An appeal to the global health community for a tripartite innovation: an ‘‘Essential Diagnostics List,’’ ‘‘Health in All Policies,’’ and ‘‘See-Through 21st Century Science and Ethics"

Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and nanotechnology, are emerging as companion tests to innovative medicines. In this Opinion, we present the rationale for promulgating an ‘‘Essential Diagnostics List.’’ Additionally, we explain the ways in which adopting a vision for ‘‘Health in All Policies’’ could link essential diagnostics with robust and timely societal outcomes such as sustainable development, human rights, gender parity, and alleviation of poverty. We do so in three ways. First, we propose the need for a new, ‘‘see through’’ taxonomy for knowledge-based innovation as we transition from the material industries (e.g., textiles, plastic, cement, glass) dominant in the 20th century to the anticipated knowledge industry of the 21st century. If knowledge is the currency of the present century, then it is sensible to adopt an approach that thoroughly examines scientific knowledge, starting with the production aims, methods, quality, distribution, access, and the ends it purports to serve. Second, we explain that this knowledge trajectory focus on innovation is crucial and applicable across all sectors, including public, private, or public–private partnerships, as it underscores the fact that scientific knowledge is a co-product of technology, human values, and social systems. By making the value systems embedded in scientific design and knowledge co-production transparent, we all stand to benefit from sustainable and transparent science. Third, we appeal to the global health community to consider the necessary qualities of good governance for 21st century organizations that will embark on developing essential diagnostics. These have importance not only for science and knowledge based innovation, but also for the ways in which we can build open, healthy, and peaceful civil societies today and for future generations

Do Regulatory Bioequivalence Requirements Adequately Reflect the Therapeutic Equivalence of Modified-Release Drug Products?

Purpose. To demonstrate that current regulatory requirements for bioequivalence (BE) do not always reflect therapeutic equivalence. To investigate the potential usefulness of an additional metric, the partial AUC. Methods. Pharmacokinetic information was reviewed and evaluated on the pharmacokinetics of modified-release methylphenidate and nifedipine products. Results. In studies of modified-release products of methylphenidate as well as of nifedipine, traditional regulatory criteria found two formulations to be bioequivalent even though their concentration profiles strongly diverged during the period of absorption. An additional metric, partial AUC, discriminated strongly between the concentrations of the drug products. Conclusions. The current regulatory criteria for the acceptance of BE do not always reflect the therapeutic equivalence of modified-release drug products. With some modified-release products, the application of an additional metric, the partial AUC, yields an improved discriminatory representation

Individual Bioequivalence: Attractive in Principle, Difficult in Practice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41468/1/11095_2004_Article_303981.pd

An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence

Reference-scaled average bioequivalence (RSABE) has been recommended by Food and Drug Administration (FDA), and in its closely related form by European Medicines Agency (EMA), for the determination of bioequivalence (BE) of highly variable (HV) and narrow therapeutic index (NTI) drug products. FDA suggested that RSABE be evaluated by an approximating procedure. Development of an alternative, numerically exact approach was sought. A new algorithm, called Exact, was derived for the assessment of RSABE. It is based upon the observation that the statistical model of RSABE follows a noncentral t distribution. The parameters of the distribution were derived for crossover and parallel-group study designs. Simulated BE studies of HV and NTI drugs compared the power and consumer risk of the proposed Exact method with those recommended by FDA and EMA. The Exact method had generally slightly higher power than the FDA approach. The consumer risks of the Exact and FDA procedures were generally below the nominal error risk with both methods except for the partial replicate design under certain heteroscedastic conditions. The estimator of RSABE was biased; simulations demonstrated the appropriateness of Hedges' correction. The FDA approach had another, small but meaningful bias. The confidence intervals of RSABE, based on the derived exact, analytical formulas, are uniformly most powerful. Their computation requires in standard cases only a single-line program script. The algorithm assumes that the estimates of the within-subject variances of both formulations are available. With each algorithm, the consumer risk is higher than 5% when the partial replicate design is applied

The Two Main Goals of Bioequivalence Studies.

The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product's in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered

Metrics for the evaluation of bioequivalence of modified-release formulations.

Metrics are discussed which are used for the evaluation of bioequivalence of modified-release formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and C (max). For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative