Considerations in the Assessment of Clinical Benefit with a Focus on Pain: a Regulatory Perspective.

In the USA, the regulatory standard for demonstration of efficacy of a drug is evidence of clinical benefit from adequate and well-controlled clinical trials. Understanding the natural history of disease and how treatment is expected to alter its course, and gathering input from relevant stakeholders, such as patients, caregivers, and clinicians, is essential to understand the best way to measure clinical benefit in a clinical trial. Though pain intensity has been the primary outcome measure in clinical trials for pain, an array of measures assessing clinical outcomes from multiple perspectives can allow for more comprehensive interpretation of how a treatment affects patients' lives. Careful consideration should be given to how pain affects the feeling and functioning of each distinct patient population and which outcome assessment, or combination of outcome assessments, may be necessary to provide a more comprehensive view of the patient experience. The early stages of medical product development are an important opportunity to engage with regulatory agencies to discuss potential approaches to clinical trial design and outcome measurement strategies.

Pediatric Outcomes After Regulatory Mandates for Sepsis Care.

BACKGROUND: In 2013, New York introduced regulations mandating that hospitals develop pediatric-specific protocols for sepsis recognition and treatment. METHODS: We used hospital discharge data from 2011 to 2015 to compare changes in pediatric sepsis outcomes in New York and 4 control states: Florida, Massachusetts, Maryland, and New Jersey. We examined the effect of the New York regulations on 30-day in-hospital mortality using a comparative interrupted time-series approach, controlling for patient and hospital characteristics and preregulation temporal trends. RESULTS: We studied 9436 children admitted to 237 hospitals. Unadjusted pediatric sepsis mortality decreased in both New York (14.0% to 11.5%) and control states (14.4% to 11.2%). In the primary analysis, there was no significant effect of the regulations on mortality trends (differential quarterly change in mortality in New York compared with control states: -0.96%; 95% confidence interval [CI]: -1.95% to 0.02%; P = .06). However, in a prespecified sensitivity analysis excluding metropolitan New York hospitals that participated in earlier sepsis quality improvement, the regulations were associated with improved mortality trends (differential change: -2.08%; 95% CI: -3.79% to -0.37%; P = .02). The regulations were also associated with improved mortality trends in several prespecified subgroups, including previously healthy children (differential change: -1.36%; 95% CI: -2.62% to -0.09%; P = .04) and children not admitted through the emergency department (differential change: -2.42%; 95% CI: -4.24% to -0.61%; P = .01). CONCLUSIONS: Implementation of statewide sepsis regulations was generally associated with improved mortality trends in New York State, particularly in prespecified subpopulations of patients, suggesting that the regulations were successful in affecting sepsis outcomes.

Measuring quality of urology care using a qualified clinical data registry.

PURPOSE OF REVIEW: Qualified clinical data registries (QCDRs) serve as a framework for quality improvement efforts, clinical research endeavors, and participation in reimbursement incentive programs. However, the measurement of quality and the recommendations to guide QCDRs in developing new quality measures is a complex process. In this review, we highlight the government policies that lead to the creation of QCDRs, how QCDR quality measures are developed, and the current QCDRs that focus on urological care. RECENT FINDINGS: QCDRs facilitate participation in the merit-based incentive payment system for reimbursement adjustments. Most QCDRs leverage existing clinical guidelines in the development of new quality measures. In 2018, there are four urology QCDRs with quality measures for many urological conditions. These QCDRs form the infrastructure for quality improvement and provide new resources for research endeavors. SUMMARY: Quality measurement within QCDRs will allow urologists to focus improvement efforts to deliver high-quality urological care while also facilitating reimbursement incentives and creating novel research datasets.

Association of the FDA Amendment Act with trial registration, publication, and outcome reporting.

BACKGROUND: Selective clinical trial publication and outcome reporting has the potential to bias the medical literature. The 2007 Food and Drug Administration (FDA) Amendment Act (FDAAA) mandated clinical trial registration and outcome reporting on ClinicalTrials.gov, a publicly accessible trial registry. METHODS: Using publicly available data from ClinicalTrials.gov, FDA documents, and PubMed, we determined registration, publication, and reporting of findings for all efficacy trials supporting FDA approval of new drugs for cardiovascular disease and diabetes between 2005 and 2014, before and after the FDAAA. For published trials, we compared the published interpretation of the findings (positive, equivocal, or negative) with the FDA reviewer's interpretation. RESULTS: Between 2005 and 2014, the FDA approved 30 drugs for 32 indications of cardiovascular disease (n = 17) and diabetes (n = 15) on the basis of 183 trials (median per indication 5.7 (IQR, 3-8)). Compared with pre FDAAA, post-FDAAA studies were more likely to be registered (78 of 78 (100%) vs 73 of 105 (70%); p < 0.001), to be published (76 of 78 (97%) vs 93 of 105 (89%); p = 0.03), and to present findings concordant with the FDA reviewer's interpretation (74 of 76 (97%) vs 78 of 93 (84%); p = 0.004). Pre FDAAA, the FDA reviewer interpreted 80 (76%) trials as positive and 91 (98%) were published as positive. Post FDAAA, the FDA reviewer interpreted 71 (91%) trials as positive and 71 (93%) were published as positive. CONCLUSIONS: FDAAA was associated with increased registration, publication, and FDA-concordant outcome reporting for trials supporting FDA approval of new drugs for cardiovascular disease and diabetes.

Medicare Program: Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs; Organ Procurement Organization Reporting and Communication; Transplant Outcome Measures and Documentation Requirements; Electronic Health Record (EHR) Incentive Programs; Payment to Nonexcepted Off-Campus Provider-Based Department of a Hospital; Hospital Value-Based Purchasing (VBP) Program; Establishment of Payment Rates Under the Medicare Physician Fee Schedule for Nonexcepted Items and Services Furnished by an Off-Campus Provider-Based Department of a Hospital. Final rule with comment period and interim final rule with comment period.

This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) and the Medicare ambulatory surgical center (ASC) payment system for CY 2017 to implement applicable statutory requirements and changes arising from our continuing experience with these systems. In this final rule with comment period, we describe the changes to the amounts and factors used to determine the payment rates for Medicare services paid under the OPPS and those paid under the ASC payment system. In addition, this final rule with comment period updates and refines the requirements for the Hospital Outpatient Quality Reporting (OQR) Program and the ASC Quality Reporting (ASCQR) Program. Further, in this final rule with comment period, we are making changes to tolerance thresholds for clinical outcomes for solid organ transplant programs; to Organ Procurement Organizations (OPOs) definitions, outcome measures, and organ transport documentation; and to the Medicare and Medicaid Electronic Health Record Incentive Programs. We also are removing the HCAHPS Pain Management dimension from the Hospital Value-Based Purchasing (VBP) Program. In addition, we are implementing section 603 of the Bipartisan Budget Act of 2015 relating to payment for certain items and services furnished by certain off-campus provider-based departments of a provider. In this document, we also are issuing an interim final rule with comment period to establish the Medicare Physician Fee Schedule payment rates for the nonexcepted items and services billed by a nonexcepted off-campus provider-based department of a hospital in accordance with the provisions of section 603.

[Biosimilars and the efficiency principle]. / Biosimilars und das Wirtschaftlichkeitsgebot.

Biosimilars are subject to the efficiency evaluation according to section 106 Social Code Book Five (SGB V). The specific evaluation method influences the physician's prescription behaviour. In the case of an individual prescription limit evaluation (Richtgrößenprüfung), the prescription of biosimilars would usually not result in recourse but, as a start, in the initiation of the evaluation proceedings. Starting from 2017, the individual prescription limit evaluation will be cancelled. The active ingredient evaluation (Wirkstoffprüfung) expected instead at a regional level may provide for biosimilar to original drug ratios and result in recourses if these ratios are missed. First agreements on specific evaluation proceedings at a regional level are expected for this year.

[Functional Electrical Stimulation in a Case of Drop Foot and Atactic Gait: Expert Assessment of Contested Medical Aids]. / Funktionelle Elektrostimulation bei Fußheberschwäche und ataktischem Gangbild: Gutachterliches Vorgehen bei streitiger Hilfsmittelversorgung.

