Program On Regulation, Therapeutics, And Law (PORTAL)
Literature Scan

Each month, the Program On Regulation, Therapeutics, And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital/Harvard Medical School reviews the peer-reviewed medical literature to identify interesting empirical studies, in-depth analyses, and thoughtful editorials on pharmaceutical law and policy.

Current and previous scans may be found below:

January 2017

December 2016

October 2016

September 2016

August 2016

July 2016

June 2016

May 2016

April 2016

March 2016

February 2016

Please visit the Archived PORTAL Scans to refer to scans dating back to August 2014.

January 2017

  1. Ahn R, Woodbridge A, Abraham A, Saba S, Korenstein D, Madden E, Boscardin WJ, Keyhani S. Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ. 2017 Jan; 356:i6770.
  2. OBJECTIVE: To examine the association between the presence of individual principal investigators’ financial ties to the manufacturer of the study drug and the trial’s outcomes after accounting for source of research funding.
    DESIGN: Cross sectional study of randomized controlled trials (RCTs).
    SETTING: Studies published in “core clinical” journals, as identified by Medline, between 1 January 2013 and 31 December 2013.
    PARTICIPANTS: Random sample of RCTs focused on drug efficacy.
    MAIN OUTCOME MEASURE: Association between financial ties of principal investigators and study outcome.
    RESULTS: A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9).
    CONCLUSIONS: Financial ties of principal investigators were independently associated with positive clinical trial results. These findings may be suggestive of bias in the evidence base.

  3. Califf RM. Benefit-Risk Assessments at the US Food and Drug Administration: Finding the Balance. JAMA. 2017 Jan 20. [Epub ahead of print]
  4. The US Food and Drug Administration’s (FDA’s) independent evaluation of medical products for safety and effectiveness prior to granting approval for marketing or new labeled indications is fundamental to assuring the public and clinicians that marketed products have a positive balance of benefit to risk when used according to labeling. Ever since this foundational protection was established in 1962, a body of evidence has supported the use of a flexible but consistent standard when making decisions about marketing approval: Do the benefits of a product outweigh the risks when used as intended and labeled?

  5. Hakim A, Ross JS. High Prices for Drugs With Generic Alternatives: The Curious Case of Duexis. JAMA Intern Med. 2017 Jan 23. [Epub ahead of print]
  6. Approximately 13% of health care expenditures in the United States are for prescription drug spending, nearly $420 billion in 2015. High-priced pharmaceuticals, therapies that cost more than $600 per month, are projected to eclipse 50% of total drug spending by 2018. Price increases for these therapies have been persistent, with unit costs increasing 164% between 2008 and 2015. Pharmacy benefit managers are third-party administrators that process and pay prescription drug claims and negotiate drug prices with manufacturers. Pharmacy benefit managers have sought to manage prescription drug use and mitigate cost increases through such measures as prior authorization and step therapy requirements for physicians, increased copayment requirements for patients, and exclusion of some expensive medications from health plan formularies. Using the illustrative example of Duexis, a single-tablet, fixed-dose combination of the nonsteroidal anti-inflammatory (NSAID) ibuprofen and the histamine H2-receptor antagonist famotidine marketed by Horizon Pharma (Dublin, Ireland), we describe how some pharmaceutical companies have sought to circumvent such restrictions and maintain high prices for drugs, even for those with generic alternatives.

  7. Kesselheim AS, Rome BN, Sarpatwari A, Avorn J. Six-Month Market Exclusivity Extensions To Promote Research Offer Substantial Returns For Many Drug Makers. Health Aff (Millwood). 2017 Jan 18. [Epub ahead of print]
  8. To incentivize pharmaceutical manufacturers to invest in areas of unmet medical need, policy makers frequently propose extending the market exclusivity period of desired drugs. Some such proposals are modeled after the pediatric exclusivity patent extension program, which since 1997 has provided six additional months of market exclusivity for drugs studied in children. The most recent proposal would encourage rare disease research by providing six months of extended exclusivity for any existing drug that is granted subsequent FDA approval for a new rare disease indication. Yet the economic impact of such proposals is rarely addressed. We found that for the thirteen FDA-approved drugs that gained supplemental approval for a rare disease indication from 2005 through 2010, the median projected cost of clinical trials leading to approval was $29.8 million. If the exclusivity extension had been in place, the median discounted financial gain to manufacturers would have been $94.6 million. Median net returns would have been $82.4 million, with higher returns for drugs with higher annual sales. Extending market exclusivity would provide substantial compensation to many manufacturers, particularly for top-selling products, far in excess of the cost of conducting these trials. Alternative strategies to incentivize the study of approved drugs for rare diseases may offer similar benefits at a lower cost.

