New in Cureus: we outline how independent Medical Monitors safeguard patient safety, ensure regulatory alignment, and deliver unbiased, real-time oversight from protocol design through signal detection. Drawing on practical duties, escalation pathways, and cautionary case examples (e.g., first-in-human and CAR-T), we argue that medical monitoring is a strategic necessity—not just a compliance checkbox.
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. Click here to access this article.
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
Potential Errors and Corrections in Early Phase Drug Development
Clinical Trials and Practice / Open Journal
by Gerald L. Klein, MD and Roger Morgan, MD
ABSTRACT: Many foreign and small companies trying to enter the United States biopharmaceutical market make avoidable errors in their early clinical phase drug development and clinical trials. They need to first understand the risks that they must endure with patent law, regulatory hurdles, the complexity and duration of the necessary clinical trials, and the large cost of drug development, which often necessitates raising substantial capital from investors. If appropriate capital for these clinical studies must be raised, then the company must be able to clearly articulate a realistic expected return on investment to these individuals. So, they must also understand the market, its exclusivity, and the competition. This must all be put together in a sleek pitch deck. Early errors frequently begin with too few, inadequate, or poorly constructed patents. These and other risks and errors may be prevented by the use of an experienced product development team. Many of these errors could be avoided if companies used more experienced drug development professionals to assist them in selecting the optimum patent strategy, regulatory plan, budget, contract research organization (CRO), clinical investigators, and etc. It is hoped that this opinion piece will help make early clinical trials more effective and save time and money.
The Case for Digital Pill Use in Clinical Trials
Clinical Trials and Practice - Open Tournal (CTPOJ)
by Gerald L. Klein, MD / Published August 17, 2021
Abstract: Medication adherence in clinical trials is significantly overestimated through every phase of drug development. This can cause a reduction in statistical power, potentially resulting in incorrect conclusions regarding efficacy, safety, tolerability, and dose-response relationships, in addition to major cost overruns. Digital pill systems enable adherence measurement through an embedded ingestible sensor paired with an external receiver. An oral pharmaceutical product is over-encapsulated by a pharmaceutical-grade shell containing a biocompatible sensor. Upon exposure to gastrointestinal fluid, the shell dissolves and the sensor is activated. Medication ingestion data is transmitted via a digital signal. Clinicians and researchers use this data to track, in real time, when and if a medication was taken. These systems have demonstrated a 99.4% rate of accuracy, and have over 15-years of supporting experience and safety data. Spurred by the accelerated adoption of technology in healthcare and in everyday life, patients have become tech-savvy. They quickly adapt to these devices, and are able to use them safely and effectively. Digital pills can be implemented in most types of studies. In early-stage trials such as pharmacokinetic and pharmacodynamic studies, or dose-finding studies, accurate information on maximum-tolerated dose levels is essential and cannot be established unless study participants are highly adherent. In later-stage pivotal trials, effective medication adherence tracking can strengthen the dataset and confidence in the study results. Significant nonadherence may generate results that do not meet statistical or clinical significance for the critical endpoints, resulting in at worst, a failed trial, or at best, the need to enroll additional patients at substantial additional cost. Most clinical trials fail to achieve statistical significance, and poor medication adherence is often an important contributor. A digital pill system can ensure the quality and integrity of adherence data, increase confidence in the overall study data, and improve clinical trial efficiency.
The Importance of Teaching and Fostering Clinical Research in Primary Health care
Gerald L. Klein, MD and Mark A. Brown, PhD
It is important for primary health care (PHC) teaching institutions and hospitals to create an atmosphere fostering clinical investigation for all health care practitioners (HCP). This involves not just clinical trials, but observations, examinations, and investigations are a critical part of the education of any health science students. This is the basis of science. Without knowing how to apply a scientific thought process and methodology to a clinical situation, it will prevent one from reaching their optimum abilities. Continue reading…
Recognizing High Risk Traumatic Wounds and Preventing Infections and Complications
Review Article / Emergency Medicine and Trauma Care Journal
by Gerry L. Klein and Peter C. Johnson, MedSurgPI, LLC
Abstract: Simple traumatic wounds are a frequent event that can usually be managed without sequelae, unless the wound is of high risk. High risk wounds have a greater propensity to become infected and complicated. Such wounds are characterized by a specific type of wound (i.e. jagged), location of the wound (i.e. lower leg); and patient’s underlying medical condition (i.e: diabetes).If these wounds become infected, they have a negative impact on morbidity, mortality, quality of life, and costs. The take-away should be a wake-up call to physicians specifically and healthcare professionals more broadly that a much more aggressive and effective treatment regimen to prevent wounds from becoming infected is required. Such a regimen should likely include a comprehensive understanding of wound types, the degrees of microbial contamination, and novel ways to prevent infections through wound debridement and irrigation.
