The scientific credibility of findings from clinical trials can be undermined by a range of problems including missing data, endpoint switching, data dredging, and selective publication. Together, these issues have contributed to systematically distorted perceptions regarding the benefits and risks of treatments. While these issues have been well documented and widely discussed within the profession, legislative intervention has seen limited success. Recently, a method was described for using a blockchain to prove the existence of documents describing pre-specified endpoints in clinical trials. Here, we extend the idea by using smart contracts - code, and data, that resides at a specific address in a blockchain, and whose execution is cryptographically validated by the network - to demonstrate how trust in clinical trials can be enforced and data manipulation eliminated. We show that blockchain smart contracts provide a novel technological solution to the data manipulation problem, by acting as trusted administrators and providing an immutable record of trial history.
In this thesis, I explore how blockchain technology can improve pharmaceutical supply chain operations and discuss how the technology should be implemented. Furthermore, I study how the life science company Bayer's pharmaceutical division can utilize blockchain technology in its supply chain operations. I begin by defining the concepts of blockchain technology, smart contracts and pharmaceutical supply chain. Then I discuss the benefits and implementation in different sections: participating entities and information flow, contracts and payments, logistics, transparency and product security and blockchain infrastructure and governance. Both Bayer and the industry as a whole can benefit from blockchain technology. Blockchain enables for example efficient, safe and private transactions, product transparency and security and open information sharing without exposing trade secrets. For the first time a platform for all stakeholders can be developed that enables transacting information and value simultaneously.
Background: Accessibility to essential drugs is a public right, therefore it's the government responsibility to make them available.Previously before the era of regional autonomy, public drug management in all districts/cities was performed by the so-called District Pharmaceutical Warehouses (GFK).However, nowadays the situation has changed because of the difference in vision and perception of each regional government on the former warehouses.Some public drug management units in certain districts/cities are not functioning optimally.Inefficient drug procurement regarding the number and kind of drugs as well as timeliness results in gap between drug need and procurement.Furthermore, loosening in drug supply procedure makes essential drugs more unavailable to public.On the other hand, decentralization policy in drug management also undeniably brings advantages to the districts, for example capacity building in drug procurement, increasing capability in budget management and negotiation with district decision makers as well as enhancing regional economic activity.In revitalizing district pharmaceutical warehouses so as to attain minimal health care standards in districts/cities, baseline data in drug management and financing in several districts/cities should make a valuable contribution.Methods: A cross sectional descriptive study had been carried out during July-December 2006 in 26 districts/cities out of 11 provinces.Samples were 26 district health offices (Dinas Kesehatan Kabupaten/Kota) and 26 District Pharmaceutical Warehouses (GFK) where as respondents were head of drug section and head of warehousing respectively.Data were collected by means of structured questionnaires and in-depth interviews as well as the collection of secondary data of drug logistics.Qualitative and quantitative analysis was performed. Results:The study shows that: 1) although health budget in general had risen, the average percentage of drug budget allocation from 21 district health authorities was only 12.06%, reflecting the low drug priority in district health policy because drug expenditures may amount up to 40% of the total health budget.2) Public drug management was mostly performed by the so-called regional technical provider unit (UPTD) with some limitations concerning human resources and material in achieving an effective and efficient drug management, and 3) there was still lack of pharmacist assistants to manage drugs in primary health care (Puskesmas) up to 20% and even more piteously the lack of pharmacist in district drug management unit (GF/UPOP Kabupaten/Kota, 12,5%).Conclusions: Apart from the achievement of predetermined indicators stated in minimal health care standards in districts/ cities, especially regarding essential and generic drugs, drug management in general has been well performed concerning planning and drug availability.More support and commitment from the district government is a must considering that regional development can not be separated from the health development of the subject themselves.
OBJECTIVE: To evaluate implementation of the National Essential Medicines Scheme (NEMS) in rural China. METHODS: Two rural counties/districts in each of three provinces where NEMS had been implemented were surveyed. Information was collected from NEMS staff at the province, county/district, township and village levels; patients with chronic disease were also interviewed. Service provision, finances, prescriptions, inpatient records and the expenditures of patients with certain diagnoses were investigated in township hospitals and village clinics. The results were compared with the corresponding data recorded before NEMS was introduced. FINDINGS: Following the introduction of NEMS, drug procurement in each study location was systematized. Total drug costs declined. This, and improved prescribing, reduced the costs of outpatient and inpatient care and led, apparently, to increased uptake of health services. However, the prices of some drugs had increased and the availability of others had declined. The compensation of health-care providers for NEMS-related reductions in their incomes had been largely ineffective. As a result of the introduction of NEMS, health facilities relied more on public financing. Many health-care providers complained about higher workloads and lower incomes. CONCLUSION: Although it was well conceived, the introduction of NEMS into China's decentralized, fee-for-service system of health care has not been straightforward. It has highlighted the problems associated with attempts to modernize health care and health financing for patients' benefit. Sustainable mechanisms to compensate health-care providers for lost income are needed to ensure that NEMS is a success.
