Blockchain Papers

Ching Lam, Michelle Helena van Velthoven, Edward Meinert

BACKGROUND Advanced therapies, including cell and gene therapies, have shown therapeutic promise in curing life-threatening diseases, such as leukemia and lymphoma. However, these therapies can be complicated and expensive to deliver due to their sensitivity to environment; troublesome tissue, cell, or genetic material sourcing; and complicated regulatory requirements. OBJECTIVE This study aims to create a novel connected supply chain logistics and manufacturing management platform based on blockchain, with cell and gene therapy as a use case. Objectives are to define the requirements and perform feasibility evaluations on the use of blockchain for standardized manufacturing and establishment of a chain of custody for the needle-to-needle delivery of autologous cell and gene therapies. A way of lowering overall regulatory compliance costs for running a network of facilities operating similar or parallel processes will be evaluated by lowering the monitoring costs through publishing zero-knowledge proofs and product release by exception. METHODS The study will use blockchain technologies to digitally connect and integrate supply chain with manufacturing to address the security, scheduling, and communication issues between advanced therapy treatment centers and manufacturing facilities in order to realize a transparent, secure, automated, and cost-effective solution to the delivery of these life-saving therapies. An agile software development methodology will be used to develop, implement, and evaluate the system. The system will adhere to the EU and US good manufacturing practices and regulatory requirements. RESULTS This is a proposed study protocol, and upon acceptance, grant funding will be pursued for its execution in 2021. CONCLUSIONS The successful implementation of the integrated blockchain solution to supply chain and manufacturing of advanced therapies can push the industry standards toward a safer and more secure therapy delivery process. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/17005

