How clinical trials work

We, as patients, tend to take for granted the availability of ever-more sophisticated new drugs to aid us in treating our diseases.

Most of us are quite knowledgeable about the positive and negative attributes of the drugs we are taking, their interactions with each other and their relative merits, but know little about how the drug was developed or what processes were followed to declare it safe for human consumption.

From lab to shelf
It takes an average of 12 years for an experimental drug to travel from laboratory to pharmacy shelf, according to the office of Research and Development at the Pharmaceutical Manufacturer’s Association.

In 2000, the cost was estimated at $802 million per new drug.

Only one in every 1000 compounds that enter pre-clinical testing actually makes it to some form of human testing.

All drugs intended to treat people have to be tested on people first. These tests, called clinical trials, determine if a drug is safe and effective, what dosage form works and what side-effects can be expected.

The process starts with a drug sponsor, usually a pharmaceutical company, seeking to develop a new, useful and profitable drug for the market.

Designing a new drug
Contrary to earlier trial-and-error methods, scientists now design new chemical compounds relying on their knowledge of medical chemistry.

Before clinical testing, the drug’s main chemical and physical properties are analysed and the pharmacological and toxic effects tested on laboratory animals.

If the laboratory and animal studies show promise, the sponsor can file an IND (New Investigational Drug Application) with the US Food and Drug Administration (FDA). If approved, the sponsor may test the drug in people.

Phase I trials
The first set of human clinical trials for a new drug is called Phase I trials.

The new drug is given to a small number (20 to 80) of healthy volunteers (sometimes to sick patients with cancer or Aids) under strict observation to attempt to establish the dose range tolerated for single and multiple doses.

Researchers also investigate the effect of the drug on the body and measure the metabolism, absorption, distribution and elimination of the product.

These studies are called pharmacokinetic and pharmacodinamic studies and usually take up to one year.

If the drug does not have unacceptable toxicity and no major problems are revealed, the next step is to conduct a clinical trial in which the drug is given to patients who have the condition it is intended to treat, called Phase II studies.

Phase II studies
Phase IIa studies evaluate the efficacy and safety in selected populations of about 100 to 300 patients.

These studies often involve hospitalised patients who can be closely monitored. Objectives may focus on dose response, type of patient, frequency of dosing or other issues involved in safety and efficacy.

Safety is the primary concern in phase IIa trials.

Phase IIb studies (pivotal trials) are well-controlled trials to evaluate safety and efficacy in patients who have the condition the drug is indicated for. Here the efficacy is mainly demonstrated.

Phase II trials usually take about two years. If after the Phase II trials, the drug still looks viable, the clinical Phase III trials begin.

Phase III trials
Phase III trials can take three years or longer and involves populations of 1000 to 3000 patients for whom the medicine will be intended eventually.

They generate additional safety and efficacy data from large numbers of patients in controlled and uncontrolled designs.

Phase III trials provide much of the information needed for the package insert and labelling of the medicine.

Only one in five drugs that enter clinical trials will make it to this stage. The sponsor can now file a NDA (New Drug Application) with the FDA. The NDA must contain all of the scientific information the company has gathered and can consist of 100 000 pages or more.

Once the FDA approves the NDA, physicians are allowed to prescribe the drug to patients. The company must still submit periodic reports to the FDA, including reports on adverse reactions.

Phase IV trials
Phase IV trials are frequently undertaken by the manufacturer, in order to provide ongoing, additional safety and efficacy data on the product.

Phase IV trials may also investigate drug interactions, different formulations, dosages and duration of treatment.

Patients of different demographic groups may be studied. These trials are sometimes called post-marketing surveillance.

Bets Breedt, MBChB, B Med Sci, M Fam Med
Manager Investigator Services: Quintiles

1. Code of Federal regulations.
2. International Conference on Harmonisation guidelines.
3. Ken Flieger. Testing drugs in people. FDA Consumer July-August 1994.
4. Joanne Kabak. Clinical Trials: How drugs get from the test tubes to us.
5. T.A.M. Kramer. Drug Development. Medscape Psychiatry & Mental Health eJournal, 24 July 2002.

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