Dec 04, 2013

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

In drug safety, pharmacovigilance, drug development and many other areas that we are involved in there are extensive discussions and even more extensive documents written to evaluate benefits and risks.  Most of us don’t think too much about the concept of risk itself from a more theoretical and conceptual point of view.    Let’s take a look at risk in this framework.  There is a large literature on risk in the medical, financial, psychiatric and philosophical worlds.  Here is an idiosyncratic review of risk.

What is risk?  To a degree the definition depends upon the context and the subject we are talking about.  There are several definitions of varying complexity.  Have a look at the Wikipedia article on “risk” for a broad overview.  For practical purposes good working definitions of risk in the pharma world could be:

  • Exposure to a chance of loss or damage
  • The quantitative or qualitative expression of possible loss that considers both the probability that a hazard will cause harm and the consequences of that event.
  • The probability of an undesirable outcome
  • The probability or likelihood of an adverse effect or event (e.g., injury, disease, or death) resulting from the actual use of a substance in the quantity and manner proposed.

Definitions of risk in the business world usually revolve around loss of money.  Although that plays a role of sorts in medical risk, it is health that is the primary variable at play.

There is an evolutionary view of risk.  Risk is a relic of earlier, more dangerous times when odds of survival were smaller.  Hunting, scavenging & food gathering forced man to take great risks.  Non risk- takers failed to survive and their genes were eliminated from the gene pool.

There is a psychoanalytic view of risk dating back to Freud and other workers in the area of the “mind”.  This view of risk in which the stress is on the constant of safety and basically says that “normal” don’t take risks when they don’t have to.  So when people do take risks, particularly unnecessary risks, this risk taking is evidence of a diseased mind.  There is no logical reason for people to take risks with their lives or other critical areas such as their health or their family’s finances.  Further some works felt that risk taking is evidence of suicidal tendencies.  Freud and others talked about the life instinct (“eros”) and the death drive (“thanatos”).  It is this death drive that pushes people to take great risks and perform risk acts which could be fatal.  So it was postulated that taking wild risks, thrill seeking and aggression were due to the death instinct. Many have disagreed and this view has fallen into disrepute.

There are various contemporary views of risk that some feel better explain why people do risk things.  Some say that personality and its traits are better able to explain people’s willingness to accept risk.  The psychologist Hans Eysenck developed a model of personality called P-E-N (psychoticism, extraversion and neuroticism) which produce impulsivity, sensation seeking and extreme risk taking.  Others point to extroversion vs introversion.  Some people are less sociable, more assertive and full of “energy” with less emotional stability; others point to neuroticism.  There are many theories of “risk” but some argue that these are merely descriptions of risk takers and not actually explaining why risks are taken. Others look for a chemical or physiologic basis for risk with testosterone being targeted as one of the culprits in high risk takers.  Others argue that there is a genetic component to risk and an environmentally determined risk component.  This latter would seem evident in times of war when soldiers do extremely brave (or, depending upon your point of view, foolhardy) acts to kill the enemy.

A contemporary theory (one of many) now holds that there is a “universal risk taking personality”.  These types of people are great risk takers and have a higher “sensation seeking” trait.  They are venturesome, inquisitive and eager for new and exciting experiences.  Men more than women and younger rather than older individuals tend to fall into this category.  Studies of identical twins suggest that sensation seeking may be as much as 60% genetically determined.

Work by Zuckerman has divided sensation seeking into four traits:

  • Thrill Seeking usually involving unconventional and dangerous outdoor sports and activities like skydiving.
  • Experience Seeking involving new sensory or mental sensations such as using mood altering drugs and chemicals. They want new and continued exciting situations.
  • Disinhibition.  This is a preference for “out of control” activities such as drinking and putting oneself in situations where inhibitions drop.  They are willing and happy to take social risks.
  • Boredom. Some people just get bored easily with situations or people and become restless.  They will make efforts to escape this predicament.  It is an intolerance for monotony.

These concepts are interesting and are explained in psychology texts but they do not explain everything.  Other personality traits play a role in risk taking.  Some risk takers underestimate the risks involved either through lack of objective information, denial or factors that impede judgment.  Sometimes there is simply a lack of opportunity to participate in risk taking.  Some people never sell out because no one ever made them an offer!  And some people are high risk takers in one area where the risk is clear and known (e.g. smoking cigarettes) but not in other areas where there are equally well known high risks (e.g. buying penny stocks or high-risk bonds).

