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Bioxcellerator, located in Medellin, Colombia, treats patients from around the world with its unique, expanded MSC therapy from Wharton’s Jelly. They have been tracking their patients’ outcomes for over a year, and have granted us permission to share the following early and RWE derived insights:This ongoing study focuses on every knee osteoarthritis case treated at Bioxcellerator (they have similar ongoing studies for other indications).The primary endpoint is the WOMAC scale, which is answered easily by patients from their own mobile devices.The study currently has 120 patients, 25 of whom have reached the 6-month time point.Out of those 25, WOMAC scores were reduced by an average of ~55%, indicating substantially reduced pain (+ is the plotted mean).Diving deeper, 6 of the 25 patients were non-responders, reporting very little change from their baseline measurement. Of the remaining 19, the average WOMAC score reduction was ~75%, demonstrating an even greater diminishment of pain.These follow up data are crucial to helping Bioxcellerator better understand their patients’ outcomes, communicate those expected outcomes to new patients, and achieve more predictable outcomes for all. Upcoming insights will include identifying the patient criteria more commonly associated with non-responders, as well as obtaining statistically significant 12 month follow-ups.To learn more about Bioxcellerator, click here.

TABLE OF CONTENTS‍EXECUTIVE SUMMARYKEY ELEMENTS OF A REAL WORLD STUDYKEY ELEMENTS OF REAL-WORLD STUDY PUBLICATIONINDUSTRY SUPPORTDEVELOPING A SUCCESSFUL REAL-WORLD PROGRAMABOUT REGENMEDExecutive Summary“It is the rare Society which does not wish to grow its membership, to add more value to those members, and to make a bigger impact in its chosen mission. A properly executed real-world study program can achieve each of these objectives in a substantial, sustained and self-supporting manner.”GeneralMedical societies, patient advocacy groups and other not-for-profits [1] can greatly enhance their impact and value to members by sponsoring “real- world” studies, and developing a related publication program. This white paper reviews how Societies can get started with a low-cost pilot project, achieve some “early wins”, and then build upon that pilot to exploit many significant adjacent opportunities.Real-World StudiesThe criticality of real-world evidence and data in modern healthcare is broadly recognized by regulators and in the literature. See here, here and here. Legislation such as the 21st Century Cures Act, and “Right-To-Try” laws have put a premium on the prompter release of real-world data. There are many forms of studies based on real-world data; pragmatic and n of 1 trials are but two examples. Societies in principle are in a strong position to harness the power of real-world data. Their practitioner members, and their members’ patients, represent the most important sources of such data. Many Societies also include researchers who can help establish the scientific mechanism of action underlying treatment protocols and clinical outcomes.Impact and PublicationEvery Society wishes to increase its impact. It does so – or should do so – by disseminating the meaningful results of its activities to the right audiences, at the right time, and in a professional, compelling and sustained manner. Unfortunately, it is often difficult for all but the largest Societies to achieve even a fraction of their potential due to time, budget and personnel constraints, as well as inexperience with modern communications platforms.Financial SupportLike for-profit organizations, Societies depend on funding to support their mission and everyday operations. However, their funding typically relies on membership dues, donations and, often, industry support. (This last source of funding can be an important but sensitive one, and is discussed further in this paper.) A well-designed and executed program of real-world studies sponsorship and publication can substantially increase funding opportunities for a Society, as well as for its members.Key Elements Of A Real World StudySociety executives and members can be forgiven for worrying about the cost, complexity and length of clinical trials and studies. A double-blinded, randomized controlled trial (“RCT”) intended for Premarket Approval caneasily exceed $20 million and require five or more years before regulatoryapproval. As a result, only the most well-capitalized pharmaceutical and medical device companies can afford RCT’s. However, as mentioned above, all major healthcare constituencies have recognized the importance of more efficient and less costly study formats which advance medicine in a safe and efficacious manner. To achieve that efficiency without sacrificing their value, real-world studies will greatly benefit from the following components.Electronic Data CaptureA robust turnkey and flexible EDC platform will include capabilities such as:Compliance with HIPAA, GDPR and other legal and institutional patient privacy and personal data requirements.Compatibility with 21 CFR Part 11, CDISC, FHIR HL7 and other requirements for electronic data submissions, audit trails, consent signatures, etc.Ability to use standard outcomes measures, or to design and implement custom ones.Equally efficient performance with small as well as large “n” study sizes. Flexibility in study design, report generation, investigator customization. 24/7/365 availability of aggregated datasets on any device. Ability to assign various “roles and permissions” sets to specific personnel categories involved in the study.Raw data export. Experienced technical team available for ongoing support, including EMR and other integrations.Multi-center support, including multi-lingual implementations, efficient collaboration among investigators wherever located.Seamless input and integration of third-party data sources (laboratories, call centers, team members). Ability easily to generate a variety of reports and correlations, including from various studies sharing common questions.Investigator User ExperienceThe most powerful real-world data is found in the busy clinic. Thus, each Society member is a potential study Investigator. (And each Investigator conducting a study in the Society’s field is a potential Society member.)However, today’s busy clinicians have little time or incentive to collect real-world data in a structured and sustained manner. In addition to an EDC for the capabilities listed above, practitioners conducting a real-world study require the following.Minimum BurdenThe average practitioner wants to be evidence-based, to conduct studies relevant to her specific practice. However, the realities of modern healthcare delivery are such that she has little time to do so.ValueIn addition to the daily time demands of EMR, insurance and other administrative data entry, practitioners are deluged with surveys, registry participation and similar requests. They are constantly asked to collect and provide data for others, but understandably fail to see the value it provides to them.SupportExecuting a meaningful study requires support with design, patientenrollment, collaboration with co-investigators and team members, patientfollow-up, development of correlations, dealing with IRB’s or medical ethicscommittees, publication, obtaining industry honoraria or investigator fees, andother matters.Patient User ExperienceMuch of the expense, duration and premature terminations of traditional RCT’s can be ascribed to poor patient experience. A proper real-world study will educate, follow up with and otherwise engage with each patient in a personalized manner for the full duration of the study.Key Elements Of Real-World Study PublicationGeneralTraditionally, study methodology and results have been reported at conferences, in medical journals or included as part of regulatory submissions. Often, the study design, results and other elements are “embargoed“ for many months if not years prior to such publication. The 21st century publication environment has changed dramatically. There is a proliferation of medical societies, advocacy groups, foundations, digital journals, online medical education, journal clubs, clinical trial registries – all seeking and disseminating clinical/scientific content on a much more frequent basis than in the past.Social MediaThe majority of a Society’s members have social media accounts. Many of them use social media for medical education, and otherwise to keep current in their clinical/scientific field. Many also would like to position themselves as social media “influencers”. A well-designed, modern and sustained publication program enables Societies and their members to benefit in multiple ways from their real-world studies.Bespoke Academies and Journal ClubsDespite the power of social media channels – or indeed because of that power – many practitioners and healthcare institutions are wary of them. Much of the content posted by clinicians is often more “social” than medical. That content which purports to be medical or scientific is highly variable in its quality, relevance and verifiability. Confidentiality is always a concern. The sheer volume of postings makes it difficult to find clinically relevant information. It is possible, however, to have the best of both worlds. Modern technology allows Societies to host proprietary digital properties with the utility of social media channels, but with highly curated content and membership. Such “academies” or digital journal clubs ideally offer the following features:The clinical/scientific theme of each academy can be as broad or narrow as desired by the Society or its members. (Many societies have memberships with different clinical interests. The end-points of real-world studies being carried out by members will vary.)The Society establishes the academy membership criteria. It could be only those involved in a particular real-world study or type of study. It could be all members. It could be by invitation only.The Society or its delegates could curate and add to all content posted within the academy. It could offer CME or other educational content.The academy could offer product manufacturers a digital space to communicate study sponsorship opportunities, product discounts and other item of potential interest to members.The academy can provide all of the typical utility of large social media channels – multimedia presentations, private and public chats, threaded comments, etc.Industry SupportEthical collaboration between practitioners and industry is essential to advance in medicine. However, laws and ethical policies sharply circum-scribe the ways in which these two groups can interact.Real-world studies represent an important medium through which such interaction can properly and effectively occur. As is the case with traditional RCT’s, industry is able to support investigators who are conducting independent and properly designed studies through study fees, honoraria and product discounts. Societies can serve as natural intermediators of these industry-practitioner interactions, for the benefit of both groups and medicine at large.