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TABLE OF CONTENTS‍ILLUSTRATIVE MULTICENTER STUDY USE CASES Improved Standards Of Care Clinical Decision Making Reimbursement Testing A Clinical/Scientific Hypothesis Registries Sustained Involvement Of Teaching Hospital Residents And Fellows Extend Best Practices Of Sports Medicine KOL’sFUNDINGCIRCLES AS A COMPREHENSIVE SOLUTION General Identifying Peers And Experts IRB And Other Approvals Data Collection, Aggregation, Correlations Patient Compliance And User Experience Ongoing Collaboration Publication And InfluenceCONCLUSIONCONTACT USFOOTNOTES Abstract“Impactful and professionally rewarding multicenter studies arewell within reach for all clinicians.”Illustrative Multicenter Study Use CasesThe efficiency with which multicenter studies can be designed and executed opens up a range of use cases. As but a few examples:Improved Standards of CareAn orthopedic surgeon wishes to substantiate that his specific approach to minimally invasive shoulder reconstruction is superior in safety and efficacy to the standard approach currently utilized in his hospital.Clinical Decision MakingA pain medicine doctor wishes to improve her ability to develop different treatment plans for a diverse patient population presenting with lower back pain. She wants to be able to segment her lower back pain patient panel in an evidence-based manner.Reimbursement An ambulatory surgery center wishes to support reimbursement for a particular procedure for which patients currently pay out-of-pocket. Reimbursement may come from traditional payers, or in the context of a narrow network established by the ASC with select partners.Testing A Clinical/Scientific HypothesisA clinician, intrigued by peer-reviewed literature suggesting the value of certain biologics for a specific segment of her patient panel, wishes to validate their safety and efficacy for that segment.RegistriesA regional medical society wishes to establish a registry which adds value to its members, attracts new members, attracts new industry funding in a product-agnostic manner, and simultaneously advances the mission of the society.Sustained Involvement of Teaching Hospital Residents and FellowsThe maxillofacial department of a major hospital wishes to establish a research/clinical program which not only attracts promising fellows and residents, but maintains a relationship with them throughout their careers.Extend Best Practices of Sports Medicine KOL’sA sports medicine thought leader establishes and encourages best practices among college level soccer trainers in the context of concussion protocols, by involving those trainers in his study.‍FundingTraditional studies are long, expensive and involve limited patient populations. Such studies will of course always have their place. However, as indicated above in footnote 1, there are equally legitimate, far less costly and often more impactful alternatives. Their modest budgets and clinical efficiency make funding much more accessible.In larger hospitals and clinical groups, study funding is often available from research, education, training and even marketing budgets. Another approach is Investigator-Initiated Trials. These studies are financially supported by industry, but explicitly leave to the clinician/investigator all control over study design and execution. [1] Circles As A Comprehensive SolutionGeneralCircles represent an integrated approach to multi-center studies. A successful Circle comprises two closely integrated components:inCytes™ , the technical foundation for value-added registries, studies, trials and other forms of clinical data collection.Circle Academies, which enable the collaboration, education, discussion, publication, and the “network effect” needed to realize the full potential of correlations developed through inCytes™.Circles thus represent a turnkey solution with excellent user experiences – and motivation – for clinicians, patients,and other users. The burden on providers is minimal.Identifying Peers and Experts RegenMed plays an active role in identifying – and supporting collaboration among – practitioners sharing a common clinical/scientific interest. Those “Circle Members” can be found in the same hospital department, in study-relevant medical societies, as authors of articles and conference presentations, and among RegenMed’s network.Circle Members often include scientific and clinical domain experts who can assist with study design,education and training. They also help identify and analyze useful correlations generated through aggregated datasets. A statistician can also be a valuable member of a Circle.IRB and Other ApprovalsAs mentioned, many forms of clinically- and statistically significant studies do not require the involvement of an IRB. Examples are “observational” and “quality improvement” studies. [2]Data Collection, Aggregation, CorrelationsThe statistic power and clinical value of most multicenter studies derive from their large population sizes. This also is the foundation for uncovering “serendipitous” correlations, as well as those envisioned in the original study design. The time needed to achieve that “n” is also significantly accelerated when multicenter studies are efficiently executed.Circles enable the economical and efficient collection of real-world data within the clinical setting of each Circle Member. At the same time, Circle functionality aggregates those data in real time from all Circle Members, wherever located.That aggregated data is then available - also in real-time and at any time - to all Circle Members.Importantly, aggregated is available through a powerful Report Builder allowing any Circle Member to:filter Circle data according to any study question, and compare it to patient report outcomes or other assessment scores established as part of the Study;compare his data against those of all Circle Members;compare a particular patient’s data against those of her broader patient panel;compare outcomes of two or more patient cohorts against the same