Luther Gwaza

of bioequivalence studiestreatment comparisonsAdjusted indirect

2016

Luther Gwaza

Adjusted indirect treatment com

parisons of bioequivalence studies

ADJUSTED INDIRECT TREATMENT COMPARISONS OF BIOEQUIVALENCE STUDIES

Gecorrigeerde indirecte vergelijkingen van behandelingen in

bioequivalentie studies

(met een samenvatting in het Nederlands)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge

het besluit van het college voor promoties in het openbaar te verdedigen op vrijdag 8 juli 2016 des middags te 12.45 uur

door

Luther Gwaza

geboren op 30 maart 1982 te Bikita, Zimbabwe

Promotor: Prof. dr. H. G.M. Leufkens

Copromotoren: Dr. A. García-Arieta Dr. M. Maliepaard

Adjusted indirect treatment comparisons of bioequivalence studies

Generic medicines are approved by regulatory authorities based on demonstration of bioequivalence

with the innovator, however, current regulatory systems do not require direct comparison between

all available generics of the same innovator to ensure interchangeability. As such,

interchangeability between generics of the same drug is assumed, although it has not been

addressed comprehensively by regulators. Thus, this thesis addresses three main interlinked issues

with respect to interchangeability of generic medicines particularly in low- and middle-income

countries (LMICs) in a global context.

First, this thesis shows that adjusted indirect treatment comparison is a pragmatic approach to

identify interchangeable generic products by comparing the different generics that have been

demonstrated to be bioequivalent with the same comparator product. Further, in contrast to the ±

20% acceptance range used for direct comparisons, a ± 30% acceptance range is proposed for

adjusted indirect comparisons, due to the limited precision of indirect comparisons. The outcome of

the indirect comparisons indicates that the antimalarial artemether/lumefantrine, first-line

antituberculosis, and first-line antiretroviral generics prequalified by the World Health Organization

(WHO) prequalified against the same comparator can be interchanged without any safety and

efficacy concerns in the clinical setting.

To ensure switchability between the generics, the generic and the comparator should not differ

significantly (i.e. point estimates should not exceed the 7% difference) and the original studies

should be sufficiently powered (i.e. > 80%). In this respect an additional point estimate constraint of

± 10% is proposed, particularly for LMICs where the regulators may not provide guidance to health

professionals on the switchability of approved products or when generic substitution is

recommended by national governments or the third party reimbursement agencies. A lower point

estimate constraint of ±5% is proposed for NTI drugs, especially where neither generic switching of

these drugs is restricted nor narrowed bioequivalence acceptance limits applied.

Second, this thesis shows that it is possible to have the necessary arrangements for product

registration for generic medicines that will ensure that nationally approved products are of sufficient

quality and interchangeable, and to adopt resource-efficient approaches without duplications in

LMICs. The collaborative case model in the context of global harmonisation efforts, not only in

LMICs, but also in high-income countries demonstrates that collaboration in assessments is feasible

and probably the most pragmatic approach that countries in LMICs should use to build capacity and

to ensure quality and interchangeable medicines in the market.

Third, this thesis shows that most countries follow the WHO recommendations for selecting

comparator products and require the comparator product to be obtained from their national markets.

These recommendations are only feasible in the few countries where the repetition of the

bioequivalence study is profitable, but they are impracticable in all other countries, especially

LMICs. Therefore, this thesis proposes that the innovator product from well-regulated markets

should be the global comparator as it is ineffectual to harmonize only the requirements for

performing bioequivalence studies, if such a study has to be repeated for every single country

simply because of the different comparator product.

Key words:

adjusted indirect comparisons, bioequivalence, generic products, interchangeability

Main conclusions

Adjusted indirect treatment comparison is a pragmatic approach to identify interchangeable generic

products by comparing the different generics that have been demonstrated to be bioequivalent with

the same comparator product. In addition, WHO-prequalified antimalarial artemether/lumefantrine,

first-line anti-tuberculosis and first-line antiretroviral generics can be interchanged in clinical

settings without any safety and efficacy concerns.

Main recommendations

A ± 30% acceptance range is proposed for adjusted indirect comparisons, due to the limited

precision of indirect comparisons. Further, an additional point estimate constraint is proposed for

bioequivalence studies to ensure switchability between generics of the same drug. Lastly, the

innovator product from a well-regulated market should be the global comparator product for

bioequivalence studies.