Aaron S. Kesselheim

Seizure Outcomes Following the Use of Generic versus Brand-Name Antiepileptic Drugs A Systematic Review and Meta-Analysis

AbstractBackground: The automatic substitution of bioequivalent generics for brand-name antiepileptic drugs (AEDs) has been linked by anecdotal reports to loss of seizure control. Objective: To evaluate studies comparing brand-name and generic AEDs, and determine whether evidence exists of superiority of the brand-name version in maintaining seizure control. Data Sources: English-language human studies identified in searches of MEDLINE, EMBASE and International Pharmaceutical Abstracts (1984 to 2009). Study Selection: Randomized controlled trials (RCTs) and observational studies comparing seizure events or seizure-related outcomes between one brand-name AED and at least one alternative version produced by a distinct manufacturer. Data Extraction: We identified 16 articles (9 RCTs, 1 prospective non-randomized trial, 6 observational studies). We assessed characteristics of the studies and, for RCTs, extracted counts for patients whose seizures were characterized as ‘controlled’ and ‘uncontrolled’. Data Synthesis: Seven RCTs were included in the meta-analysis. The aggregate odds ratio (n = 204) was 1.1 (95% CI 0.9, 1.2), indicating no difference in the odds of uncontrolled seizure for patients on generic medications compared with patients on brand-name medications. In contrast, the observational studies identified trends in drug or health services utilization that the authors attributed to changes in seizure control. Conclusions: Although most RCTs were short-term evaluations, the available evidence does not suggest an association between loss of seizure control and generic substitution of at least three types of AEDs. The observational study data may be explained by factors such as undue concern from patients or physicians about the effectiveness of generic AEDs after a recent switch. In the absence of better data, physicians may want to consider more intensive monitoring of high-risk patients taking AEDs when any switch occurs.

Characteristics of Clinical Trials to Support Approval of Orphan vs Nonorphan Drugs for Cancer

CONTEXT The Orphan Drug Act incentivizes medication development for rare diseases, offering substantial financial benefits to the manufacturer. Orphan products constitute most new drug approvals in oncology, but safety and efficacy questions have emerged about some of these agents. OBJECTIVES To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs. DESIGN AND SETTING We identified all new orphan and nonorphan drugs approved between 2004 and 2010 to treat cancer. We then collected data on key development variables from publicly available information on the US Food and Drug Administrations Web site and in the Code of Federal Regulations. MAIN OUTCOME MEASURES We assessed clinical testing dates, approved indications, and regulatory characteristics (regular vs accelerated review, advisory committee review, postmarketing commitments). We then compared design features (randomization, blinding, primary end point) of pivotal trials supporting approval of orphan and nonorphan drugs and rates of adverse safety outcomes (deaths not attributed to disease progression, serious adverse events, dropouts) in pivotal trials. RESULTS Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66-152] vs 290 [IQR, 185-394] patients exposed to the drug; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02-2.92; P = .04). CONCLUSION Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.

FDA Regulation of Mobile Health Technologies

Mobile health (“mHealth”) is the use of portable devices such as smartphones and tablets to improve health. This report discusses the public health benefits and risks of mHealth and the challenges facing the FDA in regulating this technology.

The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform

IMPORTANCE The increasing cost of prescription drugs in the United States has become a source of concern for patients, prescribers, payers, and policy makers. OBJECTIVES To review the origins and effects of high drug prices in the US market and to consider policy options that could contain the cost of prescription drugs. EVIDENCE We reviewed the peer-reviewed medical and health policy literature from January 2005 to July 2016 for articles addressing the sources of drug prices in the United States, the justifications and consequences of high prices, and possible solutions. FINDINGS Per capita prescription drug spending in the United States exceeds that in all other countries, largely driven by brand-name drug prices that have been increasing in recent years at rates far beyond the consumer price index. In 2013, per capita spending on prescription drugs was

Comparative Effectiveness of Generic and Brand-Name Statins on Patient Outcomes: A Cohort Study

858 compared with an average of

An Empirical Review of Major Legislation Affecting Drug Development: Past Experiences, Effects, and Unintended Consequences

400 for 19 other industrialized nations. In the United States, prescription medications now comprise an estimated 17% of overall personal health care services. The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear. CONCLUSIONS AND RELEVANCE High drug prices are the result of the approach the United States has taken to granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits. The most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.

The 21st Century Cures Act — Will It Take Us Back in Time?