  9. Kesselheim AS, Treasure CL, Joffe S. Biomarker-Defined Subsets of Common Diseases: Policy and Economic Implications of Orphan Drug Act Coverage. PLoS Med. 2017; 14(1):e1002190.
  10. Summary Points
     The Orphan Drug Act of 1983 was intended to incentivize the development of pharmaceutical products for rare diseases by providing manufacturers with the opportunity to earn grants, tax credits, fee waivers, and seven years of post-approval market exclusivity for the approved indication.
     Over the past decade, the number of orphan drug designations has roughly doubled, with a simultaneous increase in those that target biomarker-defined subsets of common diseases.
     Among all orphan-designated drugs approved in 2009–2015 indicated for biomarker-defined disease subsets, we examined the circumstances surrounding the drug’s discovery and development, secondary approvals, off-label uses, subsequent revenues, and the reported monthly cost.
     Orphan-designated drugs to treat biomarker-defined subsets of common conditions have a number of characteristics that make them ill-suited to the orphan drug designation, including short development times and rapid expansion of off-label indications after approval. Application of the Orphan Drug Act in these cases risks wasting resources that might be better focused on truly rare conditions.

  11. Rose SL, Highland J, Karafa MT, Joffe S. Patient Advocacy Organizations, Industry Funding, and Conflicts of Interest. JAMA Intern Med. 2017 Jan 17. [Epub ahead of print]
  12. Importance: Patient advocacy organizations (PAOs) are influential health care stakeholders that provide direct counseling and education for patients, engage in policy advocacy, and shape research agendas. Many PAOs report having financial relationships with for-profit industry, yet little is known about the nature of these relationships. Objective: To describe the nature of industry funding and partnerships between PAOs and for-profit companies in the United States.
    Design, Setting, and Participants: A survey was conducted from September 1, 2013, to June 30, 2014, of a nationally representative random sample of 439 PAO leaders, representing 5.6% of 7865 PAOs identified in the United States. Survey questions addressed the nature of their activities, their financial relationships with industry, and the perceived effectiveness of their conflict of interest policies.
    Main Outcomes and Measures: Amount and sources of revenue as well as organizational experiences with and policies regarding financial conflict of interest.
    Results: Of the 439 surveys mailed to PAO leaders, 289 (65.8%) were returned with at least 80% of the questions answered. The PAOs varied widely in terms of size, funding, activities, and disease focus. The median total revenue among responding organizations was $299 140 (interquartile range, $70 000-$1 200 000). A total of 165 of 245 PAOs (67.3%) reported receiving industry funding, with 19 of 160 PAOs (11.9%) receiving more than half of their funding from industry. Among the subset of PAOs that received industry funding, the median amount was $50 000 (interquartile range, $15 000-$200 000); the median proportion of industry support derived from the pharmaceutical, device, and/or biotechnology sectors was 45% (interquartile range, 0%-100%). A total of 220 of 269 respondents (81.8%) indicated that conflicts of interest are very or moderately relevant to PAOs, and 94 of 171 (55.0%) believed that their organizations’ conflict of interest policies were very good. A total of 22 of 285 PAO leaders (7.7%) perceived pressure to conform their positions to the interests of corporate donors.
    Conclusions and Relevance: Patient advocacy organizations engage in wide-ranging health activities. Although most PAOs receive modest funding from industry, a minority receive substantial industry support, raising added concerns about independence. Many respondents report a need to improve their conflict of interest policies to help maintain public trust.

