Until quite recently, most effort towards the discovery and development of new antimicrobial agents was expended on compounds active against bacteria, but the demands of the market place have caused the emphasis to shift. Of 42 new antimicrobial agents released on to the UK market between 1990 and 1998 (Table 33.1), less than half were antibacterial agents, and antiviral agents now represent the largest single group of newly marketed compounds. Moreover, most new antibacterial agents are chemically modified variants of existing compounds, whereas entirely new classes of antiviral agent are starting to emerge.
Table 33.1 Newly marketed antimicrobial agents in three-year periods 1990–1998 (UK)
The progress of a new antibiotic from discovery to marketing is outlined in Fig 33.1. When a new antimicrobial drug is discovered or invented, the first indications of its activity and spectrum are usually gleaned from fairly simple in-vitro inhibition tests against a few common representative organisms. Organisms with special growth requirements, such as chlamydiae, mycobacteria, and mycoplasmas are usually excluded from such primary screening.
Fig. 33.1 Progress of a new antibiotic from discovery to marketing.
In-vitro screening tests will not detect potentially useful activity if in-vivo metabolism of the compound is a prerequisite for the antimicrobial effect (e.g. Prontosil; see Historical Introduction); nor will such tests reveal agents which might modify microbial cells sufficiently to render them non-virulent or susceptible to host defences, without actually preventing their growth. Furthermore, conventional laboratory culture media occasionally contain substances which interfere with the activity of certain antimicrobial compounds, which may consequently go undetected.
Despite these difficulties, in-vitro screening offers an extremely simple and generally effective way of detecting antimicrobial activity which has yielded a rich harvest of therapeutically useful compounds over the years. In contrast, the
rational design of antimicrobial agents that can disable vulnerable stages of microbial development has not been very fruitful so far, although new techniques of genomics, molecular modelling, and combinatorial chemistry offer the prospect that this might change in the future. Indeed, some of the new antiviral agents have been developed by targeting specific viral processes.
Development of new compounds
Compounds that pass the initial screening tests must be made available in sufficient quantities and in sufficiently pure form to enable preliminary tests of toxicity and efficacy to be carried out in laboratory animals, and more extensive and precise in-vitro tests to be performed. Pilot-stage production usually presents little problem, although considerable difficulties may be experienced in scaling up production at a later date, when relatively large quantities are needed for clinical trials and subsequent marketing.
Animal tests of toxicity, pharmacology, and efficacy are an indispensable part of the development of any new drug, but they also have certain limitations. Idiosyncratic reactions may suggest toxicity in a compound that would be safe for human use or, more importantly, adverse reactions peculiar to the human subject may go undetected. The pharmacological handling of the drug may be vastly different from that encountered in the human subject. As regards efficacy testing, animals have important limitations in that experimental infections seldom correspond to the supposedly analogous condition in humans, either anatomically or in the relationship of treatment to the natural history of the disease process.
If preliminary tests of toxicity and efficacy indicate that the compound is worth advancing further, full-scale acute and chronic toxicity tests are carried out in animals. These include long-term tests of mutagenic or carcinogenic potential, effects on fertility, and teratogenicity. Mutagenicity tests may also be performed in microbial systems (Ames test).
Provided the animal toxicity studies reveal no serious toxicity problems, the first tentative trials are undertaken in healthy human volunteers to investigate the pharmacokinetics and safety of the new drug in man. Once these tests have
been successfully completed, application may be made to the drug-licensing authority for permission to undertake clinical trials.
The proof of the pudding is in the eating, and no amount of in-vitro or animal testing can replace the ultimate test of safety and efficacy: therapeutic use in human infection. Nevertheless, the clinical trial stage remains, in many ways, the least satisfactory aspect of the testing of any new antimicrobial drug. The reasons for this are not difficult to find: ‘infection’ is not a static condition in which therapeutic intervention produces an all-or-none effect. Many factors, such as mobilization of the patient's own immune response, drainage of pus, or treatment of an underlying surgical or medical condition, may crucially affect the response to therapy. The patient may improve subjectively, even though the antimicrobial therapy has demonstrably failed to eradicate the supposed pathogen; conversely, the patient's condition may deteriorate despite bacteriological ‘success’.
