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Statistical Methods for Assessment of Complex Generic Drugs
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
In a number of PSGs, a three-arm, placebo-controlled, parallel design is recommended for clinical BE studies. While the use of a placebo control arm in a generic drug study may have ethical challenges, as the reference products have already proved to be effective, a placebo-controlled study can provide not only evidence of BE of generic and brand-name drugs but also direct evidence of effectiveness for generic drugs. Because of these controversies, at the planning stage of a study, it should be carefully considered whether a placebo arm should be included based on the indication being treated as well as scientific necessity. To prevent a non-effective drug from being approved, BE should be concluded if the test product is clinically equivalence to the reference product, and both the test and reference product are superior to the placebo group (Peters, 2014; US FDA, 2019a).
Selected Statistical Topics of Regulatory Importance
Published in Demissie Alemayehu, Birol Emir, Michael Gaffney, Interface between Regulation and Statistics in Drug Development, 2020
Demissie Alemayehu, Birol Emir, Michael Gaffney
The most direct way to establish the efficacy of a treatment is to show it to be superior to a placebo or an active agent in a superiority study. A placebo-controlled study is not always possible; therefore, use of an active control, where there is no expectation that the test drug is superior to the active control, may be necessary. The study objective is to show the test treatment is non-inferior to the active control within a protocol-specified non-inferiority margin (NIM). The rationale for a non-inferiority study primarily arises when the use of a placebo control is not ethical. The International Conference on Harmonization guidance E10: Choice of Control Group and Related Issues in Clinical Trials (ICH E10 2001) states that the use of placebo is unethical, “In cases where an available treatment is known to prevent serious harm, such as death or irreversible morbidity in the study population.” Clearly, one does not need ICH E10 guidance to realize that withholding the available treatment is unethical. In some cases, such as oncology treatments, this ethical dilemma can be avoided by an add-on design in which the test drug or placebo is randomly added to the active treatment. However, often a direct comparison of the test drug to the active drug is called for, resulting in a non-inferiority study. A non-inferiority design may also be chosen for less critical considerations such as when randomization to placebo would make informed consent or enrollment problematic.
Platelet-Activating Factor in Sepsis: An Update
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Reuven Rabinovici, Fizan Abdullah, Guenther Mathiak, Giora Feuerstein
The effect of PAF inhibition on healthy volunteers infused with endotoxin has also been evaluated (3 in Table 6). Five subjects received pretreatment with the PAF antagonist Ro 24–4736 18 hours prior to LPS (4 ng/kg, i.v.) administration in this double-blinded and placebo-controlled study. PAF antagonist–treated subjects experienced fewer symptoms including rigors at 1 hour and myalgias at 1–4 hours. This was associated with diminished peak cortisol and epinephrine secretion and almost complete inhibition of PAF-induced platelet aggregation ex vivo.
Therapeutic potential of GABAA receptor subunit expression abnormalities in fragile X syndrome
Published in Expert Review of Precision Medicine and Drug Development, 2022
Mathijs B. van der Lei, R. Frank Kooy
In addition to the neurosteroids, gaboxadol (also known as OV101 and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) has been developed as a selective δ subunit GABAA receptor super-agonist (Table 4). This compound rescued neuronal hyperexcitability in the amygdala of juvenile Fmr1 KO mice [98]. In adult Fmr1 KO mice a significantly reduced hyperactivity and prepulse inhibition was observed after administrating gaboxadol [99]. A recent study showed similar outcomes where treatment with gaboxadol restored all aberrant behaviors, including hyperactivity, anxiety, irritability, aggression, and repetitive behavior in adult Fmr1 KO mice [100]. These promising preclinical outcomes initiated a phase II double-blind clinical trial of gaboxadol in 23 participants with fragile X syndrome aged between 13 and 22 year [101]. After 12 weeks of treatment, no adverse reactions were found and most side effects were mild. The outcomes demonstrated an initial efficacy signal for gaboxadol in fragile X syndrome based on secondary clinician- and caregiver-rated endpoint outcomes, including Clinical Global Impressions-Improvement (CGI-I), Clinical Global Impressions-Severity (CGI-S), aberrant behavior checklist-community factor score for fragile X syndrome (ABC-CFXS) and Anxiety, Depression and Mood Scale (ADAMS) scores. Although the results need to be confirmed in a larger, randomized, placebo-controlled study in the future. Thus, preclinical and clinical studies indicate positive effects of targeting the δ subunit of the GABAA receptor with gaboxadol in fragile X syndrome.
Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans
Published in Endocrine Research, 2021
Esben Stistrup Lauritzen, Mads Vandsted Svart, Thomas Voss, Niels Møller, Mette Bjerre
However, seven days of starvation are required for the circulating FGF21 concentration to increase in humans,11,12 whereas fasting for up to 72 hours does not change FGF21 levels.13,14 In a placebo-controlled study, Gaich et al. reported an increase in 3-hydroxybutyrate (OHB) levels in patients with type 2 diabetes mellitus (T2D) after treatment with an FGF21 analog (LY2405319) for four weeks15 implying that FGF21 somehow may regulate ketogenesis in humans. Mice fed a ketogenic diet express increased FGF21 levels,8 whereas one human study indicates that ketogenic dieting results in decreased FGF21 levels.13 On the other hand, increased FGF21 levels have been reported in patients with T2D and “diabetic ketosis,”16 and activity in hydroxymethylglutaryl CoA synthase 2 (HMGCS2), which is the rate-limiting enzyme of ketogenesis, is associated with increased FGF21 expression in a human liver carcinoma cell line.17 Additionally, OHB is an inhibitor of class 1 histone deacetylases (HDACs),18 and inhibition of certain class 1 HDACs results in increased FGF21 production.19,20 Despite these diverging findings and the difference between animals and humans, the effects of acutely elevated ketone bodies on FGF21 levels have never been investigated.
The prescription opioid conundrum: 21st century solutions to a millennia-long problem
Published in Postgraduate Medicine, 2020
Michael J. Brennan, Jeffrey A. Gudin
Although data support the efficacy of opioid therapy for acute pain, long-term effectiveness is a more divisive question [4,8]. Perceptions are shaped by systematic reviews and meta-analyses that have concluded that the long-term efficacy of opioids for the treatment of chronic non-cancer pain has not been established due to a paucity of high-quality, long-term studies [4,19,20]. ‘Long-term’ evidence is typically defined as randomized, controlled studies that are of 1 year or longer duration, which is an unreasonable definition for a multitude of reasons. It would be unethical, let alone difficult, to recruit patients for a yearlong placebo-controlled study. Such a study would likely have a high drop-out rate. Furthermore, the requirements for approval of opioids for chronic pain is 12 weeks, as defined by the US Food and Drug Administration (FDA). Denouncing opioids for having a lack of ‘long-term’ effectiveness data is not realistic or fair and has been a major force behind the anti-opioid rhetoric and the pendulum swing away from opioids.