Generic Substitution: Taking a Narrow View?

Date: November 23, 2010
Pages: 54
US$ 395.00
Publisher: FirstWord
Report type: Strategic Report
Delivery: E-mail Delivery (PDF)
ID: G9CEF394680EN

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Generic Substitution: Taking a Narrow View?
As health care expenditures rise, governments, payers, healthcare providers and patients alike are focused intently on one thing: capping runaway costs.

For the generics industry, it heralds a boom-time. In regulated markets, relatively inexpensive generic drugs are increasingly favoured by payers for their low cost and effectiveness. Prescribed by physicians but dispensed by pharmacists, drugs are increasingly substituted for cheaper generics somewhere between the doctor’s surgery and home.

Yet there is an exception, and as observational evidence mounts, it’s one that is worth noticing.

Narrow therapeutic index (NTI) drugs, for which small changes in concentration can lead to big alterations in efficacy and negative side effects, are the focus of much scrutiny, both by legislators and the public. As evidence in academic literature grows to indicate that formulation changes are linked to negative effects in patients, NTI substitution is becoming a hot-button topic for the generics industry.

FirstWord Dossiers tackles it head-on in our latest report, Generic Substitution: Taking a Narrow View? Based on expert views from leading thinkers such as University of Colorado immunosuppressant specialist Dr Uwe Christians, the report nimbly examines how some markets are implementing broad exclusion policies, while some American legislators are drafting ‘carve-out’ exceptions. Containing analysis, definitions, charts and interviews, the report includes an overview of immunosuppressant, antiepileptic, cardiovascular and mood-modifying drugs and the impact of substitution. Insightful, intelligent and timely, the report is critical reading for the generics industry.

The report includes:
  • FirstWord’s ExpertViews interviews with leading thinkers in the field
  • A concise overview of generics uptake in major markets and how NTI generic substitution differ

Key features
  • Analysis of how physicians, pharmacists and patients influence generic uptake
  • Insights into how bioequivalence is the key to the NTI substitution debate
  • Explanations of generic carve-outs in the US, illustrated with charts and diagrams
  • Analysis of the pros and cons of generics substitution restrictions in dealing with NTIs
  • A review of NTI drug classes, including immunosuppressant, antiepileptic, cardiovascular and mood-modifying drugs
  • Complete regulatory overview covering the Federal Drug Administration’s position

Key quotes from the report

“The generic has to be just as good as the originator’s drug. So by definition, the pharmacology of a [generic] NTI drug has to match the originator to be efficacious and not to go through cycles of toxicity. This means that NTI drugs set a pretty high bar for the generic to meet.” University of Colorado immunosuppressant expert, Dr Uwe Christians.

“There is a theoretical risk about switching between NTI drugs from two generics manufacturers, where one's product is on the left side of the bioequivalence range and the other is on the right side, leading to a very large difference between them. However, I have not seen rigorous evidence that this risk has led to bad patient outcomes in the market.” Harvard Medical School pharmacoeconomist, Dr Aaron Kesselheim.


Generic drugs use in the seven major markets
The physician-pharmacist-patient triumvirate determines the extent of generics uptake
  Physicians have historically been the most important stakeholder group
  Pharmacists require financial incentives to promote generics dispensing
    Pharmacist substitution ruled out in the UK
  The US as a mixed bag when it comes to pharmacist substitution
  Patients that are cost-sensitive have the most reason to use generics


Bioequivalence is key to the NTI generic substitution debate
  Bioequivalence defined
  Rationale for the pharmacokinetic approach
  How bioequivalence criteria differ across the seven major markets
Generic carve-outs in the US
  Key players in the generics carve-out debate – the usual suspects
    Carve-outs as a life-cycle management strategy for the branded industry?
    Generic substitution represent a major cost-saving measure for payers
    Patient groups and medical associations important proponents of carve-outs
The pros and cons of generic substitution restrictions
  The bioequivalence test
    A small number of healthy volunteers versus a large patient population
    The use of sub-therapeutic drug doses
    Reduced variability of NTI drugs
    Potentially large differences in bioavailability
Regulatory requirements for generic drugs on par with brands
Observational studies rather than randomized controlled trials highlight risks of generic substitution
  Publication bias potentially associated with observational studies
  Observational studies and confounding variables
Generic formulation changing should be no riskier than switching to a same brand formulation
Inadvertent or uninformed switching by the pharmacist
Patient compliance could be compromised


Antiepileptic drugs – the link between formulation switching and breakthrough seizures
  Patients and physicians are reluctant to switch
  Concern regarding generic substitution on online forums
  The evidence for and against
Immunosuppressant drugs – disturbing the delicate balance
  Patient dosing is a closely monitored and gradual process
  Switching between immunosuppressant brands and formulations is discouraged
  The complex treatment regime of transplant patients is a resistor to automatic generic substitution
  The evidence for and against
Some cardiovascular and mood-modifying have a narrow therapeutic index
  Warfarin as the most prominent narrow therapeutic index cardiovascular drug
  A number of mood-modifiers have a narrow therapeutic index
  Generic Wellbutrin cleared by the FDA


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