Design of trials
Clinical trials should not be undertaken lightly. They are difficult to design, tedious to perform, and are fraught with ethical difficulties. The conduct of the trial requires close supervision by a medical practitioner dedicated to the task, who needs to have the full support of reliable and motivated nursing and laboratory staff, together with well-informed and compliant patients. Before undertaking a trial, a detailed protocol should be drawn up, defining the conditions for which the new treatment is intended, the dosage regimens to be used, and the treatment with which it is to be compared. Participating laboratories should be consulted to ensure that full facilities are available for the monitoring of microbiological progress and the detection of adverse reactions. Licensing authorities now require studies to conform to strict standards of good clinical practice and good laboratory practice.
Careful consideration should be given as to whether the trial should be open, single-blind (treatment known to the prescriber only), or double-blind (treatment randomly allocated in a fashion unknown to prescriber or recipient). In general, uncontrolled, open trials are unsatisfactory, except as preliminary indicators of safety and efficacy. They may also be used to gain information on the most appropriate dose of an agent. Controlled, double-blind trials are the most desirable scientifically, but are subject to ethical difficulties in that the prescribing doctor does not have full control over the patient's treatment. Whatever format is agreed, it is important that the new agent should be compared with current ‘best practice’ to avoid spurious claims of superiority.
Ethical considerations need to be taken fully into account. The basic principles which should govern all research involving human subjects are embodied in the Declaration of Helsinki, which was adopted by the 18th World Medical Assembly in 1964, with subsequent revisions. In many countries, health authorities have ethical committees that monitor clinical trial protocols. The committee will need assurance that the safety of the new compound has been satisfactorily established and will wish to know what form of patient consent is to be obtained. It will also require adequate safeguards for the detection of unexpected adverse reactions and may have views as to whether a double-blind format, or a placebo control, are acceptable.
Many ambitious trials fail because insufficient numbers of patients are found to fulfil the criteria required for the study. Alternatively, the condition may be one (acute cystitis is a good example) in which the natural cure rate is so high, and the efficacy of standard treatment so good, that huge numbers would have to be examined to establish the superiority of a new agent, although it may be possible to establish efficacy. It is essential to be reasonably sure, before the trial starts, that sufficient patients can be recruited to satisfy statistical requirements. During the conduct of the trial, regular checks of relevant microbiological, haematological, chemical, and radiological parameters should be made. All findings should be fully documented as soon as the information is available, rather than attempting to glean information from the patients' notes retrospectively, after the trial is completed.
Most countries have enacted some sort of legislation aimed at controlling the marketing of pharmaceutical products. In the US, federal regulations are administered by the Food and Drug Administration (FDA). Within the European Union, a Committee on Proprietary Medicinal Products issues guidelines for harmonizing regulatory requirements among member nations. The European Medicines Evaluation Agency, based in London, co-ordinates drug licensing and safety throughout the European Union, although companies can still seek registration of their products by national regulatory authorities.
In the UK, the Medicines Act of 1968 invested executive powers in the government health and agriculture ministers, who constitute the Licensing Authority. Ministers are advised directly and through the Medicines Commission of the Department of Health. The Licensing Authority, through its specialist advisory committees, reviews all pharmaceutical products intended for medical or veterinary use. The manufacture, promotion, and distribution of all medicines in the UK is
supervised by the Medicines Control Agency. The Medicines Commission acts as an independent agency in relation to particular issues and concerns, including any challenge to the decisions of the Licensing Authority.
Before clinical trials can be performed on a new drug in the UK, full toxicological data must be submitted to the Licensing Authority together with a full trial protocol and the names of the proposed investigators. Such applications are scrutinized by the Committee on Safety of Medicines (CSM), who must satisfy themselves that all reasonable criteria are met before recommending that a Clinical Trial Certificate, valid for 2 years, be issued.