Naseem Naqvi

of Burgundy and Web3 Labs, to name a few

Marie Recine

The atmosphere at the 5th Annual Immuno-Oncology 360° (IO360°) Conference, which took place on February 6–8 at the Crowne Plaza Times Square in New York City, was truly collaborative. Co-chaired by Axel Hoos, MD, PhD (GSK), James Gulley, MD, PhD (National Cancer Institute [NCI]), and Andrew Baum, MD (Citi), the conference featured almost 100 speakers and 10 plenary sessions, including 4 keynote talks and 7 panel discussions. More than 400 attendees representing the pharma, biotech, academic, regulatory, and private investment communities gathered to discuss the rapid advancement in scientific, clinical, and business developments in IO, with the goal of accelerating the development of new therapeutics for patients. Over 350 partnering meetings took place over the 3-day conference.“360 degrees means we really want to speak to all stakeholders,” stated Dr. Hoos. The meeting is structured for the scientists to bring their most promising next-generation mechanisms that will help address these challenges. However, it is also important to look at therapies that haven't worked, so we don't repeat the same challenges of the past, he noted. “But IO360° is not just the science, it's about the entire ecosystem in which the science exists, and that includes the patients and those that provide the funding to make the science happen.”Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center, opened the meeting with a keynote, Chimeric Antigen Receptor (CAR) - T Cell Therapy and the CD19 Paradigm. With two CD19 CAR-T cells (CAR Ts) approved in 2017, Dr. Sadelain identified three new directions being taken to optimize CAR T therapy and develop next-generation CAR Ts. The first is addressing exhaustion (loss of functionality) using genome engineering at a carefully select locus (TRAC) to create more potent CAR Ts and incorporating new designs that modify the activating portion of the CAR and balance rapid expansion and retained memory (1XX CAR). The second is gaining insight into the pathophysiology of cytokine release syndrome, including CAR T–macrophage interactions, to try and reduce toxicity. The third is employing new strategies for circumventing antigen escape, such as use of radiosensitization and combinatorial targeting.The Discovery and Preclinical Science plenary focused on strategies being investigated to modify the tumor microenvironment and address limitations of patient-sourced therapies. According to the plenary chair, Ronald Herbst, PhD, “we are all excited about the potential for immunotherapy for patients with cancer, but many patients don't respond to checkpoint inhibitors.” Part of the problem is explained by the fact that “immune contexture varies within and across tumor types, and so-called ‘hot’ versus ‘cold’ tumors,” he noted. In order to increase the efficacy of immunotherapy, a number of areas are actively being targeted, including antigen presentation, innate mechanisms of activation, the tumor microenvironment, and overcoming immunosuppression.A variety of cells, growth factors, and cytokines in the tumor microenvironment play a pivotal role in whether or not immunotherapy is effective. Various strategies are being employed that attempt to modify the tumor microenvironment to overcome immunosuppressive mechanisms, such as blocking adenosine with an anti-CD73 monoclonal antibody (oleclumab, Medimmune) or an A2A receptor antagonist (CPI-144, Corvus), or inhibiting the IDO (indoleamine 2,3-dioxygenase) pathway (indoximod, NewLink Genetics). Other strategies are being employed to enhance the efficacy of cytokines to augment the expansion and activation of T cells, such as engineering enhanced versions of growth factors such as interleukin-2 (IL-2; NKTR-214, Nektar, and MDNA109, Medicenna) and IL-10 (pegilodecakin, ARMO). For example, pegilodecakin, a long-acting pegylated form of IL-10, induces hallmarks of CD8+ T cell immunity in cancer patients. According to Aung Naing, MD, and Martin Oft, MD, pegilodecakin demonstrated clinical benefit in studies as a single agent and in combination with both chemotherapy and checkpoint inhibitors across several tumor types. The agent is currently being investigated in a Phase 3 trial in metastatic pancreatic cancer.Off-the-shelf hematopoietic cell products are being developed to address some of the limitations of patient-sourced cell therapies, such as heterogeneity, single-patient manufacturing, need for sufficient cells, extended production time, and cost. For example, engineered CAR natural killer cells, derived from induced pluripotent stem cells, are being developed that incorporate several individual components that together help to enhance persistence and antitumor efficacy (FT596, Fate Therapeutics). Multicombinatorial strategies such as this may be key in reigniting the endogenous immune system and improving efficacy in solid tumor space.Genentech's Priti Hegde, PhD, opened the Translational Science and Emerging Biomarkers plenary, part 1, with a keynote, Biomarker Signaling: Turning Cold Tumors Hot. Individual cancer types can be characterized along the tumor immunity continuum based on immune phenotype (i.e. inflamed or noninflamed) and tumor mutational burden (TMB). How can we generate an immune response signal in noninflamed tumors when most do not achieve the TMB threshold that selects for benefit? Dr. Hedge highlighted two approaches: adaptive immunity, which has the potential to drive memory response, and synthetic immunity, which has the potential to sustain efficacy and drive log kill. An example of an adaptive immunity approach is neoantigen-specific T-cell therapy, in which there are limited but encouraging data demonstrating its ability to promote adaptive immunity in noninflamed tumors. Synthetic immunity approaches include engineered T cells (e.g. NY-ESO SPEAR T cells [GSK/Adaptimmune], BMCA CAR Ts) and bi-specific biologics (e.g. antibodies, BITEs® [Amgen], ImmTAC® [Immunocore]), in which there is a proof of concept that these approaches are feasible in solid tumors and checkpoint inhibitor-refractory hematologic malignancies.One may also need to address the underlying biology to turn cold tumors hot. According to Dr. Hegde, the future of immunotherapy may be highly personalized, and one will need to look at a variety of markers in biopsy specimens using a variety of techniques. This will only be possible if we have: (1) a tissue-conserving, regulatory-grade decentralized platform to be able to run all of these assays in trials and (2) trial designs and statistical analysis plans that enable diagnostic signal-seeking validation and a path for registration.The remainder of the plenary reported on translational data and evolving biomarkers and applications to help support decision-making for IO drug development.Negative results from the Phase 3 study of the therapeutic prostate cancer vaccine PROSTVAC (Bavarian Nordic) show that a combinatorial approach may be needed with vaccines. Similarly, oncolytic viruses may need multiple transgenes and mechanisms to reverse complex immunosuppressive microenvironments. To address this issue, T-Stealth™ oncolytic viruses (BeneVir) can incorporate multiple genes, evade clearance by the innate and adaptive immune systems, and be combined with other drugs and IO agents.With the increasing need for biomarker support, the clinical trial laboratory reality in the IO space is complex. Patrice Hugo, PhD (Q2 Solutions), summarized important features to consider when selecting a lab partner for drug development. Key strategies to successfully introduce innovation in the clinical trial lab space include joint review of pros and cons of technologies, consideration of joint investments, performing Phase 1 specialized testing in niche labs/academic settings with transfer to a central lab, and discussion and planning for regulatory requirements.Advances in positron emission tomography (PET) imaging and radiomics provide a quantitative, noninvasive way to assess the dynamic changes of the immune system. For example, CD8 PET (Imaging Endpoints) may help distinguish between hot and cold tumors and address fundamental questions regarding the role of CD8 cells in the tumor microenvironment.Other unique biomarkers and applications under investigation include MultiOmyx™ (NeoGenomics), a proprietary multi “omic” technology that enables detection and visualization of up to 60 biomarkers on a single slide; immunosequencing (immunoSEQ, Adaptive Biotechnologies), a clinical diagnostic for monitoring clonal expansion and predicting/evaluating response to therapy that can also be used in combination with cellular immunology and computational biology (Multiplexed Identification of T cell Receptor Antigen [MIRA] assay, Adaptive Biotechnologies) to map T-cell receptors; and CANscript™ (Mitra), a personalized ex vivo histoculture approach that can be used to evaluate drug-induced modulation of the tumor microenvironment and predict clinical performance.The IO Novel Technologies and Innovative Solutions plenary showcased companies that have technologies and solutions that will help stakeholders in the IO field advance developments for cancer therapeutics. Presenters included Advaxis, Bioxcel Therapeutics, IAG, Provecs Medical, Rgenix, and Sensei Bio.Andrew Baum, MD (Citi), opened the Financial and Commercial Implications plenary with a keynote, Evaluation and Forecast of the IO Space. He started off by discussing key questions on health-care investors' minds. According to Dr. Baum, “what investors don't like very much about IO is that the technology cycles are short, so you can go from here to zero very quickly very easily.” He cited ipilimumab and the fact that it was quickly eclipsed by anti-PD (L)-1 agents. Another issue is the “paradox of choice,” as there are so many different modalities. “It's almost overwhelming,” he noted, “especially for someone that doesn't have a deep scientific background to interpret a Phase one trial.” Other questions involve primary and secondary resistance, cell therapy manufacturing constraints, minimizing/managing toxicity, and financial toxicity. However, despite these questions, “the good news is the amount of capital, the enthusiasm, and the scientific advancement all mean that we're going to make huge strides in IO, I have no doubt.”Dr. Baum stressed the importance of learning from historic disappointments and noted that we need better biomarkers, better trials, and patience so that the benefits can be extended to more patients. He ended his presentation with a slide showing Citi's top 10 novel IO targets for 2020, in which IL-2/IL-15 took the top spot.Khalil Barrage (Invus) agreed that the IO revolution has led to unprecedented investor enthusiasm for oncology, unlocking massive commercial opportunities. However, the discovery of checkpoints and their curative potential has led to hype in IO drug discovery, resulting in risky behavior. In addition, the flood of capital has lowered potential returns and there are a lot of IO agents in development with poorly validated rationale. As a result, Invus' approach to investing incorporates strategies such as diversification, selectivity, exploring synergistic opportunities, investing where innovation is happening, paying a premium for validated approaches when warranted, and assessing reimbursement.The plenary concluded with a panel discussion on monetizing science: the preparation of an IPO, straight licensing with the transition to a public company, and decision-making on prioritization within portfolios. Key takeaways included strategies for building out scientific and executive talent, the importance of having a scientific advisory board to test out the research, and being prepared to be a public company.The Trends and Collaborations plenary featured presentations by three major industry media companies in the IO field, which discussed new trends and their effect on the investment landscape.BioCentury analyzes IO trends at recent medical meetings using machine learning, began Simone Fishburn, PhD, VP, and Executive Editor. Despite the huge focus on PD (L)-1, academics and companies are aggressively looking for, and finding new targets, with LAG3 topping the list in company oncology pipelines in 2019. CAR T activity is moving into solid tumors, with new constructs and multiple tumor antigens targeted. Immunometabolism and tumor mutation burden are hot topics. Funding for IO start-ups is outstripping other areas, both inside and outside oncology, drawing traditional and corporate investors.According to John D. Carroll (Endpoints News), these trends are supported by global data published by the Cancer Research Institute, which show that there were 3394 IO agents representing 417 targets in the pipeline in 2018, representing a 67% increase over 2017.How are these trends affecting the investment landscape? According to Jeff Bockman, PhD (Cello Health BioConsulting), IO dominates oncology growth, but not sales. Moreover, although IO deals have shown evidence of slowing, whether due to maturation, saturation, or fatigue, and oncology and IO investments remain robust.The Business Development plenary, hosted by Solebury Trout, included panel discussions on partnering, fundraising, and rational investing. The first panel discussed IO partnering strategies from the viewpoint of pharma and academia. According to Dr. Hoos, who the partnering in this space have but there has much and is only that companies have started their unique which will a partnering the for is tumor and the and the companies on the panel and there to be both and with some moving from and on those that can IO and agents are being by most in the and are to play which was for and discussed in the IO space and a number of For example, the panel stressed the importance of at and and on key and as a private on their ecosystem their investors with in the past, key to their than at with the top at the with key the of and companies introduce than need to so that can panel focused on IO investment investors this an time, with a future for many modalities. However, the massive of data is it to to to from a The investors on the panel on a variety of such as the of and whether the data support a or whether an agent has a or has a niche in the IO important is a in their and their to plenary ended with a with of by Solebury Trout, the discussion focused on in the company, with a an For companies looking for highlighted the fact that as a and stressed the need to and where are are some very so both and in to a with a can try and to more like in As industry are companies can be quickly with limited capital, like companies have in the began with a keynote, to led by and MD, of of According to Dr. we are at an in it has from one to has the and of tumor types, agents and trials are and there is an to use to enable to of trials are the way new therapies are developed for cancer, make better and more personalized The of are testing drugs where most (i.e. the order of therapy to about response in the of building an to evaluate drugs and using imaging and biomarker and being by is a platform trial for of biopsy is used to assess and imaging and adaptive The and the are structured to enable and release of agents the The primary is response which is a highly of and and is in biomarker The from biomarker and is to drug to Dr. we want innovation to we have to The focus of new drug development be a a from of metastatic to is a huge is also a huge goal of is to of patients to with and of therapy based on Dr. ended with one of for drug from finding out which drug be to the with two The first Science and Emerging Biomarkers Part was led by PhD, of and to focus on biology and to help predict to Technologies discussed included to enhance antibody therapeutics mechanisms of to immune the for biomarker discovery a and a receptor in second for IO was led by of and was for clinical trial who to it to an IO clinical discussed included an clinical trial study a complex Phase 1 trial in IO and clinical trial for The ended in a panel discussion on the challenges with IO data and to advance to PhD, at the and (i.e. may not the clinical benefit of IO agents. As a result, trends include the use of immune response machine learning to the of imaging and new techniques. The IO plenary up the with a discussion of novel imaging are unique challenges with the use of response at IO clinical as a of complex According to some of these challenges can be by the and of response and including a of in the can be by the use of and and analysis and PhD are being used in with to more from to as as better between and such as the CD8 PET discussed is also an evolving Similarly, imaging using PET an to assess all of a tumors for with a single PET and assess use of a novel three opened with the of with cancer, cancer 10 as metastatic chemotherapy and therapies, and of an immunotherapy trial at the The the that cancer, and those cells in the an of the cells and the cancer has the of being the first to be of metastatic cancer a of to to from in the concluded with some to patients who be in the same the same to with cancer or out as much as you can about to a cancer to to not just one of therapy but several of out about clinical trials and whether you can in The is out there and you as try and on the was a panel discussion on to IO in a The are to but be and and the of a tumor to be want to if the tumor has by the adaptive immune is it by T cells if do have an immunosuppressive factors are in the tumor However, are an important the is the of the cell types are but also and able to look in the is but it doesn't provide all the can all these be with a new plenary for Cell According to Dr. Gulley, therapy has the to on the of cancer there is activity in hematologic but it's is needed to achieve the same effect in solid tumors, so this is where there is much The is to was in studies but the benefit to a of patients. The new technologies and targets discussed in this plenary to do just technology to a T cells their However, in the of approved CAR are According to MD of this as a of of and of He cited a where CD19 in a single cell led to by the CD19 which may have important for manufacturing and other cell therapies. For and the can be with a CAR T or it can be with a new of CAR that the SPEAR are an engineered T-cell of cells that are to a that a antigen in many technology an over CAR T therapy in that it to both and results have in a cancer for which there are no therapies the of noted products a number of over CAR Ts. CAR Ts Chimeric Antigen Receptor developed using the platform are being investigated in and multiple The is to multiple to create T cells with such as the ability to or overcome may an over other therapies in solid tumors in that multiple tumor antigens and there is a of or The technology used to develop the that has and of efficacy have in and the for the has from to to and the is a therapies have the potential to enhance CAR T activity in solid tumors. combination strategies consider both and can be used to enhance cell and and factors in the tumor microenvironment, or and plenary ended with a panel discussion on and clinical to IO therapeutics that will to more and therapies. of the strategies discussed were including a to and products and addressing antigen with or combination In order to we need to address like the when moving from in to the clinical as as cell and the used to create the may the cells, manufacturing and we need to cell therapies so that more patients will have conference concluded with the IO Development plenary, which discussed recent IO clinical The plenary began with an of data for the activity has demonstrated in more than cancer types. The agent has across more than including in is moving into the of therapy, and next-generation biomarkers are to help promising were also for a a and combination immunotherapy and the tumor receptor has to more benefit in Dr. Hoos. However, there is a lot of As a result, “we need to new to the benefit PD Cell therapy has really to the of engineered and we are to the benefit from to solid tumors and overcoming the such as T-cell that in the for patients is

