Proceedings of the Eighth Annual Santa Fe Bone Symposium, August 3–4, 2007

The Eighth Annual Santa Fe Bone Symposium convened August 3–4, 2007, in Santa Fe, New Mexico, USA, immediately preceded by the Research Symposium in Metabolic Bone Disease and Osteoporosis Update for Endocrine Fellows, and followed by the International Society for Clinical Densitometry (ISCD) Bone Densitometry Course. The symposium faculty consists of internationally recognized experts in osteoporosis and metabolic bone disease who presented state-of-the-art research data and late-breaking developments in the fields of osteoporosis, metabolic bone disease, and assessment of skeletal health. The presentations and numerous interactive discussions that followed focused on applying what is known from clinical trials, knowledge of bone pathophysiology, and the mechanisms of action of therapeutic interventions, to making real-world patient management decisions. Topics included an update on reimbursement issues for bone density testing in the United States, a report on the 2007 ISCD Pediatric and Adult Position Development Conferences, present and future therapeutic concepts, new paradigms for fracture risk assessment and intervention thresholds, evaluation for secondary causes of osteoporosis, nonvertebral fracture risk reduction-medical evidence and clinical practice, epidemiological insights into the prevention of osteoporotic fractures, osteonecrosis of the jaw facts and fictions, and osteomalacia. Presented here are short essays based on the key clinical presentations of the 2007 Santa Fe Bone Symposium.     

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient‐centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient‐centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature‐based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty‐two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.     

2008 Santa Fe Bone Symposium: Update on Osteoporosis

The Ninth Annual Santa Fe Bone Symposium was held on August 1–2, 2008, in Santa Fe, New Mexico, USA. The symposium faculty presented the current best evidence on selected topics of clinical relevance in the fields of osteoporosis, metabolic bone disease, and assessment of skeletal health. The educational venues were in the form of didactic presentations, panel discussions, challenging cases, and numerous interactive discussions. Knowledge of basic science and clinical trials was applied to real-world patient scenarios that were discussed by faculty experts and clinician participants. Topics included an update on the rationale and development of new agents for the treatment of osteoporosis, the use of bone turnover markers in clinical practice, hospital-based pathways for the management of hip fracture patients, injectable bisphosphonates for the treatment of osteoporosis, combination therapy with anabolic and antiresorptive agents, and assessment of skeletal health with devices other than central dual-energy X-ray absorptiometry. This is a collection of scientific essays based on presentations and discussions at the 2008 Santa Fe Bone Symposium.     

Designing implant trials in 2010: a recipe for success

In a recent evaluation of 1017 device trials listed on a clinical trials register (www.clinicaltrials.gov) between 2005 and 2009, only 84 (8.2%) represented orthopedic device evaluations. These device trials notably had few numbers of patients and few centers and represented approximately 7% of drug trials on the same registry. The relatively small proportion of device trials in orthopedics may represent a lack of interest; however, given the device focus of the field, the answer is more likely to be a lack of necessity?historically, regulatory pathways to implant approvals have not required clinical trials and have largely focused on preclinical and early case-series evaluations. The changing landscape of the regulatory environment necessitates a renewed interest in high-quality clinical research. Specifically, randomized trials of implants in orthopedics are poised to become major designs in the future. Given the general uncertainty in knowledge of regulatory pathways among researchers and health care providers, the current symposium was developed to clarify the design and execution of device trials in a changing regulatory environment. We focus our papers on the Food and Drug Administration (FDA) device classes and regulatory pathways (510K), design challenges in regulatory trials, site audits, and standard operating procedures. In over a decade of conducting trials, we have also realized the critical importance of data-management systems and contract research organizations. Not every clinician, device manufacturer, or researcher planning a randomized trial will have the infrastructure or experience to meet the strict regulatory compliance guidelines for the proper conduct of the trial. Understanding what to look for in a contract research organization is extremely helpful, especially in an environment of limited funding and high expectations. We hope that the current symposium will provide a broad context to clinical trials of orthopedic devices. Despite the challenges of the current regulatory arena, there has never been a more exciting time to conduct research in our field.     

Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease,Biochemical Relapse,and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022

BackgroundInnovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management.ObjectiveTo present consensus voting results for select questions from APCCC 2022.Design, setting, and participantsBefore the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members (“panellists”) who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1–3.Outcome measurements and statistical analysisConsensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement.Results and limitationsThe voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis.ConclusionsThese voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.     

