From target discovery to clinical drug development with human genetics.

The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.

Gastrointestinal toxicity of high-dose melphalan in autologous hematopoietic stem cell transplantation: identification of risk factors and a benchmark for experimental therapies.

Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20-73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1-18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.

Work-Sampling Study of an Innovative Care Coordination Program Aimed at Children With Chronic Health Conditions.

PURPOSE OF STUDY: To estimate time allocation and labor cost for care coordinators (CCs), community health workers (CHWs), and mental health workers (MHWs) to conduct care coordination tasks in a pediatric care coordination program. PRIMARY PRACTICE SETTING: A public tertiary academic medical center in Chicago, IL. METHODOLOGY AND SAMPLE: A work-sampling study was conducted using a text message-based survey on 5 CCs, 20 CHWs, and 4 MHWs who volunteered to participate. Workers were randomly sampled within working hours to collect information on who was the subject of interaction and what service was being delivered over a 6-month period. Time allocation of workers to different subjects and services was summarized using descriptive statistics. RESULTS: Care coordinators allocated 41% of their time to managing CHW teams. Community health workers allocated 37% of time providing services directly to children and 26% to the parent/caregiver. Mental health workers allocated 16% of time providing services to children and 29% to the parent/caregiver. The care coordination program serviced 5,965 patients, with a total annual labor cost of $1,455,353. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Community health workers spent the majority of time working with patients and their families to conduct assessments. Mental health workers primarily addressed children's needs through their caregivers. Care coordinators primarily supported CHWs in coordinating care. Results may be used to inform development of such programs by determining services most often utilized, and labor cost may be used to inform program implementation and reimbursement.

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

New Rheumatoid Arthritis Treatments for 'Old' Patients: Results of a Systematic Review.

INTRODUCTION: In the last 20 years, biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) have become available for treating rheumatoid arthritis (RA), and a treat-to-target strategy has been introduced. We hypothesise that these advances should have resulted in changes to the characteristics of patients with RA participating in clinical trials of the newest therapies. This study determined whether the baseline characteristics of patients with RA enrolled in clinical trials have changed in the past decade versus patients participating in earlier RA studies. METHODS: This secondary analysis was based on randomised controlled trials (RCTs) identified in a systematic literature review. Baseline characteristics of patients with RA with inadequate response to conventional synthetic DMARDs were compared between RCTs published in 1999-2009 and those published in 2010-2017 using random-effects meta-analyses. RESULTS: Forty RCTs were analysed: 22 from 1999-2009 and 18 from 2010-2017. No significant difference between the two timeframes and no obvious trend over time were observed for age, gender, disease duration, rheumatoid factor status, tender and swollen joint counts, physician and patient global assessments of disease activity, and pain scores. Variability between RCTs was high. Similar results were observed for Disease Activity Scores and Health Assessment Questionnaire-Disability Index scores, but with low variability between RCTs. CONCLUSION: The baseline characteristics of patients with RA participating in RCTs do not appear to have changed in the last decade despite the availability of new treatments and a different treatment approach. Further research should determine the impact of baseline patient characteristics on patients' response to RA treatments.

In the last 20 years, new treatments and a new treatment approach (called treat-to-target) have been introduced for rheumatoid arthritis (RA). Consequently, the characteristics of patients with RA participating in clinical trials of the newest therapies should have changed compared with those of patients who participated in clinical trials of older therapies. This is important as patient characteristics may influence patients' response to drug treatment. To determine whether characteristics of patients with RA have changed over time, we compared the baseline characteristics (e.g. age, gender, disease duration, measures of disease activity, and pain scores) of patients with RA between 22 clinical trials published in 1999­2009 and 18 published in 2010­2017. No significant difference between the two timeframes and no obvious trend over time were observed for any baseline characteristic of patients with RA, including physician and patient measures of disease activity, and patient measures of physical function and pain. Thus, the baseline characteristics of patients with RA participating in clinical trials do not appear to have changed in the last decade despite the introduction of new treatments and the treat-to-target approach. Further research is needed to determine the impact of baseline patient characteristics on patients' response to RA treatments.

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

What Is Driving Paradigm Shifts in Plastic Surgery and Is Cosmetic Surgery Keeping Up?