Although interesting, all of these explanations of risk remain theoretical and highly debated.

A more interesting area that plays a role in drug safety is perception of risk rather than “true” risk.

A part of risk perception involves “heuristics” which are defined as sort of mental strategies or methods to make judgments and solve problems.  They are experienced based.  These may play a key role in how we think about, evaluate and quantitate risk:

  • The Availability Heuristic: Events that can be more easily brought to mind or imagined are judged to be more likely than events that could not easily be imagined.
  • The Anchoring Heuristic: People will use known information and then adjust it to create an estimate of an unknown risk but the adjustment may not always be correct.
  • Asymmetry between gains and losses: People are risk averse with respect to gains, preferring a sure thing over a gamble with a big payoff but with the possibility of getting nothing. On the other hand, people will take larger risks about losses (not carrying health insurance if young and healthy).
  • Threshold effects: People prefer to risk going from something to everything over making a similar gain in something to something more but not certainty.  For example, many people would choose a vaccine that reduces the incidence of disease A from 10% to 0% over one that reduces the incidence of disease B from 20% to 10%.

Others point to cognitive issues where people have greater interest and concern about immediate, short term risks than about long term future generation risks that won’t touch them much or at all.  Others feel that emotion, intelligence (the ability to understand what a/the risk is) and environmental factors play a key role.  Undoubtedly all of this plays some role.

So people perceive risks badly.  Some findings from studies in the psychology of risk perception:

  • People will accept risks 1,000 greater if they are voluntary (e.g. driving a car) than if they are involuntary (e.g. a nuclear disaster). Social Benefits versus Technological Risks. Chauncey Starr Science 1969:165, 1232–1238
  • More information will aid people to understand true risk and lessen their opinion of danger.  Mary Douglas. Acceptability According to the Social Sciences. Russell Sage Foundation, 1985.  (This seems obvious but…).

In fact, it has been shown in some studies that more information alone does not shift risk perception.  Why is this?  Several reasons:

  • Quantification of risk is approximate.  We don’t yet have adequate tools to quantitate risk in specific patient populations or specific patients.
  • It is based on past experience which is not always a predictor of the future.
  • People do not estimate risk well.
    • A table in the British Medical Journal (27:327(7417); 694-695, 2003) attempts to give quantitative estimates of risk in the UK including, for example:
      • Death by an accident at home   1 in 7100
      • Death by rail accident 1 in 500,000
      • Dying on the road in the UK during 50 years of driving 1 in 85
      • A Lou Harris/Harvard School of Public Health survey in 2004 reported that people’s estimate of developing breast or prostate cancer was 40% when the “true” risk was only 10% or having a stroke 45% when the true risk was under 20%.
      • Littlewoods’ Law of Miracles: Cambridge University Professor John Littlewood defines a miracle as an exceptional event of special significance occurring at a frequency of one in a million. He assumes that during the hours in which a human is awake and alert, a human will see or hear one “event” per second, which may be either exceptional or unexceptional. Additionally, Littlewood supposes that a human is alert for about eight hours per day.As a result a human will in 35 days have experienced under these suppositions about one million events. Accepting this definition of a miracle, one can expect to observe one miraculous event for every 35 days’ time, on average – and therefore, according to this reasoning, seemingly miraculous events are actually commonplace. (From Wikipedia https://en.wikipedia.org/wiki/Littlewood%27s_law)

OK.  So what does this have to do with drug safety?  Well the answer lies in how people perceive risk.  This perception, or misperceptions, accounts for how people decide whether to take a drug (the risk of adverse events), sign an informed consent (the risk of the surgery or procedure) and whether to report a spontaneous SAE (the risk the SAE is due to the drug).  As psychology has shown, people do not perceive risk well.  They will incorrectly attribute or fail to attribute some adverse events to the drug.  This leads to preconceived and often erroneous notions:

  • “I’d never put a poison in my body.”
  • “All drugs give me side effects, I know.”
  • “The FDA knows about this AE already.  I don’t have to report it.”
  • “I can’t be 100% sure the drug caused this AE.  I won’t report it till I’m sure.”
  • “Only big studies can really pick up side effects.”

So what this seems to show is that drug safety is made very complex by the psychological assumptions, biases, notions, perceptions and misperceptions that health care personnel, patients, regulators and all other human beings involved in drug safety have.  We have a tough job!

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