Potential Psychological Benefits of a Regenerative Graft for Nipple Reconstruction
Link to this article appearing in the Journal of Aesthetic & Reconstructive Surgery ISSN 2472-1905
by Gerald L. Klein and Peter C. Johnson
Vol. 7 No.2:17
The Medical Monitor is one of the key players in keeping subjects safe in clinical trials. This article helps explore the role of the Medical Monitor
Journal of Clinical Research Best Practices
Medical Monitoring of Clinical Research Studies
By Gerald L. Klein, Peter C. Johnson, and Roger Morgan
Introduction
The Medical monitor’s (MM’s) primary responsibilities in a clinical trial are to oversee the safety and protection of the research subjects and to provide independent oversight to help ensure the scientific reliability, clinical integrity, and quality of the clinical trial. Although the Food and Drug Administration (FDA) has not spelled out the necessity and role of the medical monitor, MM participation is important for compliance with Good Clinical Practice (GCP) guidelines and MMs almost always play a significant role in multicenter clinical trials.1 The best practices for MMs described in this article can also help study sponsors comply with International Council for Harmonization (ICH) guidelines, Technical Requirements for Pharmaceuticals for Human Use, the United States Code of Federal Regulations (CFR), and FDA regulations and guidances.2
The MM collaborates with the project manager, safety, data management, biostatistics and quality departments, principal and sub-investigators, the site coordinator, the Data & Safety Monitoring Board (DSMB), and any other group that directly or indirectly protects the safety of study participants.
Communications
Prompt and transparent communication is an essential element underlying safety in all human clinical studies.3 The MM should be the point person for medical, scientific and safety questions posed by clinical investigators, their site personnel, and staff at the study sponsor and contract research organization (CRO) involved in the trial. The MM’s contact information should be readily available to investigators and their staff. The MM should be available essentially 24/7 with a back-up MM when the primary MM is not available.
MMs often address significant questions on the following topics:
Documentation
Protocol and investigator brochure
Inclusion criteria
Exclusion criteria
Safety
Patient concerns
Adverse events (AEs)
Serious adverse events (SAEs)
Suspected Unexpected Serious Adverse Reactions (SUSAR)
Pregnancy
Medication errors
Concomitant medications
Laboratory values
Protocol deviations and waivers
Informed consent
Unblinding
Early termination or withdraw of a subject
Protocol-stopping rules
Other topics related to clinical research
DSMB and pharmacovigilance team questions with respect to adverse events
MMs document all relevant communications in the appropriate database. When there are multiple significant errors at an investigational site, the MM may be called into an investigation to determine the cause and whether corrective actions or new training is required.4 In rare cases, the MM, together with the project manager and quality assurance, assesses whether a site must be removed from a study due to safety issues, poor data quality, or violation of GCPs.
Maintain a Question and Answer (Q & A) log. Create anticipated Q & A’s prior to the study and then maintain a log to help provide quick, accurate and consistent answers to repeat questions. The clinical sites should be able to search the log for themselves.
Protocol and Investigator’s Brochure (IB)
The MM may write all or just parts of the protocol and investigator’s brochure. At minimum, the MM should review and approve these documents.5 Since the MM is expert on the protocol and the specific therapeutic indication being studied, the best practice is to involve the MM in training sponsor and/or CRO staff as well as the investigators and their personnel on the protocol and IB.
The MM should ensure that protocol endpoints make medical and scientific sense and are safely achievable. The clinical trial’s expected benefits must outweigh its risks.6 Inclusion and exclusion (I/E) criteria must align with this goal. I/E criteria must prevent the enrollment of subjects who are unlikely to obtain a positive therapeutic clinical endpoint or would be put at unacceptable risk in the study. For instance, a patient with a childhood history of bronchial asthma may not be appropriate to enroll in a clinical trial testing a medication that has properties of beta blockers, which can exacerbate symptoms of asthma.
The MM reviews permitted and prohibited concomitant medications (including over-the- counter drugs, herbs and dietary supplements) for possible interactions with the molecule being studied. The MM also ensures that the protocol does not specify types or numbers of procedures that would pose unnecessary risks for study subjects. The MM may recommend ways mitigate such risks.
The MM ensures that the IB clearly describes non-clinical studies and any adverse events of special interest (AESIs). An example of an AESI would be an abnormal electrocardiogram when all cardiac adverse events are of special interest to the regulatory authorities. All current knowledge about the drug, device or biologic must be clearly spelled out in the IB, not hidden in esoteric study reports.7 It is unfortunate that many investigators do not read the IB in detail. Therefore, the MM should try to convey the important aspects of the pharmacokinetics, pharmacodynamics, metabolism, drug interactions and expected adverse events associated with the study therapy to the investigator and the appropriate staff at the clinical site.
Review and Discussion
The MM reviews each subject’s eligibility data, screening physical examination results, medical history, concomitant medications, and laboratory tests before approving their entry into the study. If the investigator is attempting to enroll unqualified subjects, training may be required. The MM thoroughly discusses non-trivial protocol deviations (PDs), which should be rare, with the investigator, and only the most minor ones should be approved. A major PD may affect subject safety, data integrity, or the integrity of the entire study.8 A dosing error by which a subject received twice the dose of the investigational drug during one dosing interval would be a major deviation. A subject’s labs being a few hours out of the visit window would be a trivial deviation.
If time permits, the investigator should consult with the MM before unblinding a subject so the MM can assess and document the decision. The investigator should also discuss with the MM any early unusual termination or withdrawal of a subject from the study.
Data & Safety Monitoring Board (DSMB) or Data Safety Committee (DSC)
If there is a DSMB or DSC, the MM should participate in the blinded section of any meetings to help answer any questions related to adverse events and other potential safety and enrollment issues.9
Adverse Events
One of the most significant MM responsibilities is to work with the investigator to determine the most accurate causality of Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). SUSAR expectedness determinations should be based on the Reference Safety Information section of the IB, or, in studies of marketed drugs, the applicable package insert. Many investigators do not have a good understanding of causality assessment, and poorly defined regulatory terms and examples do not help the situation.10 Following the CIOMS report recommending a binary approach of “related” or “not related” in determining causality simplifies the complex and confusing terminology.11 There is no accepted standard for assigning causality to an SAE, but employing the following Bradford Hill Criteria is an excellent way to determine causality:12,13
1. Strength of Association. A strong association between a treatment and an adverse event indicates causation. For example, each time the drug was given to a subject, it caused vomiting within a predictable time period.
2. Consistency. Established adverse event attributions or previous determinations in similar situations indicate causation.
3. Specificity. An established mechanism of action connecting the treatment and the adverse event indicates causation.
4. Temporality. Exposure to the product must occur before the disease or event, and not after a latency period. However, temporality is not sufficient to establish causation.
5. Biological Gradient. A dose response effect is a strong argument for causation.
6. Plausibility. The causal relationship is biologically plausible.
7. Coherence. The known facts fit the natural history and biology of the disease.
8. Experiment. Epidemiologic studies indicate causation.
9. Analogy. A similar agent causes the same type of AE.
Safety and Pharmacovigilance Reporting
The MM develops or reviews a brief narrative describing each SAE and SUSAR, which should include the following elements:14
Clinical event (postmortem findings if applicable)
Course of event, with temporal relationship to experimental product
Outcome of the event with the nature, severity and intensity
Relationship of the subject’s medical history and concomitant medications to the event
Significant test results or laboratory findings
Therapeutic treatment for the event
Action, if any, taken with regard to experimental product
Causality assessment by investigator and sponsor
Review and analysis of similar events with the experimental product
The MM works with the safety/pharmacovigilance team to code adverse events based on the latest edition of the Medical Dictionary for Pharmaceuticals for Human Use (MedDRA).15 The MM also reviews the coding of concomitant medications using the World Health Organization’s (WHO’s) latest edition of pharmaceutical names (when it is used in the clinical trial). The MM reviews all SAE and SUSAR reports for accuracy and completeness and is the point person to discuss such events with the sites.
Conclusion
Since there are no regulatory guidelines on MM duties, this article has discussed those that are most significant. With the possible exception of the lead principal investigator, the MM should be the person most expert on the medical and scientific aspects of a multicenter study. The principal investigator at each site and the MM, along with DSMB and the institutional review board (IRB), share primary responsibility for the health and safety of study subjects and ensure the validity of the study. They must establish working relationships to ensure that subjects are protected and study data, including SAE and SUSAR reports, are accurate. This profound responsibility means that the MM for a study must have the requisite expertise, personality, dedication and ability to use the processes outlined in this article.
References
Vijayananthan A. et al., “The importance of Good Clinical Practice guidelines and its role in clinical trials.” Biomed Imaging and Intervention Journal, 2008; 1: e5.
E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1) Guidance for Industry, FDA, March 2018.
“FDA Guidance for clinical investigators, sponsors, and IRBS: adverse event reports to IRBs-Improving human subject protection,” FDA, Jan 2009.
Knepper D. et al., ‘Detecting data quality issues in clinical trials: current practices and recommendations,’ Therapeutic Innovation 7 Regulatory Science, 2016; 50:15- 21.
World Health Organization, Guide for writing a Research Protocol for research involving human participation; 2014.
Emanuel E. et al., “What makes clinical research ethical?” JAMA, 2000; 283:2701- 2711.
Fiebig D. et al., “The investigator’s brochure: A multidisciplinary document,” Medical Writing, 2014; 23:96-100
Attachment C: Recommendation on Protocol Deviations, Office of Human Research Protection, HHS.gov.
Calis A. et al., “Understanding the functions and operations of data monitoring committees: survey and focus group findings,” Clinical Trials, 2017:59-66.
Morse M. et al., “Monitoring and ensuring safety during clinical trials,” JAMA. 2001; 285:1201-1205
“Management of Safety Information for clinical trials: Report of CIOMS VI,” 2005.
Federak, K. et al., “Applying the Bradford Hill criteria in 21st century data integration has changed causal inference in molecular epidemiology.,” Emerging Themes in Epidemiology, 2015; 12:14-23
Howick, J., “The evolution of evidence hierarchy: What can Bradford Hill’s guidelines of causation contribute?” Journal for the Royal Society of Medicine, 2009; 102; 2009:186-194
Modified from Ledade, S. et al., “Narrative writing: Effective ways and best practices. Perspectives in Clinical Research,” Perspectives in Clinical Research, 2017; 8:58-62
Brown. E. G., “Using MedDRA: implications for risk management,” Drug Safety. 2004;27(8):591-602
Authors
Gerald L. Klein, MD, is a principal at MedSurgPI. Contact him at 1.919.930.9180 or gklein@medsurgpi.com.
Peter C. Johnson, MD, is president and CEO of Cell X Technologies.
Roger Morgan, MD, is vice president of medical affairs at MedSurgPI, LLC.
Orthotopic grafting of decellularized human nipple: Setting the stage and putative mechanism of healing
A complex skin structure (such as a nipple) can be successfully decellularized under conditions that prevent extracellular matrix crosslinking or undue matrix degradation [1]. This treatment removes cellular antigens, thus mitigating immunorejection concerns and enabling allogeneic transplantation for nipple reconstruction after mastectomy. Non-human primate studies have shown that host-mediated re-vascularization and re-epithelization of the decellularized nipples occurs within six weeks and nipple projection is maintained over the same timeframe [1]. The mechanisms by which a decellularized graft located on the surface of the body heals are incompletely understood, but are likely to follow a similar path to decellularized allografts that are implanted within the body, with some modifications. The following is a description of probable temporal events leading to healing under this circumstance.