Pharmaceutical manufactures have long complained about the delays inherent in processing applications for a Clinical Trial Certificate and firms in the UK may now be granted a Clinical Trial Exemption Certificate, provided certain criteria are met. In particular, the holder of the exemption certificate must undertake to notify any adverse reaction arising during the trial, or any other matter that might reasonably cause the Licensing Authority to doubt the safety or quality of the product.
When clinical trial data have been accumulated, an application for a Product Licence may be made. All valid applications are again passed to the CSM for scrutiny. In the UK new applications are judged solely on the grounds of safety, efficacy, and quality. If a Product Licence is refused, the application may be withdrawn or the applicant may elect to answer the objections raised, either in writing or in person before the CSM. Should the application still be refused, the applicant has the right of appeal to the Medicines Commission. Product Licences, once issued, are valid for 5 years.
Over the years, the requirements of licensing authorities world-wide (particularly for toxicological testing) have become progressively more stringent. Consequently, the cost of developing a new drug has escalated enormously. Attempts are being made to harmonize the drug registration requirements of Europe, the US, and Japan, but progress so far has been modest. The period between the discovery and marketing of a new product is seldom less than 6 years and may be substantially longer, although fast-track procedures have enabled some drugs, notably those used in the treatment of HIV infection, to be licensed much more quickly. Shortening the period is important to the company marketing the new drug, since it maximizes the time during which it can recoup the cost of research and development (which may exceed £300 million) and profit from the discovery while enjoying patent protection.
All companies marketing products provided for the use of medical practitioners in the EU are required to produce a Summary of Product Characteristics (‘data sheet’) giving relevant information about the drug, including the conditions for
which its use is licensed, contraindications and known side-effects. Pharmaceutical firms in the UK collaborate in producing an annual Data Sheet Compendium, which is distributed free to registered medical practitioners.
Issue of a Product Licence is no guarantee that a compound is 100 per cent safe, nor even that all adverse reactions have been detected before marketing. Because of this, the CSM issue postage-paid ‘yellow cards’ for the notification of adverse reactions. Although the scheme is voluntary, it is important that prescribers collaborate fully with it. Such notifications are particularly important in the first few years in which a new compound is marketed. Copies of the notification form are routinely included with each issue of the British National Formulary, and compounds under particular scrutiny are flagged with a black triangle.
Relationship with the medical profession
In the UK, the conduct of pharmaceutical companies in marketing their products is governed by a voluntary Code of Practice agreed between the members of the Association of the British Pharmaceutical Industry in consultation with the British Medical Association and the Department of Health. The Code of Practice is published in the Data Sheet Compendium and on the ABPI website. It covers, among other things, the content and distribution of advertisements and other promotional literature; hospitality, gifts, and inducements to the medical and allied professions; marketing research; and relationships with the general public and lay communications media.
The subject of advertising is a perennial bone of contention between doctors and the pharmaceutical industry. The former complain that the industry tries to cloud their professional judgement under a deluge of irrelevant, mendacious, and uninterpretable gobbledegook; the latter claim their commercial right to exploit their products to their best advantage in the market place, and point to the factual data sheets and other information services that they place at the disposal of the medical profession.
The truth, as usual, inhabits the middle ground. Advertisements are subject to the usual advertising regulations and may not tell overt lies. None the less, they are intended to sway the prescriber in favour of a particular product. They are clearly cost effective and there is ample evidence of their influence on prescribing habits.
Doctors should not delude themselves by claiming that they are uninfluenced by advertisements or other promotional activities. They should make a conscious effort to separate fact from fantasy in advertisements and cultivate a critical attitude, especially towards claims for new products. In particular, doctors should
learn to distinguish between genuine advances and new products which, though effective, are no better than older, well-tried, and cheaper remedies. They should also be wary of impressive claims ostensibly based on published independent assessments which turn out, in the small print, to refer to unverifiable ‘data on file’ or papers published by, or on behalf of, the company involved.
Sources of independent advice
In the UK the British National Formulary, the Prescribers' Journal (produced by the Department of Health), and Drug and Therapeutics Bulletin (published by the Consumers' Association), offer reliable sources of objective information to the medical practitioner. In the USA, the National Formulary and the Medical Letter provide a similar service. Many health authorities now produce therapeutic guides for use by medical staff in hospital or the community. Pharmacies often offer a drug information service to which medical practitioners have access, and most medical microbiology laboratories are able to offer accurate up-to-date advice on antimicrobial therapy.