Heiner K. Berthold, Olivier Descamps, Ioanna Gouni‐Berthold
Lipoprotein(a) has been associated with cardiovascular disease risk, but no randomized study has shown yet that lowering Lp(a) decreases cardiovascular risk. One treatment option for lowering Lp(a) in high-risk patients is lipoprotein apheresis, which has been approved for reimbursement now in Germany. This decision has been coupled with the mandate to perform a controlled endpoint trial. The ELAILa trial protocol has been filed (NCT01064934), but the study is on hold because of a negative ethics committee vote after strong opposition of part of the medical community due to ethical concerns. The authors argue that a randomized trial is necessary to investigate the effectiveness of the invasive, life-long and costly therapeutic procedure. Meanwhile, reimbursement continues. The study would be the first endpoint trial investigating whether lowering isolated Lp(a) elevation decreases cardiovascular endpoints. The association between lipoprotein(a) [Lp(a)] and cardiovascular disease (CVD) risk has generated much interest in the last few years [1]. However, randomized controlled trials examining the effects of Lp(a) lowering on cardiovascular outcomes are lacking, and thus, an assumption of a beneficial effect remains speculative. In Germany, there was recently an opportunity to perform such a trial using lipoprotein apheresis to investigate whether decreasing Lp(a) improves cardiovascular outcomes in patients with isolated elevated Lp(a) concentrations and progressive cardiovascular disease. Lipoprotein apheresis for this indication is reimbursable in Germany. The study is presently on hold due to the strong opposition of part of the medical community questioning the ethical justification of randomization. The aim of this study is to raise the discussion to an international level, to foster the debate across healthcare systems and to discuss the ethical considerations of not performing such a study. Lp(a) is a low-density lipoprotein (LDL)-like particle consisting of an apolipoprotein-B100 molecule covalently linked to the large glycoprotein apolipoprotein(a) (apo(a)) [2]. The precise physiological role of these particles remains unclear. The distribution of plasma Lp(a) levels in the population is skewed, ranging from <0·1 to >300 mg/dL, and there is an interindividual variation by a factor of ∼1000 [3]. In Caucasians, the 80th percentile of Lp(a) concentrations is 50 mg/dL [1]. Numerous prospective epidemiological studies and meta-analyses [4–6] have reported associations between Lp(a) concentrations and CVD [7]. Two recent studies provided strong evidence for a causal association between increased levels of Lp(a) and coronary heart disease [8,9]. However, it remains unclear whether lowering Lp(a) concentrations reduces atherosclerosis and CVD outcomes. This situation recalls the situation at the end of the last century when many physicians refused to accept that lowering LDL was beneficial until the results of the 4S study [10] unequivocally established that it was. With Lp(a), a major problem in proving such an effect is the lack of an agent specifically and substantially decreasing Lp(a) levels [2]. The current drug treatment of choice for elevated Lp(a), niacin [1], decreases its concentrations by only 20–30% [11] and may reduce cardiovascular events [12], but at the same time affects other lipoprotein fractions so that its overall effects cannot be solely attributed, if at all, to the modest decreases in Lp(a) concentrations. Lipoprotein apheresis, besides decreasing LDL cholesterol, is able to decrease Lp(a) concentrations by 50% to 70% [13]. In Germany, the Federal Joint Committee (Gemeinsamer Bundesausschuss; G-BA), the highest decision-making body of the so-called self-governing health system, decided in 2008 to approve the reimbursement of lipoprotein apheresis for individual patients with isolated hyperlipoproteinaemia(a) (Lp(a) >60 mg/dL) and progressive CVD when all other measures to stop disease progression have failed. This reimbursement decision was coupled with a mandate to perform a controlled trial which would definitely prove (or disprove) the benefit of Lp(a)-lowering using apheresis in these patients. An independent steering committee was created, and an investigator-initiated study protocol for such a study (ELAILa trial; http://www.clinicaltrials.gov identifier NCT01064934) was duly submitted to the competent ethics committee (EC). The study was rejected, however, after lengthy discussions with and appeals from various groups of medical professionals, mainly associated with the procedure. Their criticism was based on the argument that randomization for the study is not ethically justified. The EC eventually decided that it was indeed unethical to perform a randomized trial because an observational trial addressing this issue existed [14], and the data it provided deemed adequate proof of benefit of apheresis. However, this observational study did not include a control group. The question remains whether there is enough evidence to support that Lp(a) apheresis improves the outcomes of patients with isolated elevation of Lp(a) and progressive CVD, thus obviating the need for a randomized trial. To us, the answer is a clear no, as uncontrolled observations do not fulfil the criteria of evidence-based medicine in 2012. The ELAILa trial was designed as a hybrid trial, consisting of both, a randomized controlled trial (RCT) and an observational trial (OT) for the patients not willing to be randomized. In addition, patients having reached a nonfatal endpoint in the RCT could be switched over to the OT for long-term follow-up (Fig. 1). The OT would thus also serve the purpose of establishing a national registry of Lp(a) apheresis patients, another mandate of G-BA (the respective documents can be found on http://www.g-ba.de). Flow of participants. Primary outcome measure of the trial was a composite endpoint, defined as first occurrence of one of the following: myocardial infarction, interventional coronary therapeutic procedure, coronary artery bypass grafting (CABG), cerebrovascular accident, hospitalization due to acute coronary syndrome (ACS), peripheral arterial revascularization and death from cardiovascular cause. Secondary outcome measures were the components of the primary endpoint considered individually and death from any cause. Safety of the procedure and quality of life were also to be investigated. The trial would enrol male and female patients ≥18 years of age having Lp(a) concentrations ≥60 mg/dL, LDL cholesterol <100 mg/dL and progressive CVD. As demanded by G-BA, CVD progression despite maximally tolerated conservative therapy would have to be determined not only clinically but also with imaging methods. Patients with LDL cholesterol of <100 mg/dL were selected for the trial since the effect of lowering Lp(a) and not of lowering LDL cholesterol on cardiovascular outcomes was to be investigated. After randomization (1 : 1 ratio stratified by centre), patients would be treated by lipoprotein apheresis (all approved apheresis methods will be allowed in the trial). In the control arm, patients will be treated with maximally tolerated conservative treatment to reduce cardiovascular risk. Lp(a) concentrations would be measured in a central accredited laboratory with an isoform-insensitive assay, and changes in Lp(a) levels would be modelled as a covariate. In preparation of a reliable estimate of the predicted number of events and for calculating the required sample size, statistical considerations were hampered by a lack of data on the parameters of interest. A 50% risk reduction was considered to be clinically relevant, a decision based on the effect sizes usually observed in statin trials (about one-third event reduction) and on the high-risk state of the study population. The assumptions for the final sample size calculation for the primary outcome included equal allocation of patients to the apheresis or control group, an accrual time of 48 months and an additional follow-up of 12 months, a median event-free time for the control group of 24 months and an event-free time twice as large for the apheresis group. It was furthermore assumed that patients will be accrued uniformly over time. Calculating the sample size, a relative risk reduction of 50% can be detected at a two-sided significance level of 0·05 and with a power of 80% by evaluating a total number of 135 patients. The observational trial (OT) would also consist of two arms (see Fig. 1), an apheresis arm and a control arm (for patients unwilling to either be randomized or to receive apheresis treatment). If patients in the RCT would reach a nonfatal endpoint, they would be able to switch over to the OT arm. In December 2008, G-BA had agreed to the general outline of the ELAILa trial. Moreover, the