  13. Saavedra K, O’Connor B, Fugh-Berman A. Pharmacist-industry relationships. Int J Pharm Pract. 2017 Jan 18. [Epub ahead of print]
  14. OBJECTIVES: The purpose of this study was to document, in their own words, beliefs and attitudes that American pharmacists have towards the pharmaceutical industry and pharmacists’ interactions with industry.
    METHODS: An ethnographic-style qualitative study was conducted utilizing open-ended interviews with four hospital pharmacists, two independent pharmacists, two retail pharmacists and one administrative pharmacist in the Washington, DC, metropolitan area to elicit descriptions of and attitudes towards pharmacists’ relationships with industry. Analysis of the qualitative material followed established ethnographic conventions of narrative thematic analysis.
    KEY FINDINGS: All pharmacists reported interactions with pharmaceutical company representatives. Most had received free resources or services from industry, including educational courses. Respondents uniformly believed that industry promotional efforts are primarily directed towards physicians. Although respondents felt strongly that drug prices were excessive and that ‘me-too’ drugs were of limited use, they generally had a neutral-to-positive view of industry-funded adherence/compliance programmes, coupons, vouchers, and copay payment programmes. Interviewees viewed direct-to-consumer advertising negatively, but had a generally positive view of industry-funded drug information.
    CONCLUSIONS: Pharmacists may represent a hitherto under-identified cohort of health professionals who are targeted for industry influence; expanding roles for pharmacists may make them even more attractive targets for future industry attention. Pharmacy schools should ensure that students learn to rely on unbiased information sources and should teach students about conflicts of interest and the risks of interacting with industry. Further research should be conducted on the extent to which pharmacists’ attitudes towards their duties and towards drug assessment and recommendation are influenced by the pharmaceutical industry.

    Please visit the Archived PORTAL Scans to refer to scans dating back to August 2014.

    December 2016

    1. Califf RM, Robb MA, Bindman AB, Briggs JP, Collins FS, Conway PH, Coster TS, Cunningham FE, De Lew N, DeSalvo KB, Dymek C, Dzau VJ, Fleurence RL, Frank RG, Gaziano JM, Kaufmann P, Lauer M, Marks PW, McGinnis JM, Richards C, Selby JV, Shulkin DJ, Shuren J, Slavitt AM, Smith SR, Washington BV, White PJ, Woodcock J, Woodson J, Sherman RE. Transforming Evidence Generation to Support Health and Health Care Decisions. N Engl J Med. 2016 Dec;375(24):2395-2400.
    2. Making better choices about health and health care requires the best possible evidence. Unfortunately, many of the decisions made today in our health care system are not supported by high-quality evidence derived from randomized, controlled trials or well-designed observational studies. But as rich, diverse sources of digital data become widely available for research and as analytical tools continue to grow in power and sophistication, the research and health care communities now have the opportunity to quickly and efficiently generate the scientific evidence needed to support improved decision making about health and health care.

    3. Gupta R, Shah ND, Ross JS. The Rising Price of Naloxone – Risks to Efforts to Stem Overdose Deaths. N Engl J Med. 2016 Dec 8;375(23):2213-2215.
    4. The Food and Drug Administration (FDA) first approved naloxone in 1971 as an injection (Narcan) for reversing opioid intoxication or overdose. Although the brand-name version has been discontinued, generic versions of naloxone have been available since 1985, and today injections are available in two doses (0.4 mg per milliliter and 1 mg per milliliter). In 2014, the FDA fast-tracked approval of the first auto-injector formulation (Evzio), a fixed-dose single injection designed to allow people without medical training to reverse opioid overdose. In 2015, the agency fast-tracked approval of the first nasal-spray formulation (also marketed as Narcan); previously, naloxone injections (larger vials of a 1-mg-per-milliliter dose) had routinely been used off-label with an atomizer for nasal delivery.

    5. Oye KA, Eichler HG, Hoos A, Mori Y, Mullin TM, Pearson M. Pharmaceuticals Licensing and Reimbursement in the European Union, United States, and Japan. Clin Pharmacol Ther. 2016 Dec;100(6):626-632.
    6. This article describes recent developments in licensing and reimbursement policies in the EU, US, and Japan, examines causes of changes and compares differences and projects trends. With respect to licensing, the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from postmarket experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigake strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over prices.

