments in real-time

  • Measure immediate effects of spasticity interventions

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

  • Provide objective feedback during therapy sessions

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

Neuromuscular Disorders

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

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

• How We Use It:

  • Track disease progression between clinic visits

  • Guide assistive device selection and adjustment

  • Inform home modification recommendations[10]

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

Incorporating Into Your Practice

Getting Started

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

2. Document the percentage of weight bornre on each side

3. Set symmetry targets based on diagnosis and functional goals

4. Re-measure at each visit to track progress

Reimbursement Tips

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

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

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

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Practical Case Example:

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

Initial AWD: 75% on right (unaffected side)

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

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

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

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

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References

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

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

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

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

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

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

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

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

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

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

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

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

MedSurgPI DSMB Capabilities

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

Our Approach:

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

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

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

Understanding the Safety and Regulatory Pathway

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

• Key Considerations:

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

  • Developing the DSMB Charter:

    • Assess the successes and challenges of similar products.

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

Ensuring Alignment and Effective Oversight (key elements)

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

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

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

Key Considerations for Successful Pharmaceutical Product Development

Introduction

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

1. The Pillars of Pharmaceutical Product Development

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

• Key Questions to Address:

  • What are the current gaps in treatment?

  • How does the existing standard of care fall short?

  • What do patients and providers identify as unmet needs?

• Common Drivers of Unmet Need:

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

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

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

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

• Key Considerations:

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

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

  • Do you qualify for orphan disease recognition?

• Best Practices:

  • Analyze the success and shortfalls of similar products

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

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

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

• Preclinical Essentials

  • Collaborate with experienced consultants.

  • Identify cost-effective manufacturing partners.

  • Select appropriate animal models as well as testing facilities.

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

    • Enrich enrollment

    • Accelerate the clinical trial

• Clinical Challenges and Solutions:

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

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

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

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

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

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

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

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

• Key Elements:

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

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

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

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

• Best Practices:

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

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

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

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

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

• Strategies:

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

  • Develop robust escalation and adjudication pathways.

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

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

• Evaluation Framework:

  • Examine timing between drug administration and adverse events.

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

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Wrapping it up:

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

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

Top 10 Benefits of Remote Patient Monitoring for Clinical Trials

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

Introduction

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

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

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

Mesa Science Associates and MedSurgPI announce a partnership

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

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

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

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

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

About Mesa Science Associates, Inc.

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

 About MedSurgPI, LLC

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

Practical Pointers for Product Development and Medical Affairs / July 2024

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

Product Development

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

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

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

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

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

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

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

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

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

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

  • A determination whether each task is a critical task

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

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

Medical Affairs

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

  • Clear and accessible language:

    • Avoid using jargon and technical terminology.

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

  • Conciseness and precision:

    • Present information in a clear, concise manner.

    • Keep messages focused to prevent overwhelming the audience.

  • Factual and substantiated content:

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

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

  • Enhanced visualization:

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

    • Visual aids significantly improve comprehension and retention.

  • Resources for further information:

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

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

  • Leveraging artificial intelligence (AI):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Practical Pointers for Product Development and Medical Affairs / June 2024

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

Product Development

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

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

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

Medical Affairs

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

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

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

Practical Pointers for Product Development and Medical Affairs / May 2023

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

Product Development

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

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

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

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

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

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

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

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

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

  • Increase their scientific curiosity

  • Enhance their ability to understand the scientific literature

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

  • Improve their interpretation of clinical trials

  • Be able to apply scientific literature to clinical pracctice

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

Medical Affairs

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

  • Selecting appropriate speakers

  • Timing of the event

  • Cutting edge or important subject matter

  • Promotional campaign to attract an audience

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

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

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

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

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

Practical Pointers for Drug Development and Medical Affairs

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

Drug, Device, and Diagnostic Development

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

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

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

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

  Medical Affairs

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

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

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

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

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

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

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

Appendix A

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

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

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

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

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

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

MedSurgPI is thrilled to announce the publication of Practical Pointers for Drug Development and Medical Affairs in Clinical Trials and Practice Open Journal.  In this publication, we delve into essential insights, best practices, and practical tips for navigating the landscape of drug development and medical affairs within clinical trials and practice.  Access the publication here:  https://openventio.org/wp-content/uploads/Practical-Pointers-for-Drug-Development-and-Medical-Affairs-CTPOJ-7-125.pdf

Practical Pointers for Drug/Device/Diagnostic Development & Medical Affairs

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

Drug, Device, and Diagnostic Development

• 3D printing technology is revolutionizing the field by significantly advancing pharmaceutical and medical device manufacturing, as well as playing a pivotal role in the innovation of clinical study methodologies. It can produce complicated shapes and geometric internal structures that can improve drug release.[1] For example, advanced techniques such as extrusion methods and photopolymerization are used to produce transdermal drug delivery through microneedle systems.[2] 3D printing may help accelerate drug formulation via formulation by design, in large-scale manufacturing, and personalized dosing, to name a few of these benefits. An FDA-approved example is Spritam® tables for treating epilepsy, which are designed to disintegrate within seconds after taking a sip of water, showcasing the potential for creating dosage forms with instantaneous drug release. Tailoring the size, drug release profile, and shape of dosage forms can be particularly useful for special populations, such as children who might need smaller or special doses and older adults with various physiological conditions. These will all require a close working relationship with the FDA’s Emerging Technology Team to help facilitate new guidance for this developing technology.[3]

• It’s crucial for the safety team in a clinical trial to educate the principal investigators and their teams so they understand basic pharmaceutical and clinical safety reporting requirements. Common errors include:

  • Not reporting serious adverse events (SAEs) and adverse events (AEs) of special interest in a timely fashion

  • Not providing AE/SAE follow-up reports

  • Not following up on clinically significant laboratory abnormalities

  • The inappropriate assignment of causality

  • Inadequate narrative reports for SAEs

• 510Ks do not require a clinical trial. However, a robust clinical trial is often required for other important reasons including:

  • Clinical differentiation, e.g., data for generating publications and presentations (resulting in increased physician and patient adoption)

  • Increasing product licensing potential

  • Real-world evidence (RWE) and Health Economics and Outcomes Research (HEOR) data for improved market access and insurance reimbursement

  • Data for investment opportunities

  Medical Affairs

• The use of AI may improve the efficiency of enrolling patients in clinical trials. New products are being released that have the potential to quickly match patient charts with protocols and eligibility criteria. Patient enrollment and retention is a commonplace problem in clinical trials and one of the main reasons for slow enrollment or incomplete studies.

• An often-overlooked opportunity in medical affairs (MA) is to promote recommended guidance documents for both diagnostic and therapeutic regimens.

  • It has been estimated that only 55% of the US population receives recommended healthcare services.[4] This varies from country to country but is still far below what it should be.

    • This is partially a combination of health care providers (HCPs) not prescribing recommended care and patients’ poor medication adherence.[5,6]

      • This presents an opportunity for MA teams to help improve care delivery by reminding HCPs of the current guidelines for optimum disease care and outcomes

    • A recent study of type 2 diabetic (T2D) patients found that the following would have improved their medical adherence:[7]

      • Medical information

      • Assistance with disease management

      • Increased and more informative doctor-patient interaction

      • Better information about the medication and its side effects

    • MA professionals can improve this situation by providing informative materials that can help improve patient care and increase the appropriate use of their products.

    • Many physicians are not aware of potential drug-drug interactions; MAs can augment patient safety/drug efficacy by informing HCPs of this vital information.

      • As an example, numerous medications have interactions with Cytochrome P450 enzymes, yet there is often a lack of communication from physicians regarding the risks these interactions pose. Utilizing artificial intelligence could enhance patient safety by screening all concurrent medications, ensuring that patients are not prescribed drugs that could lead to adverse interactions.

• Nursing schools and hospital nursing departments can be overlooked by medical affairs teams in favor of medical and pharmacy schools. These nursing institutions can be great places to interact with HCPs who can help with the following:

  • Initiate and conduct investigator-initiated trials

  • Educate other HCPs on the significance of the products

  • Assist in providing inappropriate education to patients

  • Provide a deeper understanding of how patients accept products and determine what additional information is required

  • Provide lectures at conferences and continuing education meetings

  • Publish articles and white papers in nursing journals and other publications

———————————-

[1] Awad, A., Yao A. et al. Advances in powder bed fusion 3D printing in drug delivery and healthcare. Advanced Drug Delivery reviews 174, 406-421.

[2] Sophia N. Economidou, Dennis Douroumis, 3D printing as a transformative tool for microneedle systems: Recent advances, manufacturing considerations and market potential, Advanced Drug Delivery Reviews, Volume 173, 2021: 60-69.

[3] Timothy Tracy, Lei Wu, Xin Liu, Senping Cheng, Xiaoling Li, 3D printing: Innovative soklutions for patients and pharmaceutical industry, International Journal of Pharmaceutics, Volume 631, 2023.

[4] McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, De Cristafaro A, Kerr EA. The quality of health care delivered to adults in the United STates. N Engl J Med. 2003 Jun 26;348(26):2635-45.

[5] Woolf SH, Johnson RE. The breakpeven point: when medical advances are less important than improving the fidelity with shich they are delivered. Ann Fam Med. 2005 Nov-Dec;3(6):545-52.

[6] Marcum ZA, Hanlon JT, Murray MD. Improving Medication Adherence and Health Outcomes in Older Adults: An Evidence-Based Review of Randomized Controlled Trials. Drugs Aging. 2017 Mar:34(3):191-201.

[7] de climens A., Pain E. et al: Understanding reasons for treatment discontinuation, attitudes and education needs among people who discontinue type 2 diabetes treatment: results from an online patient survey in the USA and UK.

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

Real‐World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe

Congratulations to Alethea Wieland, President and Founder of Clinical Research Strategies and a member of the MedSurgPI team for co-authoring the attached publication: Real‐World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe, featured in Therapeutic Innovation & Regulatory Science. #osteoporosis #tymlos #fda #ema #regulatorydecision #realworlddata #realworldevidence #abaloparatide #eladynos #tymlos #medicalresearch

Practical Pointers

Practical Pointers: Product Development and Medical Affairs

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

Product Development

1. Data Monitoring Committees in Clinical Trials: The new FDA Guidance on “Use of Data Monitoring Committees in Clinical Trials” (DMC) just came out in February 2024. [1] The FDA strongly recommends using a DMC if there is a risk of a serious mortality or morbidity due to the participant’s medical condition or if the investigation may cause serious unexpected adverse events during the trial. The agency further states that the use of such a committee is practical.

   MedSurgPI suggests that when the study is short in duration, a Safety Review Committee, (SRC) may be a more practical approach to further ensure safety of the clinical trial. This consists of a medical monitor, the principal investigator, and another medical safety expert.

2. Overview of Device Regulation: The FDA has just issued the “Quality Management System Regulation (QMSR) Final Rule”, which amends the good manufacturing practices requirements of the Quality System Regulation (21 CFR Part 820).[2]

   Medical device manufacturers of US medical devices must adhere to the following:

   US FDA Registration Guidance | US Medical Device Registration

   Device Registration and Listing

   Premarket Notification 510(k) unless exempt, or Premarket Approval (PMA)

   Investigational Device Exemption (IDE) for clinical studies

   Quality System (QS) regulation

   Labeling Requirements

   Medical Device Reporting (MDR)

3. Still a Need to Improve More Diverse Populations in Clinical Trials: Clinical Trials need to involve more diverse populations such as racial and ethnic minorities, the elderly, rural populations, women, etc.[3] The FDA has published a new guidance document that explains how this data is to be collected during a clinical trial: “Collection of Race and Ethnicity Data in Clinical Trials, and Clinical Studies for FDA-Regulated Medical Products: Draft Guidance for Industry.”[4] One resource, with tools and other information to help improve this situation, may be found at the National Institute of Minority Health and Health Disparities website.

Medical Affairs

1. Keeping Current: Presenting yourself as an expert goes beyond just understanding your product; it’s crucial to be deeply knowledgeable about the conditions it treats. This requires a commitment to continuously monitoring and analyzing relevant medical literature, including newsletters, attending conferences, and reviewing clinical trial data. Keeping abreast of advancements in the field ensures that you remain a comprehensive resource for both your product and its application. This ensures that your team can provide accurate and up-to-date information, establishing yourself as a reliable source.

2. AI Chatbots for Medical Education: Some medical information tasks can be automated by the use of AI chatbots for providing such information to health professionals and patients about medication and device indications, adverse effects, dosages, and drug interactions.

3. Medical Affairs Microgrants: Our experience suggests that a ‘microgrant’ program can be a useful tool in obtaining greater healthcare professional (HCP) engagement. This entails establishing a very modest grant program that allows HCPs who do not conduct formal clinical trials to defray the cost of such activities as creating an article (case history), small study (observational, history, etc.) of interest to your company.

[1] https://www.fda.gov/media/176107/download.

[2] https:www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/overview-device-regulation#reg.

[3] Kim J and McDaniel D.  From Words to Action: Advancing Efforts to Reduce the Racial Gap in Clinical Research. Applied Clinical Trials. Feb 7, 2024.