Francisco Curbera, D.M. Dias, Vahan Simonyan, Wan-Tae Yoon · 5 authors

Major trends in healthcare and life sciences (HCLS) include huge amounts of and longitudinal patient data, policies on a patient's rights to access and control their data, a move from fee-for-service to outcome-based contracts, and regulatory and privacy requirements. Blockchain, as a distributed transactional system of record, can provide underpinnings to enable these trends and enable transformative opportunities in HCLS by providing immutable data on a shared ledger, secure and authenticated transactions, and smart contracts that can represent rules that are executed with secure transactions. We describe HCLS use cases leveraging these facets of blockchain, including patient consent and health data exchange, outcome-based contracts, next-generation clinical trials, supply chain, and payments and claims. We then describe a blockchain-based architecture and platform for enabling these use cases. Finally, we outline a realization of this architecture in a case study and outline further research topics in this domain.

Mark E Abraham, A Vyshnavi, Chungath Srinivasan, P. K. Krishnan Namboori

No abstract is available for this record.

Quinn DuPont

This article investigates ethical research risks associated with cryptocurrencies and the related family of digital "value" technologies. It provides an empirical analysis of innovation and recommends guiding principles for ethical research and development. Ethical research risks are identified through 1) an analysis of research methods and ethics disclosure practices in published empirical research; and 2) a survey of academic research practices and researcher opinions. These data identified multiple research ethics issues. It was discovered that most researchers have extensive and undisclosed industry relationships, have undisclosed conflicts of interest arising from token ownership, and report low use of institutional review or ethics guidelines, among other issues. Three novel research risks-conflicts of interest, risky methods, and disclosure-are then introduced and compared to the risks of conventional research. It is argued that these technologies introduce ethical risks and opportunities beyond their sector. These findings suggest a new class of ethical and normative research practice, comparable to fields such as bio-or nanotechnology ethics. Based on these analyses, eight principles for ethical research are described, with practical lessons for the researcher.