Evidence supporting wound care end points relevant to clinical practice and patients’ lives. Part 2. Literature survey

Patients with wounds bear significant clinical, personal, and economic burdens yet complete wound healing is the only United States Food and Drug Administration (FDA) recognized primary clinical trial end point. The overall goal of this project is to work with FDA to expand the list of acceptable primary end points, recognizing that new and innovative treatments, devices, and drugs may not have complete healing as the focus. Part 1 of the project surveyed 628 wound care experts who identified and content‐validated 15 end points most relevant to clinical practice and benefitting patients’ lives as primary outcomes in clinical trials. Part 2 is focused on critical appraisal of the evidence in the wound care literature supporting FDA criteria to qualify these 15 end points as primary end points in clinical trials. Further research involved systematic review of the literature regarding the most promising end points. Forty volunteer, interdisciplinary, wound healing experts in fields related to the end points compiled evidence from systematic MEDLINE searches and society databases supporting the FDA criteria of reliability, clinical construct validity, capacity to detect concurrent or longitudinal change, and responder analysis. The search revealed 485 references involving over 462,000 subjects supporting FDA‐required parameters for all 15 end points More than 50 references supported FDA‐required parameters qualifying the following outcomes for use in clinical trials supporting interventions for FDA clearance: Pain reduction, Physical function and ambulation, Infection reduction, Time to heal, and Percent wound area reduction in 4–8 weeks. Among these, only Time to heal is currently recognized by the FDA as a primary wound outcome in clinical trials. These results suggest that wound science is already serving patients and professionals by improving these content‐validated outcomes that merit regulatory consideration.     

Trials and tribulations: the professional development of surgical trialists

BackgroundRegulatory and professional bodies issue an ever-increasing number of guidance documents on the ethics and methods of clinical trials, but the quality of clinical trials of invasive therapeutic procedures continues to be a concern. We interviewed aspiring and accomplished surgical trialists to understand how they use guidance documents and other resources in their work.MethodsWe performed a qualitative research study involving semistructured interviews of a diverse sample of 15 surgical trialists.ResultsProfessional development as a surgical trialist was haphazard, inefficient, and marked by avoidable mistakes. Four types of resources played constructive roles: formal education; written materials on clinical trials; experience with actual trials; and interpersonal interactions with peers, experts, collaborators, and mentors. Recommendations for improvement centered on education, mentoring, networking, participating in trials, and facilitation by department chairs.ConclusionsThe haphazard and unstructured nature of the current system is adding unnecessarily to the numerous challenges faced by surgical trialists.     

A new approach to clinical research: Integrating clinical care,quality reporting,and research using a wound care network‐based learning healthcare system

The disparity between ideal evidence from randomized controlled trials and real‐world evidence in medical research has prompted the United States Food and Drug Administration to consider the use of real‐world data to better understand safety and effectiveness of new devices for a broader patient population and to prioritize real‐world data in regulatory decision making. As the healthcare system transitions from volume‐ to value‐based care, there is a growing need to harness the power of real‐world data to change the paradigm for wound care clinical research and enable more generalizable clinical trials. This paper describes the implementation of a network‐based learning healthcare system by a for‐profit consortium of wound care clinics that integrates wound care management, quality improvement, and comparative effectiveness research, by harnessing structured real‐world data within a purpose‐built electronic health record at the point of care. Centers participating in the consortium submit their clinical data and quality measures to a qualified clinical data registry for wound care, enabling benchmarking of their data across this national network. The common definitional framework of the purpose‐built electronic health record and the 21 wound‐specific quality measures help to standardize the potential sources of bias in real‐world data, making the consortium data useful for comparative effectiveness research. This consortium can transform wound care clinical research and raise the standards of care, while helping physicians achieve success with the Merit‐Based Incentive Payment System.     

Global perspective of kidney diseases: Challenges and changes

Chronic kidney disease (CKD) is a major public health issue worldwide. Although strategies for prevention, early detection and treatment to reduce the progression of CKD should remain continuous endeavours, public funding for kidney replacement therapy is urgently needed in low-income countries (LICs) and lower-middle-income countries (LMICs). A multisectoral approach is needed to tackle the global burden of kidney disease. Getting a new drug, from first testing to final approval by a regulatory agency and ultimately to market, is a long, costly and risky process. While clinical trials and research have delivered new therapies and devices to patients with kidney disease during the last decade, there remains a significant residual risk for patients with CKD. Therefore, developing new drugs for better treatment and patient care is essential. For this purpose, the ISN held a consensus meeting entitled ‘TRANSFORM; TRAnslational Nephrology Science FOR new Medications’, which connected experts in the global kidney community and provided guidance on optimal management of translational animal studies for the development of new drugs to treat kidney diseases.     