[4] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials-and-clinical-studies-fda-regulated-medical.

Practical Pointers Special Edition - Investment Essentials

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

In light of the recent conclusion of the JP Morgan Healthcare Conference in San Francisco, a pivotal event for global investment, there’s a noticeable shift in focus among companies and investment groups. As they reassess strategies for raising capital and evaluating a wide spectrum of sectors - including biotech, tech, digital, device, pharmaceuticals, and diagnostic technologies - we find it timely and pertinent to dedicate this month’s Practical Pointers to these emerging trends, which are currently at the forefront of investor and founder discussions.

Fundamental Topics Related to the Technology and Pathway

1. What is the medical or technological need?

2. What is the background science?

3. Is there rational data proving the hypothesis?

4. What is the patent portfolio?

5. What is the regulatory pathway?

6. What is the clinical trial strategy/pathway?

7. What is the expected clinical benefit?

8. What is the reimbursement strategy?

9. Is there an experienced product development team running the organization?

10. What are the competitive products?

11. What is the exit strategy?

12. What is the market size?

13. What are the risks of the project?

What is the Medical Need? This is one of the most quintessential questions that helps determine the value of a scientific product. The more significant the medical need the more it may lead to quicker funding, quicker regulatory review, and more investigator engagement. For example, there is a huge need for better oncology treatments, so these products are highly valued, and a tremendous amount of venture capital is being poured into many of these companies. Meanwhile, cancer prevention is what has led to a recent reduction in cancer mortality in the U.S. Another example of a critical area is the need for vast improvement in cardiovascular disease.

What is the Science? Is the technology based on plausible and good scientific work? Can the results be replicated? What is the level of expertise of the scientists who have conducted the experiments? Is the scientific hypothesis convincing?

Is there Rational Data Proving the Hypothesis? Does the data support the hypothesis? Are there other plausible explanations for the observed effect? Does this stand up to critical scientific review?

What is the Patent Portfolio? What is the status of patent filings? Have provisional patents been filed? Are patents pending? Which countries are covered? How much longer do the patents last? Are the patents adequate to provide protection vis-a-vis current and future competition? Who owns the patents? If it is a university, what are the licensing terms? It is essential to answer the following questions: Are the patents on the composition of matter; formulation/process; methods of use; and is there confirmation of freedom to operate?

What is the Regulatory Strategy? Is the technology going to be regulated by the FDA? Will it require filing an Investigational New Drug (IND) application or an Investigational Device Exemption (IDE)? What regulatory division of FDA/EMA will review this? Is there potential for special designation; orphan drug, expedited review, breakthrough? Have you had preliminary discussions with FDA/EMA regarding regulatory and clinical pathways? Will Phase I be in a healthy normal population? At what stage will you attempt to obtain proof of concept?

What is the Clinical Strategy/Pathway? What kind of clinical data will be required? Do you have information from the FDA/EMA as to their requirements? How are you planning to generate the clinical data? Are there competitive products on the market or in development that will affect your development plan?

Will you utilize a contract research organization (CRO), fractional service providers, or your own team? Do you have the medical, clinical, and scientific expertise to create a clinical strategy to plan clinical development in the most direct, economic, and efficient manner? Will you work with academic institutions, a site management organization, and/or independent investigators? What will be the duration and expense of each clinical phase? What will be the geographic scope of the clinical program?

What is the Expected Clinical Benefit? Will this product significantly modify a disease, prolong life, improve quality of life, or have fewer side effects than current therapy? Will it improve disease diagnosis? In addition, are there pharmacoeconomic benefits of the product?

What is Your Reimbursement Strategy? Is the technology a novel product or a “me too” (one that closely imitates an existing product)? Will it treat a rare disease? If there are competing products on the market, does it have significant medical or economic benefits? Will it extend life or improve quality of life? Are there reimbursement codes or do you need to lobby for them? Are you planning to generate data for Medicare reimbursement if applicable? Who will provide reimbursement pathway advice to your team?

Do You Have an Experienced Product Development Team? How many people are on your team? Do you have full-time dedicated staff? Has your team developed similar products before? Have they attained a New Drug Application (NDA), Biologics License Application (BLA), or clearance? Does your group work in other countries besides the U.S.? What types of companies and roles has your senior leadership team been involved with in terms of their experience?

What are the Competitive Products? What are the competitive products already on the market or in development? What is your competitive advantage over them? How will they affect your clinical development, commercialization, and market potential? What other products are in development and how might they affect your development and/or commercialization strategy?