Eric Swanson, Tim Brown

THE PROBLEM Conflict of interest (COI) is a subject of intense interest, to the extent that an entire issue of the Journal of the American Medical Association was devoted to this subject last year.1 In 2014, the American Society of Plastic Surgeons created a task force to address this problem.2 Conflict of interest was the lead story of a recent issue of Plastic Surgery News.2 Remarkably, about half of U.S. physicians, and 61% of surgeons, received payments from the pharmaceutical and medical device industries in 2015, amounting to $2.4 billion, including 136 plastic surgeons who received >$10,000 each.3 Before the early 1980s, there was little intersection between medicine and industry. Collaboration between the medical profession and the corporate world has increased.4 The link between commercial funding and study conclusions is undeniable in plastic surgery.5,6 When industry-supported Continuing Medical Education programs are conducted at resort hotels and upscale restaurants, the boundary between education and industry marketing is blurred.7 At meetings, plastic surgeons often declare, “I have no relevant conflict of interest” or “I have no conflicts that would affect the content of my presentation.” Luce laments that sometimes the duration of the disclosure slide presentation could be measured in nanoseconds, as reported in Plastic Surgery News.2 The speaker usually decides whether a conflict is relevant. Presenters sometimes comment, wryly, “I have no conflict of interest, unfortunately,” recognizing, and trivializing, the financial benefit of a COI. Some speakers display a long list of conflicts and suggest that because they have so many, they are at least “equal opportunity conflicters.” Some investigators believe that if they previously received money but no longer receive payments, they are no longer conflicted. Is there an expiry date for financial conflicts? Although some journals specify a 3-year period before submission, full disclosure is preferred, allowing the reader to decide on the merits.8 DEFINITION Luce6 defines COI: “Conflicts in ethically problematic situations are those in which the practitioner participates in clinical investigation of new devices/technology, publishes that experience, and, in parallel, is paid a consultant’s fee by the manufacturer.” Fineberg9 believes that a COI exists when a reasonable person would interpret the financial circumstances as sufficient to influence a physician’s judgment. When the reasonable person standard is used, the “appearance of” a COI is redundant.9 Proof of patient harm is not a requisite for COI; there are no “potential” COIs.10 INDUSTRY PAYMENTS TO INDIVIDUALS The American Society of Plastic Surgeons recently introduced dollar ranges for reporting financial conflicts.2 However, no data are available regarding a monetary threshold for a COI.11 Using Open Payments data, a 2016 study found that receipt of industry-sponsored meals, even just a single meal, was associated with an increase in the rate of prescribing the promoted brand-name drug.12 The more money doctors receive, on average, the more brand-name medications they prescribe.13 The evidence shows that even small gifts induce unconscious feelings of gratitude and reciprocity. Gifts to physicians can perpetuate a mindset of entitlement.14 INDIRECT CONFLICTS OF INTEREST Incentives that are not directly financial but have financial implications such as career advancement may also represent potent COIs.15 Academic COIs may contribute to the disturbing prevalence of research irreproducibility.15 Preset convictions can cause investigators to overlook or selectively interpret data. The investigator who is so certain that the concept is correct may, even subconsciously, alter the eligibility criteria, or the number of subjects, to fit the data to the hypothesis, and reach the desired level of significance, a practice known as p hacking.16 A t test may be conducted on a tiny number of patients using data that are not normally distributed. The sample size may be kept small to ensure that adverse outcomes do not reach statistical significance. INDUSTRY PAYMENTS TO PROFESSIONAL SOCIETIES AND JOURNALS Many professional societies, including plastic surgery societies, accept large payments from industry (ie, >$1 million annually). A key recommendation of a 2009 consensus report was a preliminary reduction in industry support to <25% of the operating budget of the professional medical association, with an ultimate goal of complete freedom from industry funding.17 Companies partner with our societies and fund journal supplements, compromising the separation of science and advertising. Industry involvement may extend to writing the manuscript, called “writing support.” Many medical journals derive a substantial proportion of their operating revenue from advertising.18 Sponsored supplements are typically written to support the marketing goals of the sponsor,18 and lack counterpoint discussions written by nonconflicted plastic surgeons. Brand names are featured in the titles. Editors may argue that supplements are treated with the same degree of scrutiny as regular publications,19 but the potential for inappropriate influence cannot be excluded. Publication bias is a well-known problem.5 Researchers who are consultants, hold stock options, or receive royalties from companies, are much more likely to report positive results.5,20 Not surprisingly, industry is notoriously reluctant to publish negative findings.5,21 Some trial protocols include a provision for review of the manuscript by the funder before submission for publication, and the right to delay or even veto its publication.5,22 The timeline is pertinent. Plastic surgeons reporting on new products (eg, breast implants, implantable mesh, cryolipolysis, radiofrequency) may hold changing, often increasing, ownership stakes in successive publications, begging the question, when was this investment decision made and did it influence the research? EXAMPLES OF CONFLICT OF INTEREST IN PLASTIC SURGERY Breast Implants The promotion of shaped, textured breast implants reflects the quid pro quo between the industry and surgeons.23 The highly praised gummy bear implant was always an inferior product. Shaped implants malrotate in 42% of patients.24 These devices are firm, may have palpable edges, can cause double capsules and seromas25 and are much more costly than smooth round alternatives. Most importantly, textured implants are linked to breast implant-associated anaplastic large-cell lymphoma.26 Hidalgo and Weinstein27 and others28,29 report no aesthetic advantage. Yet for decades now, textured, shaped implants have been promoted as superior to less expensive alternatives. Hall-Findlay30 writes: “We listen to the manufacturer’s claims and then years later we find that we have been misled – both by the manufacturers themselves and by those surgeons who are burdened by a conflict of interest.” A study of nano-textured and micro-textured breast implants was recently published in a corporate-funded journal supplement.31 The authors report a complication rate of 0.3%, with 1 hematoma, no cases of implant malposition, no pain, no rippling, no ruptures, no redness, and no capsular contractures among 4,103 breast augmentations. The reoperation rate was <1%. The lead author reported no COI regarding this study, but accepted a position on the company’s medical advisory board immediately after submitting the article.31 Implantable Mesh The problem is not limited to breast implants. The COI regarding acellular dermal matrix is well documented.32 A recent article advocating the off-label use of implantable mesh in breast surgery was published by 2 authors who have a financial stake in the company that manufactures the mesh.33 A third author is a paid consultant and speaker. Galatea Surgical, a subsidiary of Tepha Inc. (Lexington, Ma.) financed the study, including medical writing, and referenced supplemental publications.33 Galatea is a corporate sponsor of the American Society for Aesthetic Plastic Surgery.34 The authors report that 100% of participating surgeons preferred to use mesh in all patients and the 1-year result was satisfactory in 100% of women.33 Such publications encourage plastic surgeons to adopt commercially driven practice patterns. A recent Continuing Medical Education article suggests that mesh support represents a paradigm shift.35 However, a nonconflicted analysis of mesh, and of the dated internal bra concept, finds no advantage.36 Radiofrequency Treatments A recent corporate-funded supplemental article, written by surgeons who are also shareholders, claims that radiofrequency-assisted liposuction (BodyTite, InMode Corp., Toronto, Canada) provides effective soft-tissue contraction, even creating an “internal brachioplasty scar.”37 This claim is based on a greater reduction in linear measurements than area measurements after radiofrequency-assisted liposuction compared with standard liposuction, a finding that is impossible to reconcile with basic geometry (the difference in area measurements must exceed linear changes).38 The authors offer a favorable return on investment analysis to justify the $205,000 purchase price, based on a $7,000 treatment fee.37 Conflicted author/investors frequently publish photographs that are not standardized in an effort to demonstrate a therapeutic benefit.33,36,39,40 A recent corporate-funded study on facial radiofrequency treatments with micro-needles was co-authored by a shareholder.39 The authors magnified the preoperative photograph of a nasolabial crease 58% to make it appear larger before treatment.40 Statistical errors included using a t test to compare nonparametric data, citing a P value of 1.00 for a comparison of nonidentical data, and a maximum range within 1 SD of the mean.40 DISCOUNTS TO INVESTIGATORS New transparency regulations help to inform the public about payments made to physicians.41 Unfortunately, it is not difficult to sidestep such reporting requirements. A well-known investigator may be given a device (eg, an ultrasonic liposuction machine) at a heavily discounted price. A breast implant manufacturer may provide its researchers with complimentary or discounted implants. There are many ways to reimburse surgeons indirectly. These considerations are substitutes for reportable cash payments, and they undermine the integrity of our research. COMPANY OFFICERS Investigators who are not only passive investors but company officers and shareholders42 have a financial obligation to the company. A fiduciary responsibility makes it impossible to remain objective.43 CLEARANCE BY U.S. FOOD AND DRUG ADMINISTRATION When a device receives clearance by the U.S. Food and Drug Administration, it is labeled with a stamp of authority that is reassuring to the public. This label also serves as a powerful marketing tool. Unfortunately, the approval process is not protected from commercial influence. For example, Coolsculpting (Allergan plc, Dublin, Ireland) gained Food and Drug Administration clearance for treatment of the thighs based on studies performed by investigators that received major financial reimbursement.44 The company itself was allowed to conduct vital ultrasound and photographic imaging.44 The lead investigator was at one time a Zeltiq Aesthetics Inc. (Pleasanton, Calif.) paid consultant and shareholder.44 Zeltiq was purchased in 2017 by Allergan plc (Dublin, Ireland) for $2.48 billion.45 HONEST REPORTING Corporate-funded studies consistently report unusually low complication rates, speedy recoveries, high rates of patient satisfaction, high “conversion rates,” and even the prospects for cross-selling.46 These sales-oriented characteristics undermine hard-won gains in honest reporting and the recognition of the importance of evidence-based medicine in our scientific journals. Adoption of unsound treatments and devices based on biased studies can have harmful long-term ramifications through a “rippling effect.”5 Biased studies may be referenced in practice guidelines.5 Physician disillusionment, especially after the purchase of an expensive yet underperforming device, may be a factor in physician burnout. CONSULTANTS Although physicians may consider themselves to be ethical professionals, many doctors remain unaware of the subconscious bias that industry relationships create.47 The practice of doctors accepting payments from companies has gone on for decades without a critical review. Are plastic surgeons truly acting as consultants, or is “consultant” a euphemism for receipt of a payment to shape one’s opinion in favor of the product and confer loyalty? Industry payments, which may be viewed as kickbacks, have created serious legal difficulties for physicians.2 Lopez et al.20 found that self-reported COIs have declined in recent years, but the proportion of consultantships has increased. In proposing an end to industry influence and regaining the public trust, a committee formed by the Institute of Medicine finds that continuing medical education “has become far too reliant on industry funding,” which “tends to promote a narrow focus on products.”48 The committee recommends restricting consultantships to the provision of objective technical advice paid at fair market value, documented in written contracts. Moreover, companies “should not involve physicians and patients in marketing projects that are presented as clinical research.”48 RECOMMENDATIONS The International Committee of Medical Journal Editors disclosure form insists that contributors disclose relevant financial relationships.49 In 2010, the Council of Medical Specialty Societies published a code for interactions with companies, with a provision that prohibits society officers and journal editors from accepting any compensation from industry.50 To facilitate transparency of disclosure, Congress passed the Physician Payments Sunshine Act, which requires commercial companies to report any “transfer of value” to any physician, with a $10 threshold.51 In October 2010, ProPublica introduced Dollars for Docs, a central search engine for physician payments.41 Luce6 proposes that plastic surgeons with conflicts be excused as manuscript discussants and reviewers. Lichter50 recommends that a presentation with a COI should be balanced by a nonconflicted counterpoint discussant. The American Society of Plastic Surgeons has adopted a requirement for disclosure of financial conflicts in dollar ranges (ie, $100–$1,000, $1,001–$5,000, $5,001–$10,000, etc.).2 These are reasonable first steps. Device evaluation does not necessarily require industry funding, as evidenced by the research efforts of investigators without financial conflicts.25,27 Publication of independent research in a highly respected peer-reviewed journal and the accolades that come with it provide more than adequate compensation, and potential for practice building and career advancement. It is impossible to reconcile corporate sponsorship with unbiased research. Physician investigators should consider declining any paid consultancies and all forms of indirect corporate reimbursement. Study design and implementation, and manuscript preparation should not be outsourced. RELINQUISHING INDUSTRY FINANCIAL SUPPORT Asking attendees to visit the exhibits, “without which none of this [i.e., the meeting] would be possible” is a familiar refrain at meetings. The physician-industry complex has gone on for so long that plastic surgeons may find it difficult to imagine an arms-length relationship. Without industry sponsorship, plastic surgeons can expect to pay more to attend meetings and Continuing Medical Education activities, but the prices of devices and implants are likely to fall as companies are relieved of the tremendous financial burden6 of payments to physicians and societies. The net overall financial effect to physicians is zero, but medical integrity is restored. Relinquishing industry financial support represents a bold step, but recent examples of the influence of financial conflicts underscore the magnitude of the problem. As reported by Rohrich et al.,52 when Goldwyn stepped down as the longtime former editor of Plastic and Reconstructive Surgery, he worried most about commercial influence and keeping the specialty “pure.” He cautioned the incoming managing editor that he would need a strong sense of ethics because “you’ll need them in this business.” Goldwyn,53 quoting his father, wrote: “It is amazing how easy it is to be truthful if one wants to be.” CONCLUSIONS It is impossible for investigators to function as highly paid consultants and remain unbiased. Disclosure, including the amount of money paid, allows the audience to determine the importance of the conflict. Separation of commerce and science in our journal publications is vital so that scientific publications do not become marketing tools. Plastic surgeons must be better advocates for our patients and their pocketbooks. Part of the privilege of caring for patients is to be mindful of their finances and their health.14 Most importantly, our societies need to reconsider corporate partnership. Editors are already aware of the professional positions of reviewers and the need to protect the article that upsets the apple cart. As Descartes famously observed, “doubt is the origin of wisdom.”54 Progress is only made possible by challenging the status quo.

