Probiotics and the Microbiome-How Can We Help Patients Make Sense of Probiotics?

The notion of probiotics as microbes that confer health benefits has its origins in the speculative ideas that are more than a century old, yet remain largely unsubstantiated by scientific evidence. The recent advances in microbiome science have highlighted the importance of intestinal microbes in human physiology and disease pathogenesis. These developments have provided a boost to the probiotics industry, which continues to experience exponential growth driven mainly by creative marketing. Consumers, patients, and most health care providers are not able to discern the underlying science or differentiate the permitted claims that promise vague health benefits from disease-specific claims reserved for drugs. No probiotic product has been able to satisfy the regulatory requirements to be categorized as a drug, a substance intended to cure, mitigate, or prevent disease. However, patients take probiotic products in the belief that they will help to treat their intestinal or systemic diseases. Thus far, the regulators have failed to create policies that would assist to inform the public in this area. In fact, the existing regulatory regime actually creates formidable barriers to research that could provide evidence for clinical efficacy of probiotic products. We propose a potential solution to this vexing problem, where a committee created through a partnership of academia, professional organizations, and industry, but free of potential conflicts of interest, would be charged with rigorous evaluation of specific probiotic products and the evidence in support of their different claims. Companies that would submit to this process would earn the trust of consumers and healthcare providers, as well as a distinction in the marketplace.

Public health implications of legalising the production and sale of cannabis for medicinal and recreational use.

We assess the current and describe possible future public health impacts of the legalisation of cannabis production, sale, and use in the Americas. First, we describe global patterns of cannabis use and their most probable adverse health effects. Second, we summarise evidence regarding the effectiveness of cannabinoids for medicinal use and describe approaches that have been used to regulate the use of medicinal cannabis and how these approaches might have affected medicinal and recreational use and harms (eg, road crashes). Third, we describe how jurisdictions that have legalised recreational use have regulated production and sale of cannabis. Fourth, we evaluate the effects of cannabis legalisation on cannabis use and harms and on the use of alcohol, tobacco, and other drugs. Fifth, we use alcohol and tobacco policy examples to identify possible long-term public health effects of cannabis legalisation. Finally, we outline policy approaches that could minimise harms to public health arising from the legalisation of a commercial cannabis industry.

The Pay-Twice Critique, Government Funding, and Reasonable Pricing Clauses.

The federal government subsidizes the research and development of prescription medications. Thus, a captivating critique of expensive medications is that prices are too high because of taxpayer co-financing. This critique is often framed in terms of "paying-twice"-first for the research and second through the above market pricing of resulting products. Reasonable pricing clauses-which place some kind of pricing limitation on the exercise of license or patent rights governing a federally funded medication-are one proposed policy tool for addressing the pay-twice critique. This article provides increased analytical clarity as well as historical context to present-day debates about the privatization of federally funded research and prescription drug pricing. It makes three arguments. First, despite its pervasiveness and intuitive plausibility, the pay-twice critique is subject to differing interpretations which has important implications for the appropriateness of proposed solutions. Second, despite their initial attractiveness, the costs, necessity, and effectiveness of reasonable pricing clauses render the wisdom of this policy tool uncertain. However, third, given continued interest in reasonable pricing clauses, the NIH's previous experience with such a policy offers some useful lessons.

Affordability Challenges to Value-Based Pricing: Mass Diseases, Orphan Diseases, and Cures.

OBJECTIVES: To analyze how value-based pricing (VBP), which grounds the price paid for pharmaceuticals in their value, can manage "affordability" challenges, defined as drugs that meet cost-effectiveness thresholds but are "unaffordable" within the short-run budget. METHODS: Three specific contexts are examined, drawing on recent experience. First, an effective new treatment for a chronic, progressive disease, such as hepatitis C, creates a budget spike that is transitory because initial prevalence is high, relative to current incidence. Second, "cures" that potentially provide lifetime benefits may claim abnormally high VBP prices, with high immediate budget impact potentially/partially offset by deferred cost savings. Third, although orphan drugs in principle target rare diseases, in aggregate they pose affordability concerns because of the growing number of orphan indications and increasingly high prices. RESULTS: For mass diseases, the transitory budget impact of treating the accumulated patient stock can be managed by stratified rollout that delays treatment of stable patients and prioritizes patients at high risk of deterioration. Delay spreads the budget impact and permits potential savings from launch of competing treatments. For cures, installment payments contingent on outcomes could align payment flows and appropriately shift risk to producers. This approach, however, entails high administrative and incentive costs, especially if applied across multiple payers in the United States. For orphan drugs, the available evidence on research and development trends and returns argues against the need for a higher VBP threshold to incentivize research and development in orphan drugs, given existing statutory benefits under orphan drug legislation.

