Medication Safety: Improving Public Health

“medication errors now occur frequently in hospitals, yet many hospitals are not
making use of known system for improving safety”

Medication are an integral part of modern life. Approximately one-half of all

Americans are taking a prescription medicine. Among persons 65 years older, 88%
are using at least one medication and 52% are taking three or more. When both
prescription and non-prescription medications and dietary supplements are
included, more than 82% of adults take at least one of these products and 29% take
five or more. The practice of prescribing multiple medication, or polypharmacy, is
increasing. From 2000 to 2006, the number of people who reported taking five or
more prescription medications weekly. The frequency with which medications are
mentioned (provided, or recommended) at physician office visits is on the rise as
well (figure 6-1).
Medications can save lives, improve the lives of people living with incurable
conditions, and in some cases prevent disease. However, medications can also cause
harm. Annually, an estimated 701,547 Americans are treated in emergency
departments for the adverse effects of drug treatment. Adverse drug events
reported to the Food and Drug Administration (FDA) have been steadily increasing
over the past decade (Figure 6-2), amid safety concerns with widely used medicines.
In the FDA’s Adverse Event Reporting System (AERS) database, the number of events
that resulted in death increased 2.7-fold from 1998 to 2005.

Adverse Drug Events

Any medication can cause an adverse event. Some adverse events may occur
because of a drug’s pharmacology (e.g., an overdose of insulin can cause
dangerously low blood glucose levels that can lead to diabetic coma and death if
untreated). Such adverse events can be predicted by the therapeutic threshold of
the agent. Drugs that have a narrow therapeutic range-that is, the dose needed for a
therapeutic effect is close to the dose at which toxicities are seen-would expected to
have higher rates of adverse events than drugs that have wider margins between
therapeutic dosing and overdosing. Second only to insulin in the number of
emergency room visits for adverse drug events is warfarin. Warfarin dose
determination is particularly difficult because of the drug's narrow therapeutic range
and considerable individual variability in metabolism. In 2007, the FDA approved the
first genetic test to identity patients with variations in two genes (CYP2C9 and
VKORCI) that alter warfarin metabolism.

Not all adverse events are predictable. Serious idiosyncratic adverse events
linked to medications include the rare skin reaction Stevens-Johnson syndrome,
certain cardiac arrhythmias (e.g., torsades de pointes), blood dyscrasias, and
anaphylaxis. The more rare such an event is in the general population (without
treatment), the more readily it may be linked to a drug exposure. Events are more
difficult to link to a drug if they occur in patients receiving drug therapy to reduce
their risk of just such an event; an example is increases in myocardial infarction or
stroke in patients with hypertension or diabetes who are receiving a drug to reduce
their risk of cardiovascular events.

The identification and study of adverse drug events falls within the field of
pharmacoepidemiology, defined as the study of the use and effects of medical
products (drugs, biological products, and medical devices) in human populations.
While the field of epidemic ology involves the study of exposures or risk factors,
several things differentiate pharmacoepidemioiogy as a unique field. First, medical
products are regulated by government entities (e.g., the FDA) and approved for a
particular use or indication. Second, exposures to medical products are made
consciously, for the treatment of a known medical condition or to prevent or delay
the occurrence of a disease. The regulated nature of pharmaceutical products
affects the type and timing of studies-and often the study’s funding source and
perspective as well. The nonrandom nature of treatment decisions introduces bias
into studies, drives many decisions about research design, and ultimately influences
the interpretation of study results.

Drug Safety in the Product Life Cycle

A drug must clear many hurdles before it can be marketed in the United States.
Drugs undergo extensive testing in vitro and in vivo prior to FDA approval. The study
data are pro- vided to the FDA in the form of a new drug application (NDA), which is
assigned to a review division according to the intended indication or the drug type.
After a major reorganization in 2005, the FDA Office of New Drugs has 17 review
divisions.
 Scientists and clinicians with expertise in the therapeutic area are assembled
into a team to review an NDA. These review teams are often led by a medical or
clinical officer but may be led by a pharmacist; typically, they include a
pharmacologist, a chemist, a statistician, a clinical pharmacologist with
biopharmaceutical expertise, a consumer safety officer and project manager, and
microbiologists. Other specialists such as drug safety evaluators may be
represented. The review team conducts a formal review of the NDA and writes a
summary report upon which the final approval decision is based. All review divisions
within the Office of New Drugs also have drug safety project managers and safety
directors, and they may have scientists or medical officers with epidemiological
expertise. With additional training and professional experience, pharmacists are well
suited to fill many of these roles. Epidemiologists from the Office of Surveillance and
Epidemiology (formerly known as the Office of Drug Safety) are available for
consultation to all review divisions.

The median FDA review time for NDAS approved in 2004 was I1.9 months for
standard reviews (n 90) and 6.0 months for priority reviews (n 29). This is a
considerable drop from 1993, when median review times were 20.8 (n- 51) and 16.3
(n= 19) months for standard and priority NDAS, respectively.

