Healthy volunteer studies

Phase 1 trials are the first in man studies of a new drug in humans. These studies are usually carried out on small samples of subjects. The idea here is to determine the safety of the drug in a small and usually healthy volunteer study population. 

The majority of healthy volunteer studies are conducted by contract research organisations (CROs), which recruit subjects from the general public by advertising and word of mouth. The composition of the volunteer database depends to some extent on the location, some being comprised mainly of students or the local residential population, others, particularly in large cities, having a preponderance of backpackers and temporary workers. The source of volunteers does have implications for safety, motivation and withdrawal rates. The more itinerant volunteers may not be available for follow-up and little may be known about their medical background. While the professional volunteer is wholly inappropriate, a stable population of volunteers who understand what is involved... 

Procedures for recruitment of volunteers vary slightly between organisations conducting healthy volunteer studies, but the checklist of procedures provided in Box 4.7 is generic. 

The requirements of GCP, as described in the ICH guidelines, are presented in Chapter 7 and will not be discussed further here. However, it is emphasised that the standards required of large clinical trials in patients apply equally to small clinical pharmacological studies in healthy subjects. Studies should be conducted in accordance with SOPs. Many SOPs will resemble those pertaining to later phase clinical trials, but some will be specific to healthy volunteer studies. Details of procedures not covered by SOPs should be specified in the protocol. Studies must be monitored by the sponsor or a representative the monitor should not be one of the investigators so that monitoring visits and assessments can maintain objectivity. 

The word "tolerability" is perhaps a little clumsy but it describes accurately what is assessed, namely how well the drug is tolerated by those to whom it is administered. This last qualification is necessary because there are many instances in which a drug is better tolerated or less well tolerated by young healthy volunteers than by patients. For example, anxiolytics and tricyclic antidepressants are usually far better tolerated by patients with depression than by healthy volunteers. However, healthy volunteer studies generally provide useful information about tolerability even if it may under- or overestimate tolerability in patients. Many adverse reactions wiU be directly related to the known pharmacological activity of the drug and are therefore predictable. 

Qrme M, Harry J, Routledge P, et al. Healthy volunteer studies in Great Britain the results of a survey into 12 months activity in this field. Br J Clin Pharmacol 1989 27 125-33. 

In the United Kingdom, healthy volunteer studies were subject to self-regulation by the pharmaceutical industry and consequently only the clinical trials in patients had to be covered by a CTC. However, as stated earlier, clinical trials in the UK are now regulated under EU Clinical Trials Directive (2001/20/EEC) fully implemented in the UK. 

Other general effects experienced by volunteers on SSRIs compared with placebo are similar to side effects noted in clinical trials. They include drowsiness, headache, nausea, diarrhoea, dizziness, general malaise, tremor, restlessness and insomnia (Lader et al. 1986 Raptopoulos, McClelland, Jackson 1989 Saletu et al. 1991). SSRIs are known to be associated with impaired sleep. Healthy volunteer studies consistently report impaired sleep (Mayers Baldwin 2005). In clinical trials around 25% of patients report insomnia (Winokur et al. 2001) but some patient studies find sleep improves overall on SSRIs (Mayers Baldwin 2005). 

While dozens of such healthy volunteer studies have been safely conducted, the catastrophic syndrome of T cell activation and depletion, cytokine release, and multi-organ failure seen in the 2006 Tegenero 1412 phase I study [34] reminded clinical investigators, sponsors, and regulatory agencies of the very... 

To avoid false conclusions. The use of placebos is valuable in Phase I healthy volunteer studies of novel drugs to help determine whether minor but frequently reported adverse events are drug-related or not. Placebos are also helpful to distinguish between real and imaginary responses in short-term trials with new analgesic agents. 

Healthy volunteers are usually paid to take part in a clinical trial. The rationale is that they will not benefit from treatment received and should be compensated for discomfort and inconvenience. There is a fine dividing line between this and a financial inducement, but it is unlikely that more than a small minority of healthy volunteer studies would now take place without a fee for service provision. It is all the more important that the sums involved are commensurate with the invasiveness of the investigations and the length of the studies. The monies should be declared and agreed by the ethics committee. 

Healthy volunteer studies designed solely to compare bioequivalence of a new medicine with one that currently has consent to distribute are not considered to be clinical trials and do not require approval. 

Another study in six healthy volunteers studied the pharmacokinetics and bioavailability of anthocyanidin-3-glycosides from either blackcurrant juice or elderberries (24). As with other studies listed previously, these investigators found very little ( 0.04% from blackcurrant juice to 0.4% from elderberry extract) of the dose recovered in the urine, suggesting low bioavailability. Though the half-life of the anthocyanidins was similar regard-... 

The design of individual studies that address possible interactions through the CYP450 metabolic pathway are, although often somewhat stereotypical, never completely standard. Usually these are phase I healthy volunteer studies which have primary end points of a pharmacokinetic nature. The studies can usually be done in an open-label fashion and without the use of placebo, because the end point is objective drug concentrations reported in the laboratory cannot be influenced by investigator bias. 

It defines clinical trial as any investigation on human subjects intended to discover or verify the clinical, pharmacological and/or other pharmaco-dynamical effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s), and /or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product with the object of ascertaining its (their) safety and/or efficacy, and it defines subject as an individual who participates in a clinical trial as a recipient of either the investigational medicinal product or a control. Thus, healthy volunteer studies are included. 

At the time of writing, the conduct of studies in non-patient volunteers in the UK is not regulated by the Medicines Act (1968). Similarly, studies in non-patient volunteers in the Netherlands, Belgium and some other European countries do not require regulatory approval. This situation is about to change, as the EU Directive issued in 2001 will require to be implemented in all European countries by 2004. All healthy volunteer studies will then require regulatory approval in addition to that of an ethics committee. The Directive, with which all member states must comply, makes no distinction between healthy volunteer studies and clinical trials in patients who may benefit from treatment. However, the precise details of documentation required for authorisation of healthy volunteer studies may vary from country to country it is possible that the application in the UK will be somewhat less detailed than the current Clinical Trials Exemption. 

There are no accurate data that provide a comprehensive picture of the extent of healthy volunteer studies and hence of the incidence of adverse reactions. However, surveys and clinical series have been published from time to time. In 1984 the ABPI requested information from its member companies on their activities in this area. Of the 43 companies that responded, 28 conducted in-house studies and 41 commissioned external work. In the in-house studies, there were 18 671 subject exposures to drugs. There were no deaths or life-threatening suspected reactions. The incidence of serious suspected reactions that might have been attributable to drug was 0-27 per 1000 subject exposures. Of the 8733 subject exposures in external studies, there was one death on which the inquest reported an open verdict and no life-threatening suspected reactions. The incidence of suspected serious reactions was 0-91 per 1000 subject exposures. 

Habit and preference form the basis for choosing cohort sizes for FTIH healthy volunteer studies. In reviewing studies reported in the literature, it was observed... 

In the healthy volunteers study, the Turbuhaler and pMDI inhalers were also analyzed in vitro. Intradevice variability, expressed as a coefficient of variation (CV), was 6.4% for pMDI and 18.2% for Turbuhaler, a significant (/kO.001) difference. Also the interdevice variability was significantly higher for Turbuhaler than for pMDI the ratio of CVs was 2.0 (p=0.023). 

Miscellaneous effects the drug has shown anticonvulsant activity and hypothermic effects in animals. In one healthy volunteers study 6 mg and 12 mg doses reduced oxygen consumption from baseline by 3-8%. Mean energy consumption also decreased by 5-9% from basehne. 

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