Orthotopic Grafting of Decellularized Human Nipple: Setting the Stage and Putative Mechanism of Healing
A complex skin structure (such as a nipple) can be successfully decellularized under conditions that prevent extracellular matrix crosslinking or undue matrix degradation (1). This treatment removes cellular antigens, thus mitigating immunorejection concerns and enabling allogeneic transplantation for nipple reconstruction after mastectomy. Non-human primate studies have shown that host-mediated re-vascularization and re-epithelization of the decellularized nipples occurs within six weeks and nipple projection is maintained over the same timeframe (1). The mechanisms by which a decellularized graft located on the surface of the body heals are incompletely understood, but are likely to follow a similar path to decellularized allografts that are implanted within the body, with some modifications. The following is a description of probable temporal events leading to healing under this circumstance.
Nipple Reconstruction
At some relevant timepoint after mastectomy and breast reconstruction, a woman will elect to have nipple reconstruction. After a review of all possible techniques, including tattooing, local flap rotation, autologous full thickness skin grafting from labia, and allogeneic or xenogeneic implants, it becomes clear that all are flawed in some way that prevents the accurate reproduction of a nipple’s 3D structure, pliancy, and color. A proposed new solution is to take advantage of the extensive evidence that a decellularized allogeneic or xenogeneic graft, an acellular extracellular matrix scaffold, can serve as the nidus for a healing event when implanted in a human (2). Although such scaffolds have long been derived from dermis, small intestinal submucosa, bladder and other organs, recent work has shown that deceased human donor nipples can be successfully decellularized and, when implanted on the surface of the body in a non-human primate model, exhibit complete healing within six weeks. Planned clinical studies will bring this technology to humans, where longed for accurate and complete nipple restoration can be evaluated.
When a woman elects nipple reconstruction with a decellularized human nipple, it is anticipated the following sequence of surgical events will occur. First, she will undergo presurgical evaluation to ensure that her reconstructed breast(s) have healed properly and bear no residual inflammation. Prior to surgery, she will be consulted regarding the relative size and placement of her new nipple(s). Markings will be made to denote these dimensions and positions and standard preparations for surgery will be made. Whether under local or general anesthesia, the breast skin will be prepped with an antiseptic, and prophylactic antibiotics will likely be administered. The surgeon will then remove the epithelial layer of the skin in the marked nipple location(s) on the breast(s), exposing the vascularized dermis, below. Punctate bleeding will likely require control by pressure or electrocautery to create a blood-free recipient field. The decellularized nipple(s) and surrounding areola will then be cut to the desired shape and sewn onto the breast(s) with either interrupted or continuous sutures. Wound dressings will be placed to encompass the nipple(s) but not compress the projecting nipple, itself. It is clear from the outset that this form of decellularized scaffold placement on the human body differs from other scaffold implantations in that it faces a vascularized interface only on one side. So, what is the likely pathway to its healing response?
Healing of Intact and Acellular Grafts
There will likely be some similarities to the healing responses of other living and non-living materials that are placed on a de-epithelialized skin base. Comparing this procedure to an autologous skin graft, it is expected that similar inflammatory steps would occur, but a salient difference is that the intact autologous graft contains micro vessels that would attach quickly to host tissue in a process known as inosculation, bringing nearly immediate life (within days) back to the skin that has been harvested (3). While not obviating interface inflammation and its effects (such as hypertrophic scarring in some cases), re-vascularization of autologous tissue such as a skin graft has the net effect of reducing the period of inflammation, since stress cytokines are no longer being sent from the tissue. In the case of an intact allogeneic or xenogeneic skin graft that is applied to de-epithelialized skin, which is common in burn treatment, inosculation will occur in a similar manner, leading to an apparent healing response that is soon truncated as an immune response develops and the graft is sloughed (4). Although this course of treatment does not lead to complete wound healing, the benefits of this application are twofold. First, the skin provides an essential moisture and infection barrier while the patient is stabilized for subsequent autografting. Second, the highly inflammatory immune response signals the underlying tissue to form a rich vascular network known as granulation tissue that serves as an optimal substrate for subsequent autografting (4).
