Joshua M. Sharfstein

A Systemic Approach to Containing Health Care Spending

Two Sounding Board articles, by Emanuel et al. and Antos et al., discuss different approaches to controlling rising health care costs in the United States. The editors hope that the range of options presented will stimulate discussion and debate on the best ways to bend the health care cost curve.

Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore, Maryland, 1995–2009

OBJECTIVES We examined the association between the expansion of methadone and buprenorphine treatment and the prevalence of heroin overdose deaths in Baltimore, Maryland from 1995 to 2009. METHODS We conducted a longitudinal time series analysis of archival data using linear regression with the Newey-West method to correct SEs for heteroscedasticity and autocorrelation, adjusting for average heroin purity. RESULTS Overdose deaths attributed to heroin ranged from a high of 312 in 1999 to a low of 106 in 2008. While mean heroin purity rose sharply (1995-1999), the increasing number of patients treated with methadone was not associated with a change in the number of overdose deaths, but starting in 2000 expansion of opioid agonist treatment was associated with a decline in overdose deaths. Adjusting for heroin purity and the number of methadone patients, there was a statistically significant inverse relationship between heroin overdose deaths and patients treated with buprenorphine (P = .002). CONCLUSIONS Increased access to opioid agonist treatment was associated with a reduction in heroin overdose deaths. Implementing policies that support evidence-based medication treatment of opiate dependence may decrease heroin overdose deaths.

Confronting the Stigma of Opioid Use Disorder—and Its Treatment

The death of Philip Seymour Hoffman from a heroin overdose tragically adds another name to the list of celebrities who have lost their lives to addiction. Increasing numbers of overdoses from prescription opioids and a more recent increase in heroin-associated fatalities have caused heartbreak in communities across the country. More than 30 000 deaths from unintentional drug overdose were reported in the United States in 2010, the most recent year for which data are available.1

Maryland's All-Payer Approach to Delivery-System Reform

Maryland, with its all-payer rate-setting system for hospital services, and the Centers for Medicare and Medicaid Services are launching a new model that will transform the states delivery system and may guide other federal–state partnerships in improving health care.

Transparency at the Food and Drug Administration.

The FDA recently released a report from its Transparency Task Force containing 21 draft proposals for expanding the disclosure of information by the agency while maintaining confidentiality for trade secrets and individually identifiable patient information. Afia Asamoah and Dr. Joshua Sharfstein from the FDA discuss the transparency initiative.

Fungal meningitis from injection of contaminated steroids: A compounding problem

INJECTIONS OF CONTAMINATED STEROIDS LEAD TO A deadly outbreak of meningitis. Investigations reveal that a compounding pharmacy manufactured the steroids under unacceptable conditions. Newspaper reports document significant gaps in oversight by state and federal agencies, and public health officials call for stronger controls. The year is 2002. According to the San Francisco Chronicle, “the case of Doc’s Pharmacy illustrates how doctors, as well as their patients, are unaware of the risks inherent in pharmacy compounding.” Not long after, the Kansas City Star reviews a series of compounding-related injuries and deaths from across the country. A pharmaceutical industry executive is quoted by the paper as saying, “It is just a matter of time before somebody makes a grossly contaminated product and scores of people die. . . . People will then be asking, ‘Why did this happen?’” Almost exactly a decade later, at the end of September 2012, the Maryland Department of Health and Mental Hygiene receives a call from the Centers for Disease Control and Prevention (CDC). Seven Maryland outpatient facilities have received suspect lots of methylprednisolone acetate injection from the New England Compounding Center. Working with these facilities and other clinicians to identify affected patients reveals that at least 17 Marylanders have meningitis and 1 has died. As of October 25, this outbreak has reached 18 states, causing 328 cases of serious fungal infection, including 323 cases of meningitis, 5 cases of peripheral joint infection, and 24 deaths. Thousands of additional patients have undergone lumbar punctures and other invasive diagnostic procedures. Tens of thousands are living in fear that they could become seriously ill at any moment. Managing the crisis has required an intensive response by federal, state, and local public health officials. With an evolving spectrum of fungal illness caused by Exserohilum and potentially Aspergillus, Cladosporium, and other species, CDC experts have developed and modified working case definitions, diagnostic recommendations, and treatment guidelines. The CDC’s emergency operations center has assisted states in contacting thousands of patients. The Food and Drug Administration (FDA) has focused its attention on the conditions at the New England Compounding Center, overseeing an increasing series of recalls. On October 18, the FDA announced that unopened vials from implicated lots tested positive for Exserohilum, the same fungus identified in meningitis cases. Health departments across the nation have coordinated local activities in emergency response mode. These efforts include investigating reports of possible cases, providing guidance to physicians on diagnosis and treatment, sharing information with the CDC and with other states, and analyzing data to better define the risk associated with exposure. State health departments have also organized outreach to scores of clinics and tens of thousands of exposed patients to assess symptoms, encourage vigilance, and answer questions. There are many questions. Patients already affected with chronic pain syndromes ask how they can identify new or worsening symptoms and endure the stress of medical evaluation and the complicated logistics of the health care system. Physicians want to know whether it is possible to reassure anxious callers who may have received one of the more than 3000 products made by the New England Compounding Center, when few clinics are able to track which lots were administered to specific patients. And everyone wants to know: Why did this happen? According to the International Association for Compounding Pharmacists, there are an estimated 7500 compounding pharmacies in the United States, and 1% to 3% of all prescriptions are compounded. Unlike pharmaceutical manufacturers, compounding pharmacies do not have to demonstrate the safety and efficacy of their products or adhere to manufacturing and labeling standards. Only about 2% participate in the industry’s voluntary accreditation program.