German Cardiac Society and the German Society for Nephrology supported this trial. Financing would be supplied by four of the largest manufacturers of lipoprotein apheresis systems in Germany, which have established a consortium that would sponsor the organizational part of the trial. Importantly, in an additional decision of July 2009, G-BA ascertained that reimbursement of the treatment costs was granted for study participants by mandatory health insurance coverage. This decision has been endorsed by the Federal Ministry of Health. In January 2010, the finalized study protocol was submitted to the ethics committee (EC) at Charité University Medicine in Berlin. After several hearings and after having been contacted by groups of medical professionals who strongly opposed the study, the EC decided that it was crucial for their final decision to have an independent biostatistical expertise on a retrospective cohort study by Jaeger et al. [14], presumably showing a reduction of major coronary events with lipoprotein apheresis. Such a report was obtained, and a final decision was made in July 2010, ruling that the proposed RCT is unethical, while the OT received a positive vote. The EC came to the conclusion that it is unethical to randomize patients ‘as long as there is no active, probably effective control group and as long as there are no data from new cohort studies that question the results of the study of Jaeger et al.’. An appeal of the study trialists against the decision of the EC was rejected. The study has been ‘on hold’ since then. We believe that this decision is very unfortunate as (i) it deprives both patients and the scientific community of the true answer to a significant question and (ii) the study on which it was based [14] has significant limitations, most importantly because it is retrospective and uncontrolled. This nonrandomized retrospective cohort study in 120 subjects showed that decreasing Lp(a) levels by 73% using apheresis associates with decreases in the annual rate of major adverse cardiovascular events (MACE) from 1·056 to 0·144 before and after starting apheresis [14]. At first sight, this finding seems very persuasive; however, potential limitations in design and statistical methodology should be considered. For example, in time-to-failure data (or person–time data in general), the basic assumption is that the risk of failure (event) in one group is the same constant multiple of the other group at any point in the follow-up time. The study violated the principle of independence of observations and used a questionable statistical test. Other problematic issues with this study are the fact that the patients were not maximally treated (e.g. only 8·3% were receiving niacin and only 3·3% cholestyramine), that there was no prospective documentation of events (events were retrospectively assigned as such) and that events were not adjudicated independently. Calculating intraindividual ‘event rates’ is a statistically dubious concept [15]. In summary, the conclusions of this study are limited by its design, and it does not meet the criteria of evidence-based medicine in 2012. We thus believe that, although laudable, this study cannot be considered as an adequate alternative to a randomized controlled trial as proof of the effectiveness of Lp(a) apheresis. Moreover, a recent small randomized trial from Italy showed that in 21 patients with angiographically documented CHD apheresis decreased Lp(a) by 57% but showed no difference in the rate of cardiovascular events in a follow-up of 1 year [16]. While in their demand for a controlled trial, the G-BA did not specifically request a randomized trial, they characterize such as the ideal design. A nonrandomized trial design bears substantial selection bias (confounding by indication). In such a study, it cannot be excluded (not to say it would be rather likely) that patients with higher cardiovascular risk will be allocated to apheresis treatment while the ones with lower cardiovascular risk will receive standard care. In conclusion, another uncontrolled trial (or registry) will not be able to prove the effectiveness of apheresis over conservative treatment. We acknowledge that the decision in Germany to reimburse this procedure, suggesting to both, medical professionals and patients, that the required evidence for superiority of apheresis exists, would make randomization and therefore recruiting difficult. On the other hand, it could be argued that it is difficult to defend offering patients an invasive, expensive, life-long procedure without having high-quality, evidence-based, proof of benefit. Even the Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs of the Institute of Medicine [17] concludes that ‘… the FDA may be justified in requiring studies that could expose patients to heightened risk–but only if a public health question of pressing importance is at stake, if no other study design could supply the needed evidence,…’. We believe that this approach exactly reflects the situation with Lp(a) apheresis. Of note, any cost-effectiveness data regarding Lp(a) apheresis for this indication are also lacking. Although observational data suggest that lipoprotein apheresis to decrease elevated Lp(a) concentrations may improve CVD risk, observational data cannot adjust for unmeasured confounders. However, they have been accepted in this particular case as adequate proof of beneficial effects of a life-long invasive procedure. How can this be explained? Certainly, the aspect of the ‘rare disease’ state of the patients was an argument involved in the decision. There is a clear need for guidance or guidelines evaluating the treatment of rare diseases to help health professionals navigate through the maze of various purportedly effective therapeutic options. On the other hand, one might ask why the scientific standards (and statistical methods) for investigating rare and common diseases should be different. Moreover, the decision may be a reflection of what has been described as ‘the illusion of validity’, the phenomenon of unwarranted confidence on a specific outcome which is produced by a good fit between the input information (significant decrease in Lp(a) concentrations) and the predicted outcome (decrease in cardiovascular events). Interestingly, this ‘illusion’, which has been observed even among the most experienced of researchers, persists even when the scientist is aware of the factors that limit the accuracy of his/her predictions [18]. The ethical basis for entering patients in randomized trials has been in general under debate. Some doctors espouse the uncertainty principle whereby randomization to treatment is acceptable when an individual doctor is genuinely unsure which treatment is best for a patient. Others believe that clinical equipoise, reflecting collective professional uncertainty over treatment, is the soundest ethical criterion [19]. Numerical modifications of surrogate markers of CVD risk do not automatically translate to an actual reduction of CVD events, as has been recently shown, for example, with CETP inhibitors, drugs that increase HDL-C and decrease LDL-C [20]. Observational and randomization data have often reached surprisingly disparate conclusions, and effects of surrogate markers were misleading in the field of cardiology, as we have seen, for example, with hormone replacement therapy and intensive glycaemic control in patients with diabetes. A randomized controlled trial to investigate the effects of lipoprotein apheresis to decrease Lp(a) needs to be performed sooner than later. Randomization is a powerful tool that cannot be reliably reproduced by statistical modelling, and therefore, observational data cannot be used as substitutes for randomized trial results [21]. The ELAILa trial may be an illustrative example where selectively missing information on a research subject does not only pertain to studies that have already been performed but for the much greater challenge to understand how many potential studies do not exist when they could readily have been conducted [22]. Drs. Heiner K. Berthold and Ioanna Gouni-Berthold are members of the ELAILa trial steering committee. The views expressed here are those of the authors and do not necessarily reflect the views of the other members. The authors have no conflict of interest associated with the subject matter. Charité University Medicine Berlin, Virchow Clinic Campus, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany (H. K. Berthold); Evangelical Geriatrics Center Berlin (EGZB), Berlin, Germany (H. K. Berthold); Département de Médecine Interne et Centre de Recherche Médicale de Jolimont, Hôpital de Jolimont, Haine Saint-Paul, Belgium (O. S. Descamps); Center for Endocrinology, Diabetes, and Preventive Medicine, University of Cologne, Cologne, Germany (I. Gouni-Berthold).