‍Developing A Successful Real-World ProgramA Society can cost-effectively and conservatively develop a successful program of real-world studies and corresponding publication through sequencing three stages: discovery, a pilot project and scaling.Discovery and DesignThis stage involves the Executive Director and board agreeing on which of the Society’s strategic objectives will most benefit from such a program. They will also establish the program’s key performance metrics (“KPI’s”). Finally, they will assess the budgetary and operational resources available to the Society to implement a program over time. It will often be useful to involve experienced vendors or other third parties in this discovery phase.A Pilot Project With “Early Wins”The discovery phase will identify a narrowly defined “pilot project”. This will reveal the operational capabilities of the Society, generate some early wins as defined by the chosen KPI’s, and set the stage for a broader implementation of the program. A sensible pilot project will comprise one or two relatively straightforwardstudy designs, a principal and one or two co-investigators, and a modest but curated publication program. Depending on the Society’s current website and other modalities used to communicate with members, these might also be improved in the context of the pilot project.ScalingIt is the rare Society which does not wish to grow its membership, to add more value to those members, and to make a bigger impact in its chosen mission. A properly executed real-world study program can achieve each of these objectives in a substantial, sustained and self-supporting manner. Each Society represents in theory a large amount of valuable real-world data generated daily among its members – if those data can be properly structured to support statistically-significant correlations. Building upon and then scaling a well-designed pilot project is the key to unlocking that value.The nature and timing of such scaling will vary according to a Society’s objectives and resources. However, several avenues can be pursued, whether singly or in parallel:Offer members a library of study designs and procedure protocols, and/or the support to develop new ones.Establish an IRB and/or medical ethics committee within the Society.Create and curate indication- and/or procedure-specific journal clubs.Establish a Society-branded platform for demonstrable, sustained and value-added collaboration among its members.Explore data-licensing, product incubation and similar Society revenue opportunities.Establish a specific program to develop the Society as an “influencer”, and/or to develop Society members as influencers.Establish a program of ethical intermediation between industry and the Society to support the improvement and development of devices, diagnostics, biologics and protocols.Develop and standardize real-world outcomes scoring systems in theSociety’s field(s).Create and curate various indication- or procedure-specific registries in the Society’s field.Utilize results from Society-sponsored real-world studies to develop productive engagement with relevant regulatory bodies.Support members in the context of legal/regulatory compliance, reimbursement, patient education and other barriers to the adoption of evidence-based procedures.Develop and disseminate educational and training modules.Expand the Society’s impact and affiliations by collaborating with other clinicians and organizations.Expand the Society’s geographic footprint.Support members in obtaining third-party research grants and/or industry study support.Exploit social media channels in a deeper manner to promote the work and brand of the Society and its members.About RegenMedRegenMed is a product agnostic firm partnering with healthcare constituencies around the world to develop financial, professional and communications value inherent in everyday clinical cases. The Company enables ethical intermediation between clinicians and industry, preserving the independence, while recognizing the business and professional realities, of each group. The Company’s platforms and processes are clinical grade, turnkey, scalable and highly cost-effective. They provide excellent user experiences for practitioners, scientists, study sponsors and patients.‍1 We refer to all such organizations as “Societies” in this paper.Copyright © 2022 Regenerative Medicine LLC