BACKGROUND: Cosmetic surgery represents 20 to 30 percent of total plastic surgical volume. The authors hypothesize that with current capitalization and market share, cosmetic surgery should be proportionally represented in scientific innovation. METHODS: All journals that may contain articles relevant to plastic surgery were selected from the 2016 edition of Journal Citation Reports. The authors identified, reviewed, and analyzed the 100 top-cited plastic surgery clinical articles using the Science Citation Index Expanded (1900 to 2017) as a proxy for innovation. RESULTS: The top-100 articles were cited a median of 329.5 times (range, 240 to 1709 times). Sixteen journals were represented, led by Plastic and Reconstructive Surgery (45 percent) and Annals of Surgery (15 percent). Fifty-six percent were reconstructive, 13 percent were breast, 11 percent were pediatric/craniofacial, 11 percent were cosmetic, and 9 percent were hand/peripheral nerve articles. Only 11 percent of articles represented level of evidence I or II, with the majority (79 percent) of articles being level IV. Sixty-seven percent of publications originated from United States. The 11 cosmetic articles originated from different subspecialties: injectables, fillers, and fat grafting (n = 7); contouring (n = 2); facial cosmetic (n = 1); and general cosmetic (n = 1). CONCLUSIONS: Cosmetic innovation is not keeping up with reconstructive innovation; it is unknown why cosmetic surgery is lacking. The authors offer several speculations as to why there is a gap in cosmetic surgical research and, by proxy, innovation.

The Introduction of New Non-Drug Health Technologies into Canadian Healthcare Institutions: Opportunities and Challenges.

INTRODUCTION: A recent pan-Canadian survey of 48 health organizations concluded that structures, processes, factors and information used to support funding decisions on new non-drug health technologies (NDTs) vary within and across jurisdictions in Canada. METHODS: A self-administered survey was used to determine demographic and financial characteristics of organizations, followed by in-depth interviews with senior leadership of consenting organizations to understand the processes for making funding decisions on NDTs. RESULTS: Seventy-three and 48 organizations completed self-administered surveys and telephone interviews, respectively (with 45 participating in both ways). Fifty-five different processes were identified, the majority of which addressed capital equipment. Most involved multidisciplinary committees (with medical and non-medical representation), but the types of information used to inform deliberations varied. Across all processes, decision-making criteria included local considerations such as alignment with organizational priorities. CONCLUSIONS: NDT decision-making processes vary in complexity, depending on characteristics of the healthcare organization and context.

Almost half of references in reports on new and emerging nondrug health technologies are grey literature.

OBJECTIVE: The research investigated how frequently grey literature is used in reports on new and emerging nondrug health technologies, which sources are most cited, and how grey literature searching is reported. METHODS: A retrospective review of references cited in horizon scanning reports on nondrug health technologies-including medical devices, laboratory tests, and procedures-was conducted. A quasi-random sample of up to three reports per agency was selected from a compilation of reports published in 2014 by international horizon scanning services and health organizations. RESULTS: Twenty-two reports from 8 agencies were included in the analysis. On average, 47% (288/617) of references listed in the bibliographies of the horizon scanning reports were grey literature. The most frequently cited type of grey literature was information from manufacturers (30% of all grey literature references), regulatory agencies (10%), clinical trial registries (9%), and other horizon scans or evidence synthesis reports (9%). The US Food and Drug Administration (FDA) and ClincalTrials.gov were the most frequently cited specific sources, constituting 7% and 8% of grey literature references, respectively. Over two-thirds (15/22) of the analyzed reports provided some details on search methodology; all 15 of these reported searching some grey literature. CONCLUSIONS: In this sample, grey literature represented almost half of the references cited in reports on new and emerging nondrug health technologies. Of these grey literature references, almost half came from three sources: the manufacturers, ClincalTrials.gov, and the FDA. There was wide variation in the other sources cited. Literature search methodology was often insufficiently reported for analysis.

Contact us for more information: an analysis of public enquiries about stem cells.

Aim: This study examines online enquiries received by two prominent stem cell science initiatives operating in different geographical jurisdictions. Materials & methods: Combined quantitative and qualitative analysis undertaken of internet-based queries (n = 1047) received by Stem Cells Australia and EuroStemCell from members of the public over a two-year period (May 2014-2016). Results: Findings reveal striking similarities between the two datasets and highlight the range of uncertainties, priorities and needs of those seeking information about stem cells online. Conclusion: Sustained and in-depth tailored guidance is needed to effectively meet the diverse stem cell-related information-based needs of communities internationally. Such efforts should be prioritized by regenerative medicine research initiatives and organizations, given the trust and hope diverse publics appear to place in these groups.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

PURPOSE: Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. METHODS: Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. RESULTS: Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. CONCLUSION: This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Defining Innovation in Neurosurgery: Results from an International Survey.

BACKGROUND: Innovation is a part of the daily practice of neurosurgery. However, a clear definition of what constitutes innovation is lacking and opinions vary from continent to continent, from hospital to hospital, and from surgeon to surgeon. METHODS: In this study, we distributed an online survey to neurosurgeons from multiple countries to investigate what neurosurgeons consider innovative, by gathering opinions on several hypothetical cases. The anonymous survey consisted of 52 questions and took approximately 10 minutes to complete. RESULTS: A total of 355 neurosurgeons across all continents excluding Antarctica completed the survey. Neurosurgeons achieved consensus (>75%) in considering specific cases to be innovative, including laser resection of meningioma, focused ultrasonography for tumor, oncolytic virus, deep brain stimulation for addiction, and photodynamic therapy for tumor. Although the new dura substitute case was not considered innovative, there was consensus among neurosurgeons indicating that institutional review board approval was still necessary to maintain ethical standards. Furthermore, although 90% of neurosurgeons considered an oncolytic virus for glioblastoma multiforme to be innovative, only 78% believed that institutional review board approval was necessary before treatment. CONCLUSIONS: Our results indicate that innovation is a heterogeneous concept among neurosurgeons that necessitates standardization to ensure appropriate patient safety without stifling progress. We discuss both the ethical drawbacks of not having a clear definition of innovation and the challenges in achieving a unified understanding of innovation in neurosurgery and offer suggestions for uniting the field.

Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments.

The increase in the popularity of non-inferiority clinical trials represents the increasing need to search for substitutes for some reference (standard) treatments. A new treatment would be preferred to the standard treatment if the benefits of adopting it outweigh a possible clinically insignificant reduction in treatment efficacy (non-inferiority margin). Statistical procedures have recently been developed for treatment comparisons in non-inferiority clinical trials that have multiple experimental (new) treatments. An ethical concern for non-inferiority trials is that some patients undergo the less effective treatments; this problem is more serious when multiple experimental treatments are included in a balanced trial in which the sample sizes are the same for all experimental treatments. With the aim of giving fewer patients the inferior treatments, we propose a response-adaptive treatment allocation scheme that is based on the doubly adaptive biased coin design. The proposed adaptive design is also shown to be superior to the balanced design in terms of testing power.

Testing of non-inferiority and superiority for three-arm clinical studies with multiple experimental treatments.

The purpose of a non-inferiority trial is to assert the efficacy of an experimental treatment compared with a reference treatment by showing that the experimental treatment retains a substantial proportion of the efficacy of the reference treatment. Statistical methods have been developed to test multiple experimental treatments in three-arm non-inferiority trials. In this paper, we report the development of procedures that simultaneously test the non-inferiority and the superiority of experimental treatments after the assay sensitivity has been established. The advantage of the proposed test procedures is the additional ability to identify superior treatments while retaining an non-inferiority testing power comparable to that of existing testing procedures. Single-step and stepwise procedures are derived and then compared with each other to determine their relative testing power and testing error in a simulation study. Finally, the suggested procedures are illustrated with two clinical examples.

Funding breakthrough therapies: A systematic review and recommendation.

BACKGROUND: Advanced therapy medicinal products (ATMPs) are innovative therapies likely associated with high prices. Payers need guidance to create a balance between ensuring patient access to breakthrough therapies and maintaining the financial sustainability of the healthcare system. OBJECTIVE: The aims of this study were to identify, define, classify and compare the approaches to funding high-cost medicines proposed in the literature, to analyze their appropriateness for ATMP funding and to suggest an optimal funding model for ATMPs. RESULTS: Forty-eight articles suggesting new funding models for innovative high-cost therapies were identified. The models were classified into 3 groups: financial agreement, health outcomes-based agreement and healthcoin. Financial agreement encompassed: discounts, rebates, price and volume caps, price-volume agreements, loans, cost-plus price, intellectual-based payment and fund-based payment. Health outcomes-based agreements were defined as agreements between manufacturers and payers based on drug performance, and were divided into performance-based payment and coverage with evidence development. Healthcoin described a new suggested tradeable currency used to assign monetary value to incremental outcomes. CONCLUSION: With a large number of ATMPs in development, it is time for stakeholders to start thinking about new pathways and funding strategies for these innovative high-cost therapies. An "ATMP-specific fund" may constitute a reasonable solution to ensure rapid patient access to innovation without threatening the sustainability of the health care system.

Promoting innovation in small markets: Evidence from the market for rare and intractable diseases.

In many medical care markets with limited profit potential, firms often have little incentive to innovate. These include the market for rare diseases, "neglected" tropical diseases, and personalized medicine. Governments and not-for-profit organizations promote innovation in such markets but empirical evidence on the policy effect is limited. We study this issue by analyzing the impact of a demand-side policy in Japan, which reduces the cost sharing of patients with some rare and intractable diseases and attempts to establish and promote the treatment of those diseases. Using clinical trials data taken from public registries, we identify the effect of the policy using a difference-in-difference approach. We find that the demand-side policy increased firms' incentive to innovate: firm-sponsored clinical trials increased 181% (0.16 per disease per year) when covered by the policy. This result indicates that the demand-side policy can be an important part of innovation policies in markets with limited profit potential.