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Lessons from TMILessons from big industrial accidents and their relevance for the Pharma industry

ARETE-ZOE, LLC

Registered address: 1334 E Chandler Blvd 5A-19, Phoenix 85048 AZ, USASolutions to complex problems in the high stakes and high consequence environment of Global Pharmaceuticals, including clinical research, healthcare informatics, and public health.Weblendestablished, Pharma sector methodologies, innovation, and adaptations/transfers from other sectors to identify and resolve consequential practices that pose risk and often result in avoidable patient casualty. Three Mile Island, PA, USA (1979)

ReactorCadmium rodsSteam generatorCooling circuit

TurbinesSteam pipes

03:58 AM, March 28, 1979Routine repair of clogged filterTrace of water left inside air circuit

Alarms went off causing confusion in the operating room

Computers interpreted water in air system as dangerous invader and shut down the pumps in cooling circuit

Steam generator Nuclear reactorPumps in cooling circuit shut downWhy: Misinterpreted information from the air circuitConsequence: Cooling system disabled, reactor heating uphttp://www.nrc.gov/reading-rm/doc-collections/fact-sheets/3mile-isle.html#animated10

Operators faced situation they were not trained for and was not covered by their procedures

Pressure is building up in primary cooling system within the reactor

Computer ordered cadmium rods to plunge into the reactor and stopped chain reaction

Pressure and heat within the reactor continues to build

Pressure operator relief valve (P.O.R.V.) opened to vent the pressure and failed to reclose

Indicator incorrectly shows that the valve has now reclosedDesign: Indicator correctly shows that the control order has been sent, not obeyedSurrogate endpointIn clinical trials, a surrogate endpoint (or marker) is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship.

DiseaseSurrogate endpointTrue clinical endpointIntervention

Valve open, reactor coolant leaking out without anyones knowledge

Stuck valve undetectedWhy: Misinterpreted information from indicatorsConsequence: cooling system disabled, reactor heating up

Communication failure Single phone line in the operating roomKey people unable to get through1

Overheated reactor Incorrect readings from instruments Volume of coolant measured indirectly Decision: to turn off reactor pumps Incorrect conclusions Loss of trust in the instrumentsSystem did not behave as expected OBSERVEORIENTDECIDE

TrainingDecisions based on incorrect, misleading or no information

7:15 AM stuck valve finally discovered Pumps were finally restarted Reactor still overheating Misleading temperature readings Why: Instruments not designed for temperatures this high

Radiation in operating room Mounting pressure

8:33 AM General emergencyMisleading and deceptive information provided to the public by the companyMinimum information provided to state administration and regulatorsPartial evacuation within 5 mile radiusFreedom of speech, anyone? U.S. v. Caronia Amarin v. FDA

Not an issue during TMI Real concern now in off-label promotion (Must be truthful)

Reactor cracked Sample of contaminated coolant

Basement full of contaminated waterRadioactive gas was eventually released into the atmosphere

Oh, BTW, it can blow up because of accumulated hydrogenFierce dispute within the NRC whether this can happen or notThis risk did not materialize. Partial reactor meltdown did not result in any additional release of radiation. Complex combination of minor equipment failures and major inappropriate human actions

Risk = Probability x Consequence 1973 oil crisis Cheap power needed Political topic Govt subsidies

Probability assessment flawed

That cant happen here mindsetRoot cause: Human factors Combination of lesser eventsMisjudged probabilityMisinformation Confusion Inadequate training Inappropriate human responseOrdinary mistakes in high stakes environment Probability Consequence XXX????The need for change RECOMMENDATIONSFundamental changes inOrganizational procedures and practices The attitude of regulatorsOperator training, updates Emergency response and planning

Organization failed to learn from previous failuresThe need for change RECOMMENDATIONSMore attention to human factorsCombination of lesser events (slower to develop, more likely)Training, fitness for dutyOrganizational structureCommunication

Focus on equipment safety and large break accidentsCompliance v. Safety culture It is the responsibility of the NRC to issue regulations to assure the safety of nuclear power plants. However, regulations alone cannot assure safety. Once regulations become as voluminous and complex as those now in place, they can serve as a negative factor in nuclear safety. The complexity requires immense efforts to assure compliance. Requirement v. ConsequenceThe satisfaction of regulatory requirements is equated with safety. Focus on compliance with regulations instead of intrinsic system safetyInspection manual voluminous and complex unclear to many inspectorsEnforcement actions limited/unusedReliance on industry own data No systematic evaluation of patternsUnclear Roles & Responsibilities

The role of regulators

NRC has erred on the side of the industry's convenience rather than its primary mission of assuring safety

The role of regulatorsHUMAN FACTORSFiduciary responsibilities of public servants

Worst problem: Loss of public trust

Misinformation Deception Misunderstanding Fear & Confusion Outcome Transformation of the industry Major regulatory reform

Chernobyl, Ukraine, USSR (1986)

Orders received to carry out tests to find out how much energy can be saved during routine maintenance shut down. Numerous safety mechanisms had to be turned off to make this test possible

Power levels lowered to perform testsEmergency core cooling system shut offOperator failed to program computer to prevent power from dropping below minimum safe level Automatic scram devices an alarms switched offControl rods withdrawn too far to reinsert quickly= Bad idea = Very bad idea http://hyperphysics.phy-astr.gsu.edu/hbase/nucene/cherno2.html#c1

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Chernobyl nuclear plant, unit 4 April 26, 1986

5 AM1:23 AMhttps://www.youtube.com/watch?v=mCGM_PTHzCE 41

Study into systemic factorsSystemic factorsLong record of sometimes fatal accidents ACCIDENT WAITING TO HAPPENNational 5-year production goals oblivious to realityTraining often suspect and shoddyLax observance of rules and regulations Causes of disasterIrresponsibility Negligence Indiscipline Flawed performance metrics HUMAN FACTORSOutcome Sweeping changes in Soviet society

Disintegration of the Empire due to loss of credibility

Volkswagen, Germany (2015)

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Martin Winterkorn, CEO of Volkswagen, AGacknowledged that 11 million vehicles were equipped with diesel engines with defeat devices to cheat pollution tests

http://www.volkswagenag.com/content/vwcorp/content/en/investor_relations/share.html47

And spreading

Criminal probe underway Root cause Cause entirely internal

Flawed performance metrics

VW very sensitive to its own image Internal pressures to improve metrics caused someone to manipulate the system in a manner that amounted to conspiracyLessons learned?

Behavior of organizations follows the same principles regardless industry Common attributes Formally regulated industriesHigh-stakes, high consequence environment Information flow within organization Communication with stakeholders Public trust essential TMIVWChernobylAccident caused by systemic factors impacts the whole industry Common root cause? Requirement v. ConsequenceIndividual and collective accountability Poor leadership Flawed performance metrics Failure to learn from previous errorsCommunication with stakeholders / public Regulatory responseDelivery/enforcement of regulationTMIVWChernobylHUMAN FACTORSRegulators and elected officials Subject to the same human frailtiesOblivious to ambiguityRequirement v. Consequence Public trust essential TMIVWChernobylHUMAN FACTORS54HUMAN FACTORSExperience, training, education CapabilitiesDemographicsFrailtiesValuesOrganizational cultureReporting structureLeadership ENVIRONMENT

EthicalWhat is risk?Probability of detrimental consequenceRiskVulnerability in processProbabilityThreatCapabilityIntent / AbilityDetrimental consequenceAccidentalMaliciousQualifying consequence Safety signal: It takes significant number of casualties with attributed causal relationship to produce a signal Statistically significant cause attributed to a drugPatient injury Qualifying consequenceAttributionDispensing error / incorrect substitution) Non-compliance with treatment Self-medication (OTC, Rx, illicit)Atypical manifestation of disease Misdiagnosis Prescribing error Wrong dose (predictable, unpredictable) Individual variability in response Misleading information on drugDrug interactions (known, unknown)Off-label use (appropriate, inappropriate)Counterfeit medicationsLimitation of science Honest mistake Omission Commission Deception False Claim

PATIENT INJURYAdverse outcome: Consequences

PatientClinician Pharmacist Regulator Drug manufacturer Healthcare facility Insurer Elected officials Individual PopulationCOMMON CONSEQUENCEThe only way how to change behavior of organizations isto create Detection of vulnerabilititesProbability of detrimental consequence RiskVulnerability in process Probability Threat CapabilityIntent / ability Detrimental ConsequenceAccidental Malicious Quality risk management Record of past events (EV, FAERS)FTA, FMEA, FMECAHAZOP, HACCP, PHASystems modeling Identify VulnerabilitiesImpose safety ConstraintsEnforce these constraintsBy DesignBy Operations

Risk assessment ICH Q9ICH E2EDefine Accountability for control of vulnerabilities and acting upon them (R&R)Enable decision-makersSystems theoretic accident process and modeling (STAMP)Imposing constraints on a system whilst ensuring enforceability of these constraints by design and operations Human supervisor(Controller)

Model of processModel of automationAutomated Controller

Model of processModel of interfacesControlled processSensorDisplaysControlsProcess inputsDisturbancesProcess outputsActuatorsControlled variablesMeasurable variablesSystem modelsSimplified models of complex environmentTools to enable decision-makersReduce ambiguity and uncertainty Accountability for acting upon vulnerabilitiesLimit liability HUMAN FACTORSTools do not substitute good leadership PUBLIC TRUST

Training Correct input accurate and timely orientation

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