US, EU, and Japanese Regulatory Guidelines for Development of Drugs for Treatment of Alzheimer's Disease: Implications for Global Drug Development.

Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer's disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.

Labeling of Disease-Modifying Therapies for Neurodegenerative Disorders.

Neurodegenerative disorders are characterized by progressive degeneration of nerve cells resulting in functional decline of cognition and/or movement. As the prevalence of many of these disorders increases with the aging global population, there is an urgent need for disease-modifying drugs that will halt or slow the progression of these devastating diseases. A summary of the scientific information needed to guide the safe and effective use of a drug is provided in the product label in which the indication section should clearly state the treatment concept, e.g., distinguish between symptomatic, preventive, and curative treatments. However, a review of the United States (US) and European Union (EU) product labels for disease-modifying multiple sclerosis (MS) drugs reveals that the indications are not aligned with the regulatory guidance on labeling. Indication claims such as "delay of accumulation of disability" and "slowing of disease progression" were previously accepted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, all recently approved MS drugs include no such specification of the treatment concept in the label indication sections despite similar clinical data packages supporting the approvals. Coincidently, the FDA and EMA therapeutic guidelines pertaining to development of drugs for treatment of neurodegenerative disorders have changed from providing recommendations for specific disease modification label claims to a more general focus on the clinical development approach. Our analysis of MS drug labels could imply that the FDA and EMA may be unlikely to accept disease modification-related indication claims for drugs to treat neurodegenerative disorders in general. We envision that a potential disease-modifying effect is more likely to be inferred from the label descriptions of the mechanism of action, clinical efficacy data and trial design, and target patient population. This poses a challenge for communication of the clinical benefit in a language that can be easily understood by patients and prescribers.

Characteristics of Single Pivotal Trials Supporting Regulatory Approvals of Novel Non-orphan, Non-oncology Drugs in the European Union and United States from 2012-2016.

For regulatory approval of a new medicine, the gold standard for demonstration of efficacy has traditionally been a minimum of two positive, adequate, and well-controlled clinical trials. Nevertheless, drugs to treat cancer and rare diseases are usually approved based on a single and often uncontrolled pivotal trial. In contrast, little is known about single pivotal trial approvals for non-orphan, non-oncology drugs. Between 2012 and 2016, 23 novel therapeutic drugs were approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for 27 non-orphan, non-oncology indications each based on a single pivotal trial. Although there was considerable variation in the nature and strength of the efficacy evidence supporting these drug approvals, the majority (85%) of the pivotal trials were randomized and controlled. For all superiority trials, the primary outcome was met with a statistical significance of P ≤ 0.005. Most approvals were supported by additional efficacy data from nonpivotal studies.

The effect of extracts of Searsia species on epileptiform activity in slices of the mouse cerebral cortex.

ETHNOPHARMACOLOGICAL RELEVANCE: Searsia dentata and Searsia pyroides are used in traditional South African medicine to treat convulsions and epilepsy. Previous studies have demonstrated that extracts of these plants comprise compounds that bind to the flumazenil-sensitive site on the GABA(A) receptor. However, their use as anticonvulsant medicinal plants cannot be adequately explained by these findings. AIMS: The aim of this study was to examine the possible involvement of the glutamatergic system of extracts from the plants. MATERIALS AND METHODS: The mouse cortical wedge preparation was used for functional characterization of the extracts. The affinity towards the NMDA and the AMPA receptor was investigated using classical [(3)H]-GP39653 and [(3)H]-AMPA binding assays, respectively. RESULTS: The extracts of Searsia dentata and Searsia pyroides inhibited the spontaneous epileptiform discharges in mouse cerebral cortical slices with ED(50) of 0.62 and 1.67mg dry extract/mL, respectively. Both extracts displaced [(3)H]-GP39653 binding and significantly inhibited the NMDA-induced response during co-administration in cortical slices. CONCLUSION: In this study, the NMDA receptor antagonistic effect of the crude ethanolic extracts of these two South African medicinal plants was demonstrated.

European Marketing Authorizations Granted Based on a Single Pivotal Clinical Trial: The Rule or the Exception?

A minimum of two positive, adequate, and well-controlled clinical trials has historically been the gold standard for providing substantial evidence to support regulatory approval of a new medicine. Nevertheless, the present analysis of European Marketing Authorizations granted between 2012 and 2016 showed that 45% of new active substances were approved based on a single pivotal clinical trial. For therapeutic areas such as oncology and cardiovascular diseases, approvals based on a single pivotal trial are the rule rather than the exception, whereas new medicines within the nervous system area were generally supported by two or more pivotal trials. While overall similar trends have been observed in the US, the recent US Food and Drug Administration approvals of nervous system medicines based on a single pivotal trial suggest that a case-by-case scientific evaluation of the totality of evidence is increasingly applied to facilitate faster access of new medicines to patients suffering from serious diseases.

Differences in kinetics of structurally related competitive GABA(A) receptor antagonists.

Previously, 4-alkyl and 4-aryl substituted analogues of the low-efficacy partial GABA(A) receptor agonist 5-(4-piperidyl)-3-isothiazole (4-PIOL) have been identified as competitive GABA(A) receptor antagonists. These structurally related competitive antagonists show marked differences in their kinetic properties. The kinetics of 20 4-alkyl and 4-aryl substituted analogues of 4-PIOL, two 4-arylalkyl substituted 3-isothiazolol analogues and the classical GABA(A) receptor antagonist SR95531 was studied in cultured cerebral cortical neurons using whole-cell patch-clamp techniques. The kinetics of the antagonists was studied indirectly by measuring the changes in the response of the full GABA(A) receptor agonist isoguvacine (IGU) induced by concurrent application of an antagonist. When added, the majority of the antagonists did not affect the rate of deactivation of the IGU-induced responses. When removed, however, the majority of the antagonists slowed the reactivation phase of IGU implying that the dissociation of the antagonist from the GABA(A) receptor is the rate-limiting step. Surprisingly, the functional off-rates of the antagonists seemed to correlate better with the lipophilicity of the compounds than with the affinity and potency. This suggests that the dissociation of the tested antagonists from the GABA(A) receptor is restricted by lipophilic interactions, perhaps with the aromatic amino acids surrounding the GABA binding site.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions.

OBJECTIVES: This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. KEY FINDINGS: Current knowledge on the intestinal expression of the apical sodium-dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3-5, the multidrug resistance associated proteins (MRP) 1-6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/ß (OSTα/ß) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in-vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in-vitro parameters for transporters (K(m) /K(i) /IC50, efflux ratio). The applicability of using a cut-off value (estimated based on the intestinal drug concentration divided by the K(i) or IC50) has also been considered. SUMMARY: A re-evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered.