The NANOSPRESSO project, described by Senti et al. in their lead article (Senti et al. 2025), is being developed to address the immense unmet medical need in the rare disease and rare cancers communities that are currently underserved by pharmaceutical industry and healthcare providers. The current situation in rare diseases, with small patient numbers (sometimes with only a single case reported worldwide) and substantial drug development costs, makes it difficult for the pharmaceutical companies to recoup their investment in this field.These commercial disincentives, combined with an uncharted regulatory landscape, impede the translation to the clinic of the scientific advances in development of nucleic acid-based therapeutics (NBTs) achieved in recent years that could have already significantly improved the lives of many patients with rare diseases and some rare cancers (Cheerie et al. 2023, Qian et al. 2025, Khorkova et al. 2023).Although the exact proportion of genetic diseases treatable by formulated NBTs (fNBTs) potentially produced by NANOSPRESSO is hard to calculate, a rough estimate based on the known types of pathogenic mutations and the proportions of genes amenable to regulation by multiple endogenous mechanisms that can be engaged by NBTs shows that it could be significant. However, in spite of the plethora of known NBT-based approaches that can be used in the treatment of genetic diseases caused by point mutations or insertions/deletions, substantial current practical challenges in this field can limit their impact (see Supplementary Materials).Although the first successful example of an "n=1" NBT (i.e., one produced for a single individual) was published in 2019 (Kim et al. 2019) it has not been widely replicated, with only 26 other cases over 16 years (Cheerie et al. 2025), and the currently available NBT treatments mostly focus on more common cases (e.g., nusinersen for spinal muscular atrophy) (Moultrie et al. 2025). The interdisciplinary team needed for development of such personalized medicines would require members with expertise in diagnosing the diseases, sequencing the mutations, designing and manufacturing NBTs to pharmaceutical standards, resolving patent issues, ensuring regulatory compliance, and administering the treatmentwith all of this provided in time to stop the progression of the disease. Assembling such a team for each individual case in limited available time is practically impossible under current conditions. This process however could be facilitated if there were institutions providing the necessary infrastructure, such as organizations capable of all the above functions.Establishing and financing such institutions represents probably the biggest challenge in translation of achievements in personalized medicine to the clinic. Other problems in this case include the need for regulatory bodies to develop the appropriate framework for personalized drugs and maintain specialized personnel for inspections, as well as multiple other legal and societal implications including treatment cost, patent issues, and ethical considerations.Senti et al. propose the NANOSPRESSO project as a solution to the challenges posed by translation of personalized NBTs to the clinic (Senti et al. 2025). NANOSPRESSO promotes decentralized personalized production of formulated NBTs, construed as drugs for magistral preparation in hospital pharmacies. Magistral preparation is used for individual patients when no approved alternatives exist, which is the case in many rare diseases.Senti et al. outline a production protocol that includes encapsulation of NBTs in lipid nanoparticles (LNPs) using microfluidics technology on location at hospital pharmacies. The NBTs will have to be custom-designed for individual patients, or small groups of patients.This could represent the most labor-intensive, unpredictable, and expensive step in the production process. The designed NBTs will then be manufactured at pharmaceutical-grade nucleic acid synthesis facilities (potentially including CelluTx LLC, siTOOLs Biotech, or Anjarium Biosciences AG). The authors envision that the final step of NBT drug manufacture, its encapsulation in LNPs (potentially designed and manufactured by companies such as Lipoid or NanoVation Therapeutics), will be accomplished at the hospital pharmacies using a specialized piece of microfluidics equipment (potentially by Solstice Act (FDCA) exempts pharmacy compounding performed for a specific patient from FDCA requirements such as compliance with current good manufacturing practices (cGMP), appropriate labeling, and US Food and Drug Administration (FDA) approval. However, due to complex and innovative nature of NBTs the regulatory bodies may need to develop the appropriate framework for personalized NBTs and maintain purpose-trained personnel for routine inspections of facilities in hospital pharmacies. Importantly, the authors stress their on-going communication with European and state regulatory authorities (Senti et al. 2025).Notably, the NANOSPRESSO project considers the implications of the patent laws, ethical considerations around gene