Clinical Pharmacology and Therapeutics

CHAPTER 15
INTRODUCTION OF NEW DRUGS
AND CLINICAL TRIALS
● History 86
● UK regulatory system 86
● The process of drug development 86
● Preclinical studies 87
● Clinical trials 87
● Clinical drug development 89
● Generic drugs 90
● Ethics committees 91
● Globalization 91
HISTORY
Many years before Christ, humans discovered that certain
plants influence the course of disease. Primitive tribes used
extracts containing active drugs such as opium, ephedrine,
cascara, cocaine, ipecacuanha and digitalis. These were probably
often combined with strong psychosomatic therapies and
the fact that potentially beneficial agents survived the era of
magic and superstition says a great deal about the powers of
observation of those early ‘researchers’.
Many useless and sometimes deleterious treatments also
persisted through the centuries, but the desperate situation of
the sick and their faith in medicine delayed recognition of the
harmful effects of drugs. Any deterioration following drug
administration was usually attributed to disease progression,
rather than to adverse drug effects. There were notable exceptions
to this faith in medicine and some physicians had a short
life expectancy as a consequence!
Over the last 100 years, there has been an almost exponential
growth in the number of drugs introduced into medicine.
Properly controlled clinical trials, which are the cornerstone of
new drug development and for which the well-organized vaccine
trials of the Medical Research Council (MRC) must take
much credit, only became widespread after the Second World
War. Some conditions did not require clinical trials (e.g. the early
use of penicillin in conditions with a predictable natural history
and high fatality rate). (Florey is credited with the remark that
‘if you make a real discovery, you don’t need to call in the
statisticians’.) Ethical considerations relating to the use of a ‘nontreatment’
group in early trials were sometimes rendered irrelevant
by logistic factors such as the lack of availability of drugs.
It was not until the 1960s that the appalling potential of
drug-induced disease was realized world-wide. Thalidomide
was first marketed in West Germany in 1956 as a sedative/
hypnotic, as well as a treatment for morning sickness. The
drug was successfully launched in various countries, including
the UK in 1958, and was generally accepted as a safe and
effective compound, and indeed its advertising slogan was
‘the safe hypnotic’. However, in 1961, it became clear that its
use in early pregnancy was causally related to rare congenital
abnormality, phocomelia, in which the long bones fail to
develop. At least 600 such babies were born in England and
more than 10 000 afflicted babies were born world-wide.
The thalidomide tragedy stunned the medical profession, the
pharmaceutical industry and the general public. In 1963, the
Minister of Health of the UK established a Committee on
the Safety of Drugs, since it was clear that some control over
the introduction and marketing of drugs was necessary. These
attempts at regulation culminated in the Medicines Act (1968).
UK REGULATORY SYSTEM
The UK comes under European Community (EC) legislation
regarding the control of human medicines, which is based upon
safety, quality and efficacy. The UK Medicines and Healthcare
products Regulation Agency (MHRA) or the European Agency
for the Evaluation of Medicinal Products (EMEA) must approve
any new medicine before it can be marketed in the UK. All UK
clinical trials involving a medicinal product must be approved
by the MHRA. The MHRA is assisted by expert advisory
groups through the Commission on Human Medicines (CHM)
to assess new medicines during their development and licensing.
The MHRA is also responsible for the quality and safety
monitoring of medicines after licensing. Product labels,
patient leaflets, prescribing information and advertising are
subject to review by the MHRA. In the UK, there is also extensive
‘self-regulation’ of the pharmaceutical industry through
the Association of the British Pharmaceutical Industry (ABPI).
The National Institute for Health and Clinical Excellence
(NICE) is independent of the MHRA.
THE PROCESS OF DRUG DEVELOPMENT
Drug development is a highly regulated process which
should be performed under internationally recognized codes