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Introduction"My name is Dr. Grant Pagdin. I live in Kelowna British Columbia and my practice focuses on anti-aging and regenerative medicine. I have a specific interest in using PRP and stem cells for regenerative procedures. Principally the focus is on orthopedic issues, so tendons, ligaments, and joints. But also we address areas of cosmetic concern, like facial rejuvenation and scalp treatments for the stimulation of hair growth. I also do regenerative injections for sexual enhancement for both men and women. I started doing regenerative procedures back in 2013. Initially we were interested in getting some feedback from our patients as to how they were doing. And typically we would just ask them questions, what do you estimate has been your improvement? And they would give us sort of a percentage, oh, I feel 60% better.More recently, we've taken an interest in tracking outcomes a bit more specifically than just asking patients subjectively how much better they feel.How do you capture patient outcomes?One of the issues that we faced initially when we made a decision to engage in some formal follow-up with symptom scores was actually get the patients to kind of buy in and participate. So the platform that we're using for gathering this data is very user friendly. We encourage the patients at the time that they enroll for a treatment of PRP to download an app that they can interact with. And the great thing is that my staff doesn't have to constantly be sending out reminders for our patients to complete these sorts of questions. The system is completely automated so that the reminders come to the patient automatically they fill in the data for us and the data comes to us directly for our analysis. So that we have been able to establish a really good percentage of participation amongst our PRP clients.How will you use these data in your practice?In terms of the reasons behind why we would be collecting this data and what we might be using it for? There's really three main areas that are important to me. Number one is I want to be able to have some actual objective numbers that I can share with prospective clients. And that way they can have a little bit better handle on exactly what I'm doing and what what kinds of outcomes I'm experiencing. The second area that I think is important for me is to be able to share some of my outcomes with my colleagues. Now we want to make sure that we're comparing apples with apples. So I make sure that my PRP for instance is concentrated at five times baseline. And so we're able to indicate the sorts of parameters around the intervention that we're doing and also share some of our outcomes data with like-minded colleagues. So in this way we could actually pull together some data that is much more powerful than just the data I'm collecting my own clinic. If there were other providers doing similar procedures, then we could say, well you know over the 200 or 300 cases that we have done together, these are the sorts of outcomes we're getting. Then the numbers start to become really very significant. And then the third important reason why I want to try to collect this data is that we are in a field that is increasingly facing regulatory oversight. And we know that you know Health Canada is particularly interested in regulating cells and biologic materials. So any use of stem cells, whether fat or bone marrow or any other sources are being classified as drugs. And the individual colleges of physicians and surgeons in each province are keeping a close eye on this field as well. So that I think that it behooves us to be acknowledging that these types of interventions are experimental in nature. We tell our patients that there's no guarantee as to the outcome, but we want to make sure that we are tracking outcomes to ensure that these procedures are being done safely and effectively.How can interested colleagues learn more?At this point in my practice, I have collected data on over 60 subjects for a variety of different indications and I am willing to share that data with my regenerative medicine colleagues. I would also encourage my colleagues to be collecting data of their own and sharing that as well because I think that's a very important way that we can really move this field forward. I think if we pool our efforts and and work together cooperatively then I think this field of regenerative medicine in Canada can really advance that by leaps and bounds. So I'd invite my colleagues to reach out and I'd be happy to give you some more information on just exactly what we're doing and share with you some of the data that I've accumulated to date."