outcomes score;export raw data; andmore.Circles accommodate variations in protocols and legal/regulatory environments across various practices, while preserving the “canonicity” of all data relevant to verifiable and useful correlations in the multi-center study’s dataset. They also provide full multilingual functionality, allowing participation among like-minded members in any country. [3]Patient Compliance And User ExperiencePatient enrollment, and timely capture of their longitudinal outcomes against a standardized scoring algorithm, are essential to a successful study. The Benchmarc™ patient user experience drives consistently high compliance rates. In addition, RegenMed offers a cost-effective Service Provider Agreement, pursuant to which it handles enrollment and outcomes reporting follow-up on behalf of clinicians.Ongoing CollaborationFor many clinicians, the opportunity to collaborate with peers in other institutions and countries is an attractive aspect of multicenter studies. Ideally that collaboration is meaningful and sustained throughout the full course of the study - from the initial design through the joint generation of correlations. Circle Academies provide the secure, always-on environment allowing them to do so.Publication and InfluenceClinicians and other healthcare constituencies around the world will be interested in one or more elements of multicenter studies – hypotheses, indications involved, study protocol, tentative correlations, methods of efficient execution. These elements are compelling data-driven content for conference presentations, articles, blog posts, training/education programs and patient materials. [4]RegenMed works closely with Circle Members to develop the appropriate content, formats and distribution channels reflecting their work. [5] ConclusionMost clinicians are capable of designing and/or participating in a multicenter study. Doing so need not be expensiveor burdensome. Properly executed, such studies are professionally rewarding, and result in genuine clinical and professional value.‍Contact UsIf you have any questions about how multicenter Circles may benefit you or your institution, please contact us.Footnotes1 See our Article of Investigator-Initiated Trials here.2 A good example is the extensive AAOS Registries. See here.3 While English is common to most clinicians around the world, most are more comfortable in their native language. More importantly, patient-reported outcomes reporting and other patient-engagement elements are essential to a successful study. That engagement should be in the patient’s native language.4 Indeed, a common criticism of traditional trials is the secrecy with which they are conducted. It is often many years, if ever, before their methodologies and conclusions are published.5 See here for more information.Copyright © 2023 Regenerative Medicine LLC

Statistical Significance and Clinical Relevance are two important concepts in the field of medicine, and particularly in clinical research.Being a bit more specific, statistical significance refers to the likelihood that a result is not due to chance. In other words, it is the probability that an observed effect (for example, a clinical effect resulting from a given treatment) is real and not just due to chance. A statistically significant result is considered meaningful in general terms when the p-value is less than 0.05, meaning that there is less than a 5% chance that the observed effect is due to chance.Clinical relevance refers to the practical importance of any effect (after a treatment) on a patient’s everyday life (i.e. less pain, higher survival rate or better quality of life). Any result can be considered clinically relevant when it has a meaningful impact on patient outcomes, for example using a patient reported outcome measure (PROM).These two concepts are related but not equivalent. For many reasons, a given result may be statistically significant but not clinically relevant, or vice versa. For example, a treatment may have a large clinical effect but fail to reach statistically significance due to a small population size or other factors, such as data dispersion or variability.‍In summary, statistical significance and clinical relevance are both important for clinical research, the first providing unbiased evidence of a relationship or effect, while the latter represents the practical implications of results obtained in terms of patient care and decision making.The ideal situation is having a result that is both statistically significant and clinically relevant. One of the best ways to achieve this in clinical trials, is deriving research data from a large number of a homogeneous group of enrolled patients (restricted by inclusion and exclusion criteria). However, in a real world scenario there is high variability and many factors affecting any clinical outcome (disease severity, age, sex, comorbidities, etc).There is also one more aspect that affects clinical relevance for any real patient population, and is called generalizability, the degree to which you can apply the results of any clinical study to a broader patient population. One good example is that many clinical trials might offer statistical significance and clinical relevance in a restricted study population, but not generalizability.The use of Real-World Data obtained from daily clinical practice could overcome the previous limitations by allowing clinicians to easily collaborate and aggregate de-identified data. This could lead to the generation of Real-World Evidence that can be considered statistically significant, clinically relevant and generalizable to different patient populations.RegenMed Circles have been developed with this goal in mind, facilitating data sharing among healthcare practitioners and their industry partners, and putting the patient at the center of their care to advance and progress in any field of medicine and healthcare.If you want to know more about Circles or how our solutions could help you in different ways, contact us.

Real-world evidence (RWE) is valuable not only for regulatory compliance, clinical decision-making and tracking adverse events. It can also drive patient engagement, profitability and professional advancement.The highest quality RWE reflects scientific rigor, long-term outcomes capture and statistical significance. For many, these parameters suggest expense and clinical burden. This need not be the case, especially in the context of Circles. An interesting use case for the efficient development of RWE, and subsequent value creation, is the recent work done by BioXcellerator (Biox) in Colombia.Biox treats patients from throughout North America, often coordinating with physicians in the U.S. and other countries. In 2022, Biox developed an observational study protocol comprising key pre-, peri- and post clinical datapoints. Outcomes are measured utilizing the Impairment Scale for traumatic spinal cord injury developed by the American Spinal Injury Association. Patients are also assessed using the Barthel Index For Activities of Daily Living.Biox has now collected real-world data against their protocol for more than 380 cases. Its preliminary reports and analysis are summarized in the charts below. These are already providing value to treating physicians, referring physicians, existing patients as well as those considering therapeutic alternatives for spinal indications.Moreover, such real-world observational studies are now standard for BIOX physicians and their patients. This will result in transparent evidence-based standards of care specific to a variety of indications and patient-cohorts.Although this use case involves biologics for degenerative spine disease, systematic collection and analysis of real-world evidence are valuable in the context of any indication or clinical setting. The generation by practitioners in any specialty of scientifically valid real-world evidence need not be burdensome or expensive. Moreover, it adds substantial benefits not only in clinical decision support, but practice growth, professional advancement, collaboration, product improvement and influence among peers.Contact us to find out more.

RegenMed’s January 2023 Newsletter. Here, we summarize client activities of interest, events and upcoming activities. Find out more on our Latest and Circle Academies pages. SELECT CLIENT ACTIVITIES Healthcare providers and medical device manufacturers around the World are using Circles to advance their clinical, scientific and commercial objectives. Following are some recent examples. More information on each Circle can be found by clicking on the Circle Academy link provided after each entry. This will allow interested clinicians to get in touch with Circle Founders for permission to follow, or join, their Circles. Get Started With Your Own Circle Singapore General Hospital Together with his colleagues, Professor Tay Boon Keng, head of orthopedics at the prestigious Singapore General Hospital, is completing a twelve month study comparing the safety and efficacy of hyaluronic acid alone with HA plus PRP for knee osteoarthritis patients. Outcomes data using the WOMAC scoring system have been collected for 118 patients. Those data suggest improved scores for the HA+PRP group, compared with that of HA alone and this group is finishing the long-term follow-up for this project. Visit Dr. Tay Boon Keng's Knee OA and PRP Circle Academy Space Pagdin Health In 2020 Health Canada issued a Policy Position Paper regarding autologous cell therapy products. The paper emphasized the importance of practitioners working with Health Canada in helping to develop evidence-based standards of care for such interventions in the context of specific indications. Dr. Grant Pagdin in British Columbia is among the leading clinicians closely following Health Canada’s policy goals. Working with RegenMed, Dr. Pagdin has designed and implemented multiple Circles covering the use of PRP for various urological and musculoskeletal indications. He has established a dedicated Outcomes Page on his website, allowing patients to follow their progress over time against standardized benchmarks. Visit Dr. Pagdin's Circles Academies Space Apex Biologix Apex Biologix has funded 4 initial Circles to support its key opinion leaders, including Dr. George Chang Chien, in the establishment and growth of quality improvement registries around the use of PRP, BMC, A2M and more. Circle design and clinical/scientific hypotheses undergirding the Circle will be discussed on the EVOLVE Conference hosted by the Advanced Regenerative Medicine Institute February 3 – 5, 2023 in Salt Lake City. Visit Dr. George Chang Chien's Circle Academy Space Gulf Coast Biologics Under the leadership of Peter Everts, Ph.D., FRSM, Gulf Coast Biologics is organizing a clinically-sophisticated Circle for knee treatments utilizing PRP. Long-term outcomes utilizing the IKDC and WOMAC scoring measures will generate correlations against key pathoanatomic real-world datapoints, including PRP preparation, dosing and specific injection locations. Respected interventional practitioners from around the country are participating, including Doctors Luga Podesta, Glenn Flanagan, Donald Buford, Timothy Mazzola, Ariana Demers, Imran Siddiqui, Alberto Panero, Gayan Poovendran and more. In addition, Christine Mahoney, Ph.D. is providing statistical analysis support. Gulf Coast Biologics expects at least 50 patients to be enrolled each month for a minimum of six months. In addition, GCB will host monthly “Circle Hours” – LiveStream discussions on Circle Academies among Circle Members and registered participants reviewing early observations. Dr. Everts and RegenMed’s Scientific