There are many commercial products (Alloderm® from Allergan being one) that are composed of extracellular matrix proteins such as collagen and elastin (and in some cases fibroblasts and epithelium – Apligraf® from Organogenesis) that mimic the matrix component of skin grafts, whether autografts, allografts, or xenografts. By providing a milieu within which a mild immune response can operate, they often lead to the development of granulation tissue, even as they are eventually resorbed, leading to an improvement in subsequent autologous skin grafting. In addition, they have been used in nipple reconstruction to achieve some or all of the desirable features mentioned earlier, though with unpredictable and often disappointing results.
Effect of Decellularization on Healing
The entry into clinical care of the decellularized nipple allograft is therefore not without precedent, but some steps will be required to ensure that healing of such structures can proceed optimally. This begins with the preparation of the tissue itself. It has become clear in work with other decellularized tissues that the processes of decellularization (including in some cases, terminal sterilization) vary widely and can have substantial impact on the healing properties of matrices (5). The decellularization process must be harsh enough to remove cellular antigens, but mild enough to retain the native extracellular matrix structure, which is critical for providing the proper signaling and support structure to ingrowing cells. If decellularization is incomplete such that cellular antigens remain in immunogenic quantities, undesirable inflammation will be exacerbated, which can slow or prevent healing of the graft. But, if the extracellular matrix is damaged or crosslinked (an outcome that is particularly associated with gamma irradiation sterilization) by excessive chemical or mechanical preparation, the graft will also be less serviceable to the healing process.
Badylak points out that all scaffolds are eventually replaced by host tissue, but that depending upon modes of preparation, this can follow one of two pathways (5). When a scaffold is decellularized to retain its native structure, contains no cellular antigens and is not from an overly aged source, it undergoes a controlled, scar-free replacement process known as “Constructive Remodeling.” Conversely, if the decellularization is incomplete, too harsh, or terminal sterilization creates unnatural crosslinking, a highly inflammatory process is instituted, leading to scar tissue formation. This is known as “Deconstructive Remodeling.” Therefore, for a decellularized nipple allograft to have the potential to be replaced in situ and retain its 3D structure, it will be critical that substantial attention be paid to its preparation process after recovery.
Healing of an Externally Placed Acellular Nipple Graft
Now, assuming that such an optimal preparation has been achieved, what are the likely biological responses to a decellularized nipple allograft from the moment of attachment to a woman’s breast? Initially, despite the achievement of gross hemostasis at the interface during surgery, a thin veneer of fibrin is likely to be present beneath the graft. Platelets, attached to the fibrin through their GPIIB-IIIa receptors, will have been stimulated to release an array of cytokines that will recruit neutrophils and macrophages to the scene. As the latter cells enter the area and probe the underlying surface of the graft, they will begin work in three directions. First, they will sense the need to scavenge the fibrin and platelets and will release cathepsins and other lytic peptides. Second, the macrophages will predominantly be of the M1 or pro-inflammatory types and will begin releasing immunomodulating agents to recruit additional macrophages, neutrophils and eventually, fibroblasts. Third, the macrophages will also sense the low oxygen tension at the tissue interface and emit vasculogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (5).
As capillaries begin to proliferate at the undersurface of the graft, and as debris is cleared away, these vessels will begin to probe the graft itself, seeking to attach themselves to the graft by binding to preserved extracellular matrix anchors via integrins on their cellular membranes. Blood flow will eventually contribute endothelial progenitor cells to the site, leading to vascular ingrowth along the oxygen gradient that is present. Vascular pericytes that bear mesenchymal stem cell properties will then, in conjunction with macrophages, govern the early population of the graft and augment the recruitment of fibroblasts. In addition, for a breast mound that remains sensate after reconstruction, there is the potential for axons to enter the graft in parallel with the blood vessels. If the tissue preparation has elicited a very minor inflammatory response at this stage, a macrophage conversion will occur from the pro-inflammatory M1 state to the anti-inflammatory M2 state. The latter macrophages will then begin to release substances such as growth factors that elicit a Th2 (T helper cell) response, which “manages” the rate and spatial deposition of fibroblasts and also controls their production of extracellular matrix proteins, such as collagen, fibronectin, vitronectin and elastin, in amounts and orientations that respect the configuration of the decellularized matrix that they are slowly remodeling through replacement. This process will occur until an emerging vascularized border is present at the edge of the implant.
