Transcript Generic Medicines: Sorting the Science from Spin

Generic Medicines:
Sorting the science from spin
Andrew McLachlan
[email protected]
Conflict statement
• I have received research funding, payment for educational sessions
and acted as a paid consultant for innovator and generic
pharmaceutical manufacturers
• I serve on government committees which review applications for new
medicines and their use
Sorting the science from spin
• Science versus clinical issues for generic
medicines
• Does the science of bioequivalence extend
to all medicines?
• How can we improve patient awareness
to enhance safety
“scientific concerns”
Bioequivalence
• Pharmacological basis of drug response
• Key principle in drug development and
regulation of BOTH branded and generic
medicinal products
Concentration-effect relationship
Effect
Probability
Toxicity
Drug Concentration
Concentration-effect relationship
Effect
Probability
Toxicity
Drug Concentration
Aus Pharmacist
July 2005
Adapted from Crawford P et al. Are there potential problems with generic substitution of
antiepileptic drugs? A review of issues. Seizure 2006
MYTH
……not supported by credible data
Adapted from Crawford P et al. Are there potential problems with generic substitution of
antiepileptic drugs? A review of issues. Seizure 2006
A cause for concern?
Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs?
A review of issues. Seizure 2006
“It was of interest to note that very few articles
described randomised controlled clinical trials
comparing generic and branded products. The
majority of articles consisted of case reports,
letters discussing case reports, or opinion
pieces without presentation of new data. “
Adapted from Crawford P et al. Are there potential problems with generic substitution of
antiepileptic drugs? A review of issues. Seizure 2006
• Few controlled trials
• Not all in patient of
interest
• Small numbers of
patients
• Not all studies blinded
• Clinical endpoints
(underpowered)
• No significant
pharmacokinetic
differences detected
• Seizure frequency
unchanged (overall)
Adapted from Crawford P et al. Are there potential problems with generic substitution of
antiepileptic drugs? A review of issues. Seizure 2006
Drug interactions
Renal disease
pregnancy
Environmental factors
Obesity
Age
Hepatic disease
Others diseases
Pharmacokinetics
adherence
Therapeutic
drug monitoring
Genetic differences
Pharmacodynamics
Variability in Drug Response
Dose individualisation
Pharmacodynamic
monitoring
• A common misconception
held by some health care
practitioners and the
general public is that
generic drug products may
differ by as much as 40%
from their brand name
equivalents.
Aus Pharmacist
July 2005
Analysis of 1636 crossover fasting BE studies from approved ANDAs (1996-2005)
Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for
BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents
AAPS conference 2006 San Antonio
Analysis of 1636 crossover fasting BE studies from approved ANDAs (1996-2005)
Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for
BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents
AAPS conference 2006 San Antonio
CONCLUSIONS
from FDA review of 1636 BE studies
􀀹 Generic drug products approved over the 10-year
period differed by an average of less than 4% in
extent of absorption (exposure) relative to their
brand name counterparts.
􀀹 The fact that observed differences have remained
quite small, illustrates the effectiveness of the BE
criteria used in the approval of generic drug
products in the US.
Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for
BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents
AAPS conference 2006 San Antonio
Narrow safety margin medicines
• Should the same criteria apply?
• How should they be tested by the same
criteria?
………Clinical (but no scientific) concerns remain
– care is needed
Between and within subject variability
Pharmacokinetic Variation (%CV)
60
50
40
BETWEEN
WITHIN
30
20
10
0
Conjugated
estrogens
Digoxin
Phenytoin
sodium
Theophylline Warfarin sodium
sustained release
Benet LZ. Relevance of Pharmacokinetics in Narrow Therapeutic Index Drugs. Transplantation Proceedings 1999
Wagner JG. Inter- and intrasubject variation of digoxin renal clearance in normal adult males. Drug Intell Clin Pharm. 1988
Benet on cyclosporin BE
….. to establish bioequivalence of generic
cyclosporine formulations, the fact that thousands of
transplant patients have safely been switched
between the innovator's bioequivalent and even
bioinequivalent cyclosporine formulations for more
than a decade, and that bioequivalence data of
generic cyclosporine formulations in healthy
volunteers and transplant patients is available, the
present FDA guidelines for approving
bioequivalence can be considered adequate and
sufficient for generic cyclosporine formulations.
Christians U, First MR, Benet LZ. Recommendations for bioequivalence testing of cyclosporine generics revisited.
Ther Drug Monit. 2000
“Clinical concerns”
QUALITY USE OF MEDICINES
• Quality Use of Medicines is defined as:
– selecting management options wisely;
– choosing suitable medicines if a medicine is
considered necessary; and
– using medicines safely and effectively.
