Human volunteer studies

Clinical trials are usually designed to study both safety and efficacy. They incorporate various design features to minimise bias such as 

In clinical trials, the data are analysed to identify adverse events that occur at significantly higher rates on the drug of the interest than on comparators. Usually the data from all trials are pooled in a global safety analysis. Clinical trials will identify most common adverse reactions but often have important limitations, including  

At the conclusion of a clinical trial, patients may be continued on treatment and followed-up for a period of months or years, generating more long-term safety experience (these are known as open-label extensions). When clinical trials are conducted entirely after marketing, they may provide important new safety information provided that they contain enough patients, and have few exclusion criteria and clinically relevant outcomes that are easily measured (e.g. mortality). Such studies are often called large simple trials.  

During the clinical trial phase of development, there is a major safety focus on the protection of trial subjects. Investigators are obliged to document and report serious adverse events promptly. If serious, unexpected and suspected to be related to the drug (this is known as a SUSAR - see Chapter 5), then a case should be unblinded and reported to regulatory authorities. The identification 

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Evidence for this human health linkage has been suggested from (a) epidemiologic studies of exposed human populations, (b) human volunteer studies, and (c) animal experiments 14). Air pollution levels measured in southwestern Ontario, for instance, have been compared with hospital... 

The critical dose of microorganisms which will irritiate an infection is largely uirknown and varies not only between species but also within a speeies. Animal and human volunteer studies have indicated that the infecting dose m be reduced significantly in the presence of trauma or foreign bodies or if aecompanied by a dmg having a local vasoconstrictive action. 

NoV can spread directly from person to person due to their low infectious dose. Human volunteer studies have estimated that a single infectious NoV particle could cause illness in a susceptible individual (Teunis et ah, 2008). 

The relationship between exposure and internal dose is known only for a few pyrethroids. Human volunteer studies have shown that, after a single oral administration, pyrethroids and the respective metabolites are excreted in urine within 24 hr and do not accumulate in the body. In field workers exposed to cypermetrin through the dermal route, urine excretion of the intact compound and its metabolites peaked 36 hr after exposure had ceased (WHO, 1989). 

Grattan T, Hickman R, Darby-Dowman A, Hayward M, Boyce M, Warrington S. A five way crossover human volunteer study to compare the pharmacokinetics of paracetamol following oral administration of two commercially available paracetamol tablets and three development tablets containing paracetamol in combination with sodium bicarbonate or calcium carbonate. Eur J Pharm Biopharm 2000 49 225-229. 

The pharmaceutical industry presents many new challenges to such a person which include the interface with pharmacy and pharmacology, toxicological research, human volunteer studies, clinical trials and post-marketing surveillance to name just a few. Product safety is a factor which impacts on all of those endeavours and the pharmaceutical physician will be expected to work and provide advice within that framework. It will be clear to anyone that evidence of lack of safety in a medical product is not good news for the company concerned and that some level of protective action will often be required which in extreme circumstances may involve product withdrawal. It is, therefore, essential that the pharmaceutical physician should be absolutely clear what constitutes lack of safety in relation to the intended use of the product. 

In view of the regulatory delay that was caused by the need to apply for a CTC, a Statutory Order (SI 1974/498) was made during 1974, to provide an exemption from the need to hold a CTC in such cases, subject to certain conditions. This order applied to trials conducted by doctors and dentists on their own responsibility (DDX). The basis of the clinical trial exemption (CTX) scheme, introduced in 1981, to include studies initiated by the pharmaceutical industry, was that together with a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and human volunteer studies, a clinical trial in patients may proceed without the need for the additional details normally required for a CTC or Product Licence application. This exemption scheme was based on the requirements that ... 

The evaluation of the contribution on relative efficacy by cathartic agents to the overall management of oral drug overdoses is often difflcult because of limitations of human volunteer studies that do not simulate clinical conditions, because of multiple therapies employed, because the dosage for cathartics used were not comparable, and because the expected theoretical effects were not observed. 

A controversial area of risk assessment concerns the possible effects of residues of antimicrobial drugs on the human gut flora, favoring the growth of microorganisms with natural or acquired resistance to the drug in question. Available risk assessment studies include studies in human volunteers, studies in germ-... 

Despite the lack of agreed guidelines for the tests involved, tests do exist and they comprise studies in human volunteers, studies in germ-free rats the intestines of which harbor human gut bacteria, and in vitro studies with bacterial populations. However, the selection of the most appropriate test system remains an open question. All tests investigate minimum inhibitory concentrations (MICs) that can be used in ADI calculations however, such ADI calculations tend to... 

The results of in vitro and human volunteer studies show that the best renin inhibitor to date is H-142. 

Tuohy, K.M., Finlay, R.K., Wynne, A.G., and Gibson, G.R., A human volunteer study on the prebiotic effects of HP-inulin-faecal bacteria enumerated using fluorescent in situ hybridization (FISH), Ecol. Environ. Microbiol., 7, 113-118, 2001. 

Thus, despite the value of human volunteer studies, the technical and ethical constraints for studying dermal absorption of pesticides in human volunteers prevail. As a consequence, only limited data on the dermal absorption of chemicals are available from human volunteer studies. This is in contrast to pharmaceutical products, where the use of human volunteers is considered to be the only relevant approach to generate data of precise relevance to man. 

In 2006, a survey in Italy revealed that herbal products were taken in combination with drugs by nearly 45% of the population. The information provided was derived from a multitude of sources that described interactions in the form of case reports, animal studies and, rarely, human volunteer studies. 

Tuohy KM, Ziemer CJ, Klinder A, Knobel Y, Pool-Zobel BL, Gibson GR. A human volunteer study to determine the prebiotic effects of lactulose powder on human colonic microbiota. Microb Ecol Health Dis 2002 14 165-73. 

Grafitt SJ, Jones K, Mason HJ, and Cocker J (2002) Exposure to the organophosphate diazinon Data from a human volunteer study with oral and dermal doses. Toxicology Letters 134(1-3) 105-113. 

No physiologically based pharmacokinetic (PBPK) models are available for tetrahydrofuran in animals. Based on human volunteer studies, a PBPK model for tetrahydrofuran was developed which predicts rapid elimination of tetrahydrofuran from the body. The human PBPK model predicts that repeated inhalation exposure of 200 ppm would yield end of the work shift levels of tetrahydrofuran of 5.1 ppm in breath, 57moll in the blood, and 100mol in the urine. 

The values estimated by allometric scaling were compared with those observed in the single-dose human volunteer study (Table 8.5). We predicted that for compound X in humans, the plasma... 

Griffin JR 1987. An international comparison on legislation regarding human volunteer studies . Ini. Pharm. J. 1 57-60. 

The basis of the CTX scheme is that, following an evaluation of a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and, when appropriate, human volunteer studies, a clinical trial may be permitted. This obviates the provision of the additional details normally required for a Clinical Trial Certificate or Product Licence application. 

The need for human volunteer studies and their nature and design will vary with the material to be studied, its use, and the route and degree of exposure. Thus, it is not possible to give a specific itemized list of human studies required on a generic basis. However, the following are some of the more frequently employed investigations ... 

Van Gelderen, C.E.M., Savelkourl, T.J.F., and Sangster, B., Safety Studies in humans, n. Human volunteer studies. Food Chem. Toxicol., 28, 775-778, 1990. 

Wilks, M.F. and Weston, B.H., Human volunteer studies with non-phase phannaceutical chemicals metabol-... 

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