The Evolution of Drug Safety Save

Does the efficacy of a new drug or its safety attract more interest? Seems these go hand-in-hand in decision-making. However, safety is one of the greatest impediments to use of any therapeutic agent. How we adopt and use newer agents is dependent on their time in the marketplace, the number of available options (the competition), the safety and the cost or access to the new drug. 

The number of treatment options in rheumatology has grown steadily in the last 30 years. A concern over safety is a prime limitation for new drug initiation by physicians, acceptance by patients and payment by those to fund healthcare. The daily practice of rheumatology is driven by efforts to promote and maintain the safety of the treatments we employ.

The efficacy of a drug is easily known at the time of FDA approval.  Interestingly, there is little differentiation between the reported efficacy of newer drugs (e.g., the Keystone 60-40-20 performance), owing to similar trial designs or a ceiling effect imposed by the ACR20 response criteria. 

Similarly, the safety profiles of many newer agents are largely similar – again linked to either trial design or the targeting of immune hyperactivity.  The warnings regarding common (e.g., URI, sinusitis, GI complaints) and rare (e.g., lymphoma, cancer, serious or opportunistic infections) adverse events are remarkably similar.  However, the full spectrum of a drug's safety profile begins with drug development and approval, but may take years to fully establish.

Ultimately, the distinctions between new and competing drugs are based on their approved indicationsm how they are administered, and,oddly enough, the rarest of safety events -- often 1 per 1000 or less (e.g., cancer, rare infections, bowel perforations, etc.). We are often forced to deselect our treatment options based on safety or comorbidity concerns. As most patients have at least one comorbidity (e.g., diabetes, hypertension, obesity, COPD), these may factor into what can or cannot be prescribed. For instance, a patient with hypertension and renal insufficiency would not be a candidate to receive leflunomide or cyclosporine, but may be well suited to receive a biologic agent. Hence, the rheumatologist must be vigilant and invest significant time to understand safety and minimize the risks of the therapies we employ.

Our enthusiasm for treatment advances is often trumped by concerns whether any agent “is truly safe”. Our mentors in medicine teach us to either let others play with new drugs until we know they are safe or that we should avoid therapeutic adventurism and marketing measures to use the "latest and greatest" in drug therapy (1). 

When a new agent or biologic is introduced and FDA approved, it comes with numerous large controlled studies performed on thousands of patients, revealing significant clinical, and possibly radiographic, benefits. Yet, the uptake of these agents by prescribers was predictably slow. This change delay has been shown in many medical disciplines. For example, despite evidence favoring the cardioprotective effects of beta-blockers, lipid-lowering agents  and low dose aspirin, the uptake of these in routine practice was also been disappointedly slow (2).  The upward slope to comfort and use is often delayed by both safety concerns and a lack of drug experience. 

Education and drug sampling are commonly employed tools designed to change the “tipping point” that alters the view or favor of a new drug.  Yet, true drug safety is defined by time and numbers of patients exposed.  First, because clinical trial patients are not the same as what Dr. Artie Kavanaugh calls “free range” patients. Second, because the defining safety features of a new drug are rare and require more than 100,000 patient-years of drug exposure to be reasonably certain.

Lastly, patients are also reluctant to change, when faced with overt disease activity and functional impairment.  While rheumatologists are more afraid of RA than the drugs, our patients are more afraid of drugs than RA. Wolfe and colleagues showed that many patients prefer “the devil you know” (their current therapy or dysfunction) "than the devil you don’t" (3). Hence the discrepancy between the patient's aversion to treatment change, even in the face of high disease activity measures, is attributed to loss of disease control,fear of side effects and the ambiguity of change. 

Seth Godin has written that “humans are quite bad at dealing with ambiguity, and even worse when there's money on the table.”  This phenomenon is encompassed by the Ellsberg paradox, named after Daniel Ellsberg the Vietnam War activist. This particular view of decision making suggests that ambiguity aversion drives decision making. Like the views of Wolfe, the Ellsberg paradox states people are more likely to choose based on what they know (specific odds preferred, even if low) and avoid what they don’t understand; even if the ambiguous or poorly understood option guarantees a better outcome (e.g., remission, return to work and play, etc.).

If fear (or risk aversion) is the foundation of safety concerns, then time, experience and study can remediate safety concerns. Change is conditionally dependent on the evolution of long-term safety data. It may take 10 years and over a billion US dollars to bring a new drug to market in the USA.  Hence safety doesn’t come cheaply, quickly or easily. As a condition of regulatory approval pharmaceutical manufacturers are heavily invested in the study of safety - pharmacovigilance. Pharmacovigilance is a commitment to identifying, assessing, understanding, minimizing and avoiding adverse effects and drug-related problems. Global pharmacovigilance spending was nearly $12 billion USD in 2010.  This begins during drug development (phase II and III trials) and is complemented by long-term trials, post-marketing trials, widespread clinical use, medical reports of safety and efficacy and population or registry based observational studies. Indeed, it is the frequent and pervasive focus on safety by many stakeholders that will establish the true safety and utility of a new agent.

The FDA is charged with ensuring the public health by ascertaining safety, efficacy and security of human and veterinary drugs, biological products, medical devices and other treatments and consumables. The FDA has evolved its focus on drug safety, especially with regard to product labeling clarity (boxed warnings, contraindications, warnings), post-marketing commitments by manufacturers (Risk Evaluation and Mitigation Strategies or REMS) and new initiatives designed to electronically gather more real-time information on drug safety at the time of approval (Sentinel Initiative).

Weighing safety against efficacy can be a complex task that may get easier with time. Therapeutic decision-making must be evidence-based, judicious and appropriate for the patient and situation. Understanding drug safety is paramount to ensuring both success of therapy and benefit to the patient. Similarly, it is important to not underestimate the impact of uncontrolled disease activity in decision making (5). The use of both conventional and novel therapies mandates an understanding of the mechanisms of action, unique toxicities, screening and monitoring measures and rules for drug avoidance. 

Future research will hopefully bring us closer to personalized medicine wherein biomarkers or genomic profiles can help us to individualize therapy while minimizing their hazardous or untoward effects. 

References

1. Schiff GD, Galanter WL, Duhig J, et al. Principles of Conservative Prescribing, Arch Intern Med. 2011;171(16):1433-1440

2. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA.  Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010 Jul 28;304(4):411-8

3. Wolfe F, Michaud K.  Resistance of rheumatoid arthritis patients to changing therapy: discordance between disease activity and patients' treatment choices. Arthritis Rheum. 2007 Jul;56(7):2135-42.

4. Moore TJ, Singh S, Furberg CD. The FDA and new safety warnings. Arch Intern Med. 2012 Jan 9;172(1):78-80.

5. Pincus T, Kavanaugh A, Sokka T.Benefit/risk of therapies for rheumatoid arthritis: underestimation of the "side effects" or risks of RA leads to underestimation of the benefit/risk of therapies. Clin Exp Rheumatol. 2004 Sep-Oct;22(5 Suppl 35):S2-11.