Corticosteroid therapy for sepsis: a clinical practice guideline


Three Steps Toward a More Sustainable Path for Targeted Cancer Drugs

Spending on cancer drugs in the United States has increased substantially over the past 5 years, from $26 billion in 2012 to more than $45 billion in 2016.1 Targeted cancer drugs, including small molecules, monoclonal antibodies, and other therapies based on genomic and related analyses, contributed 60% of this spending growth.2 One estimate suggests that by 2021, cancer drugs will comprise one-quarter of the US late-stage pharmaceutical research and development pipeline, and 87% of these products will be targeted agents.2

Imatinib, the small-molecule oral tyrosine kinase inhibitor for chronic myeloid leukemia (CML), is often cited as the model targeted cancer drug; imatinib is highly effective and has reduced toxicity vs previous therapies. For patients with CML treated with imatinib, overall 10-year survival is 84%.3 Introduction of imatinib was associated with a reduction in US age-adjusted CML deaths per 100 000 persons from 0.9 in 1996 to 0.4 in 2006. In 2015, the Medicare estimated monthly price for imatinib was $9299.4

Yet most targeted cancer drugs do not extend life to nearly the same degree. Even though many cancer drugs show improvement in surrogate measures, such as progression-free survival, substantial improvements in overall life expectancy have been rare. For example, in 2017, neratinib was approved for patients with early-stage breast cancer after improving invasive disease–free survival by 2% (from 92% to 94%) after 2 years of follow-up, without published survival data.5 The estimated monthly price of neratinib is $10 500.

Imatinib exemplifies the promise of targeted therapy, whereas neratinib exemplifies the concern: marginally effective treatments that, in aggregate, strain US health care spending. The distorted pricing of marginally effective drugs risks crowding out the capacity of the US health system to pay for highly effective cancer drugs or other therapies of public health importance, potentially jeopardizing valuable innovation and escalating out-of-pocket expenses. The combination of high prices and marginal effectiveness is unsustainable.

We propose 3 steps to promote targeted cancer drugs that yield meaningful clinical benefits while reducing overall price growth. The recommendations are informed by discussions of a group of experts from health care economics, policy, law, and regulation; cancer research and medicine; patient advocacy; and the pharmaceutical and insurance industries.

The FDA Should Define Minimum Clinically Meaningful Effect Sizes

The FDA has 2 pathways to approve new drug applications. The regular approval pathway is based on demonstration of “clinical benefit,” which is defined as prolongation of life, a better life, or “an established surrogate.” The accelerated approval pathway, in contrast, is based on a surrogate measure reasonably likely to predict clinical benefit. In 2007, the FDA issued guidance on cancer trial end points to support claims of benefit. The guidance referenced approval as being “highly dependent on … effect size” but did not specify minimum effect sizes.6 An essential question thus remains unanswered: what minimum effect size defines meaningful benefit? This ambiguity is particularly problematic in increasingly common scenarios, such as when new targeted cancer drugs demonstrate statistically significant but clinically questionable improvements in surrogate measures.

The FDA should develop guidance on minimum clinically meaningful effect sizes for cancer drugs. This would clarify prior FDA guidance and move from the current uncertain concept of meaningful clinical benefit to a consensus-driven definition. The agency could empanel multidisciplinary advisory councils of scientists, oncologists, patient advocates, and industry representatives to achieve this aim.

Clinical experts already support the principle. After convening work groups to define clinically meaningful outcomes for 4 malignancies, the American Society for Clinical Oncology (ASCO) endorsed a minimum absolute improvement of 3 to 6 months in overall survival over best available treatment for drug trials among patients with metastatic disease. Guidance could separately address cases in which, despite little or no change in median overall survival or hazard ratios, small proportions of patients experience large gains and the challenge of estimating benefits when pivotal trials involve head-to-head comparisons against active controls, thereby potentially underestimating the overall efficacy of novel agents.

By defining norms, the FDA would encourage manufacturers to design trials that demonstrate clinically meaningful benefits. The FDA could consider these thresholds in weighing benefits and risks for the purpose of approval decisions, payers could use them to better bargain on price and formulary with drug makers, guideline writers could use them to prioritize among drugs with similar indications, and clinicians and patients could use them to improve shared decision making.

Medicare Should Negotiate for Targeted Cancer Drugs

Medicare is the largest purchaser of cancer drugs. Medicare pays for targeted cancer drugs through Part B, which covers infused drugs, and Part D, which covers prescription drugs. The law, however, prevents Medicare from directly negotiating with manufacturers on drug prices. Instead, in Part B, Medicare pays for drugs under the buy-and-bill system, in which hospitals and physician offices purchase drugs and bill Medicare at 6% above the average sales price. In Part D, Medicare plan sponsors, typically insurance companies or pharmacy benefit managers, manage pricing negotiations. The law also effectively ensures that Medicare Parts B and D cover all FDA-approved cancer drugs for on-label indications as well as off-label indications listed in approved compendia, whether through “reasonable and necessary” language in Part B or “protected class” language in Part D. Consequently, Medicare cannot exercise pricing leverage through coverage determinations or formulary design.