TABLE OF CONTENTS‍INTRODUCTION Circles Overview Hospital Departments and Real-World EvidenceCIRCLE BENEFITS FOR HOSPITAL DEPARTMENTS Clinical Decision-Support Patient Engagement New Service Lines Reimbursement Exploiting Research Capabilities Publication Education and Training Industry And Other Funding RelationshipsGETTING STARTED GeneralIntroductionCircles OverviewCircles represent a powerful, flexible and cost-effective approach to outcomes capture, studies, registries, publication and other healthcare objectives. A single Circle unites clinicians, scientists, patients and industry in developing – and extracting value from -- real-world evidence (“RWE”) in the context of a specific medical condition or procedure. They enable sustained collaboration among stakeholders, and can be implemented within and across institutional and national borders. A Circle can be up and running in two weeks, can accommodate any budget and is highly scalable.Circles utilize RegenMed’s patent-pending inCytes™ and Benchmarc™ platforms. They integrate world-class technical infrastructure and excellent clinician and patient user experience. They offer powerful collaboration tools, 24/7 access, advanced reporting functions, data control/validation/security, and publication support.Key to development of RWE is minimizing the clinical burden in developing foundational real-world data. RegenMed’s platforms and processes do so by streamlining patient enrollment, long-term outcomes follow-up, Investigator and team member onboarding, and other tasks. This allows the busy clinician to focus on patient care.Circles deliver continuous value for any healthcare stakeholder. In this Article, we summarize value categories for hospital departments.Hospital Departments and Real-World EvidenceModern medicine is characterized by hyper-specialization, rapidly advancing science, sophisticated devices and products, “informed” patients, reimbursement codes, legal/regulatory complexity, literature “overload” and clinical burden (both patient care and administrative.)In addition to these challenges, the hospital department chair must also deal with clinical and research revenue goals, talent acquisition and retention, budgetary constraints, training/education, publication and inter-departmental “co-opetition”.However, that chair has two major assets to help address those challenges:A large volume of clinical interventions and laboratory analyses representing usable real-world data.Accessible medical researchers and scientific equipment.From these assets, Circles can generate several important categories of value, summarized below. Circle Benefits For Hospital DepartmentsClinical Decision-SupportThe ability of clinicians to make evidence-based diagnoses and treatment protocol decisions is hampered by several factors. These include personalized/precision medicine, systemic effects of apparently localized medications or interventions, the lack of long-term outcomes data, incomplete patient histories, co-morbidities, no or poor evidence for many interventions, and time constraints.By designing and executing large “n” Circles, a department can develop and continually improve evidence-based standards of care for specific interventions, patient cohorts, pre-and post- clinical care and products.Patient EngagementToday’s patients have multiple provider choices, are savvier about their care, and have higher expectations. They are accustomed to personalized user experiences outside of the clinical environment. They want to understand their condition, the proposed treatment protocol, the likely outcomes. They want to participate in their care, and appreciate their provider helping them do so.Circles provide an excellent user experience for patients pre-, peri- and post-clinically. This experience is customized for the treating physician, as well as the patient. It includes information on the condition, treatment protocol, expected outcomes, and outcomes of similar patient cohorts. Circles can include “digital front doors” and “outcomes pages” for the department’s (or each clinician’s) webpage, as well as data-rich content for blog posts.All patient engagement processes are HIPAA and GDPR compliant.New Service LinesBorders among traditional medical specialties are blurring; new ones are forming. Plastic surgeons are utilizing adipose-based treatments for musculoskeletal conditions. Immunomodulation science is no longer relevant only to oncology or rheumatology. Sports medicine is fast becoming a branch separate from orthopedics. Leading hospitals have established regenerative medicine centers of excellence, and even academic curricular offerings. Clinicians, and payers, recognize the importance of evidence-based rehabilitation – and even pre-habilitation – as a distinct clinical specialty.At the core of these trends is not only advancing medical science, but the results of registries, pragmatic studies and other real-world evidence sources. Circles help hospital departments identify and implement new service lines.ReimbursementThe mix of governmental, private, and out-of-pocket reimbursement differ among hospital departments according to specialty and geographic locations. Some departments benefit significantly from research grants and donations, others less so. In the near future, narrow networks, accountable care organizations and other types of value-based medicine will become increasing important factors in reimbursement.The collection of long-term outcomes, tightly correlated to specific diagnoses and interventional protocols, are becoming central to all forms of reimbursement. Circles are designed to identify and capture such real-world data, and aggregate it into statistically significant support for all forms of payers.Exploiting Research CapabilitiesGenuine clinical translation is unnecessarily slow and difficult. This has been widely recognized, including in national legislation such as the 21st Century Cures Act and “Right To Try” laws.In theory, hospital departments with research capabilities should be ideal “incubators” for evidence-based clinical translation. In