Chronic Pain, Addiction, and Zohydro

Twenty-nine state attorneys general have asked the FDA to reconsider its approval of the opioid Zohydro, which lacks abuse-deterrent features. But the FDA can do more to address the opioid-overdose epidemic.

Maryland's Global Hospital Budgets--Preliminary Results from an All-Payer Model.

In the first year of Marylands experiment in setting all-payer rates for hospital services, costs were contained and the quality of care improved, though the state still has high rates of hospital admissions and per capita spending for Medicare patients.

Role of the FDA in Affordability of Off-Patent Pharmaceuticals

This Viewpoint maintains that the US Food and Drug Administration (FDA) should have a more active role in the approval and marketing of off-patent pharmaceutical products.

Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion: A Study Interrupted

The challenge of assessing the cardiovascular safety of the recently approved naltrexone-bupropion combination for treatment of obesity originates in the complex issues involving the LIGHT trial, published in this issue of JAMA.1 In 2011, in response to concerns regarding the cardiovascular effects of this combination medication, including elevations in blood pressure, the US Food and Drug Administration (FDA) asked the sponsor, Orexigen, to support a definitive safety study.2 Investigators designed the LIGHT study to randomize approximately 9000 patients to receive treatment with naltrexone-bupropion vs placebo and follow them up for about 5 years until approximately 400 major adverse cardiovascular events had occurred. With a noninferiority design, the study was powered to exclude a 1.4-fold increase in cardiovascular risk associated with the medication. The LIGHT protocol included a preplanned interim analysis after 25% of the major adverse cardiovascular events of interest (including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) had been accrued. The goal of this interim analysis was to assess whether naltrexone-bupropion was associated with more than a 2-fold increase in the risk of major cardiovascular events. In most clinical trials, such a review is handled in confidence by the data monitoring committee, without disclosure of data to the sponsor or researchers unless the trial needs to be stopped. In this case, however, for the purpose of initial market approval, the sponsor was also required to share the results of the LIGHT interim analysis with the FDA. The FDA’s use of interim analyses of ongoing safety studies is relatively new. About 8 years ago, after several medications for diabetes were found to have previously unappreciated cardiovascular risks, the agency faced an unappealing choice: either (1) continue to approve drugs based primarily on efficacy studies of glycemic control for diabetes and risk learning about serious cardiovascular risk after approval or (2) delay consideration of new therapies until years of cardiovascular safety data had been collected. In 2008, the FDA issued a guidance statement for the development of drugs for diabetes that reflected a creative compromise between safety and new drug development.3 For initial approval, the FDA required manufacturers to provide enough data to show that the upper limit of the 95% confidence interval for the risk ratio of the risk of cardiovascular events was less than 1.8. Then, as a condition of market approval, sponsors had to conduct a postmarketing trial that, either alone or combined with the preapproval data in a meta-analysis, would demonstrate that the upper 95% confidence interval for cardiovascular risk was less than 1.3. The new approach accepted the possibility that a medication might meet its initial end point, gain approval, and then fail its final end point—an outcome that might lead to clinical confusion and regulatory uncertainty. To implement this 2-step safety evaluation more efficiently, sponsors of diabetes drug trials asked the FDA for permission to handle both parts with a single cardiovascular safety trial. In this model, interim results would be used to secure approval; the trial would continue; and the final results would determine whether the postmarketing requirement had been met. This strategy, however, introduced a new challenge to the process: keeping the interim results confidential. The 2 primary risks associated with the release of interim results are the potential to compromise the conduct of the trial and the potential to misinterpret the results of the trial.4 Early knowledge of interim results may affect the behavior of sponsors, investigators, and participants in the trial as well as the actions of physicians and patients in the community. Recruitment or retention of trial participants may be jeopardized. If the interim results are perceived to be negative, patients in the study may be inclined to drop out of the trial or stop taking their medications. If interim results are perceived to be positive, and the medication is commercially available, physicians may steer some patients to the therapy rather than to the study. These behaviors are difficult to detect and may jeopardize the integrity of the trial. At a public hearing held by the FDA in August 2014, there was broad agreement that, assuming the trial is not being stopped, the clinical community should be able to learn no more about an interim safety analysis than that the prespecified end point had been met.5 This is essentially the same level of understanding that investigators have when data monitoring committees permit their trials to continue. The new approach to cardiovascular safety for diabetes drugs, with its statistically sound design, has increased the number of clinical trials6 and has functioned as planned for several drugs, including saxagliptin7 and alogliptin.8 In both cases, the interim analyses showed a relative risk of less than 1.8 as indicated by the FDA guidance, the companies maintained the confidentiality of the results, the drugs were approved, and the final studies met their end points. For the review of naltrexone-bupropion, the FDA agreed to a similar approach for an obesity drug for the first time. Problems first became evident in fall 2013, when the interim analysis was presented to the data monitoring committee. The committee objectedtothesponsor’sdataaccessplanonthegroundsthat“business interests do not provide a sufficient justification for gaining accesstoconfidentialinformationonefficacyorsafety.”9 ThecomRelated article page 990 Opinion