Under traditional health insurance arrangements, citizens were covered by some insurance scheme.When sick, insurance arrangements allowed citizens to go to a health care provider, pay the price of the care received and be reimbursed later.Alternatively, the care provider would be owned by the insurer (like in integrated national health systems) and the patient paid nothing at the moment of consumption.In such arrangements, providers would freely set their prices or have no price to set at all (in an NHS-like system).Recent developments in health care financing include independent institutions that negotiate the prices with the financing institution.This is true with respect to health maintenance organizations (HMOs), managed care in general, but also in national health systems where decentralization and the split between provision and financing is implemented.In this scenario, negotiation over contractual terms, including prices as one major element, becomes a relevant issue in the analysis of performance of health care systems.Both empirical and theoretical analyses have been produced, and are reviewed below.This chapter reflects our views and preferences.It does not aim to be an encyclopaedic view of the existing literature on bargaining in health care.Instead, we try to highlight the new developments associated with explicit bargaining between third-party payers and providers of health care (a relation which is, in itself, only one of many that exist in the health care sector).Bargaining theory has a long tradition in the economics literature.However, it is only recently that this approach has found space in the analysis of the health care sector.The recognition of the strategic interaction among agents in the health care sector (patients, providers and third-party payers) came with the application of models borrowed from the industrial organization tradition dating from the 1970s.It was in the early 1990s when a step forward was taken with the eruption of the models of bargaining (see for example, Osborne and Rubinstein, 1990, for a nice presentation) In many situations the health care sector has the structure of a bilateral monopoly/oligopoly.In this context, bargaining becomes the natural way to approach the interactions among agents.Most economic analyses of contract design in health care in fact assume that the party that moves first, typically the payer, proposes a take-it-or-leave-it offer to the provider.We take here a broader view, looking at other types of negotiation procedures.We do not discuss issues related to contract design, which are taken up in chapter 22 by Chalkley in this Companion.We focus here on models of explicit bargaining between two parties, which we call the payer and the provider.On theoretical grounds, simple bargaining models can have their results transposed in a straightforward way: higher bargaining power and higher M2835-JONES9781849802673PRINT.
Rini Sasanti Handayani, Max Joseph Herman, Selma Siahaan
Background: Since decentralization era the health budgets including drug budget has been allocated into the development regional budget through formula-based DAU, based on regional revenues and fiscal needs. Health budget is included in DAU, though not explicitly stated. Therefore the health sector practically has to strive for their own budget in every province or every district. This is a new kind of phenomenon for regional governments especially related to the health sector. They should have strategic plan in financing while competing with other sectors to obtain it. Drug consumption in Indonesia is lower than in other ASEAN countries. To ensure access to drugs in primary heath care, the government (Ditjen Bina Farmasi dan Alkes) in the mid-year of 2003 in collaboration with WHO has facilitated a meeting among districts. This meeting leads to an agreement that the regional government should allocate Rp5.000,00 per capita annually for drug budget. Methods: A cross sectional descriptive study was done in ten districts in Indonesia in the year of 2006 on how far the realization of the district agreement of drug budget allocation, particularly in relation with improving drug access issues. District Health Office and Drug Management Unit were taken as samples and data were collected by structured interviews. Results: 1) Drug budget for most districts/cities is still less than Rp5.000,00 per capita per annum so that it can be assumed a shortage in terms of kind of, as well as, quantity of drugs. 2) Some districts showed an increase in drug budget, while the other ones showed just the opposite. 3) Not all districts had all essential and/or generic drug procurement. Conclusion: We suggest more intensive socializations for drug financing to districts in order to improve the commitment to the agreement on the allocation of drug budget and, secondly, a better technical training with topics: planning, advocacy and negotiation with relevant stakeholders. Key words: drug financing, drug budget, districts/cities
Pharmaceutical Economics and Policy
Healthcare Systems and Reforms
Health Systems, Economic Evaluations, Quality of Life
I am both humbled and honored to have been given the opportunity to serve the American Society for Artificial Internal Organs (ASAIO) as president for this past year. As some of you know, I am a cardiac surgeon and as such, I am keenly aware that governance of a society, like open heart surgery, is best accomplished by a dedicated, experienced group of individuals. Favorable outcomes in cardiac surgery and management of a society are dependent on a successful team effort. This past year I was quite fortunate to have been surrounded by a very dedicated and actively engaged group of individuals. As many of ASAIO's presidents have done in the past, I would like to thank Karen Burke, Executive Director for her commitment to ASAIO. Karen is truly the heart and soul of our society. I would also like to thank the ASAIO Board and, in particular, the members of the executive committee: Bill Holman, David Humes, Bill Wagner, and Kurt Dasse. Their collective wisdom and vision for the society made the management task far simpler than I would have imagined and assures me that our society is in very good hands for the future. In choosing a topic for the presidential address, I felt that conflict of interest considerations are not only timely but also of particular interest to the diverse membership of our society. Given that our membership roster has representatives from clinical medicine, engineering, basic science, the federal government, and industry, I believe we are in a unique position to acknowledge the potential for conflict of interest and influence the process by which such conflicts are managed. A conflict of interest has been defined as “a set of conditions in which professional judgment concerning a primary interest (such as a patient's welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).”1 Although financial gain is the most easily recognized and readily quantified, it is only one of a number of possible secondary interests. Physician-scientists are driven to participate in clinical research out of a desire to advance knowledge thereby providing better therapeutic modalities for their patients. Academic medical centers exist to foster an environment in which such advances are made possible. A successful investigative effort oftentimes results in ongoing grant support and academic recognition.2 Academic medical centers derive nonfinancial gains from research conducted by their faculty. There is great prestige associated with recognition as a leading research institute. Personal career advancement and institutional recognition are powerful secondary interests. The common perception is that any relationship between an investigator or academic institution and industry creates doubt about the validity of an investigative effort and may jeopardize the quality of care provided to a research subject. However, the presence of a conflict of interest should not be considered evidence of misconduct on behalf of the investigator, academic institution, or industrial partner. Rather, conflicts of interest are inherent in the investigative process. The goal is to manage the conflicts of interest in an ethical manner thereby ensuring that a study is conducted with unquestionable scientific validity and that the patient's care is uncompromised. It is important to understand how human subjects research evolved to the point where conflicts of interest can occur. Public Law 96-517 known as the Bayh-Dole Act, was cosponsored by Birch Bayh of Indiana and Robert Dole of Kansas.3 This legislation was enacted on December 12, 1980, became effective in July 1981, and created a patent policy that permitted universities, for the first time, to elect title to inventions made under federal sponsorship. Universities were expected to file patents and subsequently commercialize these inventions. This piece of legislation is generally credited as the originator of academic technology transfer whereby university research, inventions, and intellectual property are transferred to private industry for purposes of commercialization. By doing so, public welfare is enhanced and industrial growth made possible, as university generated technology is developed into real world products. Currently, around 5,000 licenses and options are executed annually by universities with private industry, growth of more than 500% since 1991.4 Such tech transfer translates into $1.39 billion in annual licensing income to universities, a nearly $1 billion increase since 1995. The enhanced relationship between academic institutions and industry has led to a multitude of medical advances and the creation of biotechnology markets. However, an unintended consequence of the relationship is an academic institution's increased reliance on industrial funding to support further research. Between 1980 and 2000, industry's share of the total investment in biomedical research and development increased from 32% to 62%.5,6 Support from the federal government fell during the same period. The complex financial relationship among investigators, academic institutions, and industrial partners is well documented. Of 2,052 life science faculty at 50 US universities receiving research funding from the National Institutes of Health, surveyed in a report published in 1996, 28% received research support from industry.7 In 1984, 46% of life science companies supported academic research, whereas in 1994, 57% of firms provided such support, a number that achieves statistical significance (p = 0.05).8 In 1999, the Association of University Technology Managers reported that 124 of 183 members (68%) in the United States and Canada held equity ownership in businesses that sponsored research at the same institutions.6 Patent royalties and, to a greater extent, equity holdings by investigators and academic institutions create an entirely new dynamic in their relationship with the industrial partner.6 The creation of a new revenue model for research scientists and universities has blurred the lines between academic and commercial values. The rise in institutional entrepreneurialism carries with it a responsibility for business stewardship. Such a shift in mind set can easily portend a shift in academic mission. The potential for research bias ensues. The promise of financial rewards raises justifiable concern about the conduct, interpretation, and reporting of funded research.2 There is a well documented disparity in outcomes between industry-sponsored and nonindustry sponsored research. In one review of 332 randomized controlled trials, industry funded studies were 1.9 times more likely to report positive results, a statistically significant proindustry finding.9 Bekelman et al.6 summarized eight articles that compared the outcomes of industry-sponsored versus nonindustry sponsored research studies. These eight articles collectively evaluated 1,140 original studies. The summary odds ratio from these studies was 3.60, with the conclusion favoring industry regardless of whether the study was a randomized controlled trial or other study design. Although perhaps an overstatement, industry-sponsored research is, in general, designed to affirm a hypothesis that is anticipated to be affirmed.10 Industry studies are intended, in part, to mature a concept or product along a linear fashion, whereas government-funded studies may be designed to ask broader, more conceptual questions.10 More worrisome are potential impediments to the investigator's access to data and freedom to publish the results of industry-sponsored research studies. There are reported instances where publication of the results of research that were unfavorable to an industrial product were delayed or blocked altogether by the companies that had provided financial support for the study.11–13 In one survey of academic investigators, 19.8% of 410 respondents reported publication of their research results had been delayed for more than 6 months to slow the dissemination of undesired results and to resolve disputes over ownership of intellectual property, among other reasons.13 So, why the seeming sudden interest in recognition and management of conflicts of interest? The Joint Commission defines a sentinel event as “an unexpected occurrence involving death or serious physical or psychological injury … Such events are called ‘sentinel’ because they signal the need for immediate investigation and response.”14 The event that accelerated efforts to address the influence of conflicts of interest on the safety of research subjects occurred in 1999.15,16 Jesse Gelsinger was an 18-year-old man who suffered from a mild disorder of nitrogen metabolism known as ornithine transcarbamylase deficiency.16 On September 13, 1999, as part of a gene therapy clinical trial, he received an intrahepatic injection of adenovirus vector particles containing a gene to correct the genetic defect. He died 4 days later of what was presumed to be an immune reaction to the virus vector. This death was the first in a gene therapy trial. In the firestorm that ensued, it was alleged that investigators at the University of Pennsylvania where the death occurred held patents covering several aspects of the technology employed. In a wrongful death lawsuit, it was further alleged that James Wilson, the Director of the Institute for Human Gene Therapy at the University of Pennsylvania, and the University itself were reported to have equity holdings in Genovo, the private sector biotechnology company collaborating on the project.15,16 These conflicts of interest were allegedly never disclosed to the trial participant. The fallout from the tragedy in Philadelphia and elsewhere called into question physician–industry relationships and the impact of those relationships on the clinical investigative process. Kim et al.17 from the Psychiatry Department at the University of Rochester looked specifically at potential research participants' views of researcher and institutional financial conflicts of interest. In their article published in 2004, the authors presented seven different scenarios of financial conflicts of interest to 5,478 individuals. The majority of individuals surveyed responded that knowing conflict of interest information was “extremely” or “very” important. Sixty-four to 87% of respondents (depending on conflict of interest scenario) felt that financial conflicts of interest should be disclosed as part of the informed consent process. Although the majority of those individuals surveyed would chose to participate in a study in the face of a known financial conflict of interest, the effect of such a conflict of interest resulted in a sizeable minority to be less inclined (range, 3%–44%) to participate or would chose not to participate (range, 2%–32%). The erosion of trust was further reflected in the fact that pharmaceutical and medical technology companies paid more than $2.5 billion in healthcare fraud settlements in 2001 and 2002.10 Public trust had to be regained, and potential research participants needed assurance that clinical investigation could be conducted free of bias. The question to be answered was where to begin. On May 23, 2000, in direct response to the death of the patient