editing and the implications for social equity and human diversity, all of which are essential for the wide adoption of personalized NBTs. Notably, the NANOSPRESSO project also plans to develop a unified platform for technology and data sharing with blockchain security and consistent data formats across the network. Such platform can ensure patient privacy and intellectual property protection and provide easy interface with AI tools.The current NANOSPRESSO-NL project is supported by a Netherlands Science Agenda-Netherlands Organization for Scientific Research grant. However, it is only a 6-year project, which does not allow sufficient time given the scope of the undertaking. Other financing sources may be available. Notably, the potential market for personalized drug technology is substantial, as more than 300 million people worldwide suffer from genetic disorders (The Lancet Global Health, 2024, Cavaller-Bellaubi et al. 2023). Additionally, new genetic disease-and cancer-causing mutations are discovered every year. From the reimbursement point of view, treatment with NBTs could significantly decrease lifelong spending compared to the currently available treatments. For example, average inpatient admission costs over a 12 month period post treatment with nusinersen (an NBT for spinal muscular atrophy (SMA))were reduced by 63% in pediatric patients and by 79% in adult patients as compared to the 12 months pre-nusinersen treatment with prior standard care (Zhu et al. 2024). Treatment with single injection gene therapy drug for SMA, onasemnogene abeparvovec, further reduced the annual numbers of inpatient admissions (by 66%) and emergency department visits (by 50%) compared to nusinersen treatment (Toro et al. 2023). These numbers are especially significant given that direct non-healthcare informal cost for families of SMA patients can reach 63% of total annual disease cost (Landfeldt et al. 2023;LĂłpez-Bastida et al. 2017).Experience gained in the NANOSPRESSO project may help obtain a more realistic estimate of the benefits afforded by personalized drugs.Furthermore, data and expertise gained in the treatment of rare diseases could be instrumental in developing drugs for common diseases. The 'intervention-outcome' type datasets in uniform format generated by NANOSPRESSO could be essential for training AI tools for discovery of novel gene-disease associations, structure-activity relationships, assessing delivery efficiency of the LNP formulations and toxicity of NBTs, etc. Reports on drug preparation procedures and treatment outcomes provided by clinics utilizing the NANOSPRESSO approach are likely to be an important asset generated by the NANOSPRESSO program. Licensing access to data and reports generated in the NANOSPRESSO project to pharmaceutical and biotechnology companies could provide revenue to extend the project beyond the current 6-year funding period. However, fundraising (and associated expenses) may be needed to engage these and other financing sources, including rare disease foundations, charitable organizations, and government programs.At present the NBT treatments might not lead to a complete cure, due to late diagnoses, incomplete knowledge of disease biology, poor delivery to target tissues, suboptimal dosing regimens, toxicity, immunogenicity, etc. However, these issues can be resolved with more experience using NBTs in the clinic. Importantly, even in their current form, NBTs can bring significant improvements in patients' and caregivers' quality of life and relief to the financial burden (Zhu et. al 2024, Toro et al. 2023).As significant as the challenges with magistral production of personalized fNBTs are, they are surmountable given the measures proposed by NANOSPRESSO. Furthermore, as Senti et al. point out, there are successful precedents of personalized technologies being used at the point of care, e.g., the Prodigy system (Miltenyi Biotec, Inc) that automated the entire process of chimeric antigen receptor (CAR)-T cell manufacturing from cell activation to reinfusion.The NANOSPRESSO project could also tap into a pro-active network of rare disease foundations. Notably, NANOSPRESSO could enhance community participation by improving their website and posting frequent updates on the project plans, progress, crowdsourcing efforts and citizen scientists' initiatives, as the website could be the project's
