Pharmacodynamic Endpoint Bioequivalence Studies

Zou, Peng; Yu, Lawrence X.

doi:10.1007/978-1-4939-1252-0_9

Cited by 7 publications

(8 citation statements)

References 22 publications

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“…However, there are a number of challenges in the design and conduct of reliable N-of-1 TE studies. Generally, comparison of drug formulations using TE studies are recommended if the PK approach is not possible [ 26 , 27 ]. TE studies demonstrate that a test formulation has equivalent efficacy to a reference one.…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic equivalence studies with biomarkers reflecting efficacy endpoints (e.g., BP reduction) are more sensitive than TE studies with clinical endpoints (e.g. survival rates, myocardial infarction and stroke) [ 26 , 27 ]. Beside, N-of-1 trials are suitable only in chronic conditions where the drugs or interventions that are to be tested have a relatively short half-life [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…Though they are cheap, people distrust local drugs. Pharmacodynamic (PD) endpoint bioequivalence studies can be used to establish bioequivalence of drug products when pharmacokinetic (PK) data is not possible [ 26 , 27 ]. Compared with clinical endpoint bioequivalence studies, PD studies are more cost-effective, sensitive and less complicated methods for detecting drug formulation differences.…”

Section: Introductionmentioning

confidence: 99%

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A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: study protocol for a randomized controlled trial

Alemayehu

Mitchell

Aseffa

et al. 2017

Trials

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BackgroundHypertension is one of the leading causes of morbidity and mortality in Ethiopia. Treatment usually involves lifelong medication use. Enalapril is a common drug for the treatment of hypertension in Ethiopia. However, the drug is expensive and, therefore, there is limited capacity for people to afford the treatment. Locally produced Enalapril is a cost-effective solution to treat the disease. However, as local medicines regulation does not include bioequivalence tests on locally produced drugs, physicians and patients need assurance about the effectiveness and safety of local generics. Evidence on therapeutic equivalence is needed on these untested local drugs.MethodsThis is a hospital-based, randomized, partially blinded, three-cycle crossover trial in single patients, comparing a locally produced version of enalapril with enalapril imported from Europe. Patients involved in this trial are not blinded, as there is no local facility to produce relatively small numbers of placebos or encapsulated drugs. To ensure blinding of study investigators and data analysts, study medications are prepared by an independent pharmacy unit using opaque medication packaging. The importance of maintaining blinding is also part of patient pre-trial education. Each N-of-1 trial will consist of three successive 14-day treatment pairs, each pair comprising 7 days of 5–20 mg local and 7 days of 5–20 mg imported enalapril taken once daily in the morning. The primary outcome will be the average difference in systolic blood pressure as measured by home blood pressure measurements.DiscussionThe number of locally produced products, such as enalapril, being approved without proof of bioequivalence is dramatically increasing. By bridging the information gap on bioequivalence, the trial will give rigorous evidence on therapeutic equivalence of locally produced enalapril in the treatment of hypertension. If there is no difference, the hypothesized result, then patients can take the local medicine with confidence. This trial will also will determine whether aggregated N-of-1 studies are feasible to evaluate untested generic drugs in resource-limited countries where bioequivalence testing centers are unavailable.Trial registration numberAustralian and New Zealand Clinical Trial Registry, ID: ACTRN12616001088437p. Registered on 12 August 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2212-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: study protocol for a randomized controlled trial

Alemayehu

Mitchell

Aseffa

et al. 2017

Trials

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“…Other types of drugs, such as corticosteroids or drugs with systemic indications, must use clinical endpoint studies. Endpoint studies are PD assessments that use a specific indicator to assess a pharmacological effect [ 63 ]. Some of these indicators include a potential change in a pharmacological response, the occurrence of an event or time elapsed without an event of interest occurring.…”