    7. Knopf K, Baum M, Shimp WS, Bennett CL, Faith D, Fishman ML, Hrushesky WJ. Interpretation of surrogate endpoints in the era of the 21st Century Cures Act. BMJ. 2016 Dec;355:i6286.
    8. The rationale behind medical practice distils to three principles: maintaining health (wellbeing), improving quality of life, and extending length of life. For patients with incurable cancer, quality and length of life are of prime importance and should therefore be the primary outcome measures in all randomised clinical trials of innovative treatments. All other measures are surrogates that do not always translate into improvements in prime outcomes. This concern will only increase as the 21st Century Cures Act is implemented in the United States.

    9. Robertson C, Kesselheim AS. Regulating Off-Label Promotion – A Critical Test. N Engl J Med. 2016 Dec;375(24):2313-2315.
    10. In 2012, the U.S. Court of Appeals for the Second Circuit handed down a landmark decision in the case of pharmaceutical sales representative Alfred Caronia. The Food and Drug Administration (FDA) had approved sodium oxybate (Xyrem) for treating narcolepsy, but Caronia promoted it for a wide range of nonapproved (off-label) indications, including insomnia, Parkinson’s disease, and fibromyalgia. Off-label use is common, especially in specialties such as oncology, in which it may even be considered the standard of care. However, surveys have revealed that supporting evidence is lacking for a majority of off-label uses of medical products. The uses Caronia proposed were not based on high-quality data and were likely to cause patients substantial harm (sodium oxybate, or gamma-hydroxybutyrate, is also known as the “date-rape drug” in nonclinical use).

    11. Sinha MS, Kesselheim AS. Regulatory Incentives for Antibiotic Drug Development: A Review of Recent Proposals. Bioorg Med Chem. 2016 Dec ;24(24):6446-6451.
    12. Two primary regulatory mechanisms have been proposed to incentivize new antibiotic development: (1) changing Food and Drug Administration (FDA) approval processes to expedite antibiotic approval; and (2) offering enhanced possibilities for market exclusivity. Changes to the FDA regulatory approval process include greater reliance on surrogate endpoints such as biomarkers, use of noninferiority hypothesis designs for key preapproval clinical trials, and development of an expedited development track specific for antibiotics called the Limited Population pathway. The second strategy intended to encourage new antibiotic development has been to provide additional market exclusivity incentives based on regulatory approval. While these pathways have some positive attributes, they also present enhanced risks to patients associated with lower regulatory barriers and the market exclusivity incentives may not efficiently direct resources to the true origins of antibiotic innovation.

    13. Wolf MS, Davis TC, Curtis LM, Bailey SC, Knox JP, Bergeron A, Abbet M, Shrank WH, Parker RM, Wood AJ. A Patient-Centered Prescription Drug Label to Promote Appropriate Medication Use and Adherence. J Gen Intern Med. 2016 Dec;31(12):1482-1489. PubMed PMID: 27542666; PubMed Central PMCID: PMC5130952.
    14. BACKGROUND: Patient misunderstanding of prescription drug label instructions is a common cause of unintentional misuse of medication and adverse health outcomes. Those with limited literacy and English proficiency are at greater risk.
      OBJECTIVE: To test the effectiveness of a patient-centered drug label strategy, including a Universal Medication Schedule (UMS), to improve proper regimen use and adherence compared to a current standard.
      DESIGN: Two-arm, multi-site patient-randomized pragmatic trial.
      PARTICIPANTS: English- and Spanish-speaking patients from eight community health centers in northern Virginia who received prescriptions from a central-fill pharmacy and who were 1) ≥30 years of age, 2) diagnosed with type 2 diabetes and/or hypertension, and 3) taking ≥2 oral medications.
      INTERVENTION: A patient-centered label (PCL) strategy that incorporated evidence-based practices for format and content, including prioritized information, larger font size, and increased white space. Most notably, instructions were conveyed with the UMS, which uses standard intervals for expressing when to take medicine (morning, noon, evening, bedtime).
      MAIN MEASURES: Demonstrated proper use of a multi-drug regimen; medication adherence measured by self-report and pill count at 3 and 9 months.
      KEY RESULTS: A total of 845 patients participated in the study (85.6 % cooperation rate). Patients receiving the PCL demonstrated slightly better proper use of their drug regimens at first exposure (76.9 % vs. 70.1 %, p = 0.06) and at 9 months (85.9 % vs. 77.4 %, p = 0.03). The effect of the PCL was significant for English-speaking patients (OR 2.21, 95 % CI 1.13-4.31) but not for Spanish speakers (OR 1.19, 95 % CI 0.63-2.24). Overall, the intervention did not improve medication adherence. However, significant benefits from the PCL were found among patients with limited literacy (OR 5.08, 95 % CI 1.15-22.37) and for those with medications to be taken ≥2 times a day (OR 2.77, 95 % CI 1.17-6.53).
      CONCLUSIONS: A simple modification to pharmacy-generated labeling, with minimal investment required, can offer modest improvements to regimen use and adherence, mostly among patients with limited literacy and more complex regimens. Trial Registration ( NCT00973180, NCT01200849.