At this stage, epithelial cells at the border of the graft will have a toehold on the vascularized matrix and can begin to divide and migrate toward the center of the nipple as a function of the accretive vascularization of the implant. The migrating epithelial cells will likely include melanocytes when present. While fibroblast proliferation and volumetric remodeling of the graft itself continues to be governed by M2 macrophages and pericytes, the epithelium will continue to cover the nipple until this is complete. At that point, oxygen tension within the remodeled and now re-vascularized (and potentially re-innervated) nipple becomes normal and macrophages substantially recede, except for a population that will govern final remodeling of the nipple structure, an event that will be augmented by their mechanotransduction receptors as they are exposed to normal orthotopic breast stresses (6). When remodeling has achieved an “equal and opposite” relationship to those breast forces, remodeling will stop and potentially, some sensation will recover. Depending upon the degree of melanocyte participation in the epithelial migration (or, depending upon conversion of epithelial cells to melanocytes), the nipple will exhibit a hue that is reflective of their participation. In some cases, nipple tattooing may be performed to augment hue after remodeling has been complete. If re-innervation does occur, it is likely that the quality of sensation will continue to mature for some time after complete remodeling.
This constitutes a putative mechanism for the engraftment of a decellularized nipple allograft that is likely to follow the principles of engraftment of other foreign, decellularized tissues, albeit in the context of a unique placement on the surface of the human body.
References
1. Graham, D, et al, Abstract P6-14-13: New Approach To Nipple Reconstruction: In Vivo Evaluation Of Acellular Nipple-Areolar Complex Grafts, Cancer Res February 15 2020 (80) (4 Supplement) P6-14-13; DOI:10.1158/1538-7445.SABCS19-P6-14-1
2. Badylak, SF, The Extracellular Matrix as a Biologic Scaffold Material, Biomaterials, 28:25, 3587-3593, 2007.
3. Laschke, MW, et al, Inosculation: connecting the life-sustaining pipelines, Tissue Engineering, Part B: Reviews, 15:4, 455-465, 2009.
4. Yamamoto, T, Skin xenotransplantation: Historical review and clinical potential, Burns, 44:7, 1738-1749, 2018.
5. Badylak, SF,Decellularized Allogeneic and Xenogeneic Tissue as a Bioscaffold for Regenerative Medicine: Factors that Influence the Host Response, Annals of Biomedical Engineering, 42:7, 1517-1527, 2014.
6. Chamberlain, MD, et al, In Vivo Remodelling of Vascularizing Engineered Tissues, Annals of Biomedical Engineering, 43 1189–1200, 2015.
A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease
Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 20-26
Michael Grundmana, Roger Morgan, Jason D. Lickliter, Lon S. Schneider, Steven DeKosky, Nicholas J. Izzo, Robert Guttendorf, Michelle Higgin, Julie Pribyl, Kelsie Mozzoni, Hank Safferstein, Susan M. Catalanog
We would like to congratulate Roger Morgan, MD; for being a co-author on this new publication
Roger is the VP of Medical Affairs at MedSurgPI LLC. MedSurgPI is a medical consulting group specializing in strategy for product development, medical affairs, medical monitoring, and fractional medical officer services. For additional information about MedSurgPI services contact gklein@medsurgpi.com
Abstract:
Background: Elayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Ab oligomers to neurons. By stopping a key initiating event in Alzheimer’s disease, this first-in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer’s disease.
Methods: A phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (,65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65-75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment.
Results: Treatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment.
Conclusions: CT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer’s disease. 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license: http://creativecommons.org/licenses/by-nc-nd/ 4.0/
The Case for Vendor Oversight for Small Sponsors →
The New C-Suite →
Peter C. Johnson, MD*, Matthew J. Pattison**, MSc, Jan Creidenberg***, Gerald L. Klein, MD*
* MedSurgPI, LLC, Raleigh, NC
** Anatomy HCD, Ltd, Brighton, UK
*** Strand Hill Resources, LLC, Kansas City, MO