Computerised assessment of maximum urinary flow: an efficient,consistent and valid approach

OBJECTIVES: To evaluate the relative accuracy of a computerised method to quantitatively assess maximum urinary flow. METHODS: A total of 1147 uroflows were evaluated by the computerised method and by three experts from different European countries. The sample consisted of uroflows from the respective visits by a 20% sample of randomly chosen patients (n = 223) with lower urinary tract symptoms with participation in two clinical trials in which the efficacy and safety of Permixon was evaluated. The proportions of automated maximum flow values included in the 10% extended range of experts (and their 95% confidence intervals) were assessed, as well as the concordance coefficients between experts and the computerised method and the paired Student's t-test for the average differences between experts and computer. RESULTS: The rate of agreement between experts and computer varied between about 95 and 100% over factor levels for visit, type of machine and country. Concordance coefficients indicated good agreement between experts and the automated method. When looking at average differences between experts and the computer, the smallest differences were observed between experts 2, 3 and the computer (differences not statistically significant). Statistically significant average differences were observed between expert 1 and the other experts as well as between expert 1 and the computer. CONCLUSIONS: The computerised assessment decreases the fraction of variability of maximum urinary flow caused by artifacts as well as intra- and inter-expert variation. The computerised assessment of maximum urinary flow is an efficient, consistent and valid approach to quantitatively assess maximum urinary flow in clinical trials.     

Innovation in organ transplantation: A meeting report

This workshop targeted opportunities to stimulate transformative innovation in organ transplantation. Participants reached consensus regarding the following: (1) Mechanisms are needed to improve the coordination of policy and oversight activities, given overlapping responsibilities for transplantation and clinical investigation among federal agencies. Innovative clinical trials span traditional administrative boundaries and include stakeholders with diverse interests. Participants identified the need for a governmental interagency working group to coordinate nationwide transplant‐related activities. (2) Improvements are required in clinical metrics for transplantation, with alignment of performance goals across transplantation organizations and any development of data requirements being consistent with those goals. Database coordination among clinical centers, organ procurement organizations, regulatory agencies, and payers would facilitate research and better inform policy. New data requirements should provide actionable insights into clinical performance. (3) Innovative research seen as potentially adversely affecting Program‐Specific Reports may reduce centers’ participation. Cutting‐edge research requires mitigation of risk‐aversive behaviors created by reporting of clinical outcomes data. Participants proposed a new review process in advance of implementation of clinical trials to guide “carve‐outs” of transplant center outcomes data from Program‐Specific Reports. Clinical transplantation will be advanced by the development of a shared and comprehensive research agenda to facilitate coordination of research and policy.     

Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects

During the last years, progress has been made in survival and function of pig-to-non-human primate organ xenotransplantation using organs from genetically modified pigs and immunosuppression regimens that are clinically acceptable. This, together with increased insights into a low risk of pig-to-human transmission of porcine endogenous retrovirus, has opened the perspective of starting with first-in-human trials with xenogeneic organs. The regulatory path to clinical development is complex. Unlike an organ from human donors, an organ from pigs, either genetically modified or wild-type pigs, is considered a medicinal product for human use and hence is under regulatory oversight, in the United States by the Food and Drug Administration and in Europe by the national competent authorities of the member states as well as the European Medicines Agency. Related to the status of medicinal product, “(current) good practices” apply in the process of generating a xenogeneic organ through to the transplantation into a patient and life-long follow-up. In addition, guidances for xenotransplantation products and genetically modified organisms do apply as well. This commentary focuses on regulatory aspects of transplantation of organs from genetically modified pigs into humans, with the intention to facilitate the interactions between regulatory agencies and institutions (sponsors) in research and clinical development of these organs, to support the perspective of speeding up the process with a proper entry in clinical application, to fill an unmet medical need in patients with end-stage organ disease.     

Expert Opinion Is Necessary: Delphi Panel Methodology Facilitates a Scientific Approach to Consensus

Our current trend and focus on evidence-based medicine is biased in favor of randomized controlled trials, which are ranked highest in the hierarchy of evidence while devaluing expert opinion, which is ranked lowest in the hierarchy. However, randomized controlled trials have weaknesses as well as strengths, and no research method is flawless. Moreover, stringent application of scientific research techniques, such as the Delphi Panel methodology, allows survey of experts in a high quality and scientific manner. Level V evidence (expert opinion) remains a necessary component in the armamentarium used to determine the answer to a clinical question.     

