Select Committee on Health Written Evidence


APPENDIX 42

Memorandum by The Association for Human Pharmacology in the Pharmaceutical Industry (PI 107)

1.  AHPPI

  The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) was founded in 1988. We have 152 members—physicians, nurses, clinical scientists, project managers and various types of support staff ( who work for organisations, such as pharmaceutical companies and contract research organisations (CRO), involved in the early development of new medicines. Most of the big pharmaceutical companies and CRO in the UK are represented among the membership.

  The purpose of the AHPPI is to provide a forum for continuing education in clinical pharmacology—the discipline that underpins early development of new medicines—and in the regulatory aspects of the early development of new medicines. We hold symposia with invited speakers, twice yearly. Membership of the AHPPI is £15 per year and attendance at symposia is free.

  We have links with other organisations involved in developing new medicines, such as the ABPI, Institute of Clinical Research, and Contract Clinical Research Association. Also, we share some of our symposia with the Clinical Section of the British Pharmacological Society, an organisation whose members are mostly from university departments of clinical pharmacology. The AHPPI is run by a committee and provides information to members via a website (www.ahppi.org.uk).

2.  PHASES OF DEVELOPMENT OF A NEW MEDICINE

  Medicines research is traditionally separated into four phases, although in practice they often overlap. Phases 1 to 3 are done before a licence to market the new medicine is applied for, and phase 4 is done after a licence has been granted. During phases 1 to 3, the material being tested is called an investigational medicinal product (IMP), whereas after licensing it becomes a medicinal product or simply a medicine. Phases 1 to 3 of a successful IMP can take up to 10 years. Few IMP survive all of the phases. The failure rate is highest in phase 1. The phases of development of a "typical" new medicine in humans are shown below.


PhaseNumber and type of subject Questions asked

1.100-200

healthy subjects
Is the IMP safe in humans?

What does the body do to the IMP? (pharmacokinetics)

What does the IMP do to the body? (pharmacodynamics)

Might the IMP work in patients?

2.200-500
patients with the target disease
Is the IMP safe in patients?

Does the IMP seem to work in patients? (efficacy)

3.1,500-5,000

patients with the target disease
Is the IMP really safe in patients?

Does the IMP really work in patients?

4.many thousands

patients with the target disease
Just how safe is the new medicine? (pharmacovigilance)

How does the new medicine compare with similar medicines?



  Trials of IMP in healthy subjects were excluded from the Medicines Act 1968, simply because healthy subjects derive no therapeutic benefit from an IMP. However, all clinical trials, including ones in healthy subjects, have been regulated since the EU Clinical Trials Directive 2001/20/EC was implemented in the UK on 1 May 2004. The main impact of the Directive is on phase 1 trials in healthy subjects.

3.  PHASE 1 TRIALS IN HEALTHY SUBJECTS

  IMP must not be tested in humans before the necessary pre-clinical studies (the chemistry, pharmacology, toxicology and pharmacy of the IMP ( have been completed.

  Most IMP can and should be tested first in healthy subjects. But the risk must be minimal. The first trials of an IMP in healthy subjects are usually of single doses of the IMP of increasing size. The next trials are usually trials of repeated doses. The aims of the early trials in healthy subjects are to assess the tolerability, safety, pharmacokinetics, and pharmacodynamic effects of the IMP, and to compare the findings with those in animals. Subsequent trials in healthy subjects may:

    —  assess the efficacy of an IMP or to define the dose for trials in patients, by measuring biomarkers or using challenge agents against which the IMP is tested;

    —  compare the bioavailability (how much gets into the bloodstream) or the bioequivalence (if the amount that gets into the bloodstream is not significantly different) of different formulations of an IMP;

    —  assess the effects of things such as food, gender, age and genetic differences on the activity of an IMP;

    —  assess the possible interaction of an IMP with marketed medicines; and

    —  assess the absorption, breakdown and elimination of a radiolabelled IMP.

  Some of these trials, such as interaction trials, may be done during any phase of IMP development. Compared with patients, healthy subjects are easier to find, more robust, free of other medicines, more likely to respond uniformly, and better at completing long and complex trials. Trials of IMP in healthy subjects have a good safety record.

