The approved product information (PI) is an important outcome of the drug registration process and provides the basis for prescribing practice. There is increasing emphasis on regular revision and updating to maintain the usefulness of the PI. This has required innovative changes to be made to the drug regulation process.The approved PI is a powerful tool in the selfregulation of the pharmaceutical industry, particularly with regard to advertising and promotion. It also limits the indications for which drugs may be subsidised under the Pharmaceutical Benefits Scheme (PBS). The consumer product information (CPI) is based on the approved PI. Although health professionals are not medically or legally constrained by the PI, it is essential for them to be familiar with the PI of drugs prescribed for their patients.

The pharmaceutical industry regards the approved product information (PI) as an extremely important outcome of the drug development and regulatory process. One suspects that it has a much more significant place in the conduct of a pharmaceutical company's business than it does in the affairs of the practising doctor. This is regrettable as the industry believes the PI represents the most accurate, secure and conservative information about a drug. However, the PI occasionally falls short of this ideal1, but there are reasons for this and improvements are possible.

Development of draft product information
In the early stages of a drug's development, the manufacturer considers the possible contents of the PI. This vision does, to some extent, fashion the development process. As the burden of proof rests with the sponsoring company, every attempt is made to ensure that data are generated to categorise and support virtually every statement in the PI. The contents of this embryonic PI will change as knowledge is accumulated. Eventually, after extensive review and critique by company clinicians and scientists, a standard (international) company PI, with supporting documentation, will emerge. This document forms the basis of negotiations with regulatory agencies throughout the world. Although companies would prefer and aim for a consistent PI worldwide, in practice the final approved PI may vary considerably between countries due to the differing attitudes of national regulatory agencies.

The regulatory process and approved product information
The underlying philosophy is that the PI should ensure the safe and effective use of the drug, be a scientific, objective account of the drug's usefulness and limitations, and be devoid of promotional material.

A draft PI forms part of the information submitted to the Therapeutic Goods Administration (TGA) for the registration of a new drug or variations to an existing drug in Australia.

The legal requirements of the drug regulatory process are defined in the Therapeutic Goods Act 1989 and associated Therapeutic Goods Regulations 1989. The practical requirements regarding submissions are outlined in the Australian Guidelines for the Registration of Drugs: Vol. 1 September 1992. Since the implementation of the recommendations in the Baume report2, the Australian drug registration process has been aligned with that of the European Union so submissions can be made in a format similar to that required in Europe. The submitted data are evaluated to see if they support the information in the draft (international) PI.

The PI is negotiated by company medical and scientific staff with officers of the TGA and is influenced by the recommendations of the Australian Drug Evaluation Committee (ADEC). The TGA also takes into account overseas PI, particularly from the U.S.A., Canada and Sweden.

For many years, negotiations surrounding the PI were lengthy and tortuous, usually starting late in the evaluation process and generally after the ADEC approval of a new product. The mean duration of this process for the 1990 calendar year was 299 days.2

Following the Baume report, the process has become much more streamlined. Negotiations start during the review of the submission and the PI is presented, virtually agreed, to the ADEC for ratification. Any changes proposed by the ADEC must be finalised within 30 working days.

It is important to remember that the PI does not represent all that is known about a particular drug. Increased knowledge about the drug results from continuing research. However, these data will only be incorporated into the PI when company clinicians and scientists feel the information is complete enough to satisfy the regulatory authorities. The prescriber may feel frustrated that the PI does not contain the latest indication, but should be reassured that the integrity of the PI is preserved and that subsequent revisions receive adequate appraisal. With this understanding, the PI should be a major source of information to be consulted before prescribing.

Mode of dissemination
The PI is meant to assist health care professionals, particularly the prescribing doctor. To this end, the PI is available in unabridged form in the MIMS Annual and the Prescription Products Guide. Parenteral preparations are generally packaged with the PI so it can be referred to when the drug is given.

The PI is widely available via company sales representatives and is provided in full or abridged form with journal advertising. Pharmaceutical companies also have medical departments which can provide information about their products.

Could the dissemination of the PI be improved? The answer probably lies in the greater use and acceptance of computers in medical practice as the PI could be made available on an electronic database. At present, all prescribing doctors should have access to a hard copy of the current version of the PI.

The product information and advertising
The Therapeutic Goods Act 1989 restricts a pharmaceutical company to promoting a product within the limits of the agreed PI. There is a legal framework for the TGA to police this activity and apply sanctions. In practice, there is self regulation by companies which follow the code of conduct of the Australian Pharmaceutical Manufacturers Association (APMA).* The code defines how companies may promote and advertise their products, and the relationship of these processes to the PI is clearly detailed. For instance, the code requires that the full, approved PI must accompany all promotional material for the first 24 months that a new chemical entity is advertised. There are also requirements regarding type size, major headings, position of PI in a journal relative to the advertisement and procedures for recent changes relating to product safety and the ongoing promotion of established products. The code has been given 'teeth' through the Code of Conduct Subcommittee which reviews possible infringements and can apply sanctions. This committee is broadly based, with legal, medical, academic, consumer and industry representatives. A representative of the TGA has observer status. The committee has effectively applied sanctions to infringing companies and publishes some of its findings in the Medical Journal of Australia. Self- regulation helps to keep advertising accurate and within the framework of the PI.

* The code of conduct is available from:
77 Berry Street
North Sydney 2060
Tel. (02) 922 2699 Fax. (02) 959 4860

Recent improvements
A major criticism of the PI is that it may not reflect the actual use of a drug in clinical practice. Although occasionally this criticism applies to recently registered drugs, it is more likely to apply to older products which have not been subject to the current regulatory process. Pharmaceutical companies do not like this state of affairs any more than prescribers and are endeavouring to rectify the situation. There are a number of initiatives which will help.

After product registration, the PI is not permitted to be changed without TGA approval. However, following the Baume report, companies may make safety changes which restrict the use of a drug by simply notifying the TGA. This sensible approach will ensure that information on adverse drug reactions is up to date. Possibly some other changes to the PI could be safely introduced by notification.

Following consultation between the ADEC, the TGA and the APMA, it was agreed that for older drugs marketed for more than 10 years, submissions may be based on journal articles and literature reviews, rather than on the detailed data which are required for new products. Drugs marketed within the past 5 years will continue to require individual studies and appropriate new data for evaluation. For drugs falling between these extremes, i.e. those marketed for more than 5 years but less than 10 years, requirements will be assessed on their merits.3 These initiatives will gradually facilitate the update of PI to reflect current clinical practice.

Further discussions are taking place on how to update the PI of products marketed before 1970. Some of these elderly PI documents require major improvements to bring them up to modern standards.

With the improved approval processes for new products, the harmonisation with the European Union and a more cooperative atmosphere between the industry, the TGA and the ADEC, the future looks bright. The PI may still vary from country to country, but there is no legal barrier to doctors prescribing drugs outside the indications approved in Australia. However, there should be good medical reasons, and peer support, before a drug is prescribed for an unapproved indication.

Other aspects
The PI is limited in its provision of comparative information and contains no economic data. Comparative data, so useful in clinical practice, may be obtained, if available, from company medical departments.

The PI provides a basis for negotiation with the Pharmaceutical Benefits Advisory Committee (PBAC) regarding listing on the Pharmaceutical Benefits Scheme (PBS). The PBAC is not permitted to list a drug for indications not found in the PI. As the PBAC concerns itself with comparative considerations, economic aspects and perceived need, listing on the PBS is far from automatic. PBS listing may be accompanied by restrictions such as those associated with authority prescriptions.

From 1 January 1993, all newly registered prescription pharmaceutical products must have a consumer product information (CPI) document available which is consistent with the approved PI. Drugs already on the market must have CPI available by 1 January 2002, but most companies will achieve this well before that date. All involved in the production, dissemination and regulation of CPI are going along a steep learning curve. Suffice it to say that there are times when one feels a more useful approach would be to educate the public to understand the PI!

The PI cannot be all things to all people. It should be viewed as the key source of proven information about a particular drug. It is not designed to take the place of therapeutic protocols or guidelines on drugs of first choice. Although the approved PI may have deficiencies, it undergoes considerable discussion and critique during development, and bias is generally absent. The prescriber should use the PI in conjunction with other sources of information. There might well be a reduction in iatrogenic illness if doctors were more familiar with the PI of the drugs they prescribe.


H.O. Wooller

Medical Director, Pharmaco-LSR, Sydney