Director, Seve dos Anjos, Ph.D., will moderate the LiveStream event, as well as subsequent on-line Circle Academy discussions. Visit Dr. Peter Evert's Circle Academy Space JoinTechLabs Working with Doctors Mitchell Sheinkop, John Ferrell, III, Imran Siddiqui, Ariana DeMers and Janet Pearl, RegenMed has designed and implemented Circles to facilitate two studies for the delivery of micronized adipose for knee and shoulder pathologies. Endpoints will be measured using both patient-reported and clinically-assessed outcomes measures. The Circles are funded by JoinTechLabs, and will enroll over 30 patients. They will be overseen by the IRCM IRB. Visit Dr. Mitchell Sheinkop's Circle Academy Space Dr. Guillermo Álvarez Rey Guillermo Álvarez Rey, M.D. (sports medicine specialist) and Carlos Ferrer Señorans M.D. (orthopedic surgeon) from AMS Sonosurgery center - located in Málaga, Spain, have created several real-world studies using Circles out of their own clinical practice. As one relevant example for Knee Osteoarthritis, they are capturing patient outcomes up to a year using KOOS, and correlating those outcomes to various clinical factors, such as biological treatments used, and the Kellgren-Lawrence (KL) grade of each of their patients. They are capturing Real World Clinical Data for many other musculoskeletal indications such as Achilles tendinopathy, epicondylitis or shoulder pathologies. They have reached the landmark of 180 cases in all their Circles, many of which have already achieved the 12-months follow-up. Visit Dr. Guillermo Álvarez Rey's Circle Academy Space Dr. José Miguel Catalán Dr. José Miguel Catalán, orthopedic surgeon expert in the use of biological therapies for different indications, but particularly on PRP and BMC, is one of the pioneers in the use of Circles and the inCytes platform for Real World Data Collection since 2019. Dr Catalán has already collected PRP characterization data from near 300 clinical cases, including platelet dose and other variables, that he is now correlating against the longterm patient-reported outcomes using WOMAC scale. He is presenting these updated Real World Data at OrtoBioMSK specialized course in Seville on February this year, and also at the next TOBI Conference. Visit Dr. Catalan's Knee PRP Circle Academy Space Visit Dr. Catalan's Bone Marrow Aspirate, Knee and Hip Circle Academy Space THE WORLD OF REAL-WORLD EVIDENCE AAOS Real-World Evidence Registry The AAOS registries cover several traditional orthopedic interventions. The Academy is now discussing how to collect real-world evidence to deliver efficacious, safe orthobiologic therapies, as well as the elements for biologics registries and bio-repository systems. RegenMed attended a small conference held in November of 2022 in Washington D.C. by AAOS. Other invitees included representatives from the FDA, HHS, the Biologic Association and clinicians from around the country. For more information on approaches to and benefits of biologics registries, this RegenMed Article may be useful. Sunsetting Of Arthrex’s Surgical Outcomes Center About ten years ago, Arthrex introduced its Surgical Outcomes System (“SOS”) to help customers collect outcomes data against particular orthopedic interventions. Arthrex has announced the discontinuation of SOS effective August 1, 2023. RegenMed is working with former SOS users to transition their existing data and outcomes capture programs to Circles. Mandates, Best Practices, References The concepts of “real-world” data and evidence have existed in the literature for many years. They are now playing important roles for providers, payers, manufacturers and other healthcare stakeholders due to legal/regulatory mandates, value-based medicine, and patient expectations. A good summary of references, as well as clinically efficient approaches to generating value from real-world data and evidence, can be found in this publication by the Agency For Healthcare Research and Quality, part of the U.S. Department of Health and Human Services. COMPANY NEWS New Website RegenMed’s website has been thoroughly reorganized. We hope it will help healthcare stakeholders more easily find information on PROMs, Studies, Registries, Publication and other solutions to developing and generating value from real-world clinical data. The site makes it easy to get started in generating value from Circles in a number of ways. These include free Demo Circles, as well as Open Outcomes Circles and Open Registry Circles. These allow providers to be up and running with value-added Circles in a matter of minutes, and at minimum cost. Circle Academies RegenMed has now launched Circle Academies in two versions. The Open Academy is available to anyone in the healthcare field. The Members Only Academy is accessible only to clinicians who register. It provides a secure, moderated forum to clinicians to teach, learn and observe in the context of real-world data pertaining to specific clinical conditions and procedures. Circle Academies provide all of the functionality of modern social media platforms, without the multiple disadvantages. Events Circle Members and RegenMed regularly present their study designs and observations at medical and scientific conferences around the world. Recent and upcoming events include: CASEM, Quebec City September 2022 EVOLVE, Salt Lake City, February 3- 5, 2023 IOF Max Experience, Scottsdale, February 16 – 19, 2023 TOBI 2022, June 2022, Hollywood Fl. OrthoBioMSK, February 9 – 11, Seville, Spain Sport AMS Ultrasound, April 20-22 2023, Malaga Spain Fidia Academy, October 28 – 29, 2022, Praglia Abbey, Italy Gulf Coast Biologics

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."