There are many sources of information about drugs varying from strictly factual details of tablet size, cost, etc., to theoretical disquisitions on pharmacology and pathology. The statements which make up the product information (PI) occupy a special but incompletely defined place among these sources. The PI is a document negotiated between the sponsoring company and the Therapeutic Goods Administration (TGA). The official origin of the PI should not be interpreted as indicating that the statements are complete or balanced. However, it does define what the pharmaceutical company sponsoring the drug can do when applying for listing by the Pharmaceutical Benefits Scheme and when promoting the product. The relevance of limitations implied by the PI is not clear-cut for the individual prescriber. These limitations are the topic of much current concerned discussion which also impinges on other sources of drug information e.g. therapeutic guidelines.

Creation of the product information
When a sponsoring company applies to the TGA for approval to market a medicine, it must supply a large amount of data. For new chemical entities, these data concern chemistry and quality control, pre-clinical studies and the results of clinical trials in support of the proposed indications. These data are accompanied by a draft of the PI.

The PI is defined in the Australian Guidelines for the Registration of Drugs as follows:

`The product information is to be regarded as a document which contains information sufficient to ensure safe and effective use of the drug under nearly all circumstances. It is to present a scientific, objective account of the drug's usefulness and limitations as shown by the data supporting the application. It is to be devoid of promotional material.

After registration, the product information must not be changed without TGA approval, except in the case of safety-related changes which may be notified to the TGA ...'.

Much of the content of the PI is valuable factual information concerning a drug's chemical properties, pharmacology, pharmacokinetics and interactions. In general, this material is not subject to controversy. However, frequently, there are differences between the sponsoring company and the TGA in the interpretation of the data relating to indications and safety. This may lead to long negotiations before agreement can be reached on the document to be considered by the Australian Drug Evaluation Committee (ADEC) with the evaluation of the actual data presented. Safety issues may sometimes cause problems, but usually only over the wording in the PI. Industry is often receptive to the inclusion of additional warnings, presumably for legal considerations. Indications are based on the clinical studies submitted and, while this is proper, it does lead to some problems.

Problems and inconsistencies
The PI is rooted in enactments and regulations of the Commonwealth which give it the aura of a legal document. Because of this special status, it is important to examine problems which may arise when the document is used to curtail freedom of action.

Although the guidelines for registration state clearly that changes in indications cannot be inserted into the PI without the approval of the TGA, the need to update indications in the light of new information is not stated. Our knowledge of a drug matures after marketing and it is uncommon for all the indications to be defined when the marketing application is lodged. Of course, if a lucrative new market opens for a drug, the sponsoring company is likely to institute formal studies to support that use. It is willing to undergo the expense and pain of applying for the new indication and negotiating the required changes in the PI. Conversely, official acceptance of the new indication may not have any commercial advantage e.g. if only a few patients needed the drug or if it was already being prescribed for that indication, despite its absence from the PI. Common sense would be on the side of the company ignoring the PI problem. An example of this is the common use of calcium channel blockers for the treatment of angina, although some drugs or dosage forms do not have official approval for this indication.

Obsolescence of PI has been even more obvious for drugs of such antiquity that their introduction pre-dates the regulations. In the recent past, some of these hoary documents included indications no longer having currency in medical practice. The pharmaceutical industry is making considerable efforts to update these, but the problem will recur unless there is a continuing revision. This is a formidable task, but the issue has been addressed in discussions between representatives of the industry, the TGA and the ADEC.1

The omission of a major potential indication from the PI can occur because the data submitted by a drug company have been influenced quite reasonably by marketing or other commercial considerations. This can distort markedly the relationship between the PI and clinical practice.

This type of failing could be remedied even under the present system, with the expenditure of sufficient money and effort, by the sponsor conducting and submitting adequate trials to justify the omitted indication. This is more difficult in some areas such as oncology or infectious diseases as it is impossible to assemble sufficient numbers of patients with comparatively uncommon tumours or infections for a trial.

A consequence of the way drugs are developed is that several similar products frequently reach the market sequentially over several years. Each is required to go through the regulatory process which means that data must be submitted to support each proposed indication. The studies undertaken by companies may well differ, sometimes in quite substantial ways. Therefore, due to the data submitted, one angiotensin converting enzyme (ACE) inhibitor could be approved only for hypertension and another only for cardiac failure, even though their properties were effectively identical. Adverse effects may also be a source of problems. If oligohydramnios and fetal death are reported for one ACE inhibitor, is it a property of the whole group or not? Should these effects be noted in the PI of a drug for which they have not been reported? There may be no reports because pre-marketing trials have excluded pregnant women or those likely to become pregnant. In the past, the ADEC generated guidelines for certain classes of drugs, e.g. beta blockers and ACE inhibitors, to define those statements which had to be included in the PI or for which convincing arguments had to be provided to justify their omission. However, this practice has been discontinued.