Congress could direct the Centers for Medicare & Medicaid Services (CMS) to conduct a demonstration project in which Medicare negotiates the prices of targeted cancer drugs paid for by Parts B and D. The demonstration also should authorize Medicare to apply limited formulary tools, such as coverage restrictions or tiering, to marginally effective targeted cancer drugs or targeted cancer drugs with therapeutic alternatives. Alternative drugs should include not only biosimilars but also chemically or biologically different drugs with overlapping indications and benefit-risk profiles. Protected classes could be narrowed to permit exclusion of drugs with overlapping indications or mechanisms of action. An appeals process could address special cases. Advisory panels with diverse and relevant expertise, including patient advocates, could inform pricing discussions and formulary design.

Granting Medicare the ability to negotiate on price and use a formulary is politically challenging. The National Academies, the Medicare Payment Advisory Commission, and others have recommended that the federal government use its bargaining power to negotiate drug prices. This step could be operationalized either by Congress granting CMS authority as a single entity to negotiate with pharmaceutical companies or through competitive bidding. The program could phase in over multiple years, starting with clinical settings where therapeutic alternatives exist. This approach could foster evaluation and refinement based on lessons learned.

Guidelines Should Prioritize Drugs by Benefit and Price

Physicians and patients should be able to consider the prices of targeted cancer drugs along with their benefits and harms when selecting treatments. Evidence-based guidelines are best positioned to meet this need. Such guidelines should demarcate marginally effective from highly effective drugs. In addition, for cases in which 2 or more drugs or regimens have comparable benefit-harm profiles for an indication, guidelines should prioritize the lower-priced alternative.

Although organizations that produce practice guidelines have taken steps to incorporate costs, they should go further. ASCO could extend its value framework, which displays cost alongside net health benefit, to prioritize treatment regimens in its clinical practice guidelines. The National Comprehensive Cancer Network could rank-order treatment regimens in its practice guidelines, informed by its Evidence Blocks, which already evaluate affordability alongside other measures. In addition, other groups have developed reports on pricing, effectiveness, and value for cancer treatments and drugs more broadly that merit the attention of guideline writers.

Guidelines should also promote price transparency. To do so, they could report the estimated monthly price of cancer drugs, perhaps by using the amount reimbursed by Medicare. Although estimates of out-of-pocket expenses would be most useful to patients, and prices vary by payer, the Medicare payment amount correlates with patient co-insurance expenses and has the advantage of being a reference standard. Practice guidelines that rank-order targeted cancer drugs by clinical benefit and price and deprioritize marginally effective drugs could be influential, informing insurer value-based reimbursement programs and clinical pathways.


Successfully implementing steps to limit the use of high-priced, marginally effective drugs will be difficult; patients with life-threatening diseases may expect access to drugs despite their high costs and limited benefits. Nevertheless, the ultimate beneficiaries of these changes will be patients, who deserve the substantial efficacy, reduced toxicity and enhanced value that were the original promise of targeted cancer drugs.

Source: JAMA


Risk of Unnatural Mortality in People With Epilepsy

Key Points

Question  What is the risk and medication contribution to cause-specific unnatural mortality in people with epilepsy?

Findings  In this population-based cohort study, more than 50 000 people with epilepsy and 1 million matched individuals without epilepsy were identified in 2 data sets from the general populations of England and Wales. People with epilepsy had a 3-fold increased risk of any unnatural mortality and a 5-fold increased risk of unintentional medication poisoning; psychotropic and opioid, but not antiepileptic, drugs were most commonly used in poisoning.

Meaning  Clinicians should provide advice on unintentional injury and poisoning and suicide prevention and consider the toxicity of concomitant medication when prescribing drugs for people with epilepsy.


Importance  People with epilepsy are at increased risk of mortality, but, to date, the cause-specific risks of all unnatural causes have not been reported.

Objective  To estimate cause-specific unnatural mortality risks in people with epilepsy and to identify the medication types involved in poisoning deaths.

Design, Setting, and Participants  This population-based cohort study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014). Each person with epilepsy was matched on age (within 2 years), sex, and general practice with up to 20 individuals without epilepsy. Unnatural mortality was determined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes V01 through Y98 in the Office for National Statistics mortality records. Hazard ratios (HRs) were estimated in each data set using a stratified Cox proportional hazards model, and meta-analyses were conducted using DerSimonian and Laird random-effects models. The analysis was performed from January 5, 2016, to November 16, 2017.

Exposures  People with epilepsy were identified using primary care epilepsy diagnoses and associated antiepileptic drug prescriptions.

Main Outcomes and Measures  Hazard ratios (HRs) for unnatural mortality and the frequency of each involved medication type estimated as a percentage of all medication poisoning deaths.