practice, however, there are many challenges. These include differing revenue incentives, operational environments, and legal/regulatory parameters. Busy clinicians are unable to keep up with sophisticated medical science. Researchers do not understand clinical realities.Nevertheless, a hospital department can achieve the promise of regular evidence-based clinical translation by implementing Circles:Researchers can work with the department chair or other practitioners to develop a clinically efficient Observational Protocol (study design) focusing on the safety and efficacy specific condition or treatment protocol.Practitioners can collect the real-world data generated by their everyday cases, and corresponding to that Observational Protocol. This would include longitudinal and standardized patient-reported outcomes.The research laboratory can assist with the collection of scientific data requiring laboratory equipment.The researchers and clinicians can jointly analyze the resulting aggregated datasets for hypothesized or serendipitous correlations (real-world evidence).The researchers and clinicians can jointly prepare journal articles, conference presentations, education/training materials.Circles provide the turnkey platforms and processes to achieve genuine clinical translation, with sustained value for both “sides”: research and patient care.PublicationThe reputation and influence of a hospital department is closely related to its data-supported standards of care and outcomes. Those defining characteristics are traditionally propagated through peer-reviewed articles and conference presentations. In today’s world, digital platforms, online education forums, and select social media are equally important.Circles provide departments with the real-world evidence at the heart of any influential healthcare content. Circle Academies allow department members Circle Members to securely present and discuss individual cases, study designs, tentative observations, or publication content. RegenMed also supports social multi-media presentations, website outcomes pages, and digital front doors for efficient patient enrollment.Education and TrainingHospital departments have various education and training components. These typically include from medical student internships, formal residents and fellows programs, mortality and morbidity conferences, lecture series and grand rounds. Circles can provide several valuable forms of education within any of these contexts:Developing real-world study designs.Executing real-world studies, from the informal to formal research assignments.Integrating modern medical science with everyday clinical care.Identifying key elements of interventions constituting real-world data.Determining statistical and clinical significance of aggregated datasets.Use of appropriate outcomes measures for specific indications.Developing evidence-based standards of care.Engaging with patients through longitudinal, personalized and data-driven conversations.Industry And Other Funding RelationshipsIn today’s complex and expensive healthcare environment, only industry has the resources necessary to develop, test and bring to market new products. Meanwhile, only the busy clinic can provide the data evidencing long-term safety and efficacy. Thus, medical advances, as well as the delivery of everyday care, rely on close collaboration between product manufacturers and clinicians. However, legal and institutional policies often pose obstacles to that collaboration.Real-world studies provide a potent and ethical bridge between providers and industry enabling provider funding, product development and improved patient care. A common version of such studies is the “investigator-initiated trial”, for which Circles are commonly used.Circle-supported studies are also an effective way to demonstrate to corporate and private donors the real-world impact of their gifts. Getting StartedGeneralThere are several ways, detailed here, to experience the functionality and value-creation of Circles. A major benefit of Circles is their broad flexibility. They can accommodate any real-world evidence goal, regardless of size or complexity, without forfeiting functionality. Moreover, it is easy to scale a Circle, or add new ones, at any time.For hospital departments, Circles may need to be implemented in the context of a business associate agreement, internal system integration, IRB policies and other institutional requirements. RegenMed is able to do so.Copyright © 2022 Regenerative Medicine LLC

TABLE OF CONTENTS‍OBSERVATIONS Risks of Multiple/Mixed Objectives Incentives and Motivation Clinicians Patients Funding Sources Other Common Challenges With Registries Burden of Execution Poor Integration of Systems and Processes Balancing Flexibility With Standardization The Implications of “Real-World” E Pluribus Unum: Sub-Registries - Master RegistryONE POTENTIAL PATH Determining The Registry’s Principal Objective What Is Achievable? What Will Have The Greatest Impact? Motivations Proof of Concept Scaling FundingRegenMed partners with various healthcare stakeholders around the world to develop and execute registries having various levels of complexity. The following observations and suggestions derive from that experience. They will assist medical societies, foundations and other healthcare stakeholders as they consider the design and execution of real-world evidence (“RWE”) registries.ObservationsRisks of Multiple/Mixed ObjectivesWithout a clear and realistic definition of its principal objective, the effectiveness of any registry is impaired.A registry may have one or more of the following objectives:Safety and efficacy of specific products.Safety and efficacy of specific procedures.Compilation of conditions susceptible to primary or adjunct therapies.Specific types of regulatory submissions: IND, IDE, 510-K, PMA, post-market, other.Advancing the science of a specific medical sub-discipline.Support for clinical decision-making.Establishing standards of care for particular indications or treatment protocols. There is of course overlap among the foregoing and other possible objectives, but there are also major differences among them which have large implications for the design, execution and ultimate value of a registry.Incentives and MotivationRegistries – and indeed traditional randomized controlled trials (“RCTs”) – often struggle to achieve their potential due to inadequate motivation of clinicians and patients to provide the necessary data in a verifiable, timely and complete manner.