Understanding the barriers to,and facilitators of,ovarian toxicity assessment in breast cancer clinical trials

BackgroundDetailed toxicity data are routinely collected in breast cancer (BC) clinical trials. However, ovarian toxicity is infrequently assessed, despite the adverse impacts on fertility and long-term health from treatment-induced ovarian insufficiency.ObjectivesTo determine the barriers to and facilitators of ovarian toxicity assessment in BC trials of anti-cancer drugs.MethodsSemi-structured interviews were conducted with purposively selected stakeholders from multiple countries involved in BC clinical trials (clinicians, consumers, pharmaceutical company representatives, members of drug-regulatory agencies). Participants were asked to describe the perceived benefits and barriers to evaluating ovarian toxicity. Interviews were transcribed verbatim, coded in NVivo software and analysed using inductive thematic analysis.ResultsSaturation of the main themes was reached and the final sample size included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives); half were female. The main reported barrier to ovarian toxicity assessment was that the issue was rarely considered. Reasons included that these data are less important than survival data and are not required for regulatory approval. Overall, most participants believed evaluating the impact of BC treatments on ovarian function is valuable. Suggested strategies to increase ovarian toxicity assessment were to include it in clinical trial design guidelines and stakeholder advocacy.ConclusionLack of consideration about measuring ovarian toxicity in BC clinical trials that include premenopausal women suggest that guidelines and stronger advocacy from stakeholders, including regulators, would facilitate its more frequent inclusion in future trials, allowing women to make better informed treatment decisions.     

Hypoparathyroidism in the adult: Epidemiology,diagnosis, pathophysiology,target‐organ involvement,treatment, and challenges for future research

Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease. © 2011 American Society for Bone and Mineral Research     

Spondyloarthritis update: new insights regarding classifcation, pathophysiology, and management

There has been a burgeoning interest in the spondyloarthritides (SpAs) due to a confluence of elements. Basic science research has provided new insight into the unique pathophysiology of synovium, enthesium, and bone, highlighting the important differences from rheumatoid arthritis (RA). Through collaborative research of international working groups, classification criteria for psoriatic arthritis (PsA) and ankylosing spondylitis (AS) have been developed or are being refined to aid characterization and diagnosis of SpAs and aid in research. These same working groups, under the umbrella of Outcome Measures in Rheumatology Clinical Trials (OMERACT), have developed domain core sets to be measured in clinical trials and registries, and which allow validation of reliable outcome measures. Both through clinical trials and observational data from national clinical registries, the relative effectiveness and safety of old and new therapies are being demonstrated. This has been particularly shown with long-term data on anti-TNF therapy. Newer anti-TNF therapies are being developed, as are treatments with different mechanisms of action in order to treat patients who do not have long-term effectiveness or develop side effects to older disease modifying therapy and anti-TNFs. International treatment recommendations have been or are being developed based on the evidence base from clinical trials.     

Defining the research agenda for surgical infection: a consensus of experts using the Delphi approach

BACKGROUND: A substantial proportion of operative procedures are complicated by infections, either remote from or related to the surgical site. These infections account for substantive morbidity and health care costs. With limited research funds available to study interventions designed to either prevent or reduce the morbidity associated with infections in surgical patients, we developed a research agenda to develop priorities to aid in study design and to focus both human and capital resources more effectively. METHODS: A Delphi survey approach was used. Consensus was developed among experts in the field of surgical infection and the membership of the Surgical Infection Society. RESULTS: Thirty-six experts generated a total of 62 questions that were submitted for two rounds of consensus ranking. A total of 31 questions were ranked in the final round and are available at www.sisna.org. The most highly ranked question was "Does strict glycemic control compared with standard care reduce the risk of surgical site infection in patients undergoing abdominal surgery?" Most of the questions had little available data, suggesting these are both important and necessary areas for further research. CONCLUSIONS: This research agenda, developed by a consensus of experts, provides direction and focus to the development of interventional trials geared toward reducing the morbidity associated with infections in surgical patients.     

Pharmacologically active: clinical trials and the pharmaceutical industry.

Multinational pharmaceutical companies ( 'pharmas') import and produce pharmaceuticals and also conduct clinical trials which are an important aspect of research and development (R&D). This may raise the question: Is South Africa a guinea pig for the pharmas? The Department of Trade and Industry National Industrial Policy Framework(1) designates chemicals, plastic fabrication and pharmaceuticals as a key value chain. So a second question could be: Can South Africa be a manufacturer for the pharmas, or can it leverage strengths in medical research and the conducting of clinical trials so as to develop a discovery-led industry? This paper analyses and quantifies the state of the clinical trials industry in South Africa, and concludes that: (i) a sizeable clinical trials industry exists, and that these trials are predominantly phase 3 and global in scope; (ii) South Africa is not a specific or unique guinea pig--a range of conditions is studied as part of global trials; and (iii) while South Africa has excellent prospects for increased clinical trials activity, R&D investment is too low to make it a major pharmaceutical contender.