Results  In total, 44 678 individuals in the CPRD and 14 051 individuals in the SAIL Databank were identified in the prevalent epilepsy cohorts, and 891 429 (CPRD) and 279 365 (SAIL) individuals were identified in the comparison cohorts. In both data sets, 51% of the epilepsy and comparison cohorts were male, and the median age at entry was 40 years (interquartile range, 25-60 years) in the CPRD cohorts and 43 years (interquartile range, 24-64 years) in the SAIL cohorts. People with epilepsy were significantly more likely to die of any unnatural cause (HR, 2.77; 95% CI, 2.43-3.16), unintentional injury or poisoning (HR, 2.97; 95% CI, 2.54-3.48) or suicide (HR, 2.15; 95% CI, 1.51-3.07) than people in the comparison cohort. Particularly large risk increases were observed in the epilepsy cohorts for unintentional medication poisoning (HR, 4.99; 95% CI, 3.22-7.74) and intentional self-poisoning with medication (HR, 3.55; 95% CI, 1.01-12.53). Opioids (56.5% [95% CI, 43.3%-69.0%]) and psychotropic medication (32.3% [95% CI, 20.9%-45.3%)] were more commonly involved than antiepileptic drugs (9.7% [95% CI, 3.6%-19.9%]) in poisoning deaths in people with epilepsy.

Conclusions and Relevance  Compared with people without epilepsy, people with epilepsy are at increased risk of unnatural death and thus should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts, and behaviors. The suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions.


Effect of self-administration versus provider-administered injection of subcutaneous depot medroxyprogesterone acetate on continuation rates in Malawi: a randomised controlled trial


Injectable contraceptives are popular in sub-Saharan Africa but have high discontinuation rates due partly to the need for provider-administered re-injection. We compared continuation rates of women who self-injected subcutaneous depot medroxyprogesterone acetate (DMPA-SC) and women who received DMPA-SC from a health-care provider, including community health workers (CHWs).


We did an open-label randomised controlled trial based at six Ministry of Health clinics in rural Mangochi District, Malawi. Health-care providers recruited adult women who presented at the six clinics or to CHWs in rural communities in the clinic catchment areas. Participants received DMPA-SC and were randomised (1:1) to receive provider-administered injections or training in how to self-inject DMPA-SC. Randomisation was done via a computer-generated block randomisation schedule with block sizes of four, six, and eight and stratified by study site, generated by an independent statistician. Self-injectors administered the first injection under observation and were sent home with three doses, written instructions, and a calendar. The provider-administered group received a DMPA-SC injection and a calendar, and were asked to return for subsequent injections. Data collectors contacted participants after the 14-week re-injection window at 3, 6, and 9 months to collect continuation data. At 12 months after enrolment or early discontinuation, women had their final interview, which included pregnancy testing. The primary outcome was discontinuation of DMPA-SC, as assessed in the intention-to-treat population. We used Kaplan-Meier methods to estimate the probabilities of continuation and a log-rank test to compare groups. Safety was assessed in the as-treated population, which consisted only of participants who successfully received at least one DMPA-SC injection after randomisation. This trial is registered with, number NCT02293694.


This study lasted from Sept 17, 2015, to Feb 21, 2017. 731 women underwent randomisation, with 364 assigned to the self-administered group and 367 to the provider-administered group. One woman in the self-injection group withdrew at month 0. Treatment was discontinued by 99 women in the self-administered group and 199 women in the provider-administered group. The 12 month continuation rate was 73% in the self-injection group and 45% in the provider-administered group, giving an incidence rate ratio of 0·40 (95% CI 0·31–0·51; p<0·0001). Adverse events deemed to potentially be treatment-related were reported by ten women (20 events) in the self-administered group and 17 women (28 events) in the provider-administered group. Five serious adverse events were reported during the trial by four women; two events related to DMPA-SC (menorrhagia and anaemia requiring hospital admission) were reported by the same woman in the provider-administered group and resolved without sequelae. The other serious adverse events, including one death, were deemed to be unrelated to DMPA-SC.


Women who self-injected DMPA-SC had significantly higher rates of continuation than those receiving provider-injected DMPA-SC. Community-based provision of injectable contraception for self-injection in low-resource settings seems to be safe and feasible. Self-administration of DMPA-SC should be made widely available.


The Blossoming of Contraceptive Implant Use in Africa

Contraceptive implant use is rising rapidly, substantially, and equitably in many sub-Saharan African countries, across almost all sociodemographic categories. Gains in implant use have exceeded combined gains for IUDs, pills, and injectables. Key contributing factors include sizeable reductions in commodity cost, much-increased commodity supply, greater government commitment to expanded method choice, and wider adoption of high-impact service delivery practices that broaden access and better reach underserved populations. Continued progress in meeting women’s reproductive intentions with implants calls for further investment in quality services for both insertion and removal, and for addressing issues of financing and sustainability.


