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What we need to know for clinical drug safety

IntroducingNewDrugsIsAwkward|Unknown factorsKnown factors

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Therapeutics

Benefit Harm

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Harm is hard to detect

• Look at a group and see no event:

• What is the true rate?

n = 300

The 3/n rule

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95% confidence interval

LCL = 0 – you never see the event…

UCL = 3:300 = 1:100

you missed three events

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Pre-marketing studies

• Trial: 1500 – 3000 on active treatment

• So could miss fatal ADR rate of 1:500 –1:1000

• Could be very important for drugs used for prophylaxis or symptoms

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SO

DrugsAreSometimesHarmful

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What do we need to know about an identified ADR?

Dose TimingSusceptibility factors

Aronson & Ferner 2003

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DoTS 1. Dosage

HypersusceptibilityLog dose

response

Collateral

Toxic effect

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DoTS 1. Dosage

Hypersusceptibility Collateral Toxic effect

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DoTS 2: Time

intermediate

time

treatment

early

first dose

rapid late delayed

unrelated

treatment

withdraw

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Time dependence summarized

time

early

first dose

rapid

first dose

intermediate

intermediate

latelate

delayedwithdraw

delayed

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DoTS 3: Susceptibility

Sources of susceptibilityGeneticAgeSexPhysiology alteredExogenous factorsDisease

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DoTS 3: SusceptibilityThe young The elderly

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How this helps

1. Is there a susceptible subgroup?• E.g. digoxin in patients with renal

impairment

2. Can you identify the susceptibility factor?

• E.g. by serum creatinine concentration

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How this helps

• If you can identify a susceptible subgroup, then

• contra-indicate or warn specifically

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If not, what about dose?

• Is the reaction a hypersusceptibilityreaction?

• If so, consider a test dose (e.g. amphotericin)

• Is the reaction a toxic reaction?• If so, consider TDM (e.g. gentamicin)

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If collateral or unknown

• Consider the time course: e.g.– first-dose > advise precautions (keep adrenaline nearby with penicillins)– intermediate > if past the danger period,

reassure (clozapine)– late > screen for ADR, limit exposure, give

prophylaxis…( corticosteroids and bisphosphonates)

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What else we need to know

• If an ADR has been identified, can we monitor patients for it?

MonitoringRequiresSystematicEvaluation

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Monitoring & screening

• ADR• Test• Response• Strategy

potentially seriousrelation between latent and overt effects known

safe, simple, precise, valid

values in exposed known, cut-off established

acceptable to patients

response to postive test agreed

There is an effective intervention

Early intervention improves outcome

Good evidence

Strategy improves outcome

Strategy is acceptable

Benefits outweigh harm

Costs are proportionate

Quality is assured

Alternative ways of reducing harm have been fully utilized

Pirmohamed & Ferner 2003

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Is monitoring possible?

• There is a potential “sensor” or testEg INR with warfarin treatment

Potassium concentration with spironolactone• The test result is related to the harm

NB statins, creatine kinase, and rhabdomyolysisamiodarone, oxygen diffusion, and pulmonary fibrosis

• The results demanding action are knownNB antiTB therapy, liver function tests, and liver failure

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Is monitoring possible?Slow change

Treatment

start

Time

Laboratory Value

Opportunity for action

Treatment starts

Acceptable range

Danger zone

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Treatment

start

Time

Laboratory Value

Treatment starts Opportunity for action

Acceptable range

Danger zone

Is monitoring possible?Rapid change

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Is monitoring worthwhile?

Not if• Testing is unacceptable

Eg dangerous, costly, frequent• Results are un-interpretable

Eg not specific for ADR• Action to take is undefined

Eg warning is too late to alter outcomeADR is trivial

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Is monitoring worthwhile?A question of balance

• Benefit of detecting ADR depends onfrequency, severity, inevitability

• Harm of monitoring depends on nature, cost, and frequency of test

• Comparevenlafaxine, blood pressure test, hypertension trastuzumab, myocardial biopsy, myocardial damage

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So Clinicians need to know

1. how likely serious ADRs arelarge preclinical studies

2. how to prevent them, if possible• Susceptibility, dose, time

contra-indications, special precautions

3. how to detect them early if possiblemonitoring strategy

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• DASH• DoTS• MoRSE

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Monitoring: baseline value

Yes

Check baseline value

Within acceptable

range?

Make decision to treat patient

Start Treatment

Alter Plan

No

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Monitoring: during treatment

Y

N

Treatment course

complete?

Time to monitor?

Check current value

Within acceptable

range?

Continue treatment

Stop or alter the

treatment

Y

YY

N

Y N

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Monitoring: and perturbations

• ‘Nodes’: points during the course of treatment when P(ADR) changes

E.g. increases:– adding a new drug that may interact

(warfarin)– intercurrent febrile illness

(lithium salts)• E.g. decreases:

– after initial dose (ACE-I therapy for heart failure)

– After a time(clozapine treatment after 6/12)

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You also need to know about the patient

The ideal person

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The real patient…

Roth: Leonardo at workRoth: Leonardo at work

“To advise, warn, and remind... ”

Monitor, from Latin monēre to advise, warn, remind

c. To observe, supervise, or keep under review; to keep under observation; to measure or test at intervals, esp. for the purpose of regulation or control.

1944 Times 20 Mar. 5/7 American and British control officers work … ‘monitoring’ the aircraft as they travel across the 3,000 miles of ocean.

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Monitoring for ADRs

• What monitoring is• What is possible• What is worthwhile• What is done • What needs to be done

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A working definition

Monitoringis a process ofplanned examinationof a system that changes with timein order to guide alterations to the systemthat will maintain it or improve it.

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Prospective monitoring, systems, and control

adjusted input

measure related to

output

target value for measure

comparator

process OutputInputsensorcontroller

Coleman et al, 2006

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Dealing with uncertainty

"In this world nothing can be said to be certain , except death and

taxes"

Benjamin Franklin

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Pre-marketing studies

• pre-clinical pharmacology gives clues• phase I and II studies give clues• phase III studies look carefully

• But they are usually designed to detect benefit

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Is monitoring possible?

Not if • Change is catastrophic

Eg penicillin, mast cell tryptase, anaphylaxis

• System is chaotic or confoundedEg ACE-inhibitors, urine output, renal failure

• Tests give very inaccurate results