What my own Agenda for Change will encompass
After years in the doldrums clinical trials are back, thanks to the new contract, says Dr Peter Stott
Ten years ago, clinical trials on licensed and unlicensed medicines were common in general practice. Since then, stringent changes to the regulatory requirements for clinical studies have made them less usual. However, clinical research is still a major interest for a few practices and there is every reason why it should expand. The new GP contract has created an environment where computerisation, patient registers and standardisation of clinical practice are becoming the norm. This is exactly the kind of environment in which clinical research can flourish.
Four phases of clinical trials
Phase I studies: clinical pharmacology studies on volunteer humans and other animals to determine the pharmacokinetic, metabolic, pharmacodynamic and safety data of the product.
Phase II studies: to confirm kinetics, dynamics, efficacy and safety in relatively small groups of patients. Before phase II trials can begin, the drug must receive a clinical trials certificate or clinical trial exemption certificate.
Phase III studies: formal therapeutic trials to establish the safety and efficacy in large groups of patients. The results of these trials will be submitted to the Medicines Commissions Agency (UK), the European Medicines Agency (EU) or Federal Drug Agency (US) so that the product can receive a licence for marketing. The majority of these series will be randomised controlled trials against placebo or the current 'gold standard' competitor drug.
Phase IV studies: formal therapeutic studies once a licence has been issued and the product has been marketed. These studies will consider the product's place against its competitors.
GP clinical studies
Most GP studies (but not all) will be phase III and IV. A further class (post-marketing surveillance) involves observational studies involving many GPs and thousands of patients aiming to provide an indication of adverse reactions, cost-efficacy or quality of life data. Southampton's prescription event monitoring (PEM - green card) system is an example of this. These are actually a sub-class of phase IV.
Good clinical practice
Clinical trials in general practice became less common when the regulatory requirements known as 'good clinical practice' (GCP) were introduced.
GCP affects the sponsors of studies and their staff, the investigators (eg GPs and nurses) and the ethics committees. It is intended to improve patient protection and the quality of trials; to encourage good science and meticulous documentation; and by so doing improve decisions which stem from the data.
It is all good, interesting stuff, but it is also time-consuming. Because of GCP, practices that wish to become clinical trials centres now have to demonstrate much more than motivation. Sponsors will be looking for excellence in clinical style and real commitment, for example:
·evidence that site personnel have attended training sessions on GCP and its implications for primary care
·previous experience of trials run to GCP standards
·attendance at training days for doctor and nurse on the investigatory drug and the clinical trial
·practice organisation conducive to the requirements of GCP
·doctor motivated to become involved
·trained/dedicated research nurse
·clinic staff able to recruit, inform and monitor patients
·sufficient available time in the working week
·necessary basic skills and equipment (eg spirometry, electrocardiography, venesection, centrifuge); more complicated equipment required is usually provided on a loan basis
·facilities for archiving data for up to 15 years
·sufficient time for the investigator to meet with the sponsor's clinical research assistant (CRA) on a bi-weekly basis so as to audit the data and standards achieved; usually two-three hours every two weeks is sufficient
·doctor and other staff able to demonstrate meticulous ability to keep records and to act according to standard operating procedures (SOPs).
When investigators act according to SOPs, adverse consequences are covered by the study indemnity. When they do not, they must rely on their own medical protection cover.
For this reason, it is now less common for single practices to be chosen as investigators. Instead groups of practices act together under the supervision of a research director. Larger groups can provide the continuity and financial security that GCP requires. Larger groups are favoured by the sponsors too, because they create opportunities for cost-efficacy in recruitment and training of centres and in the deployment of CRAs.
Clinical research organisations
A second factor that has changed the clinical trials landscape has been the development of clinical research organisations (CROs). Ten years ago it was common for individual pharmaceutical companies to develop and trial their own drugs.
Now it more common for them to buy in promising molecules from third parties and for them to be developed via CROs international research-based companies that can bring the economies of scale to the understanding of international regulatory requirements, running of phase I-IV trials, recruitment and training of investigators, education of CRAs, laboratory services, data handling and publication of results.
Remuneration for practices involved in clinical trials usually follow BMA recommended fees which suggest £148 per hour, but payment is usually made per patient entered into the study costed at an estimate of the work involved.
Against this should be set the costs in time spent on training days, involvement with ethical committees and clinical work, and payment for a locum to cover NHS work. Some work must be done by a doctor. Some can be delegated to a trained nurse.
The costs of screening patients is usually not covered. I have done several trials in which transport to a local private hospital and costs of pre-study screening X-rays were born by the study, yet payment was only made according to the number of patients finally recruited.
Involvement in clinical trials is, however, about much more than money. Doctors who do this work learn to be well-organised and meticulous in their record-keeping. They must enjoy patients, their clinical medicine and the process of drug development.
Patients gain too. They not only learn a lot about their condition but the relationship which evolves during the course of a clinical study is by necessity one of full clinical honesty which inevitably extends to other facets of their care.
The doctor-patient relationship changes and, in my experience, usually for the better.
Doctors who wish to become involved in clinical studies should contact the medical department of relevant pharmaceutical companies or CROs. Often registration can be made online.
Peter Stott is a GP in Tadworth, Surrey, a former clinical trialist and adviser to several CROs
Related example websites
Description of clinical trials: www.royalmarsden.org/patientinfo/booklets/clinicaltrials/index.asp
Pharmaceutical company: www.lillytrials.com/
Review of current studies: www.drugsontrial.com/
BMA learning: www.bma.org.uk/ap.nsf/Content/