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Generic Medicines: Sorting the science from spin. Andrew McLachlan [email protected] I have received research funding, payment for educational sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

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Generic medicines sorting the science from spin

Generic Medicines:Sorting the science from spin

Andrew [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

Conflict statement


Sorting the science from spin
Sorting the science from spin sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

  • Science versus clinical issues for generic medicines

  • Does the science of bioequivalence extend to all medicines?

  • How can we improve patient awarenessto enhance safety


Scientific concerns

“scientific concerns” sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers


Bioequivalence
Bioequivalence sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

  • Pharmacological basis of drug response

  • Key principle in drug development and regulation of BOTH branded and generic medicinal products


Concentration effect relationship
Concentration-effect relationship sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

Effect

Probability

Toxicity

DrugConcentration


Concentration effect relationship1
Concentration-effect relationship sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

Effect

Probability

Toxicity

DrugConcentration


Aus Pharmacist sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

July 2005


Adapted from sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers Crawford P et al. Are there potential problems with generic substitution of

antiepileptic drugs? A review of issues. Seizure 2006


MYTH sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

……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
A cause for concern? sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers

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 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. “

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 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. “

Environmental factors

Renal disease

Obesity

pregnancy

Genetic differences

Age

Hepatic disease

Others diseases

Pharmacokinetics

Pharmacodynamics

Variability in Drug Response

adherence

Pharmacodynamic

monitoring

Therapeutic

drug monitoring

Dose individualisation


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
CONCLUSIONS ANDAs (1996-2005)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
Narrow safety margin medicines ANDAs (1996-2005)

  • 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 ANDAs (1996-2005)

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
Benet on cyclosporin BE ANDAs (1996-2005)

….. 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

“Clinical concerns” ANDAs (1996-2005)


Quality use of medicines
QUALITY USE OF MEDICINES ANDAs (1996-2005)

  • 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

Guidelines, co-morbidities, polypharmacy

Boyd CM et al. Clinical Practice Guidelines and Quality of Care for

Older Patients With Multiple Comorbid Diseases. JAMA Aug 2005


Polypharmacy
“Polypharmacy” pulmonary disease, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis

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


DRPs = Drug Related Problems pulmonary disease, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis

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
www.nps.org.au pulmonary disease, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis


http://www.nps.org.au/resources/Case_Studies/Case_41/case.pdfhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf


www.nps.org.au/resources/Case_Studies/Case_41/results.pdfhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf


Practitioner responses
Practitioner responseshttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

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 responses1
Practitioner responseshttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

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
How can patients avoid being confused by thehttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdfbrand 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 Talkhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf, Autumn 2007


Make a list and check it twice
Make a list ……and check it twice?http://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

  • 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
Extra care in those most at riskhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

  • 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
Summaryhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

  • 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


Prescribabilityhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf 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 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.


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


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