In December 2021, one of the authors of the present paper (AR) took part in the peer review of the paper âSafety and immunogenicity of an inactivated virus particle vaccine for SARS-CoV-2, BIV1-CovIran: findings from double-blind, randomized, placebo-controlled, phase I and II clinical trials among healthy adultsâ for the BMJ Open1, 2. The manuscript described clinical phases I and II of the COVID-19 vaccine BIV1-CovIran by Shifa Pharmed Industrial Group. The article was accepted for publication in March 2021 after three review rounds, with a total of six reviewers involved. On May 2022, AR received an email from Yeganeh Torbati, a Washington Post reporter who was investigating the development of BIV1-CovIran. Torbati asked AR for a general opinion about the data presented in the above article. AR replied that no serious anomalies were highlighted, although he specified that the peer review process was too superficial to guarantee complete integrity. Subsequently, through an article published in the Washington Post in August 2022, Torbati disclosed serious misconduct dynamics3. In support of her claims, an official correction was published in the BMJ Open in November 2022, in which the authors were forced to admit various conflicts of interest and the occurrence of vaccine-related adverse effects1. The relevant fact is that not even six peer reviewers and one editor have discovered such a hidden scenario. This is not intended to blame the journal or the reviewers but only to denounce that the world of scientific publication is currently subject to easy ethical violations. Although financial relationships can markedly bias biomedical research, marginal importance is given to this aspect4, 5. In this regard, this letter proposes a set of practices to counteract some major integrity problems.What can authors do?A1. Authors should facilitate research reproducibility to boost peer-review speed and accuracy. This includes i) sharing codes, calculations, and data (raw and elaborated), and ii) providing a step-by-step description of the ideas that led to the realization of the project, the implementation of the methods, and the procedures to assess the tests' assumptions.A2. Authors should adopt frameworks for enhancing quality in preclinical data since this can significantly increase transparency and trust in results and allow errors to be prevented rather than detected too late6.A3. Regarding clinical trials, authors should publicly share audit/monitoring documents, information about the contract research organization that monitored the study, and data submitted to regulatory agencies (at least on the clinical testing front, which does not seem to threaten intellectual property or industry secrets).A4. Authors should release a preprint version so as to allow the scientific community to review the results independently and rapidly.What can academic journals do?J1. Journal editors should evaluate the paperâs health sensitivity and decide whether it is a high-sensitivity topic. All research involving novel drugs, vaccines, and therapeutic strategies should be considered at high sensitivity.J2. For high-sensitivity topics, journals should compulsorily require A1-A4. Any draft version that has passed peer review should be released at the very moment of approval, explicitly indicating that it is an unedited peer-reviewed version. Reviewers' reports and authors' responses should always be published, ensuring easy citability (e.g., DOI). Reviewers' names and affiliations should also be published unless they express reasonable fears for their safety. This should help reduce the problem of coercive citations7. Finally, journals should allow authors to publicly share editorial rejection decisions, including reviewers' reports.J3. For high-sensitivity topics, journal editors should stratify the peer review to ensure the validity of the key elements. Alongside a general assessment, each methodological aspect (e.g., design, population, data collection, statistical analysis, and results) should be carefully evaluated by one or more independent specific experts, especially when dealing with high-complexity data or multidisciplinary approaches. Regarding clinical trials, editors should involve expert figures to evaluate pharmacological and public health aspects (e.g., adverse reaction reports). Journals should also include a specific mandatory section in which reviewers declare the limitations of their review (e.g., âI'm not an expert on Bayesian methodsâ), so that editors and readers have a clear understanding of what the reviewers assessed. Finally, double-blind review should be required to reduce authorship bias8.J4. For high-sensitivity topics, journal editors should create a dedicated section made up of two or more journalists experienced in detecting ethical violations. Such supervision should extend to the authors but also the reviewers, who could voluntarily influence the publication process. The inquiry must only concern researchers' professional relationships and activities, without affecting the private sphere, in order to safeguard their privacy. The academic journal should propose to the reporters to sign a non-disclosure agreement regarding the data found and guarantee the quality of the investigation.J5. For high-sensitivity topics, journals should compulsorily require that the data are suitably standardized to allow decentralized analysis through automated tools, software, or artificial intelligence algorithms6, 9. Specific guidelines should be provided to help authors with the A1 point. Means for decentralized analysis should be provided to reviewers. Should a unique international standardization be chosen by regulatory agencies, journals would have to adhere to it.J6. For high-sensitivity topics, journals should pay peer reviewers and editors. Indeed, paying peer reviewers â a sustainable practice, as shown by