Giovanni Scarso Borioli, Jérôme Couturier

This article applies ‘outcome-driven innovation’ methodology, developed by Anthony Ulwick and popularised by Clayton Christensen, to the domain of clinical trials. Data were collected through in-depth, open interviews with doctors, nurses and researchers in the UK, France and Italy. Pain points for key players of the value chain were identified. The findings supported a multi-stakeholder approach to fully exploit the transformative potential of blockchain technology to resolve issues. The research identified a set of opportunities for innovators to improve the way hospitals conduct clinical trials using smart contracts and blockchain technology generally.

Kenneth Colon

Over the past decade, there have been many innovations in new payment and care delivery models and technology, from telemedicine to artificial intelligence (AI) to blockchain. These innovations, however, must be used in tandem to drive real change. We review each of these innovations and propose a model for how they can be combined to be greater than the sum of their parts. In doing so, we can create a global, decentralized health system that truly puts patient care at the center, while supporting and further enabling the clinicians who make this care possible, to deliver higher quality care at a fraction of the cost. Keywords: Artificial Intelligence, Behavioral Health, Blockchain, Collaborative Care, Decentralization,Direct Primary Care, Ethereum, Integration, Payment Models, Telemedicine, Virtual Assistants

Angela Guo

No abstract is available for this record.

Mehdi Benchoufi, Raphaël Porcher, Philippe Ravaud

<ns4:p>Clinical trial consent for protocols and their revisions should be transparent for patients and traceable for stakeholders. Our goal is to implement a process allowing the collection of patients’ informed consent, which is bound to protocol revisions, storing and tracking the consent in a secure, unfalsifiable and publicly verifiable way, and enabling the sharing of this information in real time. For that, we will built a consent workflow using a rising technology called Blockchain. This is a distributed technology that brings a built-in layer of transparency and traceability. From a more general and prospective point of view, we believe Blockchain technology brings a paradigmatical shift to the entire clinical research field. We designed a Proof-of-Concept protocol consisting of time-stamping each step of the patient’s consent collection using Blockchain; thus archiving and historicising the consent through cryptographic validation in a securely unfalsifiable and transparent way. For each revision of the protocol, consent was sought again. We obtained a single document, in a standard open format, that accounted for the whole consent collection process: timestamped consent status with regards to each version of the protocol. This document cannot be corrupted, and can be checked on any dedicated public website. It should be considered as a robust proof of data. However, in a live clinical trial, the authentication system should be strengthened in order to remove the need for third parties, here the trial stakeholders, and give participative control to the peer-to-peer users. In the future, we think that the complex data flow of a clinical trial can be tracked using Blockchain, that a blockchain core functionality, named Smart Contract, could help prevent clinical trial events not to happen in the right chronological order: for example including patients before they consented or analysing case report forms data before freezing the database. Globally, we think Blockchain will help with reliability, security, and transparency, and could be a consistent step towards reproducibility.</ns4:p>