Section: Current Regulation and Official Methodologies For Inhaled Bioequivalencementioning

confidence: 99%

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

Gallegos-Catalán

Warnken²,

Bahamondez-Canas

et al. 2021

Pharmaceutics

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Orally inhaled drug products (OIDPs) are an important group of medicines traditionally used to treat pulmonary diseases. Over the past decade, this trend has broadened, increasing their use in other conditions such as diabetes, expanding the interest in this administration route. Thus, the bioequivalence of OIDPs is more important than ever, aiming to increase access to affordable, safe and effective medicines, which translates into better public health policies. However, regulatory agencies leading the bioequivalence process are still deciding the best approach for ensuring a proposed inhalable product is bioequivalent. This lack of agreement translates into less cost-effective strategies to determine bioequivalence, discouraging innovation in this field. The Next-Generation Impactor (NGI) is an example of the slow pace at which the inhalation field evolves. The NGI was officially implemented in 2003, being the last equipment innovation for OIDP characterization. Even though it was a breakthrough in the field, it did not solve other deficiencies of the BE process such as dissolution rate analysis on physiologically relevant conditions, being the last attempt of transferring technology into the field. This review aims to reveal the steps required for innovation in the regulations defining the bioequivalence of OIDPs, elucidating the pitfalls of implementing new technologies in the current standards. To do so, we collected the opinion of experts from the literature to explain these trends, showing, for the first time, the stakeholders of the OIDP market. This review analyzes the stakeholders involved in the development, improvement and implementation of methodologies that can help assess bioequivalence between OIDPs. Additionally, it presents a list of methods potentially useful to overcome some of the current limitations of the bioequivalence standard methodologies. Finally, we review one of the most revolutionary approaches, the inhaled Biopharmaceutical Classification System (IBCs), which can help establish priorities and order in both the innovation process and in regulations for OIDPs.

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“…Clinical endpoint bioequivalence studies test the clinical bioequivalence of a medicine in patients [22, 23]. They can be used to establish the bioequivalence of drug products when pharmacokinetic studies are not possible [13].…”

Section: Introductionmentioning

confidence: 99%

Acceptability and barriers to implementation of N-of-1 tests in Ethiopia - a qualitative study

Alemayehu¹,

Mitchell²,

Nikles³

et al. 2019

BMC Med Res Methodol

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Background Locally produced generic drugs offer a cost–effective alternative to imported drugs to treat patients in Ethiopia. However, due to a lack of bioequivalence testing, additional assurance tests are needed to build trust in cheaper, locally made drugs. By testing bioequivalence of local drugs to gold standard, N-of-1 tests have the potential to promote patient centred quality use of medicines. Method We sought to assess the acceptability of, and explore barriers to, conducting N-of-1 tests to evaluate local medicines in a resource limited clinical setting. We conducted a descriptive qualitative study, analysing four focus group discussions and five key informant interviews. Participants were senior drug regulatory authority members, institutional review board members, physicians and patients. All interviews were audio taped and transcribed verbatim. Patient interviews were conducted in Amharic and translated to English prior to analysis. Data analysis used an inductive, thematic process. Results Five major themes were identified; (1) Appropriateness of N-of-1 tests to determine the therapeutic equivalence of local drugs, (2) N-of-1 therapeutic equivalence tests: clinical care or research? (3) Ethical and regulatory requirements (IRB), (4) Potential barriers to implementing N-of-1 tests and (5) Possible solutions to identified challenges. The study demonstrated considerable support for using N-of-1 tests for clinical equivalence studies between local and imported medicines, but important impediments were very likely to impact the feasibility of conducting N-of-1 tests in Ethiopia. Key informants from the regulatory authority did not support additional tests of local drugs. There were also mixed opinions regarding ethical requirements for conducting N-of-1 tests. The Institutional Review Board (IRB) members believed that IRB approval was sufficient to conduct N-of-1 tests, however, the regulatory authority members considered that N-of-1 tests constituted a clinical trial, and required approval at the regulatory level. Conclusion This study showed that there were key uncertainties that could impact the feasiblity of using N-of-1 testing local drugs in Ethiopia. Therefore, a number of protocol amendments to address contextual threats and regulatory challenges, would be needed before progressing to conducting these tests.

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Pharmacodynamic Endpoint Bioequivalence Studies

Cited by 7 publications

References 22 publications

A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: study protocol for a randomized controlled trial

A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: study protocol for a randomized controlled trial

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

Acceptability and barriers to implementation of N-of-1 tests in Ethiopia - a qualitative study

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