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BackgroundBHRT’s are estimated to account for one third of menopausal hormone therapy prescriptions. 1 Since the Women’s Health Initiative Hormone Therapy Trials, 2 the debate over relative safety and efficacy between conventional hormone therapeutic approaches and BHRT’s for women remains vibrant. Similar discussion surrounds BHRT’s andropause and other male-specific conditions. As stated by The American College of Obstetricians and Gynecologists 3: “Compounded preparations are not regulated by the FDA. Although technically all compounded prescription drug preparations could be considered unapproved new drugs, the FDA has adopted a policy of enforcement discretion, allowing legitimate preparation of compounded formulations to be regulated by state boards of pharmacy, with a provision of stepping in when dangerous practices must be addressed and when drug manufacturing occurs under the guise of compounding. There are currently no specific regulations by the FDA on what constitutes a legitimate claim for compounded drug preparations. In general, states regard compounding to be part of the practice of pharmacy. In addition, individual states’ pharmacy acts usually permit other licensed practitioners (e.g., physicians, nurse practitioners, and others with prescriptive authority) to engage in the practice of pharmacy compounding for their own patients.”BHRT’s are thus an important manifestation of a much broader healthcare trend -- personalized/precision medicine. 4 The Need For BHRT StudiesRWE studies and registries are needed to focus on many safety and efficacy issues specific to bio-identical hormone products and interventions. Examples include: Testosterone Replacement Therapy “TRT) for symptomatic hypogonadism.Other TRT claims such as beneficial effects on bone density, strength, muscle, cardioprotective effects. Potential TRT side-effects such as polycythemia, peripheral edema, cardiac and hepatic dysfunction.Comparison of bio-identical estradiol, estriol and progesterone with synthetic and animal derived versions.Specific compounding ingredients and proportions for a given product as used for a specific indication, and with reported long-term outcomes.Long-term outcome assessments capturing increased incidence of breast cancer, cardiovascular disease, venous thromboembolism, hirsutism, and other for specific dosages of specific products.Identification of outcomes, including adverse events, against various administration routes – subcutaneous pellets, injections, oral, other.Dosage measurement of key compounded ingredients in the context of specific indications and long-term outcomes assessments.Integrating longitudinal laboratory blood, saliva, and other analyses into the study protocol.Publications such as The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review, by the National Academies of Science, Engineering and Medicine suggest other important real-world study topics regarding BHRT. Practical Considerations The need for clinically significant datasets addressing many BHRT issues is evident. Patients, providers, and regulators will increasingly require such evidence. Equally clear is that such datasets will ultimately depend on busy clinicians designing and executing such studies. Those clinicians will also need to enroll their BHRT patients into their studies, and ensure maximum compliance with long-term outcomes reporting. These factors normally imply cost, time, administrative burden, and distraction from patient care. Circles eliminate these traditional obstacles. At the same time, they enable providers to support clinical decision making with relevant aggregated datasets. They provide the foundation for evidence-based communications with patients. Circles also allow compounding pharmacies and other manufacturers to develop auditable, statistically significant product and treatment registries to support marketing claims. Illustrative Use CaseDr. Grant Pagdin is utilizing two Circles – one for men and a second for women – to develop BHRT clinical decision support. Pre-treatment and long-term outcomes assessments include the Cervantes Short-Form Scale and the Aging Males’ Symptom Scale. Aggregated outcomes are explained and shared with patients, as described on the Outcomes Page on Dr. Pagdin’s website. Dr. Pagdin’s initial BHRT Circles and associated datasets will focus on standardized outcomes assessments and patient compliance. Subsequent Circles will also collect data on specific types, dosages and other characteristics of bio-identical product used. For Further InformationRgnMed.com / Circles / GeneralJoin/Start A CircleKnowledgeBaseLinkedInLatestContact Us‍1 Compounded Bioidentical Hormones: Myths and Realities. Santoro and Liss. Clin. Obstet. Gynecol. 2021 Dec1;64(4):793-802.2 See The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases, Manson et al.3 Committee on Gynecologic Practice and the American Society for Reproductive Medicine Practice Committee. 4 See for example Personalized Medicine: A Biological Approach to Patient Treatment (FDA), and From Hype to Reality: Data Science Enabling Personalized Medicine, Froehlich et al.

RegenMed is proud to announce that Dr. Bert Mandelbaum has joined its Clinical/Scientific Advisory Board.Dr. Mandelbaum is an internationally recognized orthopedics thought leader. He serves on the Cedars-Sinai Kerlan-Jobe Institute board of directors, and is its co-chair of medical affairs. Dr. Mandelbaum has held governing positions at many major orthopedic medical societies. He also exercises senior medical responsibilities with U.S. major league soccer, USA Gymnastics, FIFA, and the US Men’s National Soccer Team (team physician), among others.RegenMed values highly the strategic support provided by Dr. Mandelbaum and his fellow C/SAB Members. It is particularly gratified by their shared belief in the clinical, professional and financial value inherent in real-world evidence, and the ability of Circles to deliver that value for healthcare providers and industry around the world.

RegenMed works with hospital systems, medical societies, and large medical product companies around the world. Circles help them generate clinical and financial value from real-world evidence in established as well as emerging medical specialties.We are also proud to work with independent clinicians such as Dr. Luis Gallego. Dr. Gallego practices in the historic city of Almeria, Spain, performing about 350 shoulder and knee surgeries annually. He would perform another 800 if he did not feel those patients would have better outcomes with alternative approaches. His data show that 80% of the patients he treats with biologics enjoy long-term improvement on standardized scores such as WOMAC.Real-world data are an essential part of any medical research – whether formal trials or clinical decision support. Those data remain a major untapped asset of most medical practices. Circles ensure that the cost and burden of developing real-world evidence are negligible, but that the returns are manifold and substantial.‍Contact us to learn more.‍

Dear Healthcare Professionals, Our August 2023 Newsletter summarizes:Recent provider and industry Circles use cases, including cognitive impairment and nutraceuticals.Migration to Circles of clinical clients’ data from Arthrex’s Surgical Outcomes System.The establishment of a dedicated Research Page, with pre-designed Circles, for a U.S. medical society.The issuance to RegenMed of a U.S. patent for Method and System For Processing Large Amounts of Real-World Evidence. The addition of Doctors Kenneth R. Zaslav and Bert R. Mandelbaum to our Clinical/Scientific Advisory Board. Cordially, RegenMed

TABLE OF CONTENTS‍ELEMENTS COMMON TO MOST STUDIESRE-THINKING STUDY FORMATSGOING FORWARDElements Common To Most StudiesRegenMed has had the honor of working with providers and industry around the world for many years on studies and trials. Several broad themes emerge:Clinical Burden: Most providers wish to conduct studies. Virtually all product manufacturers must regularly conduct studies.However, time requirements, cost and design/execution complexity make traditional studies prohibitively expensive for all but the best capitalized entities.Restrictive inclusionary and exclusionary criteria in study populations render most study results of questionable value for the majority of patients.Ownership of, and access to, study data are often delayed and/or restricted.Most studies are terminated prematurely or, if “completed”, do not in fact result in statistically significant, auditable datasets.Most studies which fail to reach positive are not published.What most providers, patients, regulators, and payers are looking for in studies is everyday clinical decision support. Remarkably few studies provide this support.Re-Thinking Study FormatsNational authorities recognize the negative impact on broad healthcare metrics of over-reliance on traditional forms of medical studies. The European Medicines Agency and the U.S. FDA have stressed the importance of real-world data and evidence.Similarly, the AHRQ publication Registries For Evaluating Patient Outcomes provides an independent and thorough review of efficient study formats. The 21st Century Cures Act, Right To Try Act and similar legislative initiatives are designed to expedite the availability of safe and efficacious treatment protocols and products. This means, necessarily, improving the efficiency and lowering the costs of trials and other studies.The U.S. government’s recently announced RECOVER initiative represents a major validation of the importance of more pragmatic study formats. RECOVER builds upon and expands a $1 billion “long-COVID” research initiative already underway at the U.S. National Institutes of Health. It encompasses several key elements of modern approaches to studies: Scale: Intends to sign up 48,000 individuals with and without long-COVID symptoms.Regular Reports: First one scheduled for later in 2023.Purpose: Development of evidence-based best practices and guidance for providers and patients. Development of Centers of Excellence to develop templates for care.Reimbursement: Provide datasets needed to support reimbursement by government and private payers.Patient Focus: The primary goal of RECOVER, its studies and its research are improving health of long-COVID patients (estimated in the millions in the U.S. alone).Patient Cohorts: Distinguish among specific patient groups (age-based, race-based, etc.) in terms of symptoms, etiologies, treatment protocols.Research: Answer long-unanswered questions on systemic causes underlying the wide variety of symptoms.Going ForwardThere will always be legitimate needs for randomized, controlled, double-blinded clinical trials. However, their cost and narrow scope – virtually all are now industry sponsored – implies little genuine support in everyday clinical decision-making. As the foregoing governmental initiatives imply, there are often other equally valuable study approaches with greater benefits to broader patient populations.There can be little question that contemporary technology, better clinician and patient user experiences, and thoughtful study designs can support clinical decision-making leading to better outcomes across much larger population groups. Circles are designed precisely to enable such studies of any scale or complexity – in a turnkey, clinical-grade, and low-cost manner. Please contact us to find out more.Copyright © 2023 Regenerative Medicine LLC