4.  UK PHASE 1 TRIALS

  The AHPPI surveyed 29 UK phase 1 units that did trials of IMP for the pharmaceutical industry during 1999 and 2000. The total number of trials per year was just over 600. 82% were done by CRO, 17% by pharmaceutical companies with their own phase 1 units, and 1% by academic departments that provide a service to the pharmaceutical industry. Ethics committees took an average of 14 (range seven to 28) days from submission of an application to written approval. That response time formed the basis of the target of an average of 14 (maximum 21) days that the MHRA set itself to review an application for a phase 1 trial, after implementation of Directive 2001/20/EC.

  Since the AHPPI survey, the academic departments have stopped their service and two of the pharmaceutical companies have closed their phase 1 units. So, probably 90% of commercial phase 1 trials in the UK are now done by CRO. Some of the CRO are based in or are close to NHS hospitals, for safety reasons.

  One of the CRO (HMR) surveyed over 300 phase 1 trials that it carried out from 1993 to 2001. About one third of the trials came from UK sponsors, one third from sponsors in other European countries, and one third from countries outside Europe, mainly Japan and the USA. The average income per study in 2002 was £284,000 (range £40,000 to £830,000). If we assume that the data for HMR apply to the 600 phase 1 trials done in the UK each year, the total income is about £170 million per year, two thirds of which are exports. If companies do their phase 1 trials in the UK, they are more likely to do their late phase trials in the UK ("pull-through trials") as well. Also, phase 1 units use various subcontractors and support services, which need to be taken into account when assessing the overall contribution of phase 1 trials to the UK economy. Although income from phase 1 trials is small in comparison with that from the pharmaceutical industry as a whole, phase 1 trials are a vital part of medicines development.

5 .  COMPARISON OF EARLY AND LATE PHASE TRIALS

  Clinical development of a new medicine can take 10 years and cost up to £500 million, so time is money. At one time, only academic clinical pharmacology units did phase 1 trials in healthy subjects in the UK. In recent years, CRO have taken over that role because they can provide an efficient, effective and high-quality service that enables companies to plan and execute the early clinical development of their IMP to tight timelines. The ABPI estimates that the UK does over half of the commercial phase 1 trials done in Europe.

  The pharmaceutical industry would like but rarely gets such a service for phase 2 and 3 trials in the UK, which are usually done in a hospital setting. Recruitment of patients is often slow. Failure to keep to the protocol can render data unusable. Also, failure to comply with good clinical practice may impair the quality of the data, even if usable. Payments demanded by investigators vary widely for the same trial, and can be excessive. Academic institutions add overheads, often high, to investigators' charges. A strong pound sterling makes matters worse for overseas' companies. For those reasons, companies are increasingly placing their phase 2 and 3 trials outside the UK, in low cost areas such as Eastern Europe, Russia and India.

6.  IMPACT OF DIRECTIVE 2001/20/EC ON UK PHASE 1 TRIALS

  Feedback from AHPPI members since implementation of the Directive on 1 May 2004 indicates that the MHRA has been keeping to its target of 14 to 21 days to review applications for phase 1 trials, whereas the time for ethics committees to review applications for phase 1 trials has increased. Also, the MHRA and ethics committees are both proving slow to review and approve substantial protocol amendments, which are often essential to during phase 1 trials. That is causing serious difficulties for many CRO. Also, there is uncertainty about the future of many of the ethics committees that are currently allowed to review phase 1 trials in healthy subjects.

  The evidence so far suggests that the Directive has reduced the number of phase 1 trials being done in the UK. Some pharmaceutical companies are choosing to do their phase 1 trials in EU countries that have not yet fully implemented the Directive. Pharmaceutical companies from countries, such as the USA and Japan, that are outside the EU are deterred by the extra bureaucracy involved in doing their trials in the EU, and not just the UK.

  We intend to repeat our AHPPI survey of UK phase 1 units one year after implementation of the Directive, to get more objective information about its impact.

7.  REFERENCES

  Calder N, Boyce M, Posner J, Sciberras D. UK phase 1 units: an AHPPI survey 1999-2000. Br J Clin Pharmacol 2003; 56: 76-79.

  Boyce M, Warrington S. 312 studies of IMP in healthy subjects.

  Int J Pharmaceut Med 2002; 16: 179-183.





 
previous page contents next page

House of Commons home page Parliament home page House of Lords home page search page enquiries index

© Parliamentary copyright 2005
Prepared 26 April 2005