It takes on average about 12 - 15 years to develop a drug from an idea through to a product that can be sold for use in patients. A little more than half of this time is spent testing the drug in the laboratory (known as 'pre-clinical' testing). The remainder is spent testing the product in humans (known as 'clinical' testing) and having the data reviewed by the regulatory authorities.

Preclinical Testing

The first step normally involves testing the new drug in the test tube with animal and human cells.  These tests help confirm that the drug has the type of effect on cells that might be helpful in treating the target disease.  They also help provide an understanding of how the drug might work in the body.  The second step normally involves testing the new drug in animals that display a similar disease to the target disease in humans.  The purpose of these studies is twofold - to confirm that the drug works and to establish the drug's harmful side-effects.Before moving onto testing in humans, various other steps are required such as:

• being able to manufacture the drug so that the product is completely standardised;
• determining the best way to administer the drug; and
• knowing what happens to the drug in the body.

Clinical Testing

Once the drug is ready to be tested in humans, for registration in the USA an application is made to the Food and Drug Administration (FDA) for permission to carry out such testing.  In Australia the regulatory body is the Therapeutic Good Authority (TGA).  This is an extensive review process where the FDA considers all the pre-clinical study results are considered to determine whether or not the drug has sufficient merit and safety to warrant being tested in humans.  If approved with this process in the USA, the drug is said to have Investigational New Drug (IND) status.  An application then is made to the Investigational Review Board or Ethics Committee of a particular hospital or clinic where the study is to be conducted.  The study needs to reach certain standards of scientific merit and ethical conduct before being approved.  The clinical program then is conducted in a series of steps known broadly as Phase I, II and III.

Phase I

Phase I clinical trials are mainly intended to answer questions regarding the safety and tolerability of a new drug.  It is not usual to look for or even expect any beneficial health outcome of the drug at this stage.  In fact, many Phase I studies involve healthy volunteers.  A common approach in Phase I is to give the drug to people on the basis of an increasing dosage.  The dosage is increased slowly over days or weeks until unwanted side-effects begin to appear.  The highest dosage that can reasonably be tolerated is known as the maximum tolerable dose (MTD).  Usually the MTD is the maximum dosage selected to be used into later studies. Apart from safety, other matters often studied in Phase I are bio-availability and pharmacokinetics:

1. bio-availability refers to the ability to deliver the drug in a usable form to the disease target.  Phase I studies are meant to determine whether the drug is best delivered orally, or by injection, or through the skin;
2. pharmacokinetics refers to the behaviour of the drug in the body.  This measures factors such as how long the drug remains in the body, whether the body breaks it down to other compounds and how it leaves the body.

Phase I studies usually only involve small number of individuals, typically 15-30.  Sometimes Phase I testing is divided into two steps known as Phase Ia and Phase Ib.  Phase 1a studies normally are conducted as a short-term study to ensure safety before embarking on the longer and more comprehensive Phase Ib study.

Phase II

Phase II clinical trials primarily are intended to demonstrate whether or not the new drug will provide any benefit ('efficacy'), and whether that benefit is sufficiently better than standard treatments to warrant further development.  Often a range of dosages is employed to define the best dosage in terms of safety and efficacy to adopt as the final dosage to be tested in later, larger studies.  Phase II trials are often placebo-controlled and double-blinded. T hat is, neither the patient nor their doctor knows whether the patient is receiving the drug or a dummy placebo.  Exceptions are life-threatening diseases such as cancer where there is no effective alternative therapy and it would be unethical to offer such patients a placebo treatment, or when the new drug is given in addition to the patient's usual drugs.  Phase II patients normally are very carefully selected and must meet certain strict criteria on such things as disease status, age, previous therapies and other diseases and medications.  For cancer therapies Phase II studies typically involve 50-200 patients and take 18-24 months to complete.

Phase III

The drug will only progress to a Phase III study if there is sufficient evidence from the Phase II study of clinical benefit and safety.  The primary purpose of a Phase III study is to evaluate the benefit of a new drug under real-life conditions.   Phase III studies usually are conducted in a number of different hospitals and clinics to ensure a range of operating conditions.  Phase III studies usually are placebo-controlled and double-blinded and can involve hundreds or even thousands of patients.  As a general rule, the number of patients is a function of how more beneficial a new drug is compared to standards therapies - the smaller the benefit, the greater the number of patients.  Testing under 'real life' conditions in larger numbers of patients provides the opportunity to observe any rare side effects of treatment or possible interactions with other treatments.

Regulatory Approval/Phase IV

The results from all the Phase I, II and III studies are submitted to the FDA (in the USA) and other regulatory authorities in other territories for review.  If the regulators agree that the data proves the efficacy and safety of the drug, and that it provides sufficient benefit over existing therapies, then the drug is granted New Drug Approval (NDA) status and can be marketed.  Once a drug is on the market and freely available, the Company is required to maintain a constant watch for adverse events and to report these to the FDA.  This ongoing review is known as Phase IV.

Some facts about drug development

Companies are bound by a number of constraints during drug development:

1. companies are forbidden by the FDA to make unsubstantiated claims about the product.  Until the new drug is approved by the FDA for a particular purpose, the Company cannot make any reference to its likely benefit to patients;
2. companies are unable to discuss clinical trial results during a trial.  Novogen conducts its clinical trials in accordance with international guidelines and these guidelines are intended to protect the privacy of individual patients and the integrity of the trial.  Generally, this means that Novogen cannot divulge any results until the trial is completed.  Also, while Novogen is the Sponsor of its different clinical trials, they are conducted under the auspices of hospitals and clinics who under the terms of the contract have total responsibility for announcing any results;
3. recruitment of trials. Novogen is unable to participate in recruitment of subjects to its clinical trials.  This responsibility is borne entirely by the hospitals and clinics running the trials.