These problems are not confined to Australia. Not infrequently, there is considerable variation in the content of PI approved in different countries. The Australian document may differ not only from the PI produced by countries with poorly developed regulatory procedures, but also from the PI approved by sophisticated agencies such as those in Canada, Sweden and the U.S.A.

Implications for the pharmaceutical industry
A drug company is constrained by the conditions of registration to promote only those indications which are approved in the PI. This sets limits on the claims which are made in public promotional material, although what happens privately between doctor and detailer is less easily controlled. One need only look at the advertisements in a 30 year old journal to be convinced that there are many benefits from this constraint on promotion. Furthermore, this rule encourages the systematic study of a drug by its sponsoring company. Conversely, if a particular drug is in widespread use for an unapproved indication, perhaps it would be better if the best information were made available to prescribers rather than have them prescribe on the basis of hearsay or an incomplete presentation of the facts. It would seem reasonable that drug companies should have freedom to respond to individual prescribers' requests with factual information about the use of their drug, even outside approved indications. Wide distribution of reprints recommending unapproved uses is closer to the line, and there is no doubt that imaginative marketing can sail pretty close to the wind at times. Some middle course respecting the spirit but not necessarily the letter of the law is desirable.

Implications for prescribers
Prescribers in the lawful practice of their professions are specifically excluded from the operation of the Therapeutic Goods Act and it is thus silent about the obligations of prescribers with regard to the PI. Given the origin of the PI, it cannot be regarded as necessarily a complete or up-to-date statement of acceptable practice. The consequences of any suggestion that it is somehow reprehensible to prescribe a drug for an unapproved indication is to put clinical practice into legal and bureaucratic shackles which would be intolerable for doctor and patient. The use of calcium channel blockers in angina is an example of how absurd this would be. In the case of antibiotics, the PI should not impede the use of a drug based on intelligent extrapolation of microbiological and pharmacokinetic data, even though that indication had not been supported by clinical trial data.

However, litigation related to the liability of prescribers may result in decisions which are at odds with rational medical practice. Although there appear to have been no examples where this question has been raised successfully, a practitioner would be wise to have good reasons for using a drug for indications not included in the PI. This issue needs wide discussion by interested parties to avoid, on the one hand, unacceptable distortions of medical practice and, on the other, undue vulnerability of the sensible prescriber.

Implications for therapeutic guidelines
There has been much recent discussion of the benefits of peer-consensus therapeutic guidelines in assisting prescribers to make the most cost-effective use of medicines.

Antibiotic Guidelines, now in its 8th edition, has been produced since 1978, and there are 5 companion volumes:

Analgesic Guidelines

Psychotropic Drug Guidelines

Cardiovascular Drug Guidelines

Gastrointestinal Drug Guidelines

Respiratory Drug Guidelines

Antibiotic Guidelines has been recommended by the Health Departments of all States and Territories, but it must be remembered that the guidelines are not proscriptive, but serve as a benchmark. As far as possible, the recommendations in the guidelines do not deviate from the approved PI, but they are designed to serve the needs of the prescriber. They give recommendations for all common and many uncommon clinical presentations, since the prescriber does not have the luxury of declining to treat patients because they do not fit the definitions in some arbitrary document. The guidelines are therefore prepared to make recommendations based on evidence which would not justify inclusion of an indication in the PI.

The PI is an excellent source of authentic information. However, it is not a complete statement of acceptable prescribing practice, nor can it automatically be accepted as being up-to-date. Because of these shortcomings, there are significant problems in regarding the PI as the final arbiter of good prescribing. On the other hand, it is reasonable that active promotion by the pharmaceutical industry should be based on acceptable evidence and thus promotion should be limited to indications included in the PI. However, at what level does provision of factual information become promotion? There should be wide debate within the community to define more clearly the status of the PI as a yardstick for judging prescribing practice.


Self-test questions

The following statements are either true or false.

1. Drugs cannot lawfully be prescribed for unapproved indications.

2. The approved product information provides the most up-to-date information about a drug.

Answers to self-test questions

1. False

2. False


M.L. Mashford

Reader in Clinical Pharmacology, University of Melbourne, Department of Medicine, St Vincent's Hospital, Melbourne