‍CliniciansFor an RWE registry, clinicians will be called upon to:collect data,implement data verifiability processes,follow-up with patients,coordinate with laboratory or other scientific data sources,train and oversee existing and perhaps new staff,create and maintain documentation.Clinicians are already overburdened with legal and administrative requirements regarding each of these items. Participating in a proper registry will substantially add to this burden, typically without a benefit commensurate with that additional burden.‍PatientsThe collection of long-term follow-up data from patients is of course a critical part of an RWE registry. There are many dozens of PROMs platforms available, but most fail to drive longitudinal patient compliance due to no perceived value. While an RCT will financially compensate patients, this may not be feasible for an RWE registry where a large “n” value is necessary to achieve statistical significance.‍Funding SourcesRegistry costs can be considerable, and the registry sponsor is likely to seek third-party sources to underwrite at least some of them. Sources include government research grants, foundations, product manufacturers and distributors, and payers (including self-insured employers and employer groups.Other Common Challenges With RegistriesBurden of ExecutionReal-world evidence is derived from the busy clinic. Without minimizing the burden imposed on a clinician and her staff, a registry is unlikely to achieve the necessary amount of verifiable, longitudinal and relevant data. Regardless of financial and other incentives, the minimization of burden involved in registry participation is critical.‍Poor Integration of Systems and ProcessesBy definition, an RWE registry need not involve the cost, duration and complexity of an RCT. However, for any objective, it will share certain requirements – data verifiability, patient-privacy and often consents, robust data analytics, defensible clinical/scientific hypotheses, a study design integrated across pre, peri-, and post- clinical information, longitudinal patient engagement and, of course, funding.Separate process categories which should be integrated include scientific, clinical, commercial, communications, IT and data analytics.These basic requirements have major implications for efficient, integrated systems and processes – not only to minimize cost, but to avoid errors and allow scaling.‍Balancing Flexibility With StandardizationMost PROMs and other components of registry “protocols” are one-size-fits-all, with little or no flexibility for the clinician to adapt them to her specific practice. This need not be the case, especially in the context of RWE registries. Modern technical platforms allow the design and implementation of registry protocols which can be customized to the specific clinical protocols of the participating practitioner. The Implications of “Real-World”In establishing its principal objective for a “real-world” registry, the sponsor will benefit from carefully defining the term “real-world”. “Real-World” For The FDAThe Cures Act and associated FDA publications provide extensive guidance on what can be characterized as real-world data and evidence for purposes for regulatory decision-making. Taking these requirements as a whole, the development of such FDA-compliant RWE implies costs, processes, personnel and timing which often would not be significantly less than traditional RCTs. This will be particularly true in the case of biologics and other “regenerative medicine” therapies, which can involve systemic effects and mechanisms of action dependent on individualized measures. Thus, establishing an RWE registry compliant with FDA requirements will have significant implications in terms of cost, personal and processes.“Real-World” For the Real WorldThere is also a medical/scientific “real-world” which deserves consideration – that of the busy orthopedic surgeon and other practitioner, and of their patients. This involves an assessment of clinical decision-making, product evaluation, provider selection, reimbursement, time and cost burdens, staff and laboratory constraints, and other realities.This real-world is necessarily less rarefied and “messier” than that of the FDA’s; however, it is arguably the more important “real-world”. It is where the vast majority of the over one billion annual patient/physician interactions take place. It is also where the registry sponsor can make a product-agnostic, substantive and sustained impact by adapting the best practices of RCT methodologies to the realities and needs of the typical clinician and his patients.E Pluribus Unum: Sub-Registries - Master RegistryAt least four major factors argue in favor of multiple RWE registries:In the modern world of personalized medicine, many therapies are by definition specific to the patient’s specific glucose, erythrocyte, platelet, growth factor, leukocyte and other “counts”.Many therapies currently in common use involve various hypotheses regarding efficacy in the context of concentration levels, activation agents, dosage, injection site, number and interval of injections, and other parameters.The markets for many products used in many treatment protocols are fragmented and unstandardized.The members of a medical society often represent a wide variety of sub-specialties and patient cohorts, for each of which one or more of various therapies are likely to be in use and or of clinical interest.Nevertheless, the principal initial scientific hypotheses for a specific registry dedicated to a specific treatment protocol may also be relevant to certain “adjacent” therapies. Implementing common protocol elements across various registries will allow the derivation of “serendipitous” as well as initially presumed hypotheses.One Potential PathDetermining The Registry’s Principal ObjectiveThere are many potential objectives for a real-world registry. Two initial criteria may help define an overarching goal:What Is Achievable?A medical society typically is pursuing multiple initiatives, of which an RWE registry will be only one. A sober assessment of the personnel, funding and time available to execute this registry consistent with the society’s reputation and standards is an important element in determining the registry’s principal objective.