This article draws from national surveys of every sub-Saharan African country with at least 1 recent survey published between 2015 and 2017 and 2 prior surveys from 2003 to 2014. Twelve countries comprising over 60% of the region’s population met these inclusion criteria. The analysis considers recent and longer-term changes in 3 key variables: modern contraceptive prevalence rate (mCPR), method-specific prevalence, and a method’s share of the current modern method mix. As recently as 2011, implant CPR in sub-Saharan Africa was only 1.1%. Since then, sizeable price reductions, much-increased commodity supply, greater government commitment to rights-based family planning, broader WHO eligibility guidance, and wider adoption of high-impact service delivery practices have resulted in expanded client access and marked increases in implant prevalence and share of the method mix. Ten of the 12 countries now have an implant CPR around 6% or higher, with 3 countries above 11%. Increased implant use has been the main driver of the increased mCPR attained by 11 countries, with gains in implant use alone exceeding combined gains in use of injectables, pills, and intrauterine devices. In countries as diverse as Burkina Faso and Ethiopia, Democratic Republic of the Congo and Ghana, Kenya and Senegal, implant use now accounts for one-fourth to one-half of all modern method use. Implants have become the first or second most widely used method in 10 countries. In the 7 countries with multiple surveys conducted over a 2- to 3-year span between 2013–14 and 2016–17, average annual gains in implant prevalence range from 0.97 to 4.15 percentage points; this contrasts to historical annual gains in use of all modern methods of 0.70 percentage points in 42 sub-Saharan African countries from 1986 to 2008. Implant use has risen substantially and fairly equitably across almost all sociodemographic categories, including unmarried women, women of lower and higher parity, women in all 5 wealth quintiles, younger and older women, and women residing in rural areas. A notable exception is the category of nulliparous married women, whose implant use is mostly below 1%. These attainments represent a major success story not often seen in family planning programming. With continued program commitment and donor support, these trends in implant uptake and popularity are likely to continue for the next few years. This implies even greater need for the international family planning community to maintain its focus on rights-based programming, ensuring reliable access to implant removal as well as insertion services, and addressing issues of financing and sustainability.


Acne in Adolescents Linked With Dairy Intake–Again

The association between acne in adolescents and dairy consumption is supported by 2 recent studies, bringing renewed interest in the long-established hypothesis of this link.

The association between dairy intake and acne in teenagers has gained renewed interest with 2 new studies supporting the hypothesis that acne is linked with diet. Conflicting accounts exist about the significance of different types of milk as contributing factors, however, and the cause of acne is still unknown despite several studies.


Dermatologists are still somewhat polarized in their opinion on the role of diet in acne, and it remains a controversial topic.


A new study by Professor Maria Ulvestad and colleagues of Oslo University Hospital, Norway, published in the March 2017 issue of the Journal of the European Academy of Dermatology and Venereology, supports the argument for a connection between high consumption of milk and moderate-to-severe acne in adolescents.

According to the researchers, acne affects a significant percentage of adolescents. It leads to a reduced quality of life similar to chronic conditions like diabetes and arthritis, so it is of scientific and economic importance to understand the underlying cause.


“Considering the extensiveness of acne, a great interest exists to reveal and comprehend its possible causative factors,” the authors point out. “Much is known about the pathophysiology of acne that eventually leads to a chronic inflammation in pilosebaceous units. What provokes these events to happen, however, is not fully understood. During the last decade, the acne-diet connection has been brought back to credibility, after being considered a myth for a long time. This hypothesis suggests that consumption of different foods influence the occurrence of acne.”


In this latest study, adolescent participants were provided with a questionnaire for the self-assessment of their acne, and analyses of the results were done by separating the adolescents into 2 groups: those with no-to-little acne vs those with moderate-to-severe acne. The researchers then compared the level of dairy product consumption between the 2 groups, with further subgroup analyses differentiating the dairy consumed based on fat content, whether intake was low or high, as well as on gender.


The investigators were unable to establish a link between low-fat or skim milk and acne, but instead, found that a correlation exists between high intakes of full-fat dairy products, defined as greater than or equal to 2 glasses per day, and moderate-to-severe acne.


Low-fat dairy and acne

A slightly earlier study by Andrea Zaenglein, MD, and colleagues from the Pennsylvania State University College of Medicine, “Consumption of dairy in teenagers with and without acne,” was published in the August 2016 issue of the Journal of the American Academy of Dermatology. This study, which was supported by the American Acne and Rosacea Society, also showed a positive link with acne when including milk in the diet, but the association was only found with low-fat or skim milk, not full-fat milk or other dairy products.


In this study, a dermatologist classified acne using the Global Acne Assessment Scale and, as with the 2017 study, self-reporting of dairy intake was included.


“There are 4 main factors in the pathogenesis of acne: increased sebum (or oil) production from the glands in the skin, increased hyperkeratinization where the skin cells at the pores get sticky and build up blocking the pore outlet, an increase bacteria in the pore called Propionibacterium acnes, and inflammation. All of these factors are intertwined, each making the other worse. They are also influenced by such factors as diet and genetics,” Dr. Zaenglein told MedPage Today.

“The discussion was quiescent for years until a study found virtually no acne in select non-Westernized populations, leading researchers to infer that a Western diet may be to blame. Subsequent studies suggested an association between dairy, particularly skim milk and acne,” the authors also report.


These contradictory findings in the literature may be a direct result of methodological limitations, and this should be given consideration when interpreting the results. However, whether full-fat or low-fat/fat-free dairy plays a significant role in the prevalence of acne in adolescents, both recent studies support the previous data linking milk intake with acne.


