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Generic Medicines: Sorting the science from spin

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Conflict statement I have received ... .as recommended by the TGA in the 'Best practice guideline on prescription medicine labelling' Make ... MEDICINE OF INTEREST. – PowerPoint PPT presentation

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Title: Generic Medicines: Sorting the science from spin


1
Generic MedicinesSorting the science from spin
Andrew McLachlanandrewm_at_pharm.usyd.edu.au
2
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

3
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 awarenessto enhance
    safety

4
scientific concerns
5
Bioequivalence
  • Pharmacological basis of drug response
  • Key principle in drug development and regulation
    of BOTH branded and generic medicinal products

6
Concentration-effect relationship
Effect
Probability
Toxicity
Drug Concentration
7
Concentration-effect relationship
Effect
Probability
Toxicity
Drug Concentration
8
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9
Aus Pharmacist July 2005
10
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11
Adapted from Crawford P et al. Are there
potential problems with generic substitution of
antiepileptic drugs? A review of issues. Seizure
2006
12
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
13
A cause for concern?
Crawford P et al. Are there potential problems
with generic substitution of antiepileptic drugs?
A review of issues. Seizure 2006
14
  • 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
15
  • 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
16
Drug interactions
Environmental factors
Renal disease
Obesity
pregnancy
Genetic differences
Age
Hepatic disease
Others diseases
Pharmacodynamics
Pharmacokinetics
Variability in Drug Response
adherence
Pharmacodynamic monitoring
Therapeutic drug monitoring
Dose individualisation
17
  • 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
18
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
19
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
20
CONCLUSIONSfrom 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
21
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22
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

23
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24
Between and within subject variability
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
25
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
26
Clinical concerns
27
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
28
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
29
Polypharmacy
More than 5 medicines 75 13 years Less than 5
medicines 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
30
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
31
www.nps.org.au
32
http//www.nps.org.au/resources/Case_Studies/Case_
41/case.pdf
33
www.nps.org.au/resources/Case_Studies/Case_41/resu
lts.pdf
34
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/resu
lts.pdf
35
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/resu
lts.pdf
36
How can patients avoid being confused by
thebrand 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'

37
Medicine Talk, Autumn 2007
38
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39
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
40
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

41
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

42
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43
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.
44
Currently, individual bioequivalence is a
theoretical solution to solve a theoretical
clinical problem.
  • Individual bioequivalence takes a possible
    subject-by-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.

45
The individual bioequivalence assessment did not
show a subject-by-formulation interaction, nor
did it add value to the bioequivalence assessment
of warfarin.
46
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