Limitations of Clinical Trial Data

The evaluation of a therapeutic effect is based on the clinical trial data. Clinical trials
are designed to maximize the ability to detect variations in the clinical outcome or
efficacy end- point, so that endpoint is well documented and validated. These trials
also provide the bulk of the clinical safety data, although safety endpoints are
generally identified post hoc. Because they are identified post hoc, well after the
clinical data were collected, safety end- points are not collected and validated in the
same rigorous manner as efficacy endpoints. Three major problems that arise from
this post hoc perspective are that (1) events presumed to be part of the disease
process may not be recorded as adverse events, (2) case descriptions in the
narrative summary may be limited and lacking in critical markers such as laboratory
and pathology results, and (3) coding events using preferred terms from the Medical
Dictionary for Regulatory Activity (MedDRA) may obscure information because of
the level of detail.
 The total number of patients exposed to the drug under evaluation and the
duration of exposure directly affect the number and type of adverse events that will
be accumulated (Table 6-1). This in turn will determine the statistical power of any
post hoc analyses com- paring the rates of adverse events in exposed patients with
control or comparator patients. Common adverse events can be identified in
numbers that are adequate to compare frequencies and potentially to identify major
risk factors. However, there may not be enough power to conduct valid statistical
analyses beyond a comparison of frequencies among those exposed and unexposed.

As defined in the International Conference on Harmonisation of Technical

Requirements of Registration of Pharmaceuticals for Human Use (ICH) Guideline on
Clinical Safety Data Management, a serious adverse event (experience) or reaction is
any untoward medical occurrence that at any dose results in death, is life-
threatening, requires inpatient hospitalization or prolongation of existing
hospitalization, results in persistent or significant disability or incapacity, or is a
congenital anomaly or birth defect. These serious adverse events are summarized in
the NDA using graphs and tables, listings of individual patient data, and, for
important events, individual patient narratives. Few drugs, except those for treating
high-mortality conditions, would be approvable with serious adverse events that
occurred frequently in clinical testing. Therefore, serious adverse events associated
with approved drugs occur with low frequency.

Increasing the size of the clinical safety database would not rectify many of
the sample- size-related issues (Table 6-2). Increasing the number of rare events
would require exponential increases in sample size. Such large trials would be
prohibitive in terms of cost, length, and the ability to recruit patients, with only
small gains in terms of characterizing rare adverse events. However, it can take
years to develop a comprehensive medication risk profile through reliance on
postmarketing studies, particularly passive surveillance of adverse events. The best
solution is to collect coplete aid accurate safety data and to use evaluation
techniques that maximize their predictive value.

While the approval decision is often couched in terms of weighing a drug's

benefits against its risks, or calculating a risk-to-benefit ratio, the decision-making
process is not a mathematical exercise. There are no currently accepted methods of
quantifying risks or benefits, or weighing them for the purpose of comparison. The
risk-to-benefit ratio is a qualitative judgment made by experts on the basis of
available data.

Evaluating Risk and Benefit

The regulatory decision to approve a drug requires that the benefits of the drug
outweigh its inherent risks (i.e., a favorable risk-benefit ratio). Although referring to
a ratio implies a quantitative comparison of benefits and risks, in practice the
weighing of benefits and risks is qualitative and subjective. Benefits are assessed in
terms of the impact of the agent on the disease process for the intended indication
(labeled indication) and patient population. Risks are considered in terms of the
probability and severity of adverse effects. The risk-benefit ratio for an agent is
considered in the context of available alternative treatments, the extent to which
known risks can he minimized and benefits maximized, and the remaining
uncertainties.

The evaluation of risks and benefits is limited by the available data. In risk
assessment. a lack of information limits the ability to estimate event rates, compare
them across treatment groups, and evaluate causality. Safety signals may appear in
clinical trials, but the number of adverse events occurring in these trials often is too
small for statistical analysis. However, safety signals from clinical trials should not be
summarily dismissed because of this limitation.

Benefit data are also limited by what is missing. Information on important

subgroups of patients (e.g., those with severe disease, multiple comorbidities) may
be lacking; the number of patients exposed to any one dose may be small; the
duration of exposure may be limited alternative treatments may not be considered
(i.e., head-to-head trials); and surrogate outcomes may be used.

Risk assessment is not unique to pharmaceutical products, and the FDA is

one of many federal agencies involved in risk assessment. The National Research
Council under contract to the FDA conducted a study of risk assessment in the
federal government. The study looked at the interplay of science and policy in the
context of evaluating the risk of cancer and other adverse effects associated with
human exposure to potentially toxic chemicals. The final report, published in 1983,
differentiates between risk assessment and risk management, with risk assessment
defined as the characterization of adverse health effects, including the uncertainties,
and risk management as the process of evaluating and selecting among potential
regulatory actions.

Risk assessment is divided into four components: hazard identification, dose-

response assessment, exposure assessment, and risk characterization. While many
of the examples in the report are of environmental exposures, much of the
information is applicable to drug risk assessment. As noted, a primary limiting factor
in risk assessment is missing information. Other limitations include the lack of
quantitative data and the absence of accepted methods of modeling risks and
weighing benefits versus risks.