Context Some patients do not adhere to their prescribed statins and thus do not fully benefit from the decreases in blood lipid levels that these medications provide. Contribution This study found that, compared with those who initiated a brand-name statin, patients who initiated a generic statin had better adherence and fewer occurrences of a composite outcome that included death from any cause plus hospitalization for an acute coronary syndrome or stroke. Caution All patients were Medicare beneficiaries aged 65 years or older with prescription drug coverage. Implication The lower cost of generic statins allowed patients to adhere to the medication better. The Editors Statins are the most frequently prescribed drugs in the United States (1) and are effective in reducing low-density lipoprotein (LDL) cholesterol levels and cardiovascular events (24). Randomized, controlled trials have found that statins reduce the relative risk for major vascular events by 21% for each 1.0-mmol/L (39-mg/dL) reduction in LDL cholesterol level in patients at low risk for vascular disease (3). Patients assigned to statin therapy in trials tended to achieve reductions in LDL cholesterol level of 1.8 mmol/L (70 mg/dL) with doses used regularly in practice (2). However, a large body of evidence suggests that, in routine practice, patients do not fully adhere to statins and therefore may not receive their full benefit (5, 6). Approximately half of patients in ambulatory care settings discontinue statin therapy within 1 year of initiation (68). Medication nonadherence is a complex multifactorial process (9). Among its many determinants, drug cost may be one of the most easily modifiable (10). Reducing patient spending for prescription drugs can improve adherence (11, 12) and, in some cases, clinical outcomes (13). Generic drugs have been shown in small, short, randomized trials(14, 15) to be clinically equivalent to their brand-name counterparts, as required for approval by the U.S. Food and Drug Administration (FDA). They are usually less expensive than brand-name products and have been associated with better adherence (12). However, no study has investigated whether use of generic versus brand-name statins also leads to improved health outcomes (16). We sought to determine whether patients in a large cohort of Medicare beneficiaries were more adherent to therapy after initiating a generic statin versus a brand-name statin and whether this resulted in differences in health outcomes. Methods The study was designed by the authors and approved by the Institutional Review Board at Brigham and Womens Hospital. Study Cohort The study cohort comprised Medicare beneficiaries (aged 65 years) who had prescription drug coverage through either a stand-alone Medicare Part D plan or a retiree drug plan administered by CVS Caremark, a large national pharmacy benefits manager. For each patient, we linked claims for filled prescriptions to diagnostic, health care utilization, and demographic data from Medicare Parts A and B files and enrollment files. The cohort included patients who initiated a statin (lovastatin, pravastatin, or simvastatin) between 2006 and 2008 and had continuous Medicare and CVS Caremark eligibility in the 6 months before initiation. We restricted the cohort to patients initiating these drugs because they were the only statins for which generic versions were available in the United States during the study. Initiation was defined as a new (index) prescription for a study drug with no prescription for any single statin or statin combination product in the preceding 180 days. To maximize the generalizability of this comparative effectiveness study, we did not impose any other exclusion criteria. We classified patients as exposed to a generic or brand-name statin on the basis of the National Drug Code associated with the index prescription claim. We used the FDAs National Drug Code Directory (17) to determine the manufacturer of each drug and the FDAs Approved Drug Products with Therapeutic Equivalence Evaluations publication (18) to determine whether each manufacturers products were approved via a new drug application (brand-name) or abbreviated new drug application (generic). Outcomes and Follow-up The primary outcomes were adherence to the index statin and a composite cardiovascular outcome. Adherence was measured as the proportion of days covered (PDC) by the index statin up to 1 year after the index prescription date. The PDC is calculated by dividing the number of days of medication supplied by the number of days in a given interval (19). For each patient, the denominator interval began on the index date and ended at death, hospitalization, prescription for any other lipid-lowering drug (for example, a different statin or another lipid-lowering agent, such as a fibrate or bile acid sequestrant, although switches between brand-name and generic versions of the index statin were allowed), the end of the study (31 December 2008), or 365 days after the index prescription date, whichever occurred first. The numerator was the sum of the number of days in the interval for which medication was available based on the days supplied by each prescription. The primary clinical outcome comprised hospitalization for an acute coronary syndrome or stroke and all-cause mortality. We also examined each of these outcomes separately. We used a validated claims-based definition for each outcome, with positive predictive values ranging from 86% to 96% (2022). In the primary analysis, we followed patients from the day after index drug initiation until an occurrence of an event of interest, the end of the study (31 December 2008), or 365 days after initiation, whichever came first. Covariates We measured potential confounders in the 180-day baseline period preceding each patients index date. Demographic variables included age, sex, and race. Health service utilization variables included the number of unique drugs dispensed, number of hospitalizations, number of cardiovascular diagnoses, number of days in the hospital, number of physician office visits, and number of physician office visits with cardiovascular diagnoses. In addition to a comorbidity score that captured patients general health status (23), we determined whether patients had health care encounters with diagnoses for specific cardiovascular conditions (such as atrial fibrillation, congestive heart failure, or peripheral vascular disease) and other disorders (such as chronic obstructive pulmonary disease, diabetes, musculoskeletal conditions, and endocrine disease). Furthermore, we determined whether patients initiated statin treatment for primary or secondary prevention, with the latter defined as having been hospitalized for an acute coronary syndrome in the baseline period. We also measured use of preventive services, including screening mammography and vaccinations, to account for healthy-user effects (24, 25) and ascertained proxies of frailty, such as use of supplemental oxygen, to account for the propensity to stop preventive medications in patients who are very ill (26). Finally, we geocoded patients street addresses and linked them to U.S. census data at the block group level, which is the lowest level for which data are publicly available. We identified the unemployment rate and the median household income in each patients census block group as proxies for socioeconomic status (SES). Statistical Analysis We used propensity score matching (27) to mitigate confounding due to different characteristics between the brand-name and generic groups. The propensity score, which was estimated with a logistic regression model, was defined as a patients probability of receiving a generic statin versus a brand-name statin and was conditional on measured baseline covariates. We matched generic and brand-name drug recipients by using a nearest-neighbor algorithm and within calipers of 0.05 units on the propensity score scale in the primary analysis. Because the cohort included many more generic than brand-name drug recipients, we matched each patient in the brand-name group to as many patients as possible in the generic group with similar propensity scores within the specified caliper. We matched brand-name drug recipients only to recipients of the generic version of the same product (for example, brand-name and generic simvastatin) to compare patients who had initiated molecularly identical drugs. This ensured that differences in outcome rates between treatment groups could be attributed to the generic versus brand-name status rather than to differences among the 3 statins. To assess the performance of the propensity score matching process, we evaluated balance in each baseline covariate and overlap in propensity score distributions between treatment groups before and after matching. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs. To account for the variable ratio matching, the Cox models were stratified by matching set. We also estimated rate differences. We performed several prespecified secondary, sensitivity, and subgroup analyses to assess the validity of our study assumptions. We altered our primary analysis by shortening (to 90 days) and lengthening (to 720 days) the maximum follow-up time, excluding events that occurred within 30 and 60 days after index drug initiation, and performing 1:1 fixed-ratio matching on the propensity score. Furthermore, outcome event rates were compared between recipients of the generic and brand-name versions of each drug separately. The primary analysis was also repeated separately for primary prevention and secondary prevention patients. We conducted an on treatment analysis in which we censored patients when they discontinued statin therapy, defined as a gap of more than 30 days without filling a statin prescription beyond the number of days supplied by the last prescription or switching to another lipid-lowering

Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

CONTEXT With the development of transformative drugs at a low point, numerous commentators have recommended new legislation that uses supplementary market exclusivity as an incentive to promote innovation in the pharmaceutical market. METHODS This report provides an historical perspective on proposals for encouraging drug research. Four legislative programs have been primarily designed to offer market exclusivity to promote public health goals in the pharmaceutical or biomedical sciences: the Bayh-Dole Act of 1980, the Orphan Drug Act of 1983, the Hatch-Waxman Act of 1984, and the pediatric exclusivity provisions of the FDA Modernization Act of 1997. I reviewed quantitative and qualitative studies that reported on the outcomes from these programs and evaluated the quality of evidence generated. FINDINGS All four legislative programs generally have been regarded as successful, although such conclusions are largely based on straightforward descriptive reports rather than on more rigorous comparative data or analyses that sufficiently account for confounding. Overall, solid data demonstrate that market exclusivity incentives can attract interest from parties involved in drug development. However, using market exclusivity to promote innovation in the pharmaceutical market can be prone to misuse, leading to improper gains. In addition, important collateral effects have emerged with substantial negative public health implications. CONCLUSIONS Using market exclusivity to promote pharmaceutical innovation can lead to positive outcomes, but the practice is also characterized by waste and collateral effects. Certain practices, such as mechanisms for reevaluation and closer ties of incentives programs to public health outcomes, can help address these problems.

Pharmaceutical Marketing and the New Social Media

In recent months, the FDA has declined to permit use of eight new sunscreen ingredients (that are already in use in Europe) without additional data. The controversy says as much about how the agency works as it does about sunscreen regulation.

How Does Medical Device Regulation Perform in the United States and the European Union? A Systematic Review

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices.