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:

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.

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 (ClinicalTrials.gov): 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.

      October

    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