in the gene therapy clinical trial, former Secretary of the Department of Health and Human Services, Donna Shalala, announced five new initiatives that were specifically designed to ensure patient safety and increase public confidence in clinical trials.18,19 Two of the five new initiatives specifically addressed conflicts of interest. The purpose of these initiatives was to “clarify and enhance the informed consent process” and specific mention was made “that any researchers' financial interest in a clinical trial be disclosed to potential participants.” A conference that specifically addressed financial conflicts of interest was held in Bethesda, MD, on August 15–16, 2000. Subsequent to that conference, a draft interim guidance document was prepared and made available for public comment on January 10, 2001. A second draft guidance document appeared in 2003, whereas the Final Guidance document entitled “Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subjects Protection” was made available in 2004.20 In part, these guidelines suggested that institutions establish a Conflict of Interest Committee to identify and address potential individual or institutional conflicts of interest. The Conflict of Interest Committee was to function in concert with the Institutional Review Board (IRB). The mandate of the latter committee is to protect the rights and welfare of human research subjects. As the Department of Health and Human Services was in the process of developing guidelines to address financial conflicts of interest in human subjects research, the Association of American Medical Colleges (AAMC) announced their own intent to examine the same process. In October 2000, the president of the AAMC, Jordan Cohen, announced the formation of a task force whose assignment was to revise and extend the AAMCs existing conflict of interest guidelines based on contemporary events and increased concern about the impact of financial conflicts of interest on public trust in the objectivity of human subjects research.21 Jordan charged this task force to address three issues: 1) To recommend upper limits of allowable financial interests that would motivate investigators to pursue the clinical research with due diligence but not raise concern that remuneration for research serve as a financial windfall for those providing oversight for the scientific process. 2) To consider inaugurating a voluntary, institution-based certification process for research faculty. The certification process would function much like board certification and would ensure that those involved with funded research were cognizant of the rules and regulations governing such research. 3) To consider additional safeguards that might be necessary to “address the potential downside of financial conflicts at the institutional level,” recognizing that institutions, as opposed to individual scientists, might also have a financial stake in the outcomes of clinical trials conducted onsite. The task force ultimately published two documents: one dealing with individual22 and the second with institutional23 financial conflicts of interest in research involving human subjects. Recommendations in these two reports also include the creation of a Conflict of Interest Committee or, in lieu of a committee, a conflict of interest official. The Conflict of Interest Committee is responsible for identifying, quantifying, and potentially reducing the financial conflict of interest of any individual conducting human subjects research. Findings from the Conflict of Interest Committee are to be made known to the IRB. Institutions were tasked with developing written policies detailing substantive prohibitions and restrictions, reporting, implementation, disclosure, monitoring, and review of financial conflicts of interest. The AAMC task force recommendations specific to managing institutional conflicts of interest make particular reference to the makeup of the Conflict of Interest Committee. The membership roster is to include only individuals who are independent of the direct line of authority for clinical research oversight within the institution. The task force further recommended the inclusion of at least one or more individuals with to the institution The institutional of Technology is to report to the Conflict of Interest Committee any licensing into by the institution that equity interest, and the reporting guidelines are recommended for institutional In potential financial conflicts of interest should be disclosed by the individual conducting the research. The should be into the patient consent and the financial interest in question should be and not to additional to the welfare of the research participants or to the of the industrial representatives also to their own of dealing with investigators and academic The Research and of developed a on with This effect on July and was in January Of greater interest to the membership of this society is the of on with Health by the Medical Technology Association is a of medical technology and the of was on January The of the into effect on July This and document such important as company conducted product and with healthcare and research and to the of the include guidelines that address with healthcare and the of companies that their of the for public review on The of have also done their part to for and the scientific of human subjects research. The two leading in the of surgery, the of and and the of that authors report any financial conflicts of interest a is for The of those have the of such conflicts on the title of the article at the of However, the of only one of a conflict of interest. To ensure that authors of research data and the freedom to publish the results of clinical research, the Committee of Medical the for to and for to of potential conflicts of interest, this document that authors potential conflicts to study participants and that they have done within the of the The document further that in reference to conflicts of interest to support should not into an that with their access to the data and their to and to and publish To ensure that investigators are for their own research, authors of a study funded by a with a or financial interest in the may also be to a to the effect that had access to the data in this study and I responsibility for the of the data and the of the data The of the of and and the of have new to their for that a policy in which a a study in which “an other than the investigator had of the data or had over might be on that Such policies serve two to research scientists in their with industrial in developing and to ensure of the have information to make an informed judgment about potential bias in the research In the since the death in the gene therapy clinical trial, significant has been made in the and management of of conflicts of interest. However, this is a process in The majority of management policies are in the of recommendations or There has been a response from institution to institution with to developing and on policies and that are a number of in which potential conflicts of interest can be and In clinical trials, investigators be involved in aspects of trial the of and In funded research, investigators of data and data The research scientists be the freedom of publication of a conflict of interest on behalf of the investigator or the institution at which funded research is should be should be in the consent document that a potential research to the presence and of a possible conflict of interest. By doing so, the potential research is made aware of the conflict and is the opportunity to an as to the impact of such a conflict on the investigative process. such written should include financial the of It has also been suggested by one that informed consent should include a of the quality of medical evidence on which recommendations are should an opportunity for between the investigator and the potential research the latter is that safety is and the study is conducted bias. of conflicts of interest is the responsibility of not only the investigator but also the institution. In to the informed consent of conflicts of