Expert medical opinions are necessary in pretrial cases and other legal matters. They act as means of evidence for administrative bodies and courts. It may be necessary to adapt the method of evaluation depending upon the issue or subject matter to be evaluated. We report on a social court case, which needed to answer the question of the medical necessity of a functional electrical stimulation orthosis prescribed to improve the function of a drop foot accompanied by an atactic gait disorder. The claimant suffered from a stroke, which had occurred several years before. Her aids were an ankle-foot-orthosis for foot lift and a wheeled walker. The current treatment was to be augmented by the disputed device. The statutory health insurance declined to meet the costs. They failed to find relevant benefits after analysis of video tapes of the patient's gait while using an electrical stimulation orthosis. The social court requested an expert opinion to answer the question as to whether or not there was a relevant functional benefit to using functional electrical stimulation over the existing orthosis or to an alternative treatment. Video documentation was desired by the court. We used the clinic's gait analysis laboratory, which is equipped with a gait course and the claimed video documentation. Standardised video documentation offers substantial advantages for answering forensic questions such as these. It assures reproducibility and comparability of all tested scenarios, with objectification of the individual advantages or limitations. This gain in both validity and reliability fulfills the scientific requirements placed upon an expert assessment.

[Actual medical care situation and therapeutic needs in multiple sclerosis: Impact of the Pharmaceutical Market Restructuring Act (AMNOG)]. / Versorgungsrealität und therapeutischer Bedarf bei Multipler Sklerose : Auswirkungen des AMNOG.

BACKGROUND: The treatment of patients with multiple sclerosis (MS) is associated with constantly rising costs for the healthcare system and pharmaceuticals constitute 60 % of the direct medical costs. The Pharmaceutical Market Restructuring Act (Arzneimittelmarkt-Neuordnungsgesetz, AMNOG) came into force on 1 January 2011 with the aim of limiting the costs of pharmaceuticals by obligating newly approved products to be subjected to an early evaluation of the additional benefits by the Federal Joint Committee (FJC, Gemeinsamer Bundesausschuss, G­BA). The majority of products evaluated up to October 2015 in neurology (5 out of 8) were approved for treatment of MS. OBJECTIVE: Has the AMNOG been able to fulfill the original aims? MATERIAL AND METHODS: Analysis of available information on MS therapies evaluated by the FJC between December 2010 and October 2015. RESULTS: For various reasons an additional benefit could be shown in only 2 out of 5 assessment procedures for MS drugs. It is obvious that some methodological shortcomings of the process have to be improved. Additionally requirements for pivotal clinical trials have to be harmonized with AMNOG requirements taking the best available evidence and real-life data into consideration (e.g. non-interventional studies) and a closer collaboration between the FJC, healthcare providers and the neurological societies is necessary. CONCLUSION: The AMNOG procedure currently only partially fulfills the original aims, which could be the reason why guidelines play a more important role for therapy decision-making than FJC decisions. As the early evaluation procedure is an adaptive process methodological shortcomings might be overcome in the future; however, this requires a much closer collaboration between the FJC and neurological societies.

[Requirements for drug approval and additional benefits assessment: Regulatory aspects and experiences]. / Anforderungen an Zulassung und Zusatznutzenbewertung von Arzneimitteln : Regulatorische Aspekte und Erfahrungen.

The early assessment of benefits of newly approved drugs with novel active substances or new applications, which came into force on 1 January 2011 still represents a challenge to all parties involved. This article highlights the definitions, regulatory requirements and interaction between drug marketing approval and early assessment of benefits in Germany. The constellation of an extensively harmonized European and even international drug authorization process with a predominantly national regulation of drug reimbursement situation inevitably causes friction, which could be markedly reduced through early joint advisory discussions during the planning phase for pivotal clinical trials. During the year 2015 the Federal Institute for Drugs and Medical Devices (BfArM) carried out 300 scientific advice procedures of which 34 were concerned with applications in the field of indications for the central nervous system (CNS). In comparison 98 advisory meetings were held by the Federal Joint Committee (G-BA) of which the BfArM provided advice in 12 instances and in 2 cases on CNS indications. Study design, endpoints and appropriate comparative therapies are the key issues in exchanges and discussions between the BfArM, the G­BA and applicants. Under these aspects the BfArM and G­BA promote an early and consistent involvement in early advice procedures regarding the prerequisites for drug approval and assessment of additional benefits.