      November 2016

      1. Abola MV, Prasad V. Industry Funding of Cancer Patient Advocacy Organizations. Mayo Clin Proc. 2016;91(11):1668-1670.
      2. Cancer patient advocacy organizations (PAOs) often demand faster drug approval and easier access to cancer medications with uncertain benefits and harms. Previous research has found that a sizable percentage of PAOs across all disease types receive funding from the biopharmaceutical industry; as such, the independence of such groups has been questioned.

        To our knowledge, however, there has been no research specifically focused on the funding of cancer PAOs. These groups have influence on the regulation of cancer drugs, speaking on behalf of patients with cancer. The PAOs have supported recent legislation, including the 21st Century Cures bill and so-called Right to Try laws. For this reason, we sought to characterize declared sources of funding for cancer PAOs.

      3. Bauer SR, Redberg RF. Improving the Accelerated Pathway to Cancer Drug Approvals. JAMA Intern Med. 2016 Nov. [Epub ahead of print]
      4. The US Food and Drug Administration (FDA) must balance the need to bring potentially lifesaving drugs to market with the need to ensure the safety and effectiveness of these drugs. To balance these competing goals, the FDA has increasingly used the accelerated pathway, which is meant for drugs that treat serious conditions and fill an unmet medical need. Approval is based on a surrogate or an early clinical endpoint and is conditional on the completion of confirmatory trials, which are planned prior to the approval process.

      5. Califf RM, Sherman RE, Slavitt A. Knowing When and How to Use Medical Products: A Shared Responsibility for the FDA and CMS. JAMA. 2016 Nov [Epub ahead of print]
      6. Before a medical product can be widely used in the United States, it generally must first be approved or cleared for marketing by the US Food and Drug Administration (FDA). Then, payers such as the Centers for Medicare & Medicaid Services (CMS) must decide whether the product merits coverage and payment. Because the statutes governing these agencies evolved to meet the exigencies of particular moments in the history of medical product development, the degree of convergence in standards and in the underlying evidence needed to support regulatory and payment decisions is not always immediately obvious. The resulting fragmentation—perceived or real—has led to questions about whether FDA approval or clearance for marketing will necessarily result in approval for coverage and payment.

      7. Robertson C, Kesselheim AS. Regulating Off-Label Promotion – A Critical Test. N Engl J Med. 2016 Nov. [Epub ahead of print]
      8. In 2012, the U.S. Court of Appeals for the Second Circuit handed down a landmark decision in the case of pharmaceutical sales representative Alfred Caronia. The Food and Drug Administration (FDA) had approved sodium oxybate (Xyrem) for treating narcolepsy, but Caronia promoted it for a wide range of nonapproved (off-label) indications, including insomnia, Parkinson’s disease, and fibromyalgia. Off-label use is common, especially in specialties such as oncology, in which it may even be considered the standard of care. However, surveys have revealed that supporting evidence is lacking for a majority of off-label uses of medical products. The uses Caronia proposed were not based on high-quality data and were likely to cause patients substantial harm (sodium oxybate, or gamma-hydroxybutyrate, is also known as the “date-rape drug” in nonclinical use).