interest and Institutional Conflict of Interest should be developed with a mandate to review potential conflicts of interest and ensure that such conflicts are disclosed and Conflict of Interest Committee membership should include research scientists who have conflicts with the institution, the investigators, or the clinical trial in which the faculty of the academic institution is To one or more members of the Conflict of Interest Committee should be from the institution. The Conflict of Interest Committee should be charged with developing policies for management of potential conflicts and should with the to ensure that such policies are It has been suggested that a for to AAMC guidelines might be better accomplished by the guidelines into the companies should to of should be in and an need for the and that such was for should be with and not based on the or of the business academic medical the Conflict of Interest Committee should oversight for faculty members who into The and potential research participants should be made aware of and be that such in influence the or of clinical research. A financial be it an investigator or institution should not serve as investigator or data in a clinical trial. The of a financial on industrial support or on an investigator's or institution's equity interest in an industrial have to be In for patient care should be first and in the of involved in human subjects research. To the of the scientific such investigation be conducted free of or advances in medical in general, and in particular, a relationship among academic medical and industrial In the would that may be an increased reliance on industry for financial support in the future. The of our society since has been to advance medical technology for the of our patients. To this ASAIO is with a membership that an and of to the task at The of our society is our to a clinical a to address that the new and, in and clinical trials our the complex process and more understand the process by which new technology is to the To ensure that we to be to new to the board and technology to the clinical we be open and in our management of conflicts of interest, the of our clinical research are and our to participate in the process
Judy Lewent, Joe Fuller, David Scharfstein, Rick Passov · 9 authors
In light of the challenges facing the pharmaceutical industry, a distinguished group of pharma executives and strategic and financial advisers discusses the following corporate decisions: Strategy : What business model is most likely to maximize long‐term shareholder value? For example, is diversification by big pharma into areas like consumer healthcare and generics a reliable way to create sustainable value? Capital allocation : What are the best methods for evaluating investments in pharma R&D, and for deciding which programs should be terminated and which assets divested? If conventional DCF isn't much help in a world where R&D outcomes are so uncertain, what about proposed models like real options? Corporate governance and incentive systems : Should big pharma continue to outsource ever more of its R&D functions to biotech and venture capital? Or can it overcome the problems associated with size by creating more decentralized business units and trying to replicate the accountability and incentives of smaller biotech firms? Capital structure and payout policy : Are the large cash and equity positions and minimal payouts of big pharma, typically justified as cushioning the uncertainties associated with pharma R&D, likely to be the value‐maximizing capital structure in the future? With many biotechs struggling and venture capital scarce, where are the new sources of capital for the industry? And can future deals be structured in ways that help bring about higher returns for big pharma as well as the R&D providers? Disclosure : What should management tell investors to help ensure that their companies' policies and promising investments are reflected in their stock prices?
Implementation of decentralized drug policy brings an impact in the form of finance mechanism changes. Before decentralization, drug budget was calculated by the amount of resident and indigent resident percentage. After decentralization, the budget is specified by each regional government according to needs and existing health problems. This change leads to problems of allocation and distribution especially in some areas where Original Earnings of Area (PAD) is relatively small. The allocation is strongly influenced by the amount of Common Allocation Fund (DAU) and the drug manager ability in the area to manage the fund of drugs as efficient and effective as possible to assure the availability and sustainability of health service. The aim of the study was to calculate the adequacy rate of drug cost before and after decentralization and to determine the influence of decentralization itself toward the adequacy of drug cost in the area.\nA case study was conducted using quantitative data and the result was analyzed with regard to drug cost adequacy. The study began with calculating indicator of drug management and drug cost requirement on the therapy of top 10 diseases using morbidity method during 1999-2002. The result was analyzed with ABC analysis and compared to realization of drug cost on the same periode and interpreted to assess the drug cost adequacy before and after decentralization.\nThe result showed that the average of ability on the drugs cost procurement based on comsumtion method to fullfill drug cost requirement based on morbidity method before decentralization was 31,33%, after decentralization increased to 78,51%. And then the average of ability on the drugs cost based on comsumtion method to fullfill drug cost requirement based on morbidity method before decentralization was 15,14%, after decentralization increased to 60,67%. Nevertheless, the increase of fund adequacy and drug cost rate was not significant (p>0,05) between before and after decentralization. It was concluded that although the adequacy rate of drugs cost and fund has increased significantly after decentralization, it was not able to fulfill the requirement up to 100%. In other words, decentralization has not influenced the cost adequacy rate of primary health care drugs in the area.\n\nKeywords: availability âadequacy âdecentralization âcost of drugs.
The Danish health care system has undergone gradual changes, but not radical reforms, from 1970 until 2004. Theoretically, the development can be viewed from the perspective of fiscal federalism, decentralization, and incentives embodied in reimbursement systems. Furthermore, path dependence and incrementalism have characterized the system. The Danish health care system is decentralized politically, financially, and operationally. The counties are responsible for health care, and finance it out of county income and property taxes along with block grants from the state. Hospitals are publicly owned while general practitioners are private entrepreneurs working on contract with the counties. Hospital services and GP and specialist services are free, while there are co-payments for drugs, adult dental care, physiotherapy and the like. Co-payments make up close to 19% of total health expenditures. The system has been characterized by expenditure control, reasonable positive development in productivity, and a high degree of patient and citizen satisfaction despite waiting lists. Free choice of hospital was introduced more than 10 years ago. It has recently been expanded so that after waiting 2 months for treatments like elective surgery at public hospitals, citizens can choose either private hospitals or go abroad with full payment from public funds. The thinking behind decentralization gradually has been eroded for a number of reasons. This has led to a reform that will be effective as of January 2007. The number of counties will be reduced, but the new regions retain responsibility for health care. A national earmarked health tax will be introduced so that the regions will receive revenues from state block grants and municipal co-payment, for instance an amount per hospitalization.
