Getting a drug to market

Following on from his earlier paper,¹ Dr Ray Burnett reviews the later stages of the drug development process, involving progression from Phase II to Phase IV clinical trials

The development of a new drug leading to its introduction into clinical practice is a long and expensive process. The clinical trials in patients that are carried out over several years must be sufficiently rigorous to convince the licensing or regulatory authorities in each country where it is intended to market the drug, of its safety and efficacy. In the UK the relevant authority is the Medicines Control Agency (MCA); but other countries have an equivalent organisation (for example in the US it is the Food and Drugs Administration – the FDA).

The previous paper¹ described Phase I trials, in which the first exposure to human subjects takes place. This article will review the later stages of the drug development process.

Phase II clinical trials are generally the first in patients having the disease(s) under investigation, the major exception being the aforementioned Phase I trials of anticancer drugs in cancer patients. The aim is to demonstrate that the drug has the desired pharmacological activity without undue side effects. They may be called Phase IIA or 'proof of concept' trials. Limited numbers of patients are enrolled so as not to expose a large population to an ineffective or toxic drug – typically 50-100 in open studies.

Larger scale trials, known as Phase IIB, investigate the dose-response relationship of the potential drug. These determine the appropriate dose for Phase III trials. If clinical efficacy has been demonstrated in Phase I, then Phase IIB trials may be initiated without undertaking a Phase IIA stage trial.

Phase IIB trials may compare the investigational drug with placebo and/or established agents in small randomised treatment trials designed to estimate its efficacy relative to these controls. This enables the required patient numbers for Phase III trials to be optimally planned. Additionally, investigations of potential drug combinations in patients may take place at this stage, with the objective of estimating whether a combination is of sufficient activity to warrant a Phase III trial.

If the expectation of efficacy levels defined in the Phase II trials is fulfilled and no major safety issues have been disclosed, the decision to proceed to Phase III will be made. Sometimes the optimal dose and duration of drug treatment has been adequately defined in Phase II trials, but on other occasions two dosages, or differing durations of treatment at the same dose, will be investigated in Phase III trials.

Phase III trials must closely define both the efficacy and safety of the potential drug. Thus a large patient population with the targeted disease must be enrolled: European guidelines indicate that the usage of the drug in these trials should correspond as closely as possible to the intended use in clinical practice.

entry criteria

The intensive monitoring that patients undergo in Phases I and II does not normally take place. The entry criteria remain well-defined but are often broader than those of Phase II. These trials are called 'pivotal trials' and, due to the large numbers of patients involved, are usually multi-centre and often multi-national in scope. The majority of the clinical data upon which a marketing submission is based comes from these trials.

There is a difference in emphasis between the US FDA and the EMEA (European Agency for the Evaluation of Medicinal Products) in the requirements for approval of a new medicinal product. The former requires that efficacy of a compound is demonstrated to be superior to that of placebo in the target indication. (Clearly an exception to this would be a life-threatening disease where an established treatment is available.)

The EMEA, however, requires that efficacy is demonstrated against an active comparator, i.e. a drug that is already approved and marketed in the target indication. Note that superiority to the marketed drug would not necessarily be required, but a minimum of non-inferiority must be demonstrated within closely defined limits.

For both US and EU agencies, a minimum of two pivotal trials, with randomised allocation of treatments to patients, each showing the required efficacy, is required. (One trial versus placebo and one trial versus an approved drug may be sufficient). The only exceptions to these regulations are in rare diseases where the requisite numbers of patients cannot practically be found, and in situations where an improvement in survival and/or quality of life is clearly demonstrated against historical controls in serious diseases such as cancer or genetically inherited conditions.

side effects

With drugs intended for long-term usage, an accurate estimation of the rate of incidence of adverse events with respect to time must be made: European regulations require data on a minimum of 300 patients treated for six months and 100 patients treated for one year.

This enables not only the incidence of the characteristic side effects of the drug to be defined, but also less common side effects which might occur, say, in only 1-5% of patients treated. However, it is not unusual for several thousand patients worldwide to be treated in Phase III studies, in order to introduce the drug to opinion leaders in the relevant therapeutic area in many countries prior to launch, and to provide a broader database of the drug's efficacy and safety. Indeed, the regulatory authorities of many countries look more favourably on a new drug application if some clinical investigation has taken place in their own country.

In the 10 years or so, an evaluation of the socio-economic value of a new medicine has evolved, encompassed in a new discipline of pharmaco-economics. This is now an essential aspect of later phase clinical trials because manufacturers are required to provide evidence of the value of a product in terms of health benefits and quality of life, particularly in an era of managed health care. This information is essential in negotiations with regulatory authorities on the pricing of a new medication.

failure rates

Since the cost of a Phase III study runs into many millions of pounds, clearly the sponsoring company must be very confident prior to this stage that the drug will be accepted and will recoup the large investment. Indeed, only about 10% of potential new drugs that go forward to Phase III fail to reach the market. The failure rate is much higher at the Phase I and II levels.

Sometimes Phase III is subdivided into IIIa and IIIb. This essentially separates trials used in a marketing submission (IIIa) from those which are ongoing at the time of submission or started prior to approval (IIIb). Such studies may provide supportive data if needed or investigate new drug combinations, a different duration of treatment, etc.

Phase IV trials are those conducted in the approved therapeutic indication after marketing approval of a drug has been obtained. (Investigation of a potential new indication would require further pivotal Phase III trials.) They may be small trials designed to provide information about the characteristics of a drug in specific populations such as the elderly or children, or large-scale trials designed to investigate long-term benefits or hazards with a drug. Included in the latter group are Post-Authorisation Safety Studies (PASS), formerly known as Post-Marketing Surveillance (PMS) studies.

Primary disease prevention studies, which may enrol many thousands of patients, are perhaps the best known of Phase IV trials: these include, for example, the long-term administration of cardiovascular drugs for the prevention of heart disease, and the adjuvant therapy of various cancers.

While many of these trials will be sponsored by the pharmaceutical company which markets the drug, it is not always the case: individual physicians, independent groups or governmental organisations such as the Medical Research Council in the UK, may initiate trials with a marketed drug, with or without direct support from pharmaceutical companies.

The time taken from synthesis of a chemical compound to its appearance as a new drug for prescription can vary widely: the range today is 10-15 years. This range has increased substantially in the last 30 years, with a concomitant increase in costs.

Drugs intended for prolonged use must undergo long-term study in clinical trials, whereas those for acute illness do not need to be administered to patients for extended periods of time, and the development time is on average shortest in such compounds. The longest periods come at the stage prior to first use in man, in which extensive pharmacological and animal testing is carried out, and at the Phase III clinical trial stage, in which large numbers of patients are required to be enrolled.

important considerations

Since patent protection in Europe is limited to 20 years (from date of filing), there is an understandable emphasis placed by pharmaceutical companies on an efficient development process to ensure optimal timelines are achieved.

The pharmaceutical industry today is a highly regulated one. Drug development is a rational, stepwise process involving multi-disciplinary teams over a long period of time.

The globalisation of the clinical trials programme is now a reality. Go/no go decisions are made at the end of every phase of development, and patient safety as well as drug efficacy is of paramount importance.