Regulatory Review Of A New Drug Application

A drug regulatory authority requires the following:

• Preclinical tests

— Tests carried out in animals to allow some prediction of potential efficacy and safety in man (see Chapter 4)

— Chemical and pharmaceutical quality checks, e.g. purity, stability, formulation.

• The full process of regulatory review of a truly novel drug (new chemical entity) may take months.

• Knowledge of the environmental impact of pharmaceuticals Regulatory authorities expect manufacturers to address this concern in their application to market new chemical entities. Aspects include manufacture (chemical pollution), packaging (waste disposal), pollution in immediate use, e.g. antimicrobials and, more remotely, drugs or metabolites entering the food chain or water where use may be massive, e.g. hormones.

Regulatory review

Using one of the regulatory systems described above, an authority normally conducts a review in two stages:

1. Examination of preclinical data to determine whether the drug is safe enough to be tested for (predicted) human therapeutic efficacy.

2. Examination of the clinical studies to determine whether the drug has been shown to be therapeutically effective with safety appropriate to its use.7

If the decision is favourable, the drug is granted a marketing authorisation (for 5 years: renewable), which allows it to be marketed for specified therapeutic uses. The authority must satisfy itself of the adequacy of the information to be provided to prescribers in a Summary of Product Characteristics (SPC) and also a Patient Information Leaflet (PIL).

The PIL must also be approved by the licensing authority, be deemed fairly to represent the SPC, and be comprehensive and understandable to patients and carers. Where a drug has special advantage, but also has special risk, restrictions on its promotion and use can be imposed, e.g. isotretinoin and clozapine.

Central to the decision to grant a marketing authorisation is the assessment procedure undertaken by professional medical, scientific, statistical and pharmaceutical staff at one of the national agencies. In the UK these are employed as civil servants within the MCA and are advised by various independent expert committees (see above).

When a novel drug is granted a marketing authorisation it is recognised as a medicine by independent critics and there is rejoicing amongst those who have spent many years developing it. But the testing is not over; the most stringent test of all is about to begin. It will be used in all sorts of people of all ages and sizes and having all sorts of other conditions. Its use can no longer be so closely supervised as hitherto. Doctors will prescribe it and patients will use it correctly and incorrectly. It will have effects that

7 Common sense dictates that what, in regulatory terms is 'safe' for leukaemia would not be 'safe' for anxiety.

have not been anticipated. It will be taken in overdose. It has to find its place in therapeutics, through extended comparisons with other drugs available for the same diseases. Drugs used to prevent a long-term morbidity (e.g. stroke in hypertensive patients) can be proven effective only in outcome trials that are usually considered too expensive even to start until marketing of the drug is guaranteed. The effect of a drug at preventing rare occurrences requires many thousands of patients, more than are usually studied during development. Similarly rare adverse events cannot be detected prior to marketing, and it would be unethical to expose large numbers of trial patients to a novel drug for purely safety reasons.8

Postlicensing responsibilities

The pharmaceutical company is predominantly interested in gaining as widespread usage as fast as possible, based on the efficacy of the drug demonstrated in preregistration trials. The regulatory authorities are more concerned with the safety profile of the drug, and protection of public health. The most important source of safety data once the drug is in clinical use is spontaneous reporting of adverse events, which will generate 'signals' and raise suspicion of infrequent but potentially serious adverse events caused by the drug.9 Proving the causal link from sporadic signals can be extremely difficult, and is entirely dependent on the number and quality of these spontaneous reports. In the UK, these reports are captured through the Yellow Card system (see p. 69), which may be completed by doctors, nurses or pharmacists. Other countries have their own systems. The importance of encouraging accurate spontaneous reporting of adverse events cannot be overemphasised.

Postmarketing (Phase 4) studies are not generally regulated by legislation, although in the EU, in

8 Patients entering trials do not receive a novel drug because it may be the best drug for their condition: indeed, half (usually) are randomly assigned placebo or an alternate agent. After marketing, doctors should use a new drug only when they believe it an improvement (in efficacy, safety, convenience or cost) on the older alternatives.