Clients should never leave a clinic empty-handed because the product they need is out of stock. Health and family planning programs can succeed only if the clients they serve have access to medicines vaccines contraceptives and other essential health products whenever they are needed. Many international programs focus on improving service delivery promoting demand and donating drugs and other health commodities which fill up port warehouses and central medical stores. But most programs overlook the need to improve the logistics supply chain to ensure that products move from central warehouses to the health facilities where they are needed. Worse well intentioned changes in health delivery—including health reforms such as decentralization or integration of services—can exacerbate storage and distribution problems and in some cases wreak havoc on once smooth-functioning logistics systems. Furthermore donor support for commodities is diminishing relative to needs especially for contraceptives and vaccines. Countries are adapting to this situation by accessing a variety of multilateral funding mechanisms to finance commodity procurements. In addition to traditional World Bank loans these mechanisms include the Global Drug Facility of the Stop TB initiative the Children’s Vaccine Fund and the Global Fund to Fight AIDS Tuberculosis and Malaria. (excerpt)
The Austrian healthcare system relies mainly on physicians in private practice and on various services provided by hospitals. The social health insurance scheme is compulsory, covering 99% of the population. The system is very decentralized. While the federal state provides the framework, the nine autonomous provinces are responsible for administering health and social services. There is ongoing public discussion about centralizing the healthcare system to make it more efficient and to enforce structural reforms. Because of concerns about healthcare expenditures, in 1997 the Performance-Related Hospital Financing System (LKF), a system similar to the diagnosis-related group system, was introduced for hospitals, including a plan for large medical devices. It is too early to evaluate the success of this new system, although some effects of the LKF system that could have been anticipated, such as shortened lengths of stay and more hospitalizations, have been seen. Previously, health technologies have been almost uncontrolled in Austria. The evaluation of health technologies as an instrument to support or to control their dissemination and use or to help define policies is not institutionalized or systematically used. It seems clear that structural reforms of the Austrian healthcare system are needed. Health technology assessment should be part of such reforms.
Health Systems, Economic Evaluations, Quality of Life
Italy has a national health service (SSN) dating to 1978. Italy's system of government is characterized by a rather high degree of decentralization of power, and the health system is likewise decentralized. Most of the responsibilities for health care have been ceded to the regions. The state retains only limited coordinating and supervisory powers. The state has a financial responsibility for the national health service, but state contributions are limited and expenditures in excess of this made by the region must be financed from other sources. Health reforms of 1992-93 aimed at making the regions more sensitive to the need to control aggregate expenditure and to monitor measures to promote efficiency, quality, and citizen-patient satisfaction. The diffusion of individual health technologies has been relatively uncontrolled in many regions in Italy, although tight central constraints on capital spending have contained diffusion of new technology. Regulation of placement of services is a planning function and is the responsibility of both the Ministry of Health and the regions. Health technology assessment (HTA) activities have been expanding since the early 1990s, but these activities tend to be untargeted, uncoordinated, and without priorities. Nonetheless, the principal actors in the SSN at national, regional, and local levels are becoming more sensitive to the need to apply criteria of clinical and cost-effectiveness and to be more rigorous in deciding what services to guarantee. There are reasons to be guardedly optimistic about the future of HTA in Italy.
Health Systems, Economic Evaluations, Quality of Life
Richard Graham Halliday, A.L. Drasdo, Cynthia E. Lumley, Stuart Walker
A survey of 45 leading pharmaceutical companies has been used to investigate aspects of their Research and Development (R&D) strategies, the allocation of resources including the financing and staffing of R&D functions, and the numbers of New Chemical Entities (NCEs) in the development process. The companies included the top ten by R&D expenditure in 1992 (top 10 companies). The study identified characteristics of leading companies and provided comparative data. The principal findings are that: top ten companies had the highest R&D to sales ratios, progressed more NCEs after the drug candidate selection stage in 1992 and had achieved a greater geographical decentralization of staff than any other company. Japanese companies differed in some respects from western companies, even those of a similar size. They operated with smaller clinical and regulatory affairs functions and made detailed plans for R&D expenditure further ahead than western companies, on average, more than 5 years compared with 3 years. an increase in aggregated R&D staffing had occurred between 1990 and 1992 in 33 companies for which data for both years were available and staff numbers had decreased in only five of those companies. top ten companies differed from others in their apparent productivity measured in terms of staff or R&D expenditure per NCE after the drug candidate selection stage, utilizing more staff and having greater R&D expenditure per NCE. The results also appear to indicate early signs of a change in the structure of the industry according to R&D expenditure, which has since become more apparent. There was a distinct polarization by R&D budget size among the respondent companies: five companies were spending $900m or more on R&D in 1992 while the majority of the rest were spending less than a third of that amount.
Various ways of financing health care expenditures by communities are studied in this chapter. The first method is direct payments by patients for drugs. Application of this method presupposes that other health care expenditures are financed by other agents such as international donors and central, district or local government. A fee-for-service arrangement constitutes the second method. This is more general in that fees may cover other recurrent expenditures as well as drug expenditures. Salaries of health personnel and depreciation allowances may also be included in a fee-for service system. The third method consists of prepayments for health care or decentralized forms of health insurance. Finally, we consider community labour as a means of financing health expenditures. In the last section, evaluation criteria for projects in community financing are examined.
Healthcare Policy and Management
Pharmaceutical Economics and Policy
Health Systems, Economic Evaluations, Quality of Life