Drug safety in the digital age

Wikipedia is reportedly the most frequently consulted online health care resource globally, but it is not reliably updated after the FDA issues safety warnings on drugs.

Based on a sample of 22 prescription medications subject to a drug-safety communication between 2011-2012, FDA safety warnings were associated with an 82% increase, on average, in Google searches for the drugs during the week after the announcement and a 175% increase in views of Wikipedia pages for the drugs on the day of the announcement, as compared with baseline trends. In addition, 41% of Wikipedia pages pertaining to the drugs with new safety warnings were updated within 2 weeks after the warning was issued with information provided in the FDA announcements. However, 23% of Wikipedia pages were updated more than 2 weeks after the FDA warning was issued (average, 42 days), and 36% of pages remained unchanged more than 1 year later. The Wikipedia pages for drugs that were intended for treatment of highly prevalent diseases (affecting more than 1 million people in the United States) were more likely to be updated quickly (58% were updated within 2 weeks) than were those for drugs designed to treat less-prevalent conditions (20% were updated within 2 weeks, P=0.03).

Public health officials have historically focused on printed drug labels and “Dear Health Care Provider” letters from the FDA, but new technologies offer the opportunity to reach patients and physicians more efficiently and effectively. The FDA and others can take some steps to improve the dissemination of essential drug information.

(cite: Hwang TJ, Bourgeois FT, Seeger JD. Drug safety in the digital age. N Engl J Med 2014; 370(26): 2460-2462.)

Target small firms for antibiotic innovation

Antibiotics are an indispensable part of modern medicine. Yet, since the first β-lactam, aminoglycoside, macrolide, tetracycline, and fluoroquinolone classes of antibiotics were discovered and approved from 1940 to 1980, few antibiotics with novel mechanisms of action have been developed. At the same time, antibiotic resistance has been on the rise. Ensuring appropriate use, or stewardship, of antibiotics is critical to ensure that antibiotics retain their effectiveness against pathogens. In addition, the need for new classes of antibiotics has seen increasing international attention. To inform ongoing policy debates, we characterize trends in antibiotic research and development (R&D) over the past two decades.

(cite: Hwang TJ, Carpenter D, Kesselheim AS. Target small firms for antibiotic innovation. Science 2014; 344(6187): 967-969.)

Two decades of CNS drug development

Central nervous system (CNS) disorders, such as depression, epilepsy, and schizophrenia, account for 12 of the top 20 global causes of years lived with disability. In addition to the human costs, the economic burden of CNS disorders weighs heavily on national health expenditures. Of the estimated $157-215 billion total cost of dementia in the US, approximately $11 billion was paid by Medicare. Despite the social, clinical, and economic need for therapeutics treating CNS conditions, the pipeline of new medications may be declining, highlighting the exit of several large pharmaceutical companies from the field.

In our study, we examined the past two decades of experimental CNS drugs and assessed how they fared during pre-FDA approval clinical phases. We also determined the reasons for failures of these drugs in late-stage clinical trials. Our data support perceptions among policymakers that there has been a slowdown in CNS drug development since 1990, particularly as compared to oncology drugs. We also found that CNS drugs were significantly more likely than non-CNS drugs to fail at the final Phase 3 testing stage. Among discontinued CNS drugs, the most common reason was failure to demonstrate efficacy, which appeared to occur at a rate consistent with new drug failures overall.

(cite: Kesselheim AS, Hwang TJ, Franklin JM. Two decades of new drug development for central nervous system disorders. Nature Rev Drug Discovery 2015; 14(12): 815-816.)

In vitro diagnostics and precision medicine

In October 2014, the US Food and Drug Administration (FDA) issued a draft guidance outlining its plan to overhaul the regulation of in vitro diagnostics, which are tests conducted outside of a living body to detect or diagnose diseases, conditions and infections. Most in vitro diagnostics, specifically those developed by individual laboratories (known as laboratory-developed tests, or LDTs) for use by clinicians, have historically been exempt from premarket FDA review. As a result, medical-center laboratories have been at the forefront of precision medicine, rapidly developing tests for rare diseases and public health threats, such as HIV.

However, citing the potential for serious harms, the FDA now proposes to use a risk-based framework to determine which LDTs will be subject to regulatory oversight before marketing. Over a 9-year period, requirements for premarket review will be gradually phased in first for high-risk (or class III) LDTs, and then for moderate-risk (or class II) LDTs. Thus, before high-risk LDTs can be marketed or used by clinicians, manufacturers of these tests—like those of other class III devices such as implantable pacemakers—will have to provide evidence of safety, effectiveness and clinical validity.

In our article, we argue that this plan could be modified to minimize delays in market entry of lower-risk tests and those for pressing clinical needs. To promote innovation in precision medicine, the FDA, the CMS and other stakeholders should collaborate to ensure that rigorously validated diagnostic tests are reimbursed commensurately with their benefits to patients.

(cite: Hwang TJ, Lehmann LS, Kesselheim AS. Precision medicine and the FDA's draft guidance on laboratory-developed tests. Nature Biotech 2015; 33(5): 449-451.)

Retinal implants and Medicare reimbursement

Novel medical devices intended to treat diseases of the eye, such as retinitis pigmentosa and glaucoma, could greatly improve patient care and health outcomes. A number of factors influence the research and development process of these investigational therapeutics. Specifically, given the significant upfront investments required to develop new devices, reimbursement and payment policies of large payers, such as the Centers for Medicare and Medicaid Services (CMS), play an important role in product development and commercialization.

Recently, the Centers for Medicare and Medicaid Services granted the first ophthalmic device, a retinal prosthesis, an incentive payment through the New Technology Add-on Payment (NTAP) program. In our article, we consider how innovative reimbursement pathways may impact the pace of ophthalmological research and development. We argue that in light of ongoing efforts to make reimbursement decisions more efficient, CMS should leverage its influence as a large payer to promote the development of breakthrough devices such as through coordinating and expediting joint FDA-NTAP review.

(cite: Hwang TJ, Ciolino JB. Retinal implants and Medicare reimbursement policies for breakthrough treatments in ophthalmology. JAMA Ophthalmol 2015: 133(4): 373-374.)

Surgical applications of 3D printing

Three-dimensional (3-D) printing, which involves the construction of physical objects from digital models, may revolutionize surgical care. By using computer-aided design based on computed tomographic images or laser surface scans, clinicians can more precisely tailor therapeutics, implants, and potentially soft tissue and organs for the specific anatomy of each patient. For example, in 2013, researchers reported the successful printing and implantation of a customized, bioresorbable tracheal splint for the treatment of an infant with tracheobronchomalacia.

With the US Food and Drug Administration (FDA) expected to issue guidance on 3-D printing in the coming year, we believe it is an opportune time to examine key issues relating to the clinical use, regulation, and reimbursement of this novel technology. In our article, we examine key issues relating to the clinical use, regulation, and reimbursement of 3-dimensional printing technology. We argue that by coupling a flexible risk-based regulatory framework with novel reimbursement policies designed to encourage collection of long-term clinical data, clinicians and policymakers may better balance stimulating continued innovation in this field with the need to ensure the safety and effectiveness of personalized medical devices.

(cite: Hwang TJ, Kiang CJ, Paul M. Surgical applications of three-dimensional printing and precision medicine. JAMA Otolaryngol Head Neck Surg 2015: 141(4): 305-306.)

Reimbursement incentives for antibiotics

Antibiotics are arguably one of the great translational medicine success stories owing to their ability to reduce morbidity and mortality from infectious diseases. However, resistance to existing drugs has proliferated rapidly, while at the same time, few new antibiotics have achieved regulatory approval. One reason for the current innovation deficit is the lower perceived commercial potential of antibiotics in comparison with drugs in other classes, such as therapies for cancer and heart disease. The federal government can promote antibiotic development through greater investment in basic science research, which has supported the development of many transformative drugs. In parallel, innovations in the way antibiotics are reimbursed can alleviate economic barriers to private investment in antibiotic development. Thus far, the latter—so-called “pull” mechanisms—have been the focus of most legislative policy-making.

In our article, we examine one way in which payment policies could be adapted to promote the development of innovative antibiotics—in particular, drugs designed to treat hospitalized patients who demonstrate high rates of infection with multidrug-resistant organisms.

Approval of medical devices for rare conditions

In the US, manufacturers of high risk devices must submit data to the Food and Drug Administration (FDA) to demonstrate safety and effectiveness before the devices can be approved for wide use. The humanitarian device exemption (HDE) was established by the Safe Medical Devices Act of 1990 to encourage device manufacturers to develop products for treating or diagnosing rare diseases. Under the exemption, manufacturers do not have to provide the high quality data on effectiveness that would normally be expected for high risk devices, but they must still prove that the device is safe and that the probable benefits outweigh the risks from its use and that of alternative forms of treatment.

Policymakers in the US and Europe continue to examine and update the regulation of medical devices. Current EU proposals to require manufacturers of high risk devices to submit a clinical investigation report and publish a summary are similar to the requirements for HDE devices in the US. However, the EU proposals apply to all high risk devices not just those for rare diseases. We examine the scientific and regulatory characteristics of devices approved under the humanitarian device exemption since its inception and consider the benefits and risks of this pathway.

(cite: Hwang TJ, Carpenter D, Kesselheim AS. Assessment of US pathway for approving medical devices for rare conditions. British Medical Journal (BMJ) 2014; 348: g217.)

Innovative drugs to treat pediatric diseases

The development of safe and effective pediatric drugs continues to fall short. The paucity of new therapies is particularly stark for rare diseases, which disproportionately affect children and collectively affect an estimated 25 million people in the United States and 30 million in Europe. This paper shines a light on a new federal incentive program for pediatric drug development that has, to date, attracted little attention but may have substantial implications for clinicians and patients.

(cite: Hwang TJ, Bourgeois FT. New regulatory paradigms for innovative drugs to treat pediatric diseases. JAMA Pediatrics 2014; 168(10): 879-880.)

Global financing for multidrug-resistant TB

The spread of drug-resistant strains of tuberculosis poses a grave threat to the global public health. A key barrier to global control of multidrug-resistant tuberculosis (MDRTB) is the high cost of treatment. There is precedent for strategies to correct market failures for a number of infectious diseases prevalent in low- and middle-income countries, but the application of these strategies to other disease contexts has not yet been defined. In this article, we assess changes in MDR-TB drug prices since 2001 and identify limitations in the current system. We then examine successful alternative approaches to reducing cost barriers to treatment for infectious diseases, using pneumococcal vaccine as a case study to inform the fight against the global TB pandemic. We argue that donor resources should be pooled to link market-oriented solutions to MDR-TB drug prices with targeted investments in health systems strengthening and innovative care delivery models.

(cite: Hwang TJ, Keshavjee S. Global financing and long-term technical assistance for multidrug-resistant tuberculosis: Scaling up access to treatment. PLOS Med 2014; 11(9): e1001738.)