[The new German drug market law AMNOG from a child and adolescent psychiatry perspective]. / Das Arzneimittelmarktneuordnungsgesetz aus kinder- und jugendpsychiatrischer Perspektive.

BACKGROUND: The European Union (EU) regulation 1901/2006 plus the implementation of pediatric investigational plans by the European Medicines Agency (EMA) have contributed to more clinical studies in pediatric psychopharmacology. A new drug market law (AMNOG) has been in force in Germany since 2011 that requires an additional process of assessment of benefits of newly authorized medications by the Federal Joint Committee (Gemeinsamer Bundesausschuss, G­BA), which also holds for medications licensed for pediatric populations. OBJECTIVES: Summary of early assessments of benefits for newly registered compounds in the treatment of psychiatric disorders and critical discussion from the perspective of child and adolescent psychiatry. MATERIAL AND METHODS: Application and critical review of documents and written statements by various institutions and stakeholders related to assessment procedures and respective decisions by the G­BA for these medications. RESULTS AND CONCLUSION: Clearly differing requirements for study designs and outcome parameters characterize the conditions for market authorization and for the assessment of benefits. Further adjustments to the regulations in implementing the AMNOG appear to be essential, integrating agencies involved so far, complimented by expertise from regulatory agencies and medical scientific societies.

[Significance of the German Act on the Reform of the Market for Medicinal Products for psychopharmacotherapy]. / Bedeutung des Arzneimittelmarktneuordnungsgesetzes für die Psychopharmakotherapie.

The German Act on the Reform of the Market for Medicinal Products (AMNOG) will lead to rapid disappearance of many new psychotropic drugs from the market in Germany over the next few years or their not being introduced in the first place. This article lists the reasons and discusses possible solutions. In the long term, the AMNOG could not only lead to an improvement of psychopharmacology but also contribute to the development of psychiatry as a whole, especially if its standards become an international reference.

[Impact of early benefit assessment on patients with epilepsy in Germany: Current healthcare provision and therapeutic needs]. / Auswirkungen der frühen Nutzenbewertung auf Patienten mit Epilepsie in Deutschland : Aktuelle Versorgungsrealität und therapeutischer Bedarf.

Epilepsy is one of the most common chronic neurological diseases and represents a significant burden for patients, their families and society. In more than 75 % of patients anticonvulsant therapy consists of valproate, carbamazepine, lamotrigine or levetiracetam. There is a need for polytherapy in drug-refractory patients and they suffer from negative effects on quality of life and employment that is associated with high indirect costs. To allow a comprehensive treatment in this patient group, access to new anticonvulsants with novel modes of action is needed; however, all applications for new antiepileptic drugs failed to prove added benefits during the Pharmaceutical Market Restructuring Act (AMNOG) in Germany. One of the main reasons is the mandatory definition of a standard comparative therapy. It remains unclear whether there will be studies in the future which will fulfill the requirements of the current version of AMNOG. Observational studies after approval and marketing of new antiepileptic drugs could be better alternatives to prove added benefits for individual patients in the current German healthcare system.

Early Benefit Assessments in Oncology in Germany: How Can a Clinically Relevant Endpoint Not Be Relevant to Patients?

After 4 years of early benefit assessment (EBA) in Germany, it is becoming evident that the Federal Joint Committee (FJC) frequently considers well-established clinical endpoints as not being relevant to patients. Focusing on assessments of oncology medicines, we analysed the FJC's view on primary endpoints and compared it with the approach used by regulatory authorities. Mortality data were accepted by both stakeholders. Whereas regulatory authorities accepted primary morbidity endpoints such as progression-free survival and response rates, the FJC mostly excluded these from its assessments. Health-related quality of life (HRQoL) data have been poorly reflected in the approval process; for EBAs, those data have rarely impacted on benefit ratings. We argue that agreement between regulatory authorities and the FJC is required regarding primary study endpoints that are relevant to patients, and that clarification of acceptable endpoints by the FJC, especially in the morbidity domain, has to be provided. Moreover, in order to fully acknowledge the benefit of a new medicinal product, mortality, morbidity and HRQoL should be weighted differentially, according to the condition.