Patient Adherence & Patient Safety Bernard Vrijens, PhD Chief - - PowerPoint PPT Presentation

Patient Adherence & Patient Safety

Bernard Vrijens, PhD

Chief Science Officer, WestRock Healthcare Associate Professor of Biostatistics University of Liège, Belgium

October 2015

Adherence is Key to Therapeutic Success

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Effective Disease Management Effective Therapies Adherence to Medications “Drugs don’t work in patients who do not take them.”

– C. Everett Koop, former US Surgeon General

“Drugs may create harm in patients who do not take them appropriately.”

Medication adherence: Definition

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The process by which patients take their medications as prescribed!

time ! Initiate " Implement # Persist

Patient does not initiate treament Binary (yes/no) Patient delays,

• mits or takes

extra doses Dosing history Patient discontinues treatment Time to event

Vrijens et al. Br J Clin Pharmacol 2012;73:691-705.! EU Commission-sponsored research

Adherence Measurement Methods

Modified from Vrijens & Urquhart, 2005 Journal of Antimicrobial Chemotherapy.

Sparse Sampling Rich Sampling Biased Method Reliable Method

Retrospective" questionnaire! Pill Counts! Therapeutic" drug monitoring! Pharmacy refill data! Patient diary! Automatic compilation of dosing history data!

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Vrijens et al., Expert Review Clinical Pharmacology, 2014

Each of the 4 patients took 75% of prescribed doses during a 3-month period!

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Electronically Compiled Dosing History Data

Consequences of medication non-adherence & Specific safety considerations

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time ! Initiate

Drugs don’t work in patients who do not initiate them

# Persist

Drugs stop working in patients who discontinue them

" Implement

Drugs work partially or may create harm in patients who implement a dosing regimen sporadically

Drugs’ Forgiveness Potential Rebound Effects Recurrent first- dose effects (Titration)

7 Dosing time (Day) Concentration 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

24h

Increased risk of toxicity Periodic loss of effectiveness

The concept of drugs’ forgiveness

• r how much implementation is enough?

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Periodic loss of effectiveness & emergence of drug resistance

Occasional toxicity

Blaschke, Osterberg, Vrijens, Urquhart, 2012, Ann Rev Pharmacol Toxicol, 52:275-301

Variable adherence creates drug-specific issues of efficacy and safety

Addressing adherence is key to avoid treatment escalation, the driver for costs

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Poor adherence

Initiation-Implementation-Persistence

Disease progression More complex treatments Treatment failure

The Adherence Gap

10 Blaschke, Osterberg, Vrijens, Urquhart. Annual Review, 2012.

Method effectiveness (efficacy) Outcomes

Phase I Phase II Phase III Market

Use effectiveness Patient selection Patient follow-up Suboptimal adherence Drug development

Potential consequences

• f this gap:
• Risk of failure related

to lack of effectiveness

• Poor estimation of toxicity
• Inappropriate dosing

regimen

• Lost revenue/share

Adherence becoming a regulatory priority

Draft guidance from the US FDA explicitly addresses adherence strategies http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Dec 2012

Time (days) % of patients

100 200 300 50 60 70 80 90 100

Interactive

Extent of non-adherence in clinical trials

11 Blaschke, Osterberg, Vrijens, Urquhart, Annual Review, 2012.

16,907 participants from 95 clinical studies

Decrease in adherence due to discontinuation

• f treatment (nonpersistence)

Perfect adherence Perfect adherence Perfect adherence % of patients engaged with the dosing regimen % of patients who dosed correctly

D e c r e a s e ¡ i n ¡ a d h e r e n c e ¡ ¡ d u e ¡ t

• ¡

p

• r

¡ i m p l e m e n t a 2

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Adherence Persistence

Adherence-uninformed clinical development

Best dosing regimen?!

Efficacy Safety

Market Drug development Phase I Phase III Phase II Highest Safe Dose* Compensate for diluted efficacy Unexpected ADR’s!

Formulation Adherence? PK/PD

*based on small, controlled, (adaptive) designs

« Variability makes prediction unreliable »

Peck et al., JAMA, 1993.! 12!

Optimal dose

The Struthian Approach is No Longer An Option!

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Concentration of Drugs Efficacy / Safety Forgiveness

Vrijens & Heidbuchel, Europace 2015.!

Overview of assessment methods

• f adherence in ambulatory patients

time ! Initiate " Implement # Persist

Requires sampling after prescription Sampling is too sparse Subject to white coat adherence

Direct methods (PK/PD)!

Desirability bias Recall bias Desirability bias

Self-report!

Easily censored by patient Only aggregate summary Easily censored by patient

Pill counts!

Gold standard if both databases combined Only aggregate summary Gold standard but retrospective

Prescription & refill databases!

Gold standard in CT; needs activation Gold standard Gold standard in CT; needs patient engagement

Electronic monitoring!

Conclusions

• In drug development, adherence- informed clinical trials, based on reliably

precise measurement of adherence, will yield more informative data on both safety and the dose-dependence of efficacy, resulting in better patient satisfaction and longer persistence with treatment

• Depending on the drugs’ pharmacological properties, variable adherence leads

to under- or over-dosing that can result in lack of effectiveness and/or safety issues: narrow therapeutic window, recurrent first-dose effects, and rebound effects.

• In medical practice, when precise implementation of a dosing regimen is

required, it becomes critical to provide patients not only the drug but also a monitoring system that supports the management of adherence to medications

Thank You for Your Attention Questions?

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