Jim Vaught, Akin Abayomi, Tim Peakman, Peter H. Watson · 6 authors

Biobanking for clinical or research purposes includes the collection, processing, storage, and analysis of biological specimens. It is now well recognized that biobanking involves a complex array of technical and ethical/regulatory considerations. Biobanking policies and procedures are often documented by best practices that are usually voluntary but may be supplemented and reinforced by strict rules and regulations that govern informed consent, privacy, QC, and other critical issues. As biobanking has emerged as a global endeavor, with national networks and international collaboration becoming the norm, it has become even more critical that practices are coordinated and that quality standards are developed. Biobanking is also often a business endeavor, in that formal strategic and business plans need to be developed to ensure the long-term survival of the associated research programs. As new technologies are developed for using biospecimens to diagnose and treat disease, as well as to evaluate genetic risks, patients are becoming more aware of the importance and benefits of biobanking as part of the medical infrastructure. As a result, patients who donate biospecimens are becoming more interested in learning more about their own sample's use and in seeing the actual results of the research. One of the aspects of these evolving attitudes toward biobanking was addressed in a previous Q&A concerning biospecimen “ownership” in the January 2011 issue of Clinical Chemistry (Gronowski et al.; Clin Chem 57:540–4). From the broad array of issues that could be addressed, this Q&A focuses on a few critical issues that many biobanks are facing today: quality management, biobank network design, long-term sustainability, conveying the importance of biobanking to the public, and the return of research results to biospecimen donors. Five experts who are engaged in national and international biobanking programs discuss these complex issues here. What are some of the important issues related to quality management in sample collection, processing, and storage? Tim Peakman: Biobanks should aim to collect and store samples and associated data in the form most useful for scientific research. This means that they should represent the biological environment at the time of collection as closely as possible, and the introduction of variation through the way they are collected and processed should be avoided as much as possible. Where cases and controls come from different sources, this problem may be particularly acute (with the exception of purely genetic studies). In studies where samples are shipped to a different location for processing, the time delay between collection and stabilization may lead to loss of some unstable markers. Where samples are processed at local sites, maintenance of consistent intersite processing can be challenging. Odds ratios for many exposures are typically 1.2–1.5, so that introduction of uncontrolled or unmeasured variation may lead to weak associations' being overlooked, spurious associations' being further investigated, or significantly greater cost as sample size is increased to enhance power of the study. For many studies the greatest source of variation is at the preanalytical stage, in other words the collection, transport, and processing before stabilization at low temperature or on matrices such as blood spot cards. This can be managed by the implementation of a proper quality program that aims to make the collection and processing of samples as consistent as possible. Formal quality schemes such as ISO 9001:2008 may be suitable for larger studies, but whether a formal accreditation is obtained or a laboratory-based approach is taken, the quality management process should include full documentation of the sample processing trail (including dates, times, temperatures, location, operator, etc.), use of standard operating procedures (SOPs),7 training, audits, critical materials review, and so on. Practical steps to reduce introduced variability can be taken that aim to ensure the time from collection from the volunteer to stabilization is as consistent as possible across all samples and any preprocessing (such as clotting time for serum tubes) is standardized. Finally, quality of sample annotation should be ensured using approaches such as bar codes that maintain accuracy of sample attribution and avoid the risk of misidentification that can result in false positives. It is also important to empirically determine the stability of the samples under the particular collection protocol and whether this is sufficient for the intended purpose. Many analytes are quite stable in blood if they are transported and processed at 4 °C and, with a few exceptions, those analytes that aren't stable only degrade a small amount over 24 h. Establishing systems and processes to avoid this marginal loss may be expensive and unnecessary. Peter Watson and Lise Matzke: Quality management (QM) is an essential component of operating and maintaining a biobank. At the end of the day, it's “garbage-in, garbage-out,” or so they say. Operationally, biobanks must be able to track each biospecimen that is collected, processed, stored, and distributed from the facility to manage biospecimen quality and ensure effective future use. Quality is managed by an established system that verifies biospecimens are handled appropriately. Such quality systems involve the creation and maintenance of accurate process protocols, SOPs, and the activities that verify these protocols' being followed by biobank personnel (staff education and training). Further, standards and best practices set by international organizations such as the International Society for Biological and Environmental Repositories and the National Cancer Institute set guidance around the issues, provide a reference point for content of this documentation, and facilitate harmonization by national organizations and down to individual projects. Implementation of QM activities requires dedicated time and a resourcing strategy which can be very costly. Therefore the scope and scale of the program should be dictated by the scope and scale of the biobank and the nature of the research it is intended to support. A biobank supporting basic discovery research may choose a primary QM focus different from that chosen by a biobank that is intended to support multicenter validation studies. Adequate training and education of biobank personnel and a tracking mechanism to ensure training is current and role specific are essential parts of the overall QM strategy. This helps to ensure consistent and informed application of both quality assurance and QC measures. The process of review of a QM system allows for evaluation around what is and what is not working in the QM and the ability to make changes. There are several types of external assurance programs that are offered on the international stage that are complementary strategies to raise the standards across the discipline of biobanking. Some define an upper standard and use an external assessment process and measurement of product quality, while the focus for other programs is to define a minimal standard and concentrate on education. An example of the latter approach, which ties all these components of QM together, is the concept of biobank certification, which is broadly applicable for all entities handling biospecimens and is offered by the Canadian Tumour Tissue Repository and UBC Biobank Resource Centre. Helen Moore: Quality can mean very different things to different people. One might think of quality management as the process followed to determine that, in the end, you got what you set out to get. For biobanking, quality management would follow the complex set of procedures undertaken to enroll a research participant in biobanking and collect, process, annotate, and store biospecimens, and determine whether that process yielded biospecimens and associated data sufficient for the purpose collected. Foundational elements would include well-documented SOPs that are understood and accepted by those who are collecting, processing, and storing biospecimens, as well as training on SOPs and annotation of deviations from SOPs. Quality criteria must be set at the outset and suitable metrics and analytical tests used to evaluate the processes and determine whether the quality criteria have been met. Having a quality management plan in place for biobanking does not mean that perfection is expected; in fact, it is important that quality management be reasonable in scope and that errors be expected. For example, some level of biospecimen degradation may be unavoidable in some circumstances. Awareness of this possibility and being able to measure relative degradation is part of the quality management plan. Good quality management in biobanking at best can translate to higher quality and reproducibility of research results using the biospecimens. Akin Abayomi: In Africa, where extreme ambient temperatures are the order of the day in conjunction with potentially large geographical distances that samples may need to travel, attention to detail is critical. Clear and comprehensible SOPs and frequent training activities, particularly at sample acquisition research sites, are key to ensuring sample integrity. The emphasis is shifting towards minimizing preanalytical variables, which necessitates the need to have the capacity to bring the process of stabilizing the physiology of the sample closer to the donor. This is possible with good logistics and strategic team activity dovetailing with synchronized operations between the researchers and the biobanking teams. Communication is critical in this process. Kit development and dispatch to sites of collection with good training and harmonized operational activity all along the route of the sample until it gets to its final storage site are mandatory in this process. Where cell-line creation is part of the menu of operations, then the sooner the blood mononuclear cells are isolated and either frozen or processed the better the outcome. This process can start at the collection site to stabilize the cells and completed at a central facility. Staffing at peripheral collection sites will need to be upskilled and infrastructure adapted to this objective. Use of emerging room temperature storage and transportation technology to stabilize the whole sample at time of collection or soon after isolation of nucleic acids may be useful options in some environments. What are the advantages and disadvantages of centralized vs individual/local biobanks? Tim Peakman: There is no right or wrong answer to whether a study should adopt centralized or local sample processing and archiving. This will depend upon factors such as size of the study, daily volunteer recruitment rates and sample acquisition, sample processing throughput, complexity of the processing protocols, available budget, and the expertise of the study team. As a general rule, once studies reach a certain size and certain sample accrual rate, centralized biobanking offers a number of advantages but this does depend upon the study. Use of automation allows much higher numbers of samples to be processed on a daily basis much more consistently and with a robust, secure anonymized data trail. Quality data are recorded as part of the process and, if sample storage and retrieval are automated, samples can be stored and retrieved quickly from very stable, low-temperature environments with complete accuracy. Balanced against this, central services cost a lot to establish and maintain and often samples need to be shipped from collection centers that introduce delays in processing (although the effects of this can be largely mitigated using temperature-controlled shipping conditions) and increase transport costs significantly. Smaller single-site studies may benefit from local processing which is as quick as possible (and is therefore likely to preserve as many analytes as possible), is suitable for very complex protocols, and doesn't incur high setup or transport costs. This approach is limited to relatively small numbers of and can with process and variability the and requires maintenance of a data trail for studies with recruitment From that the cost sample for large studies is also increased with local need to the and of each for their study in their with an of the stability of the samples they are and processing and the costs of different Peter of At the biobanks are the of a complex activity biobanking, and some components of biobanking need increased to reduce research that of and biospecimen while need more to quality processing and and other components need both of networks can be centralized in but with distributed from and at the level are many quality, and factors that what is a facing organizations and research whether to or their A of these and the many and have often been to of the by the to in research is an essential and but of around infrastructure is The types of biobanks and research to be are other important is no only important considerations. as around issues such as reproducibility in research and the need for increased scale and quality in biobanks can only come with implementation of and the need for more components and of many types of biobanks Helen Moore: biobanks can advantages of increased of biospecimens, with systems for quality management, data management, and or local biobanks may provide advantages in and One way of these is biobanks so that individual biobanks use the or at and approaches to biobanking, the of biospecimens across different sites in a or biobank. An quality management program across the system would be an important of such a network and would include to different collection sites and a of collection and storage that might be in place at different It would be important to where approaches and processes could be at different sites, and for (and such where they could A network would good and education about the of the to answer such are to What is the of the is harmonization of approaches and quality management important to the final facilitate better biospecimens and better research through this Akin Abayomi: In Africa, where infrastructure is and can be through is an with a more central biobanks with effective to peripheral collection processing sites would the of the research team and ensure samples are as to that of the volunteer as possible. This would and The centralized more to the emerging of and biobanking being more to the of and able to to samples before of scale can be with and on of or This approach also to the of researchers biobanking which can have on and sample that are becoming more now and for future of biological The ability to focus more on good with to collaboration between studies and larger size studies, which are use of biospecimens for and studies. What are some of the issues facing biobanks in of long-term Peter Watson and Lise Matzke: Biobanks are expensive to and From collection of biospecimens to processing, storage, and activities, the of activities in a biobank is a biobanks are the biobanks in their and Further, as a research biobanks a complex and that is with biobank Biobank is therefore a of and usually the the importance of other aspects or should not be biobanks are often as not being secure they on or it is the complexity and variation of and that is the most important of this and it is the metrics to evaluate the relative importance of individual biobanks and the importance of biobanks other of research infrastructure that the critical of research are and all focus on the of research should in biobanks if the scope and need are not the for any and is very and not and the research to biobanking is recognized as an important part of particularly in the research their in to the research and then to a is At the end, the to to a set of the and standards by which biobanks should be able to at to ensure research quality, is the greatest to of individual The good is that these issues are now a part of an in the biobanking the of new strategies to these issues. Helen Moore: are often collected for specific research the research have been the research may be the biospecimens may have for research use. to the of biospecimen and the to support their storage and can be challenging. A greater emphasis on to the about the of biobanks in and to about the of biobanking, will be important to in biobanking. is about the actual costs of biobanking. The National Cancer Institute is a on the aspects of biobanking. The data will be in and in an that will be able to for about the costs associated with biobanking. Akin Abayomi: In environments with a of in and for the greatest for or is in and on to provide that can either as or as a strategy. Biobanking is not high on the and in environments its return in of and of a is not research that biobanking strategies have the of in to their research In such external can be used as to which will as a for the need to establish national and the right environment to the biobanking, and national research can biobanks better their to researchers and the Peter Watson and Lise Matzke: the of a biobank requires the biobank to be on and and key other words the of the For the the and to key is to researchers and the will the that is in biospecimen for while to the the emphasis is on the end biobanks are working for better these requires a different strategy from vs scientific to each in the design, and of a biobank. Helen Moore: Biobanks are an essential of the medical research and the for and in biobanks must be upon and It is important for the to that of research biospecimens, as well as the by biobanks of the biospecimens for current and future is to medical that may benefit the research and their In the the concept of for the good is to or who are for their they are to whether they would be to donate in the of an It is important now to the about of biospecimens for research. Such education must be across and Akin Abayomi: Communication in the of has to the and of national to and and to the from which samples will be requires a different strategy and of to the in The greatest will be from the of the and are important to effective and The in at the different can be quite and should not be For the national the importance of the is to bring to the advantages to be through not in of of its but also the of the benefits of biobanks requires the the of are critical in an strategy and form an important of overall An aware and informed is to but with this the evolving of The engaged is more and requires to on the emerging and role of biobanks in the return of research results to biospecimen and the that will result from review of and by Peter The issue of of research has become of the most and issues facing research and research in are in of data and the scale and of research data as by the in the of data from biospecimens. The complexity and of different are and the of of the and of biobanks that in between the and the research of the has an all an important issue and is often in the research by its nature and must be and to some from clinical There are both and to to this research biobanks not the clinical and should be to the for return of research is not the as an to raise issues or in the process of return of results from research and become to the biobank. Helen Moore: In larger and larger of research have become part of medical and technologies for and an important role in biospecimens. Such as well as established analysis approaches such as review, can some results that are as to the research In some cases the are of no or clinical but in other cases the may have clinical be such if in a research a clinical to be and researchers or biobanks not to be for the to research their as more is about and studies are for medical the between research and clinical are The of researchers and to return is a of much are the of what are and the benefits and of the to the research their Akin Abayomi: This is a complex clinical that will closer to the of as the concept of more of an It is to potentially useful from a or the the are and the ability to and data in an to the donors. The concept of will as a more to as and to patients more through on or or emerging issues that you will have on the future of biobanking. Tim Peakman: One of the for biobanks will be data This is likely to come from from use of the studies data and samples to other researchers and typically this involves the return of research data to the biobank once the is The of this is that it the for future of the of scientific that can be using these and the technologies used to biobanks will need to data data quality, and data are stored and in a data large biobanks are their expertise and to to large data on their sample For example, Biobank is the is about in the and of the whole and is an approach to collect data on people. data are very large and and of storage, and use. both from such as genetic and new analytical approaches and from by will be a data management in the of the of large biobanks is the of studies can use the should be taken to avoid using the of in a way that in the data It was on this basis that Biobank to the with the that in or it will be to the of all of the people. This a of the so that the can be used for other types of emerging are approaches for the and Helen Moore: across biobanks and research programs will be very important in the future of medical research to better individual in of disease, and to such data while the of individual research is a for the A better of biospecimen the effects of different biospecimen collection, processing, and storage on the of biospecimens, is need to attention to now so that can biospecimen practices for different analysis also need to be the by which biospecimens are and storing this with the biospecimens in This approach will be even more important in the future so that will be some assurance that collected and stored biospecimens are suitable or for for research and of specific as analysis technologies Akin Abayomi: will become an important of the future as a means of tracking samples and related can ensure the ability to track samples from to and to the use of in the should be able to a biological from a research site to primary or and the benefit that is in to a This will become particularly important with the use of cell-line technology in of both a quality assurance and a means of tracking and It will also as a means to in the scientific process and start the for on a standard operating quality

Michael A. Weber

Academic physicians are under attack in the United States. Federal and state politicians, the lay media, some regulatory agencies, medical journals, and even medical schools have voiced strong concerns over the relationships between academic physicians and the pharmaceutical and device industries. These industries have been accused of corrupting medical research, education, and practice; and so, by extension, academic physicians who participate in these activities have become a focus of unfriendly attention. In their clamor, critics have not been reluctant to use the pejorative and misleading term conflict of interest in describing these academic-industry relationships. Physicians are notoriously slow to react, but in the end a group of academics from diverse medical specialties met at Harvard in late July to conduct the inaugural public meeting of a new organization: The Association of Clinical Researchers and Educators (obviously now known as ACRE). And, in the interests of transparency, let me immediately state that not only do I participate in research and educational services supported by industry, but that I was one of the founders of ACRE and took part actively at the Harvard meeting. Why in the United States—and throughout much of the world, for that matter—have academic physicians and industry forged their collaborations? In reality, a large part of medical research and education in contemporary times is based on this relationship. Dr Jeffrey Flier, Dean of Harvard Medical School, acknowledged at the ACRE meeting that his school’s mission to promote medical education and research requires interaction with industry.1 Most of the major advances in recent decades in conditions such as cancer and heart disease, and their incorporation into medical practice, have resulted from this partnering between academia and industry. Academic physicians are uniquely qualified to identify unmet medical needs and, working collaboratively with industry colleagues, to devise and conduct the types of basic research and clinical trials that lead to therapeutic breakthroughs. It is not difficult to understand why our critics have come to question this relationship, including legitimate concerns about preserving the independence of academic physicians. But one of the dominant motivations for this negativity comes from the costs—admittedly, often quite high—of new developments in patient care. Government agencies with limited budgets and commercial health plans with financial obligations to investors understandably look with dismay as relatively more costly tests, procedures, and therapies are developed and made available by industry and its academic advisors. From the perspective of health plan operators, the situation only gets worse when academic physicians teach their practicing colleagues about the attributes of these new developments. ACRE’s first meeting, which played to a packed house in the Bornstein Amphitheater at the Brigham and Women’s Hospital, attracted a wide range of speakers. There were representatives of medical societies, including such disciplines as diabetes, lymphoma, myeloma, and hypertension. As well, there were representatives of patient advocacy groups passionately committed to preserving the productive academia-industry collaboration needed to address unmet needs across a broad range of serious illnesses. An important insight came from a nationally recognized medical ethicist, Lance Stell, who is a professor of philosophy and Director of the Medical Humanities Program at Davidson College. “Conflict of interest” in the medical context has a clear meaning. Specifically, it occurs when practitioners accept personal rewards (such as fees, grants, awards, or recognition) in return for actions that could violate their professional obligations. In essence, to accuse a clinician of conflict of interest would require empirical proof that, in return for a reward, an action was taken that resulted in diminished care or even harm to patients. Clearly, such occurrences are extraordinarily rare in the conduct of medical research and education activities. There are words that are more accurate and less emotive than “conflict,” and we are starting to see a preference for such terms as duality, concordance, or alignment of interests. It is ironical that another speaker at the ACRE meeting discussed how certain actions in the medical setting, which perhaps really do represent true conflicts of interest, go without criticism. For instance, some commercial health plans offer practitioners direct monetary rewards for switching their patients from more expensive to less expensive drugs, or, possibly, for reducing their use of tests, referrals, and therapies so as to minimize the insurers’ outlays. Much of the information received by practicing clinicians comes from events that are funded, directly or indirectly, by industry. Partly, this is by default. After all, who else has both the responsibility as well as the resources to provide ongoing education in the clinical sciences? Inevitably this type of sponsorship has been criticized on the grounds that industry is not providing support out of altruistic principles, but rather is more intent on marketing its products. Apart from unrestricted grants that industry can provide to medical schools or hospitals to support educational ventures of their own choosing, there are two main types of industry-supported education. The first of these comes under the heading of promotional activities, and the second is labeled as continuing medical education, or CME. Each of these has its share of critics. Promotional education programs can take place in hospitals, medical offices, or at outside venues such as restaurants and are designed to provide information directly about a company’s product. These types of activities are regulated by such agencies as the Food and Drug Administration. In the case of a pharmaceutical agent, the information presented must be balanced, providing information about risks as well as benefits, and must conform largely to what is stated about the drug in its approved product label. Claiming a desire to comply with these rules, many pharmaceutical companies have tightly scripted the content of these presentations, typically demanding that presenters faithfully use a company-provided slide set without allowing them the option to add, delete, or make any other changes. This requirement obviously creates fundamental problems for academic physicians invited to present at such events. After all, how can well-regarded experts stake their reputations, not to mention the reputations of their academic institutions, on material that has been created by unknown persons at the behest of a pharmaceutical company? Not surprisingly, some major medical schools have now instructed their faculty members not to give such lectures unless they have meaningful control over the content. For community practitioners who attend such events, this is an unfortunate development, for it deprives them of beneficial teaching interactions with true medical leaders. Some observers believe that industry lawyers, in imposing this censorship, have overreacted to regulatory requirements, and there is even a suspicion that these rules—rather too conveniently—enable companies to focus more directly on their marketing messages. Rescuing this situation and re-creating collegial educational experiences in the community will require negotiations between industry and academia and, in all likelihood, regulatory agencies as well. CME is a very demanding proposition. On the one hand, industry has a compelling obligation to facilitate high-quality educational opportunities and updates for the users of its products. But, at the same time, CME rules demand that industry has a “hands off” involvement in such events, merely serving as a provider of grants. The contents of CME programs usually are created by academic faculty and are subjected to peer review (similar to an article submitted to a journal) to ensure their objectivity. Even so, some critics still claim that industry can exert a bias on this process simply by selecting which types of programs they will support. But while it is true that pharmaceutical companies are more likely to support CME activities within their areas of medical interest, industry now goes to considerable pains to ensure that its grant decision processes are kept entirely separate from marketing activities. The opponents of industry support for CME activities still claim that, despite the firewalls, industry is still rewarded for its support of CME activities by increased sales of its products. Even if this were true, it is a not unreasonable proposition that if well-balanced data, presented in an unbiased fashion, affects the subsequent utilization of drugs or devices, this will very likely be to the benefit of patients. From the perspective of academic clinicians, rigorously conducted CME events in which they are free to select the content and ideas represent ideal opportunities to enhance practitioner knowledge and patient care. Attempts by legislators (and others who regard medical education as a health–care cost driver) to prevent or limit industry support of CME could have the effect of diminishing the quality of medical practice. Again, it is the responsibility of physicians and organizations like ACRE to argue the value to patients of cooperation between academia and industry in medical education as well as in research. Many medical societies, particularly small specialty organizations, depend on industry support. The operating costs of societies, as well as the cost of meetings, publications, patient education and other professional activities cannot be fully funded by member subscriptions. Support from industry is often essential and comes in the form of corporate memberships, sponsorship of CME or other activities at scientific meetings, exhibit fees, and journal advertising. This support has been criticized by the media as indicative of excess industry influence on professional activities. And, indeed, it might be appropriate for societies to consider whether funding from industry and income from members should be directed selectively to purposes relevant to those funding sources. It is worth noting that the mistrust between the provider of health services and the worlds of academia and industry became a major public issue in Great Britain about 4 years ago. In fact, a committee of Parliament issued a report expressing concern at the failure of the academic community and the health service to work more closely with the pharmaceutical industry to minimize inappropriate or suboptimal use of drugs in clinical practice.2 Subsequently, in a high-profile report issued early this year, the Royal College of Physicians (which represents a broad range of medical specialists) stated that the interests of patients and their clinicians are best served by close cooperation between academia, industry, and the health services.3 It is unfortunate that we have lagged behind on this side of the Atlantic. Indeed, one of the most telling statements made at the Harvard meeting came from Massachusetts State Representative Michael Rodrigues, who helped lead the opposition in the legislature to a now-enacted law that dramatically curtails interactions between physicians and industry in that state. It was particularly discouraging to hear from this representative that he and his colleagues lost their opportunity to block the legislation when local physician leaders gave up the fight and decided to remain silent. The responsibility of ACRE is to re-establish the partnership of academia, industry, clinicians, and patients in the United States. Among its initial goals is educating the lay public as well as the medical community about the value to patients of the research and educational collaborations between academia and industry. This will be no easy task, for so many negative items have already appeared in the media regarding the alleged manipulation of physicians by industry, usually with only weak rebuttals by academic or industry leaders. Indeed, one of ACRE’s main responsibilities will be to develop a public voice that gets heard and quoted when such issues arise. There already has been one such success: Dr Thomas Stossel, one of ACRE’s leaders and the chair of the Harvard meeting, was invited to testify at a high-profile US Senate hearing on CME in late July. Another of ACRE’s main tasks will be to set up codes of conduct or guidelines designed to ensure that relationships between academic physicians and industry are ethical and clearly targeted at improving outcomes for our patients. This, again, will take considerable thought and discussion. As Dean Flier pointed out, we still need to figure out how best to “strike a wise balance” and create “manageable tension” in optimizing productive interactions between academics and industry. From the perspective of the many of us involved in cardiovascular medicine, it is easy to see the dramatic improvements in patient care that have resulted from the academic-industry partnership in recent years. Major clinical events and mortality have been sharply reduced in such areas as hypertension, lipid disorders, diabetes, heart failure, acute coronary syndromes and chronic kidney disease by this collaboration. ACRE’s members, in common with most physicians, no longer find it acceptable to let others unilaterally set up the rules by which we are expected to function in performing these vital tasks. It is long overdue that we take responsibility for our professional activites in research, education, and practice. More information about ACRE can be found on its Web site: http://www.acreonline.org The site also has information about how to become a member.

Ulrike Neumann, Anja Hagen, Matthias P. Schönermark

Because great interest in an efficient range of effective medicinal innovations and achievements has arisen, many countries have introduced procedures to regulate the adoption of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances. With this as a background, this report will describe procedures for the adoption of innovative non-medicinal technologies by solidly financed health care insurances in Germany, England, Australia and Switzerland. This report was commissioned by the German Agency for Health Technology Assessment at the German Institute for Medical Documentation and Information.In order to find the relevant literature and information, systematic literature research, a hand search and a written survey were carried out. All the selected documents (chosen according to defined criteria for inclusion and exclusion) were qualitatively evaluated, summarized and presented on a chart using a framework developed for this purpose. All the countries in this report require that some innovative non-medicinal technologies undergo evaluation by a central governing body. This evaluation is a prerequisite for adoption into the benefit catalogue. The process of evaluation can differ (e. g. the people and institutions concerned, the division of the synthesis of evidence and overall evaluation, processing the evidence). Similarities do exist, such as the size and composition of the governing bodies or the overreaching criteria according to which institutions must make their recommendations. This is how all the countries examined in this report determine how the benefits and effectiveness of the innovations, as well as their cost-effectiveness, can be chosen as criteria for the evaluation. Furthermore, there are many criteria which differ from country to country (social and ethical aspects, possible effects on the health system, etc.) and which are also relevant to an evaluation. The preferred types of clinical studies for these evaluations are randomized controlled trials. However, all institutions do allow for other types of evidence (e. g. expert opinion) when no other study types of a higher evidence level are available. In addition, all the countries are willing to allow unpublished or confidential information (e. g. from manufacturers) to be included in an evaluation. It is important to remember that the decisions made by the central governing bodies do not necessarily become conditions for the introduction of innovative non-medicinal technologies. There is a host of other requirements which determine how these innovations can be introduced. This means that a large number of non-medicinal technologies make it into the medical care system via these other decision-making processes. Often, these innovations are unevaluated and differ from region to region. Every country has established a system of observation and registration for medicinal products. These systems are meant to document any incidents with the innovations and to confer responsibility on certain organizations. All in all, no country has a central authority which systematically investigates the effects of newly introduced innovative non-medicinal technologies on medical care in general. However, Australia and England both carry out a review of innovations in some areas (e. g. by means of special commissions). In principle, the starting point for improving regulations of innovative non-medicinal technologies lies in the extension of transparency, the shortening of decision-making time (especially the central decision-making processes), the further development of evaluation methods, more flexibility and increased capacity in the governing bodies' decision-making processes and also, if needed, in the creation of a single authority to act as contact for people who are interested in introducing an innovation into the benefit catalogue.More research is required, especially in the area of decentralized decision-makers and how they actually decide whether or not to introduce innovative technologies into the core care system (methods, criteria, etc.). In view of this, it would also be interesting to see how the application of innovations actually happens in practice once their adoption has been approved by the corresponding governing bodies.

Romuald K. Schicke

This article contends that the German social and economic situation is conductive to the rapid diffusion of innovative medical technology. While there is public control over hospital facilities, the pluralistic health care system and decentralized government responsibilities contribute to an essentially laissez faire regulatory environment. There is perfunctory planning and regulation for major medical expenditures, but the essential constraints are financial. This is no comprehensive program for the assessment of diagnostic technologies and the effective imposition of guidelines depends on the cooperative effort of various financing organizations, professional interests, and public pressure groups.

Gail Henderson, Yuanli Liu, Xiaoming Guan, Zongxiu Liu

Chinese hospitals in the 1980s are in the midst of a technological revolution. Based upon data from several regions in China, this paper describes the political, organizational, economic, and philosophical changes which have accompanied the shift in focus from primary care medicine to high technology tertiary care. The increased authority of physicians, greater contact with the West, and increased funding for medical equipment are key factors in these changes. Although the Chinese state continues to control the administration and financing of most hospitals, the decentralizing reforms of Deng Xiaoping have undermined its ability to effectively plan for, and assess new technology. At present, limited resources prevent most regions from excessive technology acquisition, but the state must rebuild its planning capacity in order to foster rational allocation of scarce medical resources.