the editorial policies of various journals â would foster excellence thanks to an economic reward proportional to the reviewer's skill (competition mechanism). One of the main obstacles to publication, namely the difficulty in finding available reviewers, would be quickly overcome. Scientists could play this role on a permanent and ongoing basis thanks to the benefits of true job performance. Paid work would increase the actual responsibility of peer reviewers and editors.What can abstracting service groups do?I1. Tiered indexing should be introduced by abstracting services. The top rank should only be granted to academic journals that meet J1-J6. Indeed, since indexing in recognized databases is a source of prestige (so much so that, in most cases, journals reserve a special section of their websites to this scope), doing so would drive health journals to adjust to the new standards. Moreover, this would help the public to identify the most authoritative and reliable journals. Similar initiatives are already underway10.What can regulatory agencies, funders, and institutions do?R1. Funders and regulatory agencies should require necessary authors' compliance with points A1-A3.R2. Regulatory agencies should agree on a unique international data standardization (see point J5) so as to strengthen and accelerate scrutiny by the whole scientific community.R3. Institutions and employers should actively encourage and support scientific refereeing. Moreover, funders should be willing to finance an extra amount to properly perform points J3, J4, and J6.In conclusion, we do ask the scientific community to take a clear position and make itself heard with a stentorian voice to protect public health from ethical misconduct. This renewal would lead not only to direct benefits to the research but also to the public image of the whole scientific world, thanks to a novel, more transparent, efficient, and effective procedure of academic publication. We are aware that these guidelines are tailored to the medical field and that some of our requests could be not applicable or not stringent enough. Therefore, if needed, specific recommendations should be added or lifted based on the research field.
Matthew L. Duenes, Djani Robertson, Jordan Lebovic, Carter J. Boyd · 5 authors
Orthopedic surgery has always been at the leading edge of innovation in medicine, from clinical applications to business practices. Cryptocurrencies have emerged as an exciting new technology where transactions and verification are secured by cryptography rather than a centralized authority, thus creating transparency, security, and immutability to payments. Large industries, including healthcare, have started accepting cryptocurrencies as alternative forms of payment. Insurance companies and private practices in specialties such as plastic surgery and dermatology already accept cryptocurrencies in exchange for services. As such, providers in orthopedic surgery should prepare themselves for inquiries from patients regarding cryptocurrencies. This paper introduces the topic and potential benefits to future orthopedic practices.
Objective: overview of Canadian practices for regulating, financing, and funding prescription drugs. Canada provides universal health coverage for hospital and physician services but excludes universal insurance of prescription medicines. Public plans provide 42% of financing, while private drug insurance covers 35% of expenditures and over 60% of Canadians â mainly through their employer. Canada has relatively high out-of-pocket expenditure (19% of spending) and is currently the tenth largest pharmaceutical market, following Brazil. It is wrestling with inequitable coverage, low use of biosimilars, and affordability and sustainability issues driven by rare disease drugs. Both federal and provincial/territorial governments and their agencies have roles in setting policy and regulating drug prices and costs. These include the federal Patented Medicine Prices Review Board (PMPRB) which ensures prices of new patented drugs are not excessive; the pan-Canadian Pharmaceutical Alliance (pCPA) which negotiates lower patented, generic and biosimilar drug prices on behalf of member jurisdictions; and the Canadian Agency for Drugs and Technologies in Health (CADTH) which provides most public drug plans with robust health technology assessment (HTA), including clinical, economic and budget impact analyses of new drugs. Private drug insurers tend to follow government initiatives, including the use of HTA and confidential Product Listing Agreements. Conclusions: Pharmaceutical coverage in Canada is a âpatchworkâ of more than 100 public drug plans and 100,000 private insurance plans. As such, it creates gaps in coverage which result in inequitable access and high out-of-pocket drug expenses for some Canadians. Canadaâs decentralized health system and the absence of universal drug insurance, among other factors, likely contribute to higher per capita drug expenditure relative to comparable nations that have broader, publicly-funded universal health insurance and more rigourous policy and program strategies.