What is Your Exit Strategy? Are you planning to sell the product (or company) when you have demonstrated proof of concept? Will you try and obtain product approval before an exit? Do you intend to manufacture, and commercialize the technology yourself, seek partnership, hand off, or some combination in different geographies?

What is the Market Size? Have you identified your Total Addressable Market (TAM)? What is the overall market size, and which is your addressable market? Which geographies and populations will you target? What is your order of entry strategy? Would there be opportunities for expanding the market?

What are the Risks of the Project? Have you characterized the project risks across the full range of functional areas? Have these been quantified in a risk register? Do you have mitigations for the relevant risks?

Practical Pointers for Drug Development and Medical Affairs

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

Drug Development

In 2023, the U.S. Food and Drug Administration (FDA) published numerous significant guidance documents. Below is a selection of these key publications.

1. Numerous types of real-world data can be analyzed in non-clinical trials such as registries, electronic health records, medical claims, and data on products used in clinical practice as part of a package for FDA regulatory product approval.[1]

   • The FDA suggests the following:

     • Early engagement will allow for timely identification of challenges in the design and planning of a non-interventional study and for discussion of how such challenges might be addressed.

     • When submitting a meeting request, sponsors should include adequate information - as outlined in FDA guidance for formal meetings - for FDA to both assess the potential utility of a meeting and to identify relevant FDA subject matter experts who should address the proposed agenda items.

2. Optimizing the dosage for oncology products now requires a strong rationale for choice of dosage which should be provided before initiating registration trial(s):

   • To support a subsequent indication and usage:

     • Especially for oncologic diseases not adequately represented in completed dose-finding trials or for new combination regimens.

     • If sufficient rationale for choice of dosage cannot be provided, additional dose-finding should be conducted.[2]

   • The FDA further states that different dosages may be needed in different disease settings or oncologic diseases based on potential differences in tumor biology patient population, treatment setting, and concurrent therapies (for combination regimens), among other factors.

     • Applicable nonclinical and clinical data should be considered to support the proposed.

   • Different dosages may be needed in different disease settings or oncologic diseases based on potential differences in tumor biology, patient population, treatment settings, and concurrent therapies (for combination regimens), among other factors.

     • Applicable nonclinical and clinical data should be considered to support the proposed.

   • For additional information, please see FDA’s Project Optimus:

     • https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

3. When developing drugs for rare indications, the FDA frequently allows the use of innovative trial designs. These should be discussed with the appropriate division very early on. This may include Bayesian methods, n-of-1 clinical studies, randomized delayed-start designs, crossover designs, and master protocol.[3] These studies require a detailed statistical analysis plan including key features of the clinical investigation design and preplanned analysis discussed with the review team before the study initiatives.

   Canadian Regulatory Pointers

   On December 4, 2023, Health Canada’s Regulatory Operations and Enforcement Branch revised the medical device establishment licence (MDEL) application form. The form is used to:

   • Apply for an MDEL

   • Apply for an MDEL after a cancellation

   • Submit changes to your existing MDEL

   • Cancel your MDEL

   • Apply for a reinstatement of your MDEL after a suspension

     For specific details, visit the following website: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/establishment-licences/medical-devices-compliance-bulletin/updates-frm0292-instructions.html

     Medical Affairs

     Direct-to-Consumer Prescription Drug Advertisements in television and radio in new guidance document:[4]

   • First Standard: The major statement is presented in consumer-friendly language and terminology is readily understandable.

   • Second Standard: The major statement’s audio information, in terms of the volume, articulation, and pacing used, is at least as understandable as the audio information presented in the rest of the advertisement.

   • Third Standard: In advertisements in television format, the major statement is presented concurrently using both audio and text.

   • Fourth Standard: In advertisements in television format, for the text portion of the major statement, the size and style of font, the contrast with the background, and the placement on the screen allow the information to be read easily.

   • Fifth Standard: During the presentation of the major statement, the advertisement does not include audio or visual elements, alone or in combination, which are likely to interfere with comprehension of the major statement.

   1. Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products. Guidance for Industry. August 2023.

   2. Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. Guidance for Industry January 2023.

   3. Rare Diseases: Considerations for the development of drugs and biological products. Guidance for industry. December 2023.

   4. Direct-to-consumer prescription drug advertisements: presentation of the major statement in a clear, conspicuous, and neutral manner in advertisements in television and radio format final rule Q&A. Guidance for Industry December 2023.