The document discusses applying John Boyd's OODA (Observation, Orientation, Decision, Action) loop model to clinical drug research and safety. It describes how each step of the OODA loop - observation, orientation, decision, and action - applies to gathering and processing information during clinical trials and post-market drug surveillance. However, it notes multiple stakeholders and long timelines between investment and returns can disrupt timely and coordinated decision-making in this context. Real-time feedback is needed at each step to make the system effective.

1. PHARMARISKMANAGEMENTSERIES
BOYDCycleinDrugSafety
Arete-Zoe,LLC
21stJune2015

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BOYD cycle in clinical research and
drug safety
To make any system oriented toward desired outcome, systems approach
is necessary to make the feedback mechanism work. Boyd’s OODA loop is
an elegantly simple grand theory that offers high quality insight into
strategic essentials. OODA loop has extensive domain of applicability,
including clinical research and post-market drug surveillance.

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Introduction
Boyd cycle, or OODA loop, explains fundamental principles of decision-making loop
based on observation, orientation, decision, and action. Author of the concept, Col. John
Boyd, was a fighter pilot and author of designs of F-15 and F-16, who challenged Air
Force orthodoxy at the heart of the service’s very identity. In his 15-hour briefing
“Discourse of Winning and Losing” Col. Boyd challenged the theory how wars were to be
fought and won in the era after Vietnam. In Vietnam, the 10 to 1 kill ratio from the
Korean War came close to 1 to 1. Boyd’s theory redefined tactical air operations after
almost 20 years under bomber generals who grew on Curtis LeMay.

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The scenario described above shows some analogies with the current situation in the
clinical research and pharmaceutical industries. Only about 2 out of 10 marketed drugs
return revenues that match or exceed R&D costs. Whilst about 2/3 of clinical trials are
still conducted in the U.S., Western Europe, and Australia, globalization has led to
outsourcing and off-shoring critical operations overseas to decrease costs and reduce
liabilities. The industry found itself in a quagmire of ever increasing costs and low
returns.

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O-O-D-A Loop
OBSERVATION
OBSERVATION: known and observable FACTS (systematic
collection of information)
Outside information
Proper background research is essential to identify potential critical points, which
can trigger additional expenses necessary to overcome obstacles or lead to halt of a
trial. Critically important information must be “observable” and “detectable” in real
time to allow processing. Obscuring information in the collection phase disrupts the
OODA loop at the very beginning.
Unfolding circumstances
Efficacy and safety profile of a new drug, changing regulatory environment, but also
organizational culture affect information coming in.
 Feed observations forward for orientation.

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ORIENTATION: INFORMATION PROCESSING
Cultural traditions
Outsourcing and off-shoring brings different cultural traditions. The same information in
exactly the same context can be evaluated very differently depending on the person’s
educational, cultural and personal background. Risk-perception or communication of
project issues may be influenced by cultural traditions.
Genetic heritage
Nature and nurture affects our ability to detect and communicate potentially critical
safety problems before they become self-evident. Different types of intelligence play a
role – recognition of patterns, risk-assessment, as well as ability to communicate the
message to the leadership. Distribution of personality types in pharma industry shall
copy distribution in other high-risk industries to achieve similar results. In pharma,
however, teams are often built to avoid personality clashes and ensure smooth function
of office environment. System thinkers, who have the capacity to identify systemic
flaws, may find it difficult to thrive in such environment.
Previous experience
Education, training, personal values, and individual biases affect reasoning and
perception of risk. In medicine, evidence comes from very diverse sources: study
findings, observations by investigators, literature screening, colleagues and conference
participants, imaging technologies, medical records, and patient feedback. Each source
has its unique strengths, weaknesses, potential or actual biases, and vulnerability to
manipulation and deception. Systematic work with meaning of the collected
information is essential to its accurate assessment. Over-specialization and focus on
immediate goals obscure long-term consequences of such choices.
New information
Unexpected surprises can emerge at any stage of a clinical trial as well as after drug
approval. Boyd’s OODA loop was designed to present decision-making and behavior of a