      9. Sarpatwari A, Gagne JJ, Levidow NL, Kesselheim AS. Active Drug Saf. 2016 Nov. [Epub ahead of print]
      10. As lower-cost versions of original biologic drugs made by different manufacturers, follow-on biologics offer the promise of meaningful savings for the US health care system and improved patient health outcomes through greater medication adherence. Fulfillment of this promise, however, is predicated on the prescribing of such products. Under state drug product selection laws, pharmacists may substitute prescriptions for brand name, small-molecule drugs with their generic equivalents, but will be indefinitely prohibited from substituting prescriptions for original biologics with their follow-on biologic counterparts given a lack of product-specific guidance on demonstrating interchangeability. Even when interchangeable follow-on biologics become available, they will face heightened barriers to substitution following the enactment of so-called carve-outs in several states. Data collected to date suggest that a substantial proportion of US physicians remain skeptical of follow-on biologics despite their long record of safe and effective use in Europe. Active surveillance of follow-on biologics within the US market using insurance claims databases can help address this skepticism and help answer key questions concerning the safety of switching between original and follow-on products or between different follow-on products, and of extrapolating to broader indications. Funding is needed to support such surveillance activities and to disseminate the findings to key stakeholders.

      11. Xu J, Gill R, Cruz M, Staffa J, Lurie P. . Effect of US Food and Drug Administration-Approved Pediatric Labeling on Dispensing of Extended-Release Oxycodone in the Outpatient Retail Setting. JAMA Pediatr. 2016 Nov;170(11):1103-1104
      12. For years, extended-release (ER) oxycodone has been prescribed to children for management of pain. In August 2015, based on studies conducted under the Best Pharmaceuticals for Children Act that are designed to better inform pediatric prescribing, the US Food and Drug Administration approved the use of OxyContin (Purdue Pharma) for management of pain requiring treatment with an ER/long-acting opioid in children 11 years and older who are already tolerating a daily opioid dose equivalent to at least 20 mg of oxycodone, as described in the labeling. The new labeling was not intended to expand pediatric use of ER opioids, but rather to help clinicians use OxyContin safely in pediatric patients.

        For years, extended-release (ER) oxycodone has been prescribed to children for management of pain. In August 2015, based on studies conducted under the Best Pharmaceuticals for Children Act that are designed to better inform pediatric prescribing, the US Food and Drug Administration approved the use of OxyContin (Purdue Pharma) for management of pain requiring treatment with an ER/long-acting opioid in children 11 years and older who are already tolerating a daily opioid dose equivalent to at least 20 mg of oxycodone, as described in the labeling. The new labeling was not intended to expand pediatric use of ER opioids, but rather to help clinicians use OxyContin safely in pediatric patients.


      13. Dafny LS, Ody CJ, Schmitt MA. Undermining Value-Based Purchasing – Lessons from the Pharmaceutical Industry. N Engl J Med. 2016 Oct. [Epub ahead of print]
      14. In 2015, the U.S. Department of Health and Human Services announced a goal of linking at least 50% of Medicare spending to value-based payment models such as accountable care organizations. Health care providers are now scrambling to reorganize in a way that delivers value while preserving or enhancing commercial success. Although it’s not yet clear how providers will respond to value-based payment models, an examination of pharmaceutical industry practices can provide insights into problems that may arise — and practices to avoid.

        Value-based plan design — a term that describes payers’ efforts to align consumer cost sharing with the value generated by a service or drug — may sound like a new development in health care, but it’s old news for prescription drugs. For years, insurers and pharmacy benefits managers have steered consumers toward generic and other high-value drugs by categorizing drugs into “tiers” and requiring lower copayments for preferred drugs. By 2000, roughly three quarters of consumers enrolled in employer-sponsored health plans had prescription plans with two or more drug tiers. Today, a similar proportion have plans with at least three tiers. Tiering not only encourages consumers to use high-value drugs, it also gives insurers leverage during price negotiations with manufacturers.