“This is very controversial and the data is mixed to be sure. There are known differences in skim versus whole milk, however. Whole milk has natural Vitamin A and D. In skim milk, it is removed and replaced after the fat is skimmed off. So, absorption might be affected. Whole milk contains some additional beneficial components such as medium chain fatty acids that promote healthy metabolism and decrease insulin resistance, as well as conjugated linoleic acid and monounsaturated fatty acids,” said Dr. Zaenglein.

The more recent results from the 2017 study suggest there may be gender differences. Data indicate an association between acne and high total dairy consumption in female adolescents, compared with a greater magnitude of association between acne and high consumption of exclusively full-fat dairy in male adolescents. It is stated though, that any gender differences observed may be confounded by other gender-specific variables such as diet preferences or some behavioral or environmental factors like smoking or exercise.


Data support dairy intake link with acne

It appears that the role of dairy in our overall health is a complex issue. Earlier studies report that milk causes an elevated insulinemic response and promotes an increase in insulin-like growth factor-1. It may be possible that this spike in insulin encourages phosphorylation of the transcription factor Foxhead box protein O1 (Fox01), thereby resulting in the activation of the mammalian target of rapamycin complex 1 (mTORC1) receptor and thus the stimulation of the sebaceous glands. These findings reveal a common mechanism of action for antiacne treatments and may provide a route to the development of new medication.


“We have no explanation for why we solely found association with full-fat dairy products, and not with semi-skimmed or skimmed products. It has been proposed that different manufacturing processes of cow’s milk might alter the composition of other bioactive substances, as well as the intended change in fat content. Milk is a complex fluid, containing different proteins, carbohydrates and steroid hormones etc., which are likely to influence endogenic and possibly acne-promoting pathways. Lately, the ability of cow’s milk to increase IGF-1 and insulin levels in vivo has received much attention,” reported the authors of the 2017 study.

Although there were certain limitations of the 2017 study, the authors did highlight that their consistent results for full-fat dairy association support the hypothesis that dairy intake may be a relevant, contributing factor to acne.


Future directions

The manufacturing process of skim milk where fat-soluble vitamins A and D are removed from full-fat milk and reintroduced later to the low-fat product may warrant further investigation to study the bioavailability and distribution of essential vitamins compared with full-fat milk.


“Since I am a dermatologist and not a nutritionist, important next steps in research that need to be done before we make firm dietary recommendations to patients would be to see if switching from skim milk to whole milk actually makes a difference in acne,” Dr. Zaenglein concluded.

Published: April 28, 2017

Recurrent Falls Associated With Depression and Urinary Incontinence

This study highlights depression and urinary incontinence as risk factors for recurrent falls in elderly men living in retirement communities, though findings may warrant further research.

A recent cross-sectional study of 871 male retirement home residents in Taiwan found that depression and urinary incontinence were associated with an increased risk of recurrent falls.

Dr. Cheng-Hao Hung and colleagues, of the National Yang Ming University, in Taipei, Taiwan published their paper entitled, “Recurrent Falls and Its Risk Factors among Older Men Living in the Veterans Retirement Communities: A Cross-Sectional Study,” in the journal Archives of Gerontology and Geriatrics in February of 2017.


The authors sought to determine the prevalence and risk factors of recurrent falls in elderly male veterans home residents.

Falls occur in over 20% of community-dwelling older adults in Taiwan, with women more likely to fall than men.


Falls are also the number one cause of injury and death from injury among elderly Americans, with an estimated 29 million falls per year taking place in the US. “Older adult falls are increasing and, sadly, often herald the end of independence,” noted US Centers for Disease Control and Prevention Director Dr. Tom Frieden.


The guidelines from the American and British Geriatric Societies recommend screening for falls to improve intervention efforts and reduce risk in individuals who have experienced multiple falls within the past year.


According to Dr. Hung and colleagues, many studies have evaluated the risk factors for falls; however, “little was known regarding to [sic] the risk factors for recurrent falls.”

Study design

The authors conducted a cross-sectional analysis of 871 elderly male veterans home residents (mean age 85.5 years) from the Longitudinal Older Veterans (LOVE) Study. Participants were all generally physically fit and cognitively normal at baseline, and were given a questionnaire to determine sociodemographics and medical history, including past falls. Women, persons under the age of 65, and those who were cognitively impaired or bed-ridden were excluded from this study.

Falls included in this study were defined as those that happened accidentally, not in association with a stroke or other incapacitating medical event or significant environmental hazard, and were stratified by number in the past year (none, one, or more than one). A battery of geriatric assessments was performed to evaluate cognition, mood, capability in performing everyday tasks, and nutrition. Vision and hearing acuity, as well as urinary and stool incontinence were also determined for each participant.

Recurrent falls, depression, and urinary incontinence

Of the 871 participants, 222 (25.5%) experienced a fall within the previous year, with 91 (10.4%) participants experiencing multiple falls. Diabetes mellitus and chronic kidney disease were both associated with an increased risk of falls. Higher levels of comorbidity, reduced ability to perform everyday tasks, depression, and poor nutrition were also associated with more falls. In addition, participants who experienced more falls were more likely to be taking more than 4 medications concurrently, and to have urinary or stool incontinence. The study did not find any association between number of falls and age, height, body weight, or BMI.