Five-Year Sales for Newly Marketed Prescription Drugs With and Without Initial Orphan Drug Act Designation.

This study evaluates sales revenue earned in the first 5 years for newly marketed brand-name drugs with and without an initial orphan drug designation.

Distribution of Abatement Funds Arising From US Opioid Litigation.

This Viewpoint discusses the settlement agreements reached against several major pharmaceutical distributors resulting from the US opioid epidemic and how those funds will be distributed amongst the states.

Drug Pricing Program Ceiling Price and Manufacturer Civil Monetary Penalties Regulation. Final rule; further delay of effective date.

The Health Resources and Services Administration (HRSA) administers section 340B of the Public Health Service Act (PHSA), known as the "340B Drug Pricing Program" or the "340B Program." HRSA published a final rule on January 5, 2017, that set forth the calculation of the ceiling price and application of civil monetary penalties. The final rule applied to all drug manufacturers that are required to make their drugs available to covered entities under the 340B Program. On August 21, 2017, HHS solicited comments on further delaying the effective date of the January 5, 2017, final rule to July 1, 2018 (82 FR 39553). HHS proposed this action to allow a more deliberate process of considering alternative and supplemental regulatory provisions and to allow for sufficient time for additional rulemaking. After consideration of the comments received on the proposed rule, HHS is delaying the effective date of the January 5, 2017, final rule, to July 1, 2018.

From Medical to Recreational Marijuana Sales: Marijuana Outlets and Crime in an Era of Changing Marijuana Legislation.

A movement from medical to recreational marijuana use allows for a larger base of potential users who have easier access to marijuana, because they do not have to visit a physician before using marijuana. This study examines whether changes in the density of marijuana outlets were related to violent, property, and marijuana-specific crimes in Denver, CO during a time in which marijuana outlets began selling marijuana for recreational, and not just medical, use. We collected data on locations of crimes, marijuana outlets and covariates for 481 Census block groups over 34 months (N = 16,354 space-time units). A Bayesian Poisson space-time model assessed statistical relationships between independent measures and crime counts within "local" Census block groups. We examined spatial "lag" effects to assess whether crimes in Census block groups adjacent to locations of outlets were also affected. Independent of the effects of covariates, densities of marijuana outlets were unrelated to property and violent crimes in local areas. However, the density of marijuana outlets in spatially adjacent areas was positively related to property crime in spatially adjacent areas over time. Further, the density of marijuana outlets in local and spatially adjacent blocks groups was related to higher rates of marijuana-specific crime. This study suggests that the effects of the availability of marijuana outlets on crime do not necessarily occur within the specific areas within which these outlets are located, but may occur in adjacent areas. Thus studies assessing the effects of these outlets in local areas alone may risk underestimating their true effects.

Evaluating the Change in Medical Marijuana Dispensary Locations in Los Angeles Following the Passage of Local Legislation.

In May 2013, Los Angeles voters approved Proposition D, a regulatory measure that set zoning restrictions and capped the number of dispensaries at those that opened before 2007. Specifically, Proposition D stated that only 135 dispensaries were allowed to be in operation and set zoning restrictions prohibiting dispensaries from operating in certain areas. We first assessed whether the legislation changed the physical availability of medical marijuana via dispensaries in Los Angeles. We then used two data points 1 year prior to and 1 year following the implementation of Proposition D to determine if the locations of where the dispensaries are located changed after the enactment of Proposition D. Using a cross-sectional, ecological design, we investigated the change in dispensaries from 2012 to 2014 for Census tracts within the city of Los Angeles (N = 1000). We analyzed data using spatial error regression models that included controls for spatial autocorrelation due to the spatial structure of the data. We found that while the total number of dispensaries in Los Angeles remained largely unchanged, the spatial distribution of dispensaries did change in meaningful ways. Census tracts with more dispensaries in 2014 were significantly and positively associated with the proportion of African American residents and negatively associated with the percent of area that was commercially zoned. In other words, dispensaries opened in areas with a higher proportion of Black residents and closed in Census tract areas that had a higher percentage of commercially zoned land. Findings from this study highlight the importance of continuously regulating dispensary locations. Results suggest that likely as a result of changing regulations, dispensaries may be attempting to conceal their presence and locate in areas that will not advocate against their presence.

Early Impacts of Marijuana Legalization: An Evaluation of Prices in Colorado and Washington.

Following the legalization and regulation of marijuana for recreational purposes in states with medical markets, policymakers and researchers seek empirical evidence on how, and how fast, supply and demand changed over time. Prices are an indication of how suppliers and consumers respond to policy changes, so this study uses a difference-in-difference approach to exploit the timing of policy implementation and identify the impacts on marijuana prices 4-5 months after markets opened. This study uses unique longitudinal survey data of prices paid by consumers and a web-scraped dataset of dispensary prices advertised online for three U.S. medical marijuana states that all eventually legalized recreational marijuana. Results indicate there were no impacts on the prices paid for medical or recreational marijuana by state-representative residents within the short 4- to 5-months window following legalization. However, there were differences in how much people paid if they obtained marijuana for recreational purposes from a recreational store. Further analysis of advertised prices confirms this result, but further demonstrates heterogeneous responses in prices across types of commonly advertised strains; prices either did not change or increased depending on the strain type. A key implication of our findings is that there are both supply and demand responses at work in the opening of legalized markets, suggesting that evaluations of immediate effects may not accurately reflect the long run impact of legalization on consumption.

Using Data Exclusivity Grants to Incentivize Cumulative Innovation of Biologics' Manufacturing Processes.

The pharmaceutical market is divided into two types of compounds: small-molecule chemical compounds and large-molecule biologics. Due to biologics' molecular sizes and the current scientific state of biologics manufacturing, manufacturing facilities and processes require frequent reassessment to ensure production of safe, pure, and potent therapeutics. Manufacturers utilize patent and drug regulatory law to protect their investments and simultaneously signal where innovation and investment are lacking. The current four- and twelve-year regimented structures of the Biologics Price, Competition, and Innovation Act do not keep pace with scientific development; biologics manufacturing processes drift with time, and if a manufacturer can obtain a higher degree of process control, then it should not feel restricted to wait until their exclusivity period lapses. Currently, the FDA rarely grants market exclusivity privileges for manufacturing process improvements alone; hence, manufacturing processes--or at least large portions thereof--are typically withheld as trade secrets or strategically claimed within companion composition claims. As a result, significant opportunity exists in regulatory framework to incentivize the research and development of biologics manufacturing processes. By creating a one- to four-year data exclusivity extension opportunity, manufacturers will feel more comfortable reinvesting their returns on investment towards manufacturing efficiency, and manufacturers can capitalize on the complex-molecule nature of their biologic.

Medicare program; changes to the requirements for Part D prescribers. Interim final rule with comment period.

This interim final rule with comment period revises requirements related to beneficiary access to covered Part D drugs. Under these revised requirements, pharmacy claims and beneficiary requests for reimbursement for Medicare Part D prescriptions, written by prescribers other than physicians and eligible professionals who are permitted by state or other applicable law to prescribe medications, will not be rejected at the point of sale or denied by the plan if all other requirements are met. In addition, a plan sponsor will not reject a claim or deny a beneficiary request for reimbursement for a drug when prescribed by a prescriber who does not meet the applicable enrollment or opt-out requirement without first providing provisional coverage of the drug and individualized written notice to the beneficiary. This interim final rule with comment period also revises certain terminology to be consistent with existing policy and to improve clarity.

[The German Pharmaceutical Market Reorganization Act (AMNOG) from an economic point of view]. / Das Arzneimittelmarktneuordnungsgesetz (AMNOG) aus ökonomischer Sicht.

Since the introduction of early benefit assessments in Germany, prices for new medicinal products are set in accordance with the "degree of additional benefit." The major aim of the present work is to point out the economic rationale for the definition of a regulatory price for patent-protected drugs. With regard to the economic objectives of efficient allocation of resources, reducing information asymmetries, and promoting high-value innovation, the applied benefit assessments represent major progress in the German health care sector. In addition to the multifaceted criticism of procedural details, there is a general risk that the institutions involved are lagging behind societal preferences. In this case, early benefit assessments may lead to suboptimal results. The pharmaceutical industry's ability to innovate, on the other hand, may be seen to be a result of the interaction between national benefit assessments and the research activities of internationally oriented drug manufacturers. Accordingly, recent trends toward the implementation of national early benefit assessments in combination with international reference pricing may be seen to be critical; however, Germany is merely following the trend of other countries.

An Administrative Meter Maid: Using Inter Partes Review and Post-Grant Review to Curb Exclusivity Parking via the "Failure to Market" Provision of the Hatch-Waxman Act.

Congress created the unique Hatch-Waxman framework in 1984 to increase the availability of low-cost generic drugs while preserving patent incentives for new drug development. The Hatch-Waxman Act rewards generic drug companies that successfully challenge a pharmaceutical patent: 180 days of market exclusivity before any other generic firm can enter the market. When a generic firm obtains this reward, sometimes drug developers agree to pay generic firms to delay entering the market. These pay-for-delay agreements give rise to exclusivity parking and run counter to congressional intent by delaying full generic drug competition. The Medicare Prescription Drug, Improvement, and Modernization Act created several statutory forfeiture provisions that proved only marginally effective at curbing the practice of exclusivity parking. More recently, Congress created new quasi-judicial administrative proceedings that effectively replace certain kinds of district court patent litigation. This Note describes the complex statutory scheme that gave rise to exclusivity parking, explains why previous and current attempts to curtail exclusivity parking were and remain ineffective, and suggests amending the "failure to market" provision to include these new administrative proceedings as a way to help curb exclusivity parking.

Retail impact of raising tobacco sales age to 21 years.

The majority of tobacco use emerges in individuals before they reach 21 years of age, and many adult distributors of tobacco to youths are young adults aged between 18 and 20 years. Raising the tobacco sales minimum age to 21 years across the United States would decrease tobacco retailer and industry sales by approximately 2% but could contribute to a substantial reduction in the prevalence of youths' tobacco use and dependency by limiting access.

Pharmaceutical R&D performance by firm size: approval success rates and economic returns.

The R&D productivity of pharmaceutical firms has become an increasingly significant concern of industry, regulators, and policymakers. To address an important aspect of R&D performance, public and private data sources were used to estimate clinical phase transition and clinical approval probabilities for the pipelines of the 50 largest pharmaceutical firms (by sales) by 3 firms size groups (top 10 firms, top 11-20 firms, and top 21-50 firms). For self-originated compounds, the clinical approval success rates were 14.3%, 16.4%, and 18.4% for top 10 firms, top 11-20 firms, and top 21-50 firms, respectively. The results showing higher success rates for smaller firms were largely driven by outcomes for the small-molecule drugs. Adjustments for the relatively small differences in therapeutic class distributions across the firm size groups showed that the success rate for small-molecule self-originated drugs was 6% below average for top 10 firms and 17% above average for top 21-50 firms. Although success rates for small firms were higher, this advantage was offset to some degree by lower returns on approved drugs, suggesting different strategic objectives with regard to risk and reward by firm size.

[Mechanics and effects of European reference pricing for vaccines in Germany according to §130a Abs. 2 SGB V: an analysis using the example of influenza vaccines]. / Funktionsweise und Auswirkungen des Referenzpreissystems bei Impfstoffen nach §130a Abs. 2 SGB V: eine Analyse am Beispiel der Grippeimpfstoffe.

OBJECTIVES: On 01 January 2011 the bill for the reorganisation of the pharmaceutical market became effective. Since that time there is a European reference pricing (ERP) system for vaccines in order to bring down the German vaccine prices to an assumed lower European level. This study describes the implementation, functioning and effect of this new system. For influenza vaccines the impact of ERP on the price level and spread of prices is analysed. METHODS: The description of the mechanism is based on the law and corresponding regulations of the head association of sickness funds (GKV-SV). The analysis of vaccine prices is based on the data of the i:data report (status of 01 September 2011) of ifap Service Institute. RESULTS: The European reference price is calculated as the average price of the manufacturer-selling-prices of the corresponding vaccine in the 4 countries of the European Union whose gross national income comes closest to the German one and in which the vaccine is distributed. The relied prices are weighted by sales and purchasing power parities of the respective countries. This analysis suggests that in particular the practical implementation of the reference price system should be further improved and specified. The calculation of the reference prices should ensure price comparability. In addition, significant problems remain in the deduction of discounts, because no distinction is made in the documentation of vaccinating doctors, whether vaccination was performed as a compulsory or statutory benefit. The comparison of the manufacturer-selling-prices of individual influenza vaccines with the corresponding reference prices shows an enlargement of the existing price differences, which have evolved in a competitive environment, after the implementation of the reference pricing -system. CONCLUSIONS: There is still a need for improvement in implementing the reference pricing system. In the most competitive vaccine market of influenza vaccines, the ERP-system lowers the prices, but seems to distort the market prices.