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 Substitution: taking a narrow view? costs $395 a copy. Click here to order

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Publication date:
 November, 2010
Product code:
$395 User Single License
$1,975 Site License
$5,925 Global License

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Content Highlights

  • Executive Summary
  • Promoting generics uptake in the seven major markets
    > 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
  • Narrow therapeutic index drugs represent a very different proposition
    > 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
  • Narrow therapeutic index drug classes
    > 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
  • Overview
  • Index