After performing a multivariate logistic regression analysis on the data, the authors found that depression and urinary incontinence were independently associated with the number of falls experienced by the participants. Depression was associated with about a 25% increased risk (OR = 1.256, 95% CI 1.094–1.441, P=0.001) for a single fall, and nearly a 50% increased risk for recurrent falls (OR = 1.480, 95% CI 1.269–1.727, P<0.001). Urinary incontinence was associated with recurrent falls (OR = 2.369, 95% CI 1.449–3.817, P<.001) but not single falls.

“Urinary incontinence may contribute to the number of falls among elderly male by increasing voiding frequency, therefore the opportunity to have fall accidents [sic],” the authors state. Dr. Hung and colleagues also discuss the possibility that falls may cause musculoskeletal damage, which could contribute to urinary incontinence. Psychomotor retardation associated with depression may influence fall frequency through impaired judgement and coordination. Although, the authors note that the cross-sectional nature of this study means that only correlations can be drawn, and not a causal relationship.

The authors highlight several important limitations to the current study. Specifically, they note that obtaining fall prevalence data through a questionnaire allows for the possibility of recall bias in the participants. “The exclusion criteria may make our results underestimate the impact of cognitive impairment on falls since those who can’t complete MMSE usually suffer from severe cognitive impairment. By excluding those subjects with ADL <20, who is [sic] bed-ridden and unlikely to suffer from falls due to complete lack of activity, we may overestimate the prevalence rate of fall,” the researchers state.

According to the authors, this study highlights depression and urinary incontinence as risk factors for recurrent falls in elderly men living in retirement communities and the findings may warrant further prospective studies.

Published: April 25, 2017

Malaria in pregnancy alters l-arginine bioavailability and placental vascular development

Malaria relief, one amino acid at a time

Malaria infection during pregnancy can disrupt placental vasculature and cause complications during the pregnancy and delivery. Nitric oxide plays a key role in placental vascular function, and its synthesis requires l-arginine. Knowing that l-arginine and nitric oxide are both depleted during malaria-induced hemolysis and that many people in malaria-endemic areas lack sufficient l-arginine in their diets, McDonald et al. examined the effects of dietary l-arginine supplementation. The authors first studied a cohort of pregnant women in Malawi and showed that the blood of patients with malaria had less l-arginine and that this was associated with worse pregnancy outcomes. Conversely, l-arginine supplementation in a mouse model of malaria in pregnancy improved fetal weight and viability, indicating the potential value of this intervention.


Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes.

Can Work Be Required in the Medicaid Program?

On January 11, 2018, a new policy encouraging states to develop work requirements in their Medicaid programs was issued by the Centers for Medicare and Medicaid Services (CMS).1 Under this policy, states can require nonelderly, nondisabled adults to work or engage in community service to qualify for Medicaid coverage, unless they are deemed medically frail or have a substance use disorder. States will be permitted to require detailed reporting on work status, decide who will be exempt from these requirements, and impose lockout periods for those who do not comply. For example, Kentucky’s newly approved program requires at least 80 hours of work or community engagement per month, or beneficiaries risk lockout.

States will pursue work requirements through waivers under Section 1115 of the Social Security Act, which gives CMS the authority to grant states’ applications for demonstration projects that are “likely to assist in promoting the objectives” of Medicaid. The law of Medicaid states that its purpose is to provide “medical assistance,” which CMS has historically interpreted as permitting waivers that demonstrate the potential for greater access to care, efficiencies in delivery of care, or expanded coverage. Section 1115 waivers have become an essential tool for states that seek to incorporate their own variables in implementing the Medicaid expansion included in the Affordable Care Act (ACA), which added a new category of Medicaid eligibility: childless, nonelderly, nondisabled adults earning up to 138% of the federal poverty level (about $16,000 for an individual). Before the ACA, the availability of employer-sponsored health insurance had declined steadily since the 1980s, so by the 2008 presidential election, many Americans could not obtain coverage through a job. Part-time and low-income workers were especially unlikely to obtain health insurance as an employment benefit, but they were not eligible for Medicaid either. After a 2012 Supreme Court decision made Medicaid expansion optional, some states negotiated with CMS to expand eligibility through Section 1115 waivers, and a few sought to institute work requirements, but the Obama administration rejected their proposals as being outside the scope of Medicaid’s objective, a policy consistent with those of prior administrations.