      15. Doshi P. Is this trial misreported? Truth seeking in the burgeoning age of trial transparency. BMJ. 2016;355:i5543.
      16. Glimpses inside SmithKline Beecham’s secret clinical trials programme for the antidepressant paroxetine began in the early 2000s. Amid a growing storm over the safety of selective serotonin reuptake inhibitors for children, a leaked memo revealed by the BBC’s Panorama programme depicted a company trying to manage the unfavourable results of two important trials. “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine,” the memo read. A reviewer for the US Food and Drug Administration considered both trials as “failed.”

        But then there was the public face of the data. One of the two trials–Study 329–was published in the peer reviewed literature. The manufacturer told its sales representatives that the “landmark study … demonstrates REMARKABLE efficacy and safety.”

      17. Hwang TJ, Carpenter D, Lauffenburger JC, Wang B, Franklin JM, Kesselheim AS. Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results. JAMA Intern Med. 2016 Oct. [Epub ahead of print]
      18. Importance: Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.
        Objective: To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results.
        Design, Setting, and Participants: Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product.
        Main Outcomes and Measures: For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval.
        Results: Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved.
        Conclusions and Relevance: Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

      19. Kesselheim AS, Avorn J. Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy. JAMA. 2016 Oct. [Epub ahead of print]
      20. In September 2016, the US Food and Drug Administration (FDA) approved eteplirsen (Exondys 51), a new drug for Duchenne muscular dystrophy (DMD), overruling the recommendations of both its scientific staff and its external advisory committee. Duchenne muscular dystrophy is a progressive and usually fatal X-linked genetic disease caused by mutations in a gene that produces the protein dystrophin that helps stabilize muscle fibers. No disease-modifying treatments are available.

        Eteplirsen was designed to offer a promising new therapeutic approach that would bypass a stop codon in a gene coding for dystrophin, allowing production of a truncated but functional version of the protein. In particular, eteplirsen targeted exon 51, the location of the stop codon in about 10% to 15% of patients with DMD (an estimated 2000-2500 cases in the United States). Despite this innovative mechanism, the development of eteplirsen was controversial, starting with its manufacturer-supported pivotal double-blind study, which involved only 12 patients: 8 were randomized to 2 different eteplirsen doses and 4 were randomized to placebo for 24 weeks. The latter were then switched to eteplirsen and all were to be followed for an additional 24 weeks. The sample size was substantially smaller than the study sample size in which a similar DMD drug, drisapersen, had been tested in 3 randomized trials that together enrolled 290 patients. The FDA declined to approve drisapersen in 2015 after these studies showed no clear benefit after 24 weeks in prespecified clinical end points, such as changes in a 6-minute walk test. Those trials also suggested the possibility of safety problems, including renal toxic effects and thrombocytopenia.

      21. Sommers BD, Blendon RJ, Orav EJ, Epstein AM. Changes in Utilization and Health Among Low-Income Adults After Medicaid Expansion or Expanded Private Insurance. JAMA Intern Med. 2016;176(10):1501-9.
      22. Importance: Under the Affordable Care Act (ACA), more than 30 states have expanded Medicaid, with some states choosing to expand private insurance instead (the “private option”). In addition, while coverage gains from the ACA’s Medicaid expansion are well documented, impacts on utilization and health are unclear.
        Objective: To assess changes in access to care, utilization, and self-reported health among low-income adults in 3 states taking alternative approaches to the ACA.
        Design, Setting, and Participants: Differences-in-differences analysis of survey data from November 2013 through December 2015 of US citizens ages 19 to 64 years with incomes below 138% of the federal poverty level in Kentucky, Arkansas, and Texas (n = 8676). Data analysis was conducted between January and May 2016.
        Exposures: Medicaid expansion in Kentucky and use of Medicaid funds to purchase private insurance for low-income adults in Arkansas (private option), compared with no expansion in Texas.
        Main Outcomes and Measures: Self-reported access to primary care, specialty care, and medications; affordability of care; outpatient, inpatient, and emergency utilization; receiving glucose and cholesterol testing, annual check-up, and care for chronic conditions; quality of care, depression score, and overall health.
        Results: Among the 3 states included i