Open access
Health Systems, Economic Evaluations, Quality of Life
Sreejith Balasubramanian, Shalini Ajayan, Cody Morris Paris
Abstract There are significant challenges facing the medical tourism industry: privacy and transparency concerns, lack of access to centralized medical records, fraudulent practices, opportunistic behavior of intermediaries, foreign currency risks, and contractual/legal issues. While blockchain technology has immense potential to address the industryâs inherent challenges and inefficiencies, the current understanding of blockchain application in medical tourism is fragmented. Through a pragmatic review of the literature, this study explores the blockchain applications and benefits for medical tourists across the stages of the medical tourism value chain, and in the process, proposes a meaningful and managerially relevant blockchain framework for medical tourism. The findings and the proposed novel framework to guide policy interventions and support mechanisms to take advantage of the full opportunities of blockchain in medical tourism.
Madison MilneâIves, Ching Lam, Najib Rehman, Raja Sharif · 5 authors
BACKGROUND: Adverse drug event reporting is critical for ensuring patient safety; however, numbers of reports have been declining. There is a need for a more user-friendly reporting system and for a means of verifying reports that have been filed. OBJECTIVE: This project has 2 main objectives: (1) to identify the perceived benefits and barriers in the current reporting of adverse events by patients and health care providers and (2) to develop a distributed ledger infrastructure and user interface to collect and collate adverse event reports to create a comprehensive and interoperable database. METHODS: A review of the literature will be conducted to identify the strengths and limitations of the current UK adverse event reporting system (the Yellow Card System). If insufficient information is found in this review, a survey will be created to collect data from system users. The results of these investigations will be incorporated into the development of a mobile and web app for adverse event reporting. A digital infrastructure will be built using distributed ledger technology to provide a means of linking reports with existing pharmaceutical tracking systems. RESULTS: The key outputs of this project will be the development of a digital infrastructure, including a backend distributed ledger system and an app-based user interface. CONCLUSIONS: This infrastructure is expected to improve the accuracy and efficiency of adverse event reporting systems by enabling the monitoring of specific medicines or medical devices over their life course while protecting patients' personal health data. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/28616.
Madison MilneâIves, Ching Lam, Najib Rehman, Raja Sharif · 5 authors
BACKGROUND Adverse drug event reporting is critical for ensuring patient safety; however, numbers of reports have been declining. There is a need for a more user-friendly reporting system and for a means of verifying reports that have been filed. OBJECTIVE This project has 2 main objectives: (1) to identify the perceived benefits and barriers in the current reporting of adverse events by patients and health care providers and (2) to develop a distributed ledger infrastructure and user interface to collect and collate adverse event reports to create a comprehensive and interoperable database. METHODS A review of the literature will be conducted to identify the strengths and limitations of the current UK adverse event reporting system (the Yellow Card System). If insufficient information is found in this review, a survey will be created to collect data from system users. The results of these investigations will be incorporated into the development of a mobile and web app for adverse event reporting. A digital infrastructure will be built using distributed ledger technology to provide a means of linking reports with existing pharmaceutical tracking systems. RESULTS The key outputs of this project will be the development of a digital infrastructure, including a backend distributed ledger system and an app-based user interface. CONCLUSIONS This infrastructure is expected to improve the accuracy and efficiency of adverse event reporting systems by enabling the monitoring of specific medicines or medical devices over their life course while protecting patientsâ personal health data. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/28616
1. Introduction to Subject: Participation in Research Trial1.1 Relevance of the Subject Conducting clinical studies includes an obligation to publish results to participants, sponsors, colleagues, and the public (Antes, 2009). ClinicalTrials.gov lists over 304,000 studies with locations in 208 countries (ClinicalTrials, 2019). The German Register of Clinical Trials (Deutsches
By combining the institutional approach and the rational model of digital innovation, there is increasingly a great interest in the implementation of blockchain solutions in healthcare but, until then concrete evidence for this type of project is missing. At the same time the healthcare sector, allergology in particular seems to face security (confidentiality, availability and integrity) issues and information audit trail weaknesses. For these reasons, our study focuses on the co-construction of a distributed ledger for patients allergies with healthcare professionals. The aim is to design and implement a reliable tool to deal with the availability , integrity and confidentiality of information about new allergies and distinguish between validated allergies and declarative allergies for the purpose of mitigating negative effects of unavailability of reliable information about patients allergies. This article defers the first step of our methodological cycle by explaining how collaboration is organized between Pikcio (blockchain technology provider) and allergists. As a result, we have first versions of some deliverables such as formal specifications, risk matrix document and a UML design (class diagram, use case diagram and sequence diagram) as the research project is iterative.
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.
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, âI have no relevant conflict of interestâ or âI have no conflicts that would affect the content of my presentation.â 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, âI have no conflict of interest, unfortunately,â 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 âequal opportunity conflicters.â 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: âConflicts 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 consultantâs fee by the manufacturer.â Fineberg9 believes that a COI exists when a reasonable person would interpret the financial circumstances as sufficient to influence a physicianâs judgment. When the reasonable person standard is used, the âappearance ofâ a COI is redundant.9 Proof of patient harm is not a requisite for COI; there are no âpotentialâ 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 âwriting support.â 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: âWe listen to the manufacturerâs claims and then years later we find that we have been misled â both by the manufacturers themselves and by those surgeons who are burdened by a conflict of interest.â 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 companyâs 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 âinternal brachioplasty scar.â37 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 âconversion rates,â 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 ârippling effect.â5 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 âconsultantâ a euphemism for receipt of a payment to shape oneâs 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 âhas become far too reliant on industry funding,â which âtends to promote a narrow focus on products.â48 The committee recommends restricting consultantships to the provision of objective technical advice paid at fair market value, documented in written contracts. Moreover, companies âshould not involve physicians and patients in marketing projects that are presented as clinical research.â48 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 âtransfer of valueâ 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, $100â$1,000, $1,001â$5,000, $5,001â$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, âwithout which none of this [i.e., the meeting] would be possibleâ 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 âpure.â He cautioned the incoming managing editor that he would need a strong sense of ethics because âyouâll need them in this business.â Goldwyn,53 quoting his father, wrote: âIt is amazing how easy it is to be truthful if one wants to be.â 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, âdoubt is the origin of wisdom.â54 Progress is only made possible by challenging the status quo.
Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact.
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 Statesâand throughout much of the world, for that matterâhave 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 schoolâs 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 costsâadmittedly, often quite highâof 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. ACREâs first meeting, which played to a packed house in the Bornstein Amphitheater at the Brigham and Womenâs 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. âConflict of interestâ 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 âconflict,â 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 insurersâ 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 companyâs 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 rulesârather too convenientlyâenable 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 âhands offâ 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 healthâcare 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 ACREâs 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 ACREâs 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 ACREâs 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 âstrike a wise balanceâ and create âmanageable tensionâ 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. ACREâs 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.
In the early 1970s physicians engaged in fierce debates over the most appropriate method of evaluating the efficacy of coronary artery bypass grafting (CABG). With millions of patients and billions of dollars at stake, CABG sparked fierce controversy. Skeptics demanded that randomized controlled trials (RCTs) be performed, while enthusiasts argued that they already had visual proof of CABG's efficacy. When RCTs appeared, they did not settle the controversy. Participants simply reasserted their preconceptions, defending a trial's strengths or exploiting its flaws. The debate centered on standards of knowledge for the evaluation of therapeutic efficacy. Specifically, cardiologists and cardiac surgeons struggled to assess the relevance of different measures of therapeutic success: physiological or clinical, visual or statistical. Many factors contributed to participants' decisions, including disciplinary affiliation, traditions of research, personal experience with angiography, and assessments of the history of cardiac therapeutics. Physicians had to decide whether angiography provided a meaningful representation of the disease and its treatment or whether demonstrations of therapeutic success could come only from long-term statistical evaluation of mortality data.
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