The Trump administration offered a new interpretation, announcing that it will generally support state innovation and allow states to experiment with requiring eligible adult beneficiaries to work or participate in community engagement to determine whether such features could lead to sustained employment and “improved health outcomes.” This shift was expected, given that CMS administrator Seema Verma was a consultant who was paid to design Indiana’s Medicaid program, which unsuccessfully sought permission from the Obama administration to create work requirements, as well as Kentucky’s recently approved waiver proposal. Also, on March 14, 2017, the day Verma was sworn into office, she and then–Secretary of Health and Human Services Tom Price issued a letter declaring to governors that Medicaid protects the “most vulnerable populations,” language that was understood as rejecting the ACA’s reliance on Medicaid for achieving universal coverage for low-income adults.2

CMS described this as a “shift from prior agency policy.” The question is whether CMS has the authority to make such a shift, which will allow states to create barriers to enrollment for eligible Medicaid beneficiaries. Federal agencies possess authority given to them by Congress to execute laws within a range of reasonable policy options, but they must follow the law. Opposition to the ACA has included resistance to using Medicaid to cover low-income people who are “able-bodied.”3 Work requirements targeting beneficiaries who became eligible under the Medicaid expansion are inconsistent with the ACA, which prevents barriers to health insurance coverage. CMS reasons that the policy shift is “anchored in historic CMS principles that emphasize work to promote health and well-being.” However, this description is not consistent with the Medicaid Act, part of which supports medical assistance for disabled beneficiaries so they can leave institutional settings and return to their communities (and therefore possibly to work), but which has never emphasized work. Unlike welfare law, which expressly requires ending “dependence of needy parents on government benefits by promoting job preparation, work, and marriage,” Medicaid focuses on ensuring that states provide all eligible beneficiaries with medically necessary care. If a state wants to help Medicaid beneficiaries find work, it may do so, but not as part of the Medicaid program.

Work Status of Adult Medicaid Enrollees in 2016 and Main Reasons for Not Working.

Even if CMS had the authority to approve work requirements, this policy offers a questionable interpretation of research correlating income and health. Verma and others stress “personal responsibility” for Medicaid beneficiaries, which seems to be rooted in the perception that Americans receive health insurance benefits from their employers, so a nondisabled adult who is enrolled in Medicaid must not be working. In fact, 60% of nondisabled adults who were covered by Medicaid for some or all of 2016 were working at some point during the year, and 78% were living in a family with at least one worker.4 Many of those who can work do work, and individuals categorized as “not working” are otherwise engaged (see figure). Income has been shown to correlate with health and mortality, but research does not indicate that working causes good health. This policy creates a condition of eligibility that does not appear to fit within the statute’s command to provide “medical assistance” and is a predictable barrier to both health and work: being healthy permits the functioning that makes work possible, but if a person cannot enroll in Medicaid because of failure to meet work requirements, the person will also lack insurance coverage and is less likely to be healthy.

History shows that states need federal funds to care for the poor, but states often balk at their portion of Medicaid’s cost and bristle at its federal rules.5 The new policy offers states flexibility and may reduce both federal and state costs by leading to disenrollment from Medicaid. Kentucky’s governor predicted that enrollment would decrease by nearly 100,000 beneficiaries. Yet states will incur expenses and significant administrative burdens, as will the managed care companies that work with state Medicaid programs. The policy makes clear that CMS will not pay for any costs imposed by instituting work requirements, such as systems for determining compliance and facilitating job assistance.

Because many Medicaid beneficiaries are already working, a small proportion of this population will be affected by work requirements, but CMS’s shift signifies a major policy change. Medicaid is a workhorse of a program, providing health insurance coverage for people historically excluded from employer-sponsored and other private health insurance, and often doing so against political headwinds. That is precisely Medicaid’s purpose: Congress passed the Medicaid Act to ensure provision of medical assistance to poor people by offering federal funding to states that adhere to baseline standards. Under those standards, states can cover more people than federal law requires, but not fewer — a statutory restriction that protects populations considered undesirable.

So far, of nine states that have requested waivers for work requirements, three have already expanded Medicaid; new expansions are likely to be shaped by this policy, taking advantage of the flexibility it offers. (CMS approved Indiana’s waiver with work requirements and other conditions of enrollment on February 2, three weeks after Kentucky’s novel waiver was granted.) If states that have rejected the ACA are enticed to expand Medicaid, an upside is that insurance coverage will become available for some people who were left in the coverage gap. But for states like Kentucky and Indiana that have already expanded Medicaid, enrollees only stand to lose coverage. Stay tuned: a legal challenge to CMS’s new policy and Kentucky’s waiver was filed on January 24, and Kentucky’s governor threatened to end Medicaid expansion if the court finds that CMS exceeded its statutory authority.

CMS’s policy offers new flexibility that may lead more states to consider Medicaid expansion under the ACA, but at a cost. This new policy may harm the health of the beneficiaries who are disenrolled, while, in my opinion, unlawfully reinterpreting the purpose of the Medicaid program.


Friction in the Path to Use of Biosimilar Drugs

Enactment of the Biologics Price Competition and Innovation Act (BPCIA) in 2010 raised expectations that new competition would blunt price increases for biologic drugs. The BPCIA defined an expedited pathway for biosimilars — products that are similar to and have no clinically meaningful differences from a biologic product approved by the Food and Drug Administration (FDA) — to compete with biologics that no longer have patent or regulatory market exclusivity. The expectations for increased competition were based on the experiences in Europe and estimates made by the Congressional Budget Office and private analysts.

