U.S. Food and Drug Administration: Review for the Emergency Physician of Approval Process and Limitations.

Emergency physicians (EP) frequently are exposed to promotion for drugs and devices through professional organizations and meetings, journals, and direct-to-consumer pharmaceutical advertising (DTCPA). To provide optimum patient care through evidence-based medicine, it is critical to be aware of the processes that regulate these drugs. Though it is uncommon for ED patients to request specific drugs or treatments for emergency conditions, it is not uncommon for patients taking newly marketed drugs with unfamiliar mechanisms of action and side effects to present to the ED. The U.S. Food and Drug Administration (FDA) rate of approval of new drugs is increasing moderately, from 22 in 2006, to 45 in 2015.1 This requires the prudent EP to query drug databases for interactions with standard ED treatments, or run the risk of new interactions. Furthermore, nonspecific symptoms may be side effects of new medications, with which the practicing EP is unfamiliar. The FDA is responsible for strictly regulating the safety and effectiveness of drugs produced by the pharmaceutical industry. The FDA has experienced increasing pressure to fulfill this regulatory role despite the increasing pace of development of medical devices and medications2 and a budget that is a fraction of other government agencies. For example, the FDA has only 1.8% of the U.S. Department of Agriculture’s budget.3,4 This balancing of public health protection and efficiency led Congress to pass the Prescription Drug User Fee Act (PDUFA)5 that enabled direct pharmaceutical company subsidization of the FDA review process. The regulatory agency is partially funded by the companies it is charged with regulating. In addition, although the FDA relies on congressional oversight to safeguard 25% of products and services consumed in the U.S.,6 robust lobbying influences regulation of these products, which enhances pharmaceutical industry profits.7 Despite precautions taken by the FDA, limited funding and external pressure to expedite approval of advanced medical therapies has led to compromises in drug safety. Properly prescribed drugs result in over 100,000 deaths annually, with prescription drugs among the top 10 causes of death, more than each of lung disease, diabetes, AIDS or automobile fatalities.8 In 2012 there were approximately 4.2 billion prescriptions written, worth some $326 billion dollars.9 Almost 7% of hospitalized patients have a serious adverse drug reaction with a fatality rate of 0.32%.10 This paper reviews the FDA’s position in government, limitation of powers and relations with the pharmaceutical industry. These factors have broad influence on the population of patients seeking care in ED. Center for Drug Evaluation and Research and Marketing The Center for Drug Evaluation and Research (CDER) is the branch of the FDA concerned with the review of over-the-counter and prescription drugs.11 CDER’s main objective is to evaluate new drugs before they are sold, and provide doctors and patients with information needed to use the medicines wisely. The FDA does not develop, test or manufacture drugs, but instead reviews full reports of clinical studies to determine benefit-to-risk relationship and approval.12 Although known as the “consumer watchdog,” concerns of drug safety and timeliness of the FDA review highlight challenges with the current system. This includes an underdeveloped Adverse Effect Reporting System, which is meant to continue surveillance and study of drugs after release in the market, as well as poor enforcement of direct-to-consumer advertising constraints. 12 Title 21 of the Code of Federal Regulations (CFR) is reserved for the FDA and outlines rules published in the Federal Register by executive departments and federal government agencies related to DTCPA.13 The need for improved surveillance and study of drugs after approval can be seen with the recent safety labeling changes for fluoroquinolones announced by the FDA in May 2016, when it was reported that the “side effects associated with fluoroquinolones generally outweigh the benefits for patients.” The drug is linked to “disabling and potentially permanent side effects” involving the musculoskeletal and central nervous systems, peripheral neuropathy and cardiovascular complications. Despite these risks and because of challenges associated with post-marketing surveillance, companies such as Bayer, the creator of ciprofloxacin (a type of fluoroquinolone), is still profiting from sales of this drug.14,15 DTCPA started in 1981. The U.S. and New Zealand are the only countries that allow these advertisements to include product claims.16 DTCPA funding from pharmaceutical companies expanded from $791 million in 1996 to $5.4 billion in 2006. The average American television viewer sees nine drug advertisements daily, which equates to about 16 hours per year. This far exceeds the time spent with a primary care physician.17 The FDA requires DTCPA to be “fairly balanced” with respect to benefits and risks, to only discuss FDA-approved indications and to explain all possible negative health outcomes whenever the name of the drug is included in the advertisement.18 When the FDA believes that an advertisement is misleading, it sends a regulatory letter to the pharmaceutical company. However, since 2002 the FDA has been required to send a draft of the letter to the Department of Health and Human Services for legal review. This substantially increases the time between identifying a violation and notifying the pharmaceutical company. Therefore, many of these letters arrive after the advertisements have already finished airing.19 In 2009 59 federal employees were responsible for reviewing 71,759 industry submissions of both DTCPA (radio, television, print, Internet, billboards and direct mailings) and direct-to-physician (DTP) promotional material (detailing brochures that pharmaceutical representatives share with office physicians). As explained above, the FDA can issue a notice of violation through a warning letter when a company violates DTCPA laws. Additionally, it could seek criminal prosecution for repeated violations. However, there are no such known cases.17 In November 2015, the American Medical Association (AMA) proposed a ban on DTCPA due to the negative effects on public health and need for transparency on drug pricing. This reflects DTCPA’s role in raising demand for costly drugs despite debate regarding clinical effectiveness in many patients.16 However, the DTCPA ban proposed by the AMA is unlikely to be implemented because of the profits gained from off-label use of drugs. For example, Pfizer paid $430 million to settle a claim for fraudulent promotion of the anti-seizure medication Neurontin (gabapentin) when the drug was advertised for non-FDA approved uses such as treatment for neuropathic pain, attention-deficit hyperactivity disorder and as an analgesic for migraine headaches, among others. At the same time, the company made approximately $2.7 billion in sales in a single year, with 90% of the profit from unapproved uses of the drug.20 These unapproved uses highlight the consequences of delayed or lax enforcement. Despite concerns regarding DTCPA, there are studies suggesting that such advertising can be beneficial to patients. There is evidence that DTCPA is a motivating factor for patients to express health concerns to their physician, improve awareness of medical conditions and adhere to prescribed treatments.21 A telephone survey of 3,000 adults found that 35% discussed a DTCPA with their physician and 25% of those visits resulted in a new diagnosis.22 These findings should be taken into consideration when discussing possible amendments to DTCPA as a promotional tool. DTCPA drives ED visits and can increase costs, as seen with asthma medications Advair, Asmanex, Singulair and Symbicort,23 but has also been shown to improve care specifically in Medicaid-enrolled pediatric patients with asthma.24 However, other studies suggest that there are no resulting health benefits from DTCPA.25 Low-income patients may be particularly influenced by DTCPA.26 As EPs care for a disproportionate share of disadvantaged patients, they need to be aware of the influence of the FDA drug approval process.