TABLE OF CONTENTS‍INTRODUCTION General Investigator Initiated Trials The Sponsor-InvestigatorKEY ELEMENTS OF AN IIT Application/Study Design Research Protocol Study Management PublicationREFERENCE MATERIALSIntroductionGeneralEthical collaboration between practitioners and industry is essential to advances in medicine. However, laws and institutional policies sharply circumscribe the ways in which these two groups can interact.Real-world studies represent an important medium through which such interaction can properly and effectively occur. As is the case with traditional RCT’s, industry can support investigators who are conducting independent and properly designed studies through study fees, honoraria and product discounts.RegenMed provides the clinical grade yet cost-effective tools and processes intermediating the funding and execution of real-world studies.Investigator Initiated TrialsAn Investigator Initiated Trial (“IIT”) is a common example of real-world study ethically accommodating the objectives of the independent provider, as well as a third party with related objectives which can provide financial support.An IIT is a study where the study investigator is also the study sponsor. In other words, the Investigator is not only responsible for execution of the study, but also for its design and oversight. In an IIT, the investigator is therefore called the Sponsor-Investigator.Many medical product manufacturers, foundations, governmental and non-governmental organizations have programs to help fund IIT’s. The Sponsor-InvestigatorThe Sponsor-Investigator may be an individual clinician, small clinic, medical society, or a hospital department.Although each category differs markedly in its capacity to design and manage an ITT, it is unlikely any will be able properly to do so without third-party support. (The only exception is a large academic/medical center, which has in place a Clinical Trial Unit or similar infrastructure.)Although real-world studies can be executed efficiently even by individual clinicians, the expectations of IIT funding sources usually demand a more robust study design and management infrastructure. Typical elements are described in the following section.Key Elements of an IITAn IIT usually involves the following important elements:Application/Study DesignAn IIT Sponsor-Investigator will apply to a suitable funding source. This process typically begins with a “concept note” which, if approved, will be fleshed out into a more thorough study design. Many IIT funding sources articulate their IIT criteria and evaluation processes on their websites. The concept note of course should be drafted in accordance with these guidelines.It is important to distinguish between two types of “audiences”: clinical/ scientific and business. Usually, both groups will be involved in evaluating an IIT application. Sometimes, however, the evaluation may be made solely by the clinical/scientific group. This factor obviously dictates the emphasis of certain elements of the application.Important components of an IIT application include:Study Rationale/Unmet Need. Why might the results of the study make a difference? For which patient population? Study rationale criteria will often include relevance to the funder’s products or therapeutic area of interest.Purpose of the Study. Examples include (i) test the safety/efficacy of two or more products; (ii) test a product in different population subsets; (iii) test a non-approved use for the product; (iv) combine the product with other technologies to improve its safety and/or efficacy; (v) develop a new product.Type of study. (Prospective randomized double blind controlled, in vitro, animal, observational, surveys, clinical, pragmatic, “n of 1”, other.)Summary of relevant prior literature.Identity and credentials of team members. (Principal and sub-investigators. Researchers. Laboratories. Statisticians. Medical writers. Support staff.)Experience of Team Members, especially with similar studies.Ability of Team Members to adhere to Good Clinical Practice. Research Protocol. (See below.)Approach to assessing clinical and statistical significance.Software and other technical support.Legal/Regulatory Compliance. (Including IRB/Medical Ethics Committee processes.)EndpointsData ownership and rights.Budget and Financial Resources.Research ProtocolThese are the parameters pursuant to which the study will be carried out. Key components include:Population size.Inclusionary and exclusionary criteria.Blinding or other approaches to remove bias.Specific comparators. (Dosages, products, patient cohorts, etc.)Outcomes measures, and timing of measurement reports.Type(s) of statistical analysis, including methods for determining statistical significance as well as clinical significance.)Reports (type, illustrative, frequency).Adverse Events Reporting.Planned regulatory submissions, and coordination with regulators.Study ManagementImportant items here include:Legal/Regulatory (Consent forms, data privacy, allocation of liability, data ownership and rights, anti-corruption, anti-bribery and anti-kickback laws.)Institutional Review Board/Medical Ethics Committee identification and processes.Quality control and assurance. (More complex in context of multi-center studies.)Allocation of financial/legal liabilities. (An IIT funding source will not accept legal liability arising from the study.)(E.g., Part 11 compliance if in the U.S., database management, source data review/verification, HIPAA/GDPR compliance, electronic Case Report Forms.)PublicationThis element includes medical writing, diagrams and tables, citations, journal selection. Some funding sources may look for publication in peer-reviewed print journals; others may be satisfied with publication through on-line journals or presentations of abstracts at conferences Reference materialsF.D.A.Important F.D.A. links relating to ITT’s include:Good Clinical Practice.Good Laboratory Practice. IIT IND’s.ICHThe International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)World Health OrganizationWHO Consent Form TemplatesCopyright © 2022 Regenerative Medicine LLC