9 Waller P C, Wood S M 1998 Regulatory Aspects of Adverse Drug Reactions. In: Davies D M, Ferner R E, de Glanville H (eds) Davies's Textbook of Adverse Drug Reactions 5th edn, Chapman & Hall Medical, ch 3, pp 20-28.

exceptional circumstances, they may be a condition of the marketing authorisation. Voluntary guidelines are in use for postmarketing studies agreed between industry and the regulatory authorities. All company-sponsored trials that are relevant to the safety of a marketed medicine are included; they clearly state that such studies should not be conducted for the purposes of promotion. Other studies investigating the safety of a medicine that are not directly sponsored by the manufacturer may be identified from various organisations, e.g. The Drug Safety Research Unit (Southampton, UK) using Prescription-Event Monitoring (PEM), the Medicines Monitoring Unit (MEMO) (Tayside, UK), and the use of computerised record linkage schemes (in place in the USA for many years) such as the UK General Practice Research Database at the MCA. All these systems have the important capacity to obtain information on very large numbers of patients, 10 000-20 000, in observational cohort studies and case-control studies which complement the spontaneous reporting system (see Chapter 4).

In the UK, many new drugs are highlighted as being under special consideration by the regulatory authorities, by marking the drug with a symbol, the inverted black triangle T, in formularies. The regulatory authority communicates emerging data on safety of drugs to doctors through letters or papers in journals, through specialist journals e.g. Current Problems in Pharmacovigilance in the UK, and for very significant issues by direct ('Dear Doctor') letters, and fax messages.

Two other important regulatory activities that affect marketed drugs are:

• Variations to licences

• Reclassifications.

Variations are substantial changes instigated usually by pharmaceutical companies, but sometimes by the regulatory authority, to the efficacy, safety or quality aspects of the medicine. Most significant variations involve additions to indications or dosing regimens, or to the warnings and contraindication sections of the SPC. They need to be supported by evidence and undergo formal assessment.

Reclassification means change in the legal status of a medicine and is the process by which a prescription-only medicine can be converted to one that is available directly to the public through pharmacies and shops. It follows a rigorous assessment process with a particular stress on safety aspects of the medicine and involves advice from the Committee on Safety of Medicines, and requires a change in secondary legislation. The purpose of reclassification is to allow easier access of the general public to effective and safe medicines.


It may be wondered why postlicensing/marketing surveillance and pharmacovigilance should be necessary. Common sense would seem to dictate that safety and efficacy of a drug should be fully defined before it is granted marketing authorisation. Pre-licensing trials with very close supervision are commonly limited to hundreds of patients and this is unavoidable, chiefly because this close supervision is impracticable on a large scale for a very long time.

Postlicensing studies are increasingly regarded as essential to complete the definitive evaluation of drugs under conditions of ordinary use on a large scale, these programmes being preferable to attempts to enlarge and prolong formal therapeutic trials.

It would also seem sensible to require developers to prove that a new drug is not only effective but is actually needed in medicine before it is licensed. But a novel drug finds its place only after several, sometimes many, years, and to delay licensing is simply impracticable on financial grounds. This ought not to be so, but it is so. A 'need clause' in licensing is not generally practicable if drug developers are to stay in that business. This is why comparative therapeutic studies of a new drug with existing drugs are not required for licensing in countries having a research-based pharmaceutical industry. A 'need clause' is, however, appropriate for economically deprived countries (see World Health Organization Essential Drugs Programme); indeed such countries have no alternative.

The licensing authority in the UK is not concerned with the pricing of drugs or their cost effectiveness. The cost of medicines does however concern all governments, as part of the rising costs of national health services. A serious attempt to control costs on drug usage by the introduction of national guidelines on disease management (including the use of individual drugs) and the appraisal of new and established medicines for cost effectiveness now operate through a government funded body called NICE (National Institute for Clinical Excellence). The impact of its recommendations on health care, on costs and the pharmaceutical companies response to it are awaited.

Licensed medicines for unlicensed indications

Doctors may generally prescribe any medicine for any legitimate medical purpose.10

But if doctors use a drug for an indication that is not formally included in the Product Licence ('offlabel' use) they would be wise to think carefully and to keep particularly good records for, if a patient is dissatisfied, prescribers may find themselves having to justify the use in a court of law. (Written records made at the time of a decision carry substantial weight, but records made later, when trouble is already brewing, lose much of their power to convince, and records that have been altered later are quite fatal to any defence.)