Unfortunately, the results to date are disappointing. Currently, there are only 7 biosimilar products on the U.S. market competing with originator brands, as compared with 14 that were on the European market at a similar point in time after a pathway was created there. FDA Commissioner Scott Gottlieb has expressed a desire to accelerate development of biosimilar competition. Currently, an estimated $3.2 billion (only 3%) of biologic spending is subject to competition from biosimilar products.1

A combination of several factors probably accounts for the slow development of competition in this market. The complexity of many biologic products has previously been identified as one factor. Historically, most drugs have been small molecules. Physicians are used to generic versions of them and are comfortable prescribing them. By contrast, multiple surveys of physicians reveal that even those who routinely use biologic products do not have a clear understanding of biosimilar products.2 Physicians are therefore naturally hesitant to prescribe biosimilars — especially given that regulations create the impression that a biosimilar may not be all that similar to its originator.

The FDA has developed regulations regarding naming of biologic drugs and biosimilar products. Labels for all FDA-approved drugs and databases used by physicians and pharmacists contain nonproprietary names. These names reflect the products’ active ingredients. The FDA guidance on biosimilar naming requires that each product include the nonproprietary name reflecting the active ingredient plus a suffix that identifies the manufacturer. For example, the first biosimilar approved in 2015 was Zarxio, which had the nonproprietary name filgrastim-sndz. The rationale for this approach is to ensure the conduct of pharmacovigilance: the nomenclature allows the FDA to attribute any adverse reactions that are reported to both the specific biologic agent and the manufacturer. One concern is that such naming creates the impression that the clinical effects of a biosimilar may differ meaningfully from the reference product. Perceived differences between competing products weaken price competition, and the existing evidence suggests that such perceptions are having this effect in the biosimilar market.3 Alternative tracking methods have been proposed that are less likely to inadvertently imply clinical differences. For example, the use of trade names for products is specific to a manufacturer but does not carry any implications about clinical effects.

Another regulatory issue involves the designation of interchangeability between a biosimilar and its reference drug. This designation makes it possible for a pharmacist to substitute the biosimilar product for the reference product without involving the prescribing physician. Interchangeability can promote strong price competition, as evidenced by competition between brand-name and generic small-molecule products. The FDA issued draft guidance in January 2017 that created confusion in the industry. Designation as a biosimilar requires demonstrating no clinical differences in outcome, but to identify a biosimilar product as interchangeable with its reference product, the FDA requires that equivalent clinical results occur within the same patient if the biosimilar replaces the reference product.

The FDA has not been clear about whether this requirement involves meeting an additional standard or producing more data. Conducting extra clinical studies is a very expensive activity, so clarity on this point is important. The FDA has concerns about immune system responses to substitution of biosimilars for reference products. Regulators in Europe and, most recently, Australia have noted that such risks are very small, and Australia is therefore narrowing the distinction between biosimilarity and interchangeability.4 The slow development of clear U.S. guidance on interchangeability means that there are no interchangeable products on the market — which limits price competition.

Payment arrangements in public insurance programs that purchase biologic drugs also deter robust competition. Medicare Part B is a key purchaser that spends roughly $16 billion per year on biologic products. Under Part B, physicians and institutions are paid a fee for administering drugs equal to the average selling price (ASP) of the drug plus 6%. Reference products and each of their biosimilars are treated as distinct products (as of November 2017), but physicians are reimbursed for each biosimilar at the ASP of the selected product plus 6% of the reference-product price. The rationale is that because the reference product generally costs more, the physician would otherwise have an incentive to prescribe it rather than the biosimilar.

Despite claims of encouraging competition, this approach fails to create an incentive that bolsters price competition. It is at best neutral with respect to choice of product on the basis of price, since the payment for administering the drug is the same for the reference product and its biosimilar. However, because physicians are less familiar with biosimilars and the economic rewards are similar (there is some room for gaming the timing of adjustment of the ASP), this payment system does not promote prescribing that will reduce prices.

To promote lower prices in Part B, the Medicare Payment Advisory Commission recommends consolidation of a reference product and all its biosimilar products under a single billing code. Thus, prices of the biosimilars and the reference product would be averaged together to establish the reimbursement level for the group. That would mean that physicians choosing a lower-priced product within the group could realize a higher net payment, which would probably generate strong price competition.

Finally, secrecy about manufacturing processes poses a potentially significant deterrent to the development of biosimilar competition. Small-molecule drugs can be fully characterized by analyzing the end products, and any of a number of simple manufacturing processes will result in an approvable generic product. In contrast, biologic products are often complex and cannot be fully characterized in this way. So whereas small-molecule pharmaceutical firms rely almost entirely on patent protection and exclusivity to preserve their market power, biologic producers also rely on secrecy about their manufacturing processes.5 The implication is that even if originator firms provide samples of their products to biosimilar manufacturers, secrecy about the manufacturing process impedes development of biosimilars after a patent has expired.

Although a number of these factors may separately have modest effects, together they are additive and most likely contribute to the slow development of competition in the biologics market. Spending on biologic drugs was estimated to be $105.5 billion in 2016, and growth in spending has been averaging 10% per year recently. Thus, competition creates the potential for considerable savings — but if the impediments continue, important savings will probably be left on the table.