‍What Will Have The Greatest Impact?The missions of a medical society will often include one or more of member education, advocacy, and developing standards of care relevant. An RWE registry sponsor will wish its parameters in the context of at least one of its missions. Properly structured and executed, such registries can deliver demonstrable impact in a relatively short amount of time.‍MotivationsMerely covering the costs for participating clinicians is often insufficient, and indeed impractical. Far more effective incentives include honoraria, investigator fees, reimbursement for conference attendance and presentations, assistance with publication, provision of part-time scribes, patient education materials, and providing systems and processes which reduce the burden of registry participation.Designing, funding and reliably executing these incentives give a registry the best chance of success and impact. Proof of ConceptTo achieve its objective(s), any registry must properly design and continually implement several scientific, clinical, financial and operational elements. Doing so is necessarily a complex undertaking. It therefore makes sense to begin with a modest “proof-of-concept” phase, allowing the sponsor first to analyze and then improve various elements of its design and execution. ScalingWhatever the initial objective and scope of the registry, the registry sponsor will wish to expand its reach. It will also seek to accommodate other objectives. In both cases, carefully designing the foundational elements of the initial registry, especially with respect to systems and processes, will enable it economically to do so.FundingThe most accessible and significant funding source for the registry is industry – usually manufacturers and distributors. However, self-insured employer groups are also likely to represent significant financial support. In all events, funding efforts will need carefully to balance RWE objectivity with perceived value for the funder. Copyright © 2022 Regenerative Medicine LLC

Millions of patients each year are affected by knee osteoarthritis. The severity of this condition is often categorized using the Kellgren-Lawrence (KL) scale, which uses the numbers 0 through 4 to represent the absence or varying grades of symptom presentation. Patients with long-term and/or severe symptoms are often indicated for surgery, while patients with minimal symptoms can employ simpler tools, such as NSAIDS. But what about the many patients who are stuck in the middle, too early for surgery and far past the role of over-the-counter medication?This is known as the treatment gap, and Drs. Guillermo Alvarez Rey, M.D. and Carlos Ferrer Señorans, M.D. of AMS Centro Médico in Málaga, Spain, are intent on shedding light on this prevalent question. Using RegenMed’s inCytes™ technology, and deploying their own non-surgical treatment methods, they have captured and correlated their own patients’ KL grade to long-term outcomes. Early and average results so far show:Patients with a lower KL grade (0-1) can expect significant improvement, almost to a perfect score.Patients with mild to moderate OA can still expect improvement, up to around 30% on average after 12 months.Even more interestingly, patient suffering from severe OA (KL 4) can experience some slight improvement, though early results do show a faster return to baseline.These data play an invaluable role in helping set patient expectations, informing Dr. Alvarez and Señorans on more personalized patient treatment decisions, and may well help inform standards in the Treatment Gap space in the future.

Gulf Coast Biologics Training and Education Center, Fort Myers FL, headed by Peter Everts, Ph.D., FRSM, is dedicated to providing the latest advancements in autologous regenerative medicine treatment options to physicians, practitioners, and health care providers across the globe. Many of those advances are increasingly dependent upon capturing and analyzing the large amounts of real-world data generated by everyday clinical cases.With the help of RegenMed, and key Gulf Coast Faculty members, such as Luga Podesta, M.D. and Glenn Flanagan, M.D., Gulf Coast Biologics will design and implement engaging, flexible, and collaborative data registries. Each registry will be condition-specific, and will make real-world data capture simple, burden-free, and engaging for providers and research faculty.Key elements of this initiative include:Burden-free patient enrollment and follow-up across a wide spectrum of clinical/scientific assessments.Patient-friendly education materials, graphs, images, and progress reporting which promotes high patient engagement and compliance.Participation in multiple registry protocols in the musculoskeletal, aesthetic, wellness, and other disciplines.The ability for a provider to create his/her own private e-study.Access to robust data analytics supporting the derivation of clinically significant correlations from common datapoints arising from members’ specific protocols, characterization results and/or products to shared outcomes.Conversion of Member’s results into content for website, patient recruitment, and social media strategies.Integration of registry data and analytics into conferences, gatherings and publications.If you are interested in learning more about Gulf Coast Biologics, or about its Real-World Evidence Registries, please contact Peter Everts at peter@gulfcoastbiologics.com.