Manufacturers are not always willing to go to the trouble and expense of the rigorous clinical studies required to extend their licence unless a new use is likely to generate significant profits. They are prohibited by law from promoting an unlicenced use.

Unlicensed medicines and accelerated licensing

Regulatory systems make provision for supply of an unlicenced medicine, e.g. one that has not yet completed its full programme of clinical trials, for patients who, on the judgement of their doctors, have no alternative amongst licensed drugs. The doctor must apply to the manufacturer who may supply the drug for that particular patient and at the doctor's own responsibility. Various terms are used, e.g. supply on a 'named-patient' basis (UK); 'compassionate' drug use (USA). It is illegal to exploit this sensible loophole in supply laws to conduct research. Precise record-keeping of such use is essential.

10 In many countries this excludes supply of drugs such as heroin or cocaine for controlled/supervised maintenance of drug addicts. In the UK such supply is permitted to doctors.

But there can be desperate needs involving large numbers of patients, e.g. AIDS, and regulatory authorities may respond by licensing a drug before completion of the usual range of studies (making it clear that patients must understand the risks they are taking). Unfortunately such well-intentioned practice discourages patients from entering formal trials and may, in the long run, actually delay the definition of lifesaving therapies.

Decision taking

It must be remembered always that, though there are risks in taking drugs, there are also risks in not taking drugs,and there are risks in not developing new drugs.

The responsibility to protect public health on the one hand yet to allow timely access to novel medicines on the other, is one shared by drug regulators and developers. It is complicated by an ever increasing awareness of the risks and benefits (real, or perceived) of medicines by the general public.

Some new medicines are registered with the high expectation of effectiveness and with very little safety information; rare and unpredictable adverse events may take years to appear with sufficient conviction that causality is accepted.

In taking decisions about drug regulation, it has been pointed out that there is uncertainty in three areas.11

• Public reaction to the facts

• Future consequences of decisions.

Regulators are influenced not only to avoid risk but to avoid regret later (regret avoidance) and this consideration has a profound effect whether or not the decision taker is conscious of it; it promotes defensive regulation.

It is self-evident that it is much harder to detect and quantitate a good that is not done, than it is to detect and quantitate a harm that is done. Therefore, although it is part of the decision-taker's job to facilitate the doing of good, the avoidance of harm

11 Lord Ashby 1976 Proceedings of the Royal Society of Medicine 69: 721.

looms larger. Attempts to blame regulators for failing to do good due to regulatory procrastination, the 'drug lag'12 do not induce the same feelings of horror in regulators and their advisory committees that are induced by the prospect of finding they have approved a drug that has, or may have, caused serious injury and that the victims are about to appear on television.13 The bitterness of people injured by drugs, whether or not there is fault could be much reduced by the institution of simple non-adversarial arrangements for compensation (see p. 10).

This is not to ridicule the regulators and their advisers. They are doing their best, and commonly make good and sensible decisions that receive no congratulations.

Counterfeit drugs

Fraudulent medicines make up as much as 6% of pharmaceutical sales worldwide. They present a serious health (and economic) problem in countries with weak regulatory authorities and lacking money to police drug quality. In these countries counterfeit medicines may comprise 20-50% of available products. The trade may involve false labelling of legally manufactured products, in order to play one national market against another; also low-quality manufacture of correct ingredients; wrong ingredients, including added ingredients (such as corticosteroids added to herbal medicine for arthritis); no active ingredient; false packaging.

The trail from raw material to appearance on a pharmacy shelf may involve as many as four countries, with the final stages (importer, wholesaler) quite innocent, so well has the process been obscured.

Developed countries have inspection and enforcement procedures to detect and take appropriate action on illegal activities.

12 Nevertheless, regulatory authorities have responded by providing a facility for 'fast-tracking' drugs for which clinical need may be urgent, e.g. AIDS (see above).

13 The very last thing a drug regulator wishes to be able to say is, 'I awoke one morning and found myself famous': Lord Byron (1788-1824) on the publication of his poem, Childe Harold's Pilgrimage.

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