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single individual, well-coordinated team, or an organization with defined structure that
behaves in a coordinated manner. Multiplicity of stakeholders within pharma may
negatively affect information flow due to their at times conflicting interests. The need
for accurate judgment is the same for a fighter pilot and for a pharmaceutical company.
The only difference is, that the first will face consequences of a bad decision very fast,
whilst the latter with long delay; the principle, however, remains the same. For sound
and timely decision-making, it is necessary to process information in a structured and
coherent manner. New information shall be passed to decision-makers along with
coherent and detailed analysis including confidence in such assessments and list of
assumptions.
Assumption is the Mother of All Debacles
Analysis & synthesis
Awareness and conscious examination of own biases and motivations facilitate self-
correction in scientific judgement. For example, some national regulators do not include
certain parts of the drug development process in their scrutiny: i.e. design of a trial, and
delegate certain tasks to the ethics committees instead. Without providing appropriate
oversight, or failure to detect reliably and consistently scientific fraud, the only focus is
on speed of key procedures. Where this happens, the regulators effectively resigned on
their role in the system.

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The process of ORIENTATION provides feedback back to
OBSERVATION to alter data collection methods in order to
provide the most relevant information for further processing.
More information does not necessarily mean better and more
accurate judgment. This applies to intelligence as well as
medicine. In horse racing selection of the right criteria and
omission of noise leads to accurate judgment and statistically
more successful prediction than indiscriminate assessment of
numerous factors without providing value to them. In drug
safety, a good example of inclusion of “noise” in assessments is
the screening of social networks rather than reliance on hard
data.
ORIENTATION LEADS TO DECISION
In clinical research, there is no structured way of documenting correctness of decisions.
At the highest levels, the most important indicator of correctness of a decision is return
on investment. The time lapse between preclinical phase, clinical phase, market
approval and launch and capitalization on the investments typically exceeds time an
average CEO spends in the office. Because of the long gap between initial investment,
and series of decisions that follow until the product enters the market, and
capitalization, there is very little incentive to make any unpopular decisions on a project
if the feedback (evaluation whether the decision was correct or not) is too far in the
future to have any impact on an individual. Hence, it is very easy to imagine how non-
existence of a real-time real-life feedback leads to fundamentally flawed decision-
making process by design. In biology, feedback mechanism matters only if the organism
can react in real-time. Postprandial insulin meaningfully decreases glucose levels if
released in bloodstream in minutes-hours, not if the feedback is delayed long enough to
become irrelevant.

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DECISION
Correctness of decision depends on accuracy and timing of information obtained, its
perceived importance, strength of the signal. Decision may lead to test of a hypothesis
or directly to action. Whilst it would make sense to halt a trial as early as possible should
the study prove non-viable, it does not always happen, and more resources are spent on
a project before it finally reaches a point when it has to be stopped. These delays are
caused by the fact that all critical activities of OODA loop are performed not by a single
well-coordinated entity but by numerous independent business units and individuals
with conflicting interests. Because the model is dynamic, new information comes in all
the time.
Decision-making centers need to adjust what information shall be gathered and how
this should be done. In drug safety, decisions on benefit:risk profile are made based on
data from clinical trials and post-market surveillance. Before a drug enters the market,
the total number of patients exposed to the drug is relatively small, the population is
well defined, and the incidence of adverse events can be established with relative ease.
Efficacy, unlike safety, is no longer actively monitored once the drug has been approved.
Post-market surveillance conducted via active reporting cannot provide reliable
information on trends, populations exposed, indications, and off-label use. Due to
disruption in observation part of the Boyd cycle, certain types of safety information
become functionally invisible after drug launch. This can be resolved by making links
between exposure to a substance and clinical outcome observable. To do that it would
be necessary to make analytical outputs from real-life use available in real-time in a
usable form.
ACTION
Action is relevant if it follows decision. If nobody acts on decision made in real time
the whole process of surveillance is fruitless and only documents activity (due
diligence) without having an actual impact. Functionality of a system must not fall
victim to observation of its outer attributes, which document “activities” without
substantive action.