Although the marketing of drugs is fairly well regulated throughout the industrially developed world, the same is not true of less favoured countries; in many nations of the world the standards of advertising and marketing often appear to overstep the bounds of what would be considered ethical in more developed countries.
When a new antibiotic is first described in the scientific literature it usually appears under a number representing the manufacturer's laboratory code for the compound. This practice is to be discouraged, since the code is forgotten once a drug is named and, in later years, source references become difficult to locate. The reason for using a code is that names proposed by the manufacturer are not always subsequently accepted by the bodies controlling drug nomenclature. These are the British Pharmacopoeia Commission in the UK who recommend a British Approved Name (BAN) to the Medicines Commission and the United States Adopted Name (USAN) Council in the US. International agreement is coordinated by the World Health Organization who specify or recommend an International Non-proprietary Name (INN; rINN). Within the European Union, standardized use of the rINN is presently being implemented.
Once the Approved Name is introduced into the national pharmacopoeia of a country, it becomes the Official Name. In addition to the Approved or Official Name, the drug may have various proprietary names under which it is marketed. Approved Names try to avoid close nomenclatural similarities, but the profusion of ‘sulpha-s’ ‘cefa-s’, ‘-cillins’, and ‘-oxacins’ still produces confusion; when the same compound is marketed under different proprietary names, bewilderment is often complete.
There has been a good deal of debate as to whether doctors should use proprietary names in writing prescriptions. On the one hand, it is pointed out that formulations differ so that the pharmacological properties of a drug may vary from product to product. Moreover, adverse reactions caused by a particular formulation may be more easily detected if the product is specified. On the other hand, non-proprietary names are less likely to cause confusion; they remove the necessity of pharmacies keeping a large and varied stock of similar products, and enable the pharmacist to dispense the cheapest version of a particular drug. The British National Formulary sensibly recommends prescribers to use non-proprietary names in all but those few instances where bioavailability problems are so important that the patient should always receive the same brand.
The number of antimicrobial drugs available to the prescriber is now enormous and, at least as far as antibacterial compounds are concerned, the undoubted value of having a wide and varied choice has been overtaken by the confusion that is caused by the conflicting claims of so many agents with similar or overlapping indications. Despite fears about antimicrobial drug resistance we currently possess more than enough antibacterial drugs to treat most common infections. Indeed, most general practitioners rely on a few favourite antibiotics which they use to cover most bacterial infections. The WHO includes only a handful of antibacterial agents in its list of essential drugs (Table 33.2). The availability of antimicrobial drugs varies widely in different countries for reasons that must be commercial rather than therapeutic: for example, over 70 β-lactam antibiotics (including 40 cephalosporins), are on the market in Japan—well over double the number available in the UK; the WHO's main list of essential drugs has a mere 7, all of which are penicillins.
Table 33.2 Antimicrobial agents (excluding topical agents) on the WHO list of essential drugs (1997)
Apart from the financial attractions of a share in a huge market, the main impetus for continuing research into antibacterial agents is the ever-present spectre of resistance and efforts are being made to harness new technologies to the discovery of compounds that will circumvent resistance mechanisms in some common pathogens.
The situation with the chemotherapy of non-bacterial infection is much less satisfactory. Although great strides have been made in the prevention of viral infection by immunization, and there have been significant developments in antiviral agents, notably for the treatment of HIV infection, chemotherapy for viral disease is still extremely limited (see Chapter 6 and Chapter 7). Some sort of effective chemotherapy is available for most fungal, protozoal, and helminth infections, but the choice is very limited and, in many ways, unsatisfactory (seeChapter 4, Chapter 5, and Chapter 31). On a global scale these conditions are responsible for much of
the morbidity and mortality from infectious disease that afflicts mankind. The greatest challenge for the future is to provide for these diseases the same sort of safe, effective chemotherapy that is now available for most bacterial infections, and to make effective therapy for all infections readily available for those who need it most.