Dosage trials multiplicity

The number of fresh varieties, dosage forms, and formulations in combination with the variability in botanical material make it impossible to evaluate all of these products in animal models or clinical trials. As a minimum, several products used by the patient community should be obtained and authenticated. The testing and selection criteria should include multiple-lot testing, cost, and product availability, and take into consideration how these products are used. Drug combinations are being examined... 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Although at first sight this definition does not appear to be clinically useful, multiples of MAC are employed in clinica trials to allow doses of different inhaled agents to be standardised and the effects compared. The term MAC hours (MACxduration of exposure in hours) is widely used as a measure of total dosage over time, and is especially useful in toxicity and pollution studies. In gas mixtures, MAC values are broadly additive so that, e.g. 0.5 MAC N20 combined with 0.5 MAC isoflurane is equipotent with 1 MAC isoflurane alone. 

Clinical (PK, PD, Safety and Efficacy) Human clinical studies can range in complexity from standard-design PK studies to complicated, long-term efficacy trials evaluating one or more indications in multiple populations. Human PK studies are used as the benchmark for establishing bioequivalence of conventional dosage forms. For traditional pharmaceuticals for which reliance on systemic exposure may not be suitable, PD or clinical safety and efficacy may be performed to show equivalence. 

In a randomized, double-blind, placebo-controlled, crossover trial the effect of the synthetic delta-9-tetrahy-drocannabinol dronabinol on central neuropathic pain was evaluated in 24 patients with multiple sclerosis (58). Oral dronabinol reduced central pain. Adverse events were reported by 96% of the patients compared with 46% during placebo treatment. They were more common during the first week of treatment. The most common adverse events during dronabinol treatment were dizziness (58%), tiredness (42%), headache (25%), myalgia (25%), and muscle weakness (13%). There was increased tolerance to the adverse effects over the course of treatment and with dosage adjustments. 

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. 

Two small comparative trials in HP-negative patients with histories of NSAID-related ulcer complications suggested that a standard dosage of a PPI and a nonselective NSAID have a GI safety profile similar to that observed with a selective COX-2 inhibitor. However, the comparative benefits and cost effectiveness of these regimens remain controversial. Cotherapy with a PPI and a selective COX-2 inhibitor should be considered in patients with multiple or life-threatening risk factors. ... 

In the case of many herbal products and nutritional supplements, evidence for their medical effectiveness based on controlled clinical studies is incomplete or nonexistent. CUnical trials of herbal products have been characterized by multiple variables, including their formulation, their chemical constitution, the dosages used, and the duration of treatment. Thus it has often been difficult to make recommendations regarding possible therapeutic benefits. 

Real proof of efficacy and safety comes from large, expensive Phase III trials. These usually involve up to several thousand patients at multiple sites around the world. These too are likely to be double-blind randomized controlled studies. By the time they re over, all the types of information—dosage, indication, efficacy, PK (including food effects, which can affect bioavailability), metabohsm, side effects, etc.—required for a package insert or product label (and hopefully one that fits with the original TPP) will be available from the combined trials. 

In other cases, a new dosage formulation is required to satisfy a new market segment. Oral solutions and chewable tablets are beneficial for a pediatric population. A slow-release preparation (such as percutaneous patches) may be preferred in elderly patients taking multiple drugs if it allows once-daily (or less frequent) dosing. Trials demonstrating safety and efficacy of new formulations are often conducted in Phase IV and typically act as the supporting information for an sNDA. 

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