“Better health through quality use of medicines”
Guidelines, co-morbidities, polypharmacy
• a hypothetical 79-year-old
woman with chronic obstructive
pulmonary disease, type 2
diabetes, osteoporosis,
hypertension, and osteoarthritis
• If the relevant Clinical Practice
Guidelines were followed, the
hypothetical patient would be
prescribed 12 medications
(costing her $US406 per
month) and a complicated
non-pharmacological
regimen
Boyd CM et al. Clinical Practice Guidelines and Quality of Care for
Older Patients With Multiple Comorbid Diseases. JAMA Aug 2005
“Polypharmacy”
More than 5 medicines
Less than 5 medicines
75 ±13 years
66.7 ± 19 years
Viktil KK et al , Polypharmacy as commonly defined is an indicator of limited value in
the assessment of drug-related problems. Brit J Clin Pharmacol 2006
DRPs = Drug Related Problems
Viktil KK et al , Polypharmacy as commonly defined is an indicator of limited value in
the assessment of drug-related problems. Brit J Clin Pharmacol 2006
www.nps.org.au
http://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf
www.nps.org.au/resources/Case_Studies/Case_41/results.pdf
Practitioner responses
n = 300 responses of 1353
Patient suitability for brand substitution
88.3% of respondents considered Anne a suitable candidate
for brand substitution.
— had no cognitive impairment (64.9%)
— could, and was interested in, saving money (33.5%)
— was independent and self-caring (11.3%)
— had family support available (10.9%)
—understands the concept of brand substitution (10.1%).
11.7% said not suitable because of potential confusion and
because some of her medicines had narrow therapeutic
windows.
www.nps.org.au/resources/Case_Studies/Case_41/results.pdf
Practitioner responses
Strategies to avoid confusion during brand substitution
Respondents (n = 299) suggested strategies to avoid
confusion could be implemented:
— when prescribing and selecting drugs (e.g. using the
same generic brand consistently)
— labelling (e.g. stating ‘this medicine replaces Brand X’ or
‘same as Brand X’)
— by informing and explaining (e.g. identifying and
discussing differences in appearance between old and new
brands).
— regular follow-up and review (e.g. considering a Home
Medicines Review),
— dose administration aids
www.nps.org.au/resources/Case_Studies/Case_41/results.pdf
How can patients avoid being confused by the
brand name of generic products?
• Patients should be encouraged to know and record
the name of the active ingredient in the medicine
• Understand that the same medicine may be
available in different brands.
• Active ingredient in the product should be displayed
with greater or equal prominence to the brand name
….as recommended by the TGA in the 'Best practice guideline on prescription medicine labelling'
Medicine Talk, Autumn 2007
Make a list ……and check it twice?
• As patients move in and out of hospital it is likely that
generic substitution will occur to a greater extent.
• reinforce the
need for patients
to be aware of
and carry a list of
the name of the
active ingredient
or generic name
of their medicines
www.nps.org.au/resources/content/medimate_medicine_list.pdf
Extra care in those most at risk
• Confusion can lead to dose
duplication
• Unless the patient or carer fully
understands the difference
between the various brands of the
same medicine.
• Older patients with cognitive
impairment and patients taking
multiple medicines for serious
chronic illness are at greatest risk
of misadventure
Summary
• important to disentangle the scientific, clinical
and business issues around generic medicines
• many of the issues raised apply equally to
branded and generic medicines
• clinical issues remain a concern when
medicines are switched without clear
communication
• where clinicians/companies/advocates have
concerns then we need rigorous controlled trials
Prescribability refers to the choice of two products
when therapy is started in a drug-naïve patient
Switchability , when a patient stabilized on the
innovator's product is switched to a generic
formulation, is of greater clinical impact
Average bioequivalence testing, which is as
discussed earlier the basis of approval of generic
drugs in the United States and most other
countries, measures prescribability rather than
switchability.
“Currently, individual bioequivalence is a
theoretical solution to solve a theoretical clinical
problem.”
• Individual bioequivalence takes a possible subjectby-formulation interaction into account in the
computation of the metric.
• A large subject-by-formulation interaction is an
indicator for a lack of switchability between the test
and the reference formulation in some individuals
• Individual bioequivalence studies require a replicate
design, where each subject receives the generic
formulation twice and the innovator formulation
twice.
• This study design allows also for estimation of
interindividual and intraindividual variances.
The individual bioequivalence
assessment did not show a
subject-by-formulation
interaction, nor did it add
value to the bioequivalence
assessment of warfarin.