Published: March 2013

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Generic Medicines and Bioequivalence

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Prescriber Update 34(1):8-9
March 2013

A generic medicine contains the same active ingredient (including different salts), in the same quantity as an innovator medicine (original brand). Generic medicines enable wider access to beneficial medicines.

Generic medicines can only enter the market following the expiration of the patent for the innovator medicine. They are manufactured to the same international quality standards and Good Manufacturing Practice requirements as those required for innovators.

As clinical trial data on the safety and efficacy of the active ingredient is already available from the innovator, these expensive, lengthy studies are not required for a generic. Instead, bioequivalence studies, performed to strict internationally agreed standards, are accepted by Medsafe and regulatory authorities worldwide¹.

Bioequivalence is the absence of a significant difference in the rate and extent of absorption of the active ingredient that reaches the systemic circulation (bioavailability). If products have equivalent bioavailability, it is considered they will have the same clinical effects. This is based on the premise that the concentration of the active ingredient in plasma is directly related to its clinical effect.

Bioequivalence studies follow well-defined procedures and are performed:

• in healthy volunteers
• in a randomised, cross-over design
• where all subjects receive both test medicines separated by a washout period (inter-subject variability is eliminated)
• to measure the rate and extent of absorption of the active ingredient in plasma
• to compare the plasma concentration time curves

The two pharmacokinetic parameters used to determine bioequivalence are:

1. the maximum plasma concentration (C_max)
2. the area under the plasma concentration time curve (AUC), which represents the extent of systemic exposure.

The products are considered bioequivalent if the 90% confidence intervals for the ratio (generic/innovator) of the means of C_max and AUC are within the range 0.80-1.25¹. The 0.80-1.25 acceptance range accounts for statistical error and is internationally considered to be clinically insignificant^2,3.

The actual difference in exposure to the active ingredient between generics and innovators is typically less than 5%. A compilation of the results from 2070 bioequivalence studies assessed by the US Food and Drug Administration during 1996-2007 showed the mean difference between generic and innovator products was 3.56% for AUC and 4.35% for C_max⁴.

A tighter bioequivalence acceptance range of 0.90-1.11 is applied for medicines with a narrow therapeutic range (eg, tacrolimus) due to the smaller difference between therapeutic and toxic plasma concentrations⁵. However, it is still advisable to closely monitor patients when switching between brands.

Some medicines, although they may have shown bioequivalence, cannot be freely changed due to the nature of the active ingredient (eg, levothyroxine due to its incomplete and variable absorption). For others, a bioequivalence study is not suitable because the oral bioavailability of the drug is not directly related to its clinical effect (eg, warfarin). Medsafe require the datasheets for such products to contain a warning that they cannot be freely changed. In these cases, extra clinical consideration is required on an individual patient basis.

For the majority of patients, changing between bioequivalent medicines should not be an issue. However, it is possible for patients to experience higher or lower exposure to an active ingredient following a change due to inter-patient variability. In this case, the patient may need to have the dose of the medicine reassessed.

References

1. European Medicines Agency. 2010. Guideline on the Investigation of Bioequivalence. Doc Ref: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **. URL: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf
2. Food and Drug Administration. 2001. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. URL: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070244.pdf
3. BPAC. 2009. What is bioavailability and bioequivalence? Best Practice Journal: Special Edition Generics 4-8. URL: www.bpac.org.nz/magazine/2009/generics/docs/bpjse_generics_2009.pdf
4. Davit BM, Nwakama PE, Buehler GJ, et al. 2009. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Annals of Pharmacotherapy 43(10):1583-1597.
5. European Medicines Agency. 2012. Questions and Answers: Positions on specific questions addressed to the pharmacokinetics working party. Doc Ref: EMA/618604/2008 Rev. 6. URL: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf