Special patient groups – hospital pharmacists creating standards for care

Editorial Consultant, HPE

“Clinical pharmacy is not yet sufficiently well integrated into curricula in universities – education should prepare students to work in the real world”, Roberto Frontini (President, EAHP) told the audience in his opening address. Pharmacy students need a good education at the foundation level and this is not yet universal, he continued.

However, in the drive to acquire clinical skills, pharmacists should not overlook the need to maintain the skills necessary to prepare individual medicines for patients as this underpins clinical services, he argued. Only this link offers the safe and comprehensive care that patients demand. “Patients have the right to pharmaceutical products of GMP quality, regardless of their source”, he said.

This year EAHP celebrates its 40th anniversary and to mark the occasion it has published a book describing its history. The Milan congress was the 17th – although EAHP was founded in 1972, it was not until 1996 that the first congress was held.

The past 50 years have seen many revolutions in medical science and hospital pharmacy cannot avoid being influenced by them, according to Umberto Veronesi (Scientific Director of the European Institute of Oncology, Milan, Italy). Organ transplantation, first undertaken in 1954 in the USA, has now become a mainstream activity.

Now better legislation is needed for organ donation and more research into immunosuppression is called for. The decoding of human DNA in 2000 had a far-reaching impact on all medical activities. It improved our knowledge of hereditary diseases, it established the genomic signature as a prognostic and predictive factor and it enables new drugs to be directed to molecular targets.

Improved imaging technology has led to improved curability and the expansion of detection programmes. The introduction of stem cell treatments has allowed the development of new treatments for chronic degenerative diseases and the potential of this technology is immense, said Professor Veronesi. Robotic surgery, sometimes called ‘mini-invasive’ surgery, has made less aggressive surgery possible, resulting in better quality of life for patients and shorter periods of hospitalisation. Some 40–50% of surgical interventions are now performed with robots, noted Professor Veronesi.

New sources of radiation, including hadrons and high-intensity focused ultrasound (HIFU), can now deliver better-targeted radiation with less damage to healthy tissue. In addition, the risk of oncogenesis is reduced. Lastly, nanomedicine is likely to lead to a re-evaluation of much of medicine and enable the development of new forms of drug delivery.

Alongside these developments, new paradigms or concepts have guided the management of cancer. The treatment paradigm has shifted from ‘maximum tolerable therapy’ to ‘minimum effective therapy’. For example, breast-conserving surgery was first introduced in 1981 by an Italian group and it is now the norm. The assessment of cancer has moved from measuring the anatomical spread of disease to measuring biological spread. This has, in turn, led to biological classifications of tumours.

Diagnosis has shifted from purely clinical to instrumental methods, for which the presence of a doctor is optional. “Now it is possible to detect tumours that are not palpable or visible, for example, breast tumours as small as 3mm in diameter”, commented Professor Veronesi. This improves the prognosis and also paves the way for screening programmes, he added. In addition, treatment has shifted from systemic to targeted approaches.

“It used to be difficult to identify clear targets for treatment but now there are biomolecular targets”, he said. Multidisciplinary management is now the norm and improved organ conservation is expected for a wide variety of tumours.

Another major change has been the recognition of ‘the centrality of the patient’ – a move from the paternalistic approach of the past – and the rights of patients to better information. Patients’ rights include the right to receive scientifically proven treatments, the right to know the truth and the right to refuse treatment, said Professor Veronesi.

The great changes of recent years have led to extensive innovation in the role and responsibilities of hospital pharmacists. There are a number of issues in hospital practice for which the opinion or presence of a pharmacist is fundamental, said Professor Veronesi. These include pain and palliative care management, prevention and control of surgical infections, clinical trials and the development of new standards in pharmacy practice. Professor Veronesi concluded that pharmacists must now be integrated into therapeutic teams but in order to develop their roles fully in the era of biomolecular drugs they would need to ensure that they had a good understanding of genetics, DNA repair mechanisms, epigenetics and stem cells.

A highlight of the EAHP congress programme was an interactive session designed to explore the implications of the recent Council of Europe resolution (see Resources) that set out recommendations for quality and safety assurance standards for medicinal products prepared in pharmacies for the special needs of patients.

Henk Scheepers (Senior Inspector, Ministry of Health, Welfare and Sport Healthcare Inspectorate, The Netherlands), chairman of the working party that drafted the resolution, set the scene by describing the differences between hospital and industrial preparation of injectable medicines. Hospital pharmacy preparation of medicines is at the core of the profession and is essential for healthcare, he noted.

Present regulations oblige a manufacturer to have a marketing authorisation and a manufacturing licence before a product can be placed on the market. Manufacturers must also comply with Good Manufacturing Practice (GMP). The medicines prepared in hospital pharmacies are essentially unlicensed. In most countries, hospital pharmacies do not need a manufacturing licence.

Moreover, industrial products are standardised whereas hospital pharmacy products are often tailor-made. The two systems are very different and they differ in their approaches to safety and efficacy. The pharmaceutical industry must also report product defects – any deviation from the marketing authorisation. In The Netherlands, such reports result in approximately one product recall per week. In contrast, hospitals are under no obligation to report defects.

There is an increasing trend for personalised therapy and industry cannot satisfy all needs in this respect. In addition, large-scale preparation in hospitals is also increasing and some hospitals distribute their products to other pharmacies.

The recent Council of Europe resolution was adopted by 36 countries in early 2011. It was inspired by a survey of hospital pharmacy preparation in 19 European countries (published in PharmEuropa, see Resources ) that identified considerable variation across Europe. The key finding of the survey was that there was a wide variation in quality assurance and safety standards between European countries. There was a gap in quality assurance between preparation in pharmacies and manufacture by the industry. There was also a quality

and safety gap between medicinal products prepared in pharmacies and in hospital wards.

The survey results were discussed at an expert workshop in Strasbourg at which 21 countries were represented, explained Dr Scheepers. The objective of the workshop was to identify criteria and key elements for standards for hospital pharmacy preparation.

One key element of the resolution is the requirement for a product dossier for stock preparations. A list of dossier contents is set out in the resolution and this includes a demonstration of the added value of the product, description of the preparation process, and the use of the product together with information for patients and prescribers. A model procedure for risk assessment is also included. This covers points such as the type of preparation, the quantity prepared annually and the pharmacological effect. Another key element is the guidance on quality assurance of preparation processes – GMP is recommended for high-risk products and Pharmaceutical Inspection Co-operation Scheme (PIC/S ) guidance for low-risk products.

What can be expected next is the implementation of the resolution, and this will involve adaptation of national frameworks. Unlike a ‘directive’, which must be put into local law, there is more flexibility with a ‘resolution’, explained Dr Scheepers. He also predicted that cooperation between hospitals would need to increase in future, as it would not be practical for every hospital to make every medicine.

Careful reading of the resolution shows that the Council of Europe strongly supports pharmacy preparation of medicines and recognises its value, according to Vagn Handlos (Senior Scientist, Capital Region Pharmacy Denmark), who was a co-author of the survey and a member of the working party on the resolution.

“We should see the resolution as an invitation to develop the quality and transparency of hospital preparation”, he said. Many people think that the standard of hospital pharmacy preparation is very low at present, he added.

The resolution has been drafted in such a way that it can be incorporated into national regulations. However, this will require collaboration between national authorities and professional bodies.

“It is a process – not just a copy and paste job, and it will take time”, he said. “This is not just a question of GMP but a matter of building up robust systems around hospital pharmacy preparation similar to those for industrial products. For example, at present there is no pharmacovigilance for hospital preparations”, he continued. The process will require investment. If hospital pharmacy preparation cannot achieve the level of quality required, then it will not exist in future, he predicted. The resolution also presents an opportunity for the pharmaceutical industry to provide ready-to-use injections.

Dr Handlos drew attention to paragraph 9 of the resolution, which states that “In general, reconstitution of medicinal products should preferably take place in a pharmacy, assuming that the requirements concerning the safe preparation of sterile products can be fulfilled. Reconstitution considered to be low risk can be done on the wards.” Pharmacists could take the first step in implementation of the resolution by proposing to their own national authorities an early implementation of paragraph 9.

He went on to say that, where hospitals are producing large batches on a regular basis, regulatory authorities may wish to require the hospitals to obtain marketing authorisations, as set out in paragraph 6 of the report.

Irene Kraemer (Director of Pharmacy, University Hospital, Mainz, Germany) suggested that the resolution should be the starting point for the development and implementation of a ‘special GMP’ for hospital pharmacy. Such a guideline already exists in The Netherlands and it would be helpful if it were implemented throughout Europe.

At present, the terms ‘reconstitution’ and ‘preparation’ are often used inconsistently, with different meanings in different countries, and clarification is needed, she commented.

“The present situation regarding global risk management is far from optimal – if not rather disorganised”, according to Michael Havbro Faber (Professor of Risk and Safety, Head of Civil Engineering, Technical University of Denmark). An engineer by training, Professor Faber described the principles of risk management and decision making using well-known examples.

In a perfect world, we would know exactly what we want, fully understand our decision options, have all the skills to carry them out and have complete information about their effects. Decision making would simply be a matter of weighing the benefits and costs. In fact, these provisions do not usually apply and so decision making becomes a matter of weighing knowledge and uncertainty.

Every day we all deal with decisions associated with uncertainties, such as car-driving, cooking and smoking and we have opinions and gut feelings to help us. However, there are some situations where we do not have gut feelings to help, for example, major catastrophes such as the SARS outbreak in 2003, which caused fewer than 800 fatalities but had an economic impact equivalent to US$200 billion. Another example was food-borne disease in the USA, which affects 76 million people each year, causes 325,000 hospitalisations and 5000 fatalities annually. “We don’t hear much about these”, commented Professor Faber.

Risk is the expected value of the potential loss and can be measured in a number of ways, including the number of fatalities or quality adjusted life years. The risk associated with an event can be calculated as the product of the probability of the event and the consequences of the event. There are several ways of estimating probability – frequentist, classical and Bayesian. The frequentist approach, based on experimental data, is most familiar to pharmacists but in many situations experimental data are not available or are scarce so there is considerable uncertainty.

The classical approach is based entirely on analysis of the possible events, for example, when tossing a coin there are two possible outcomes – heads or tails – so the probability of getting a head is ½ or 0.5. The Bayesian interpretation of probability is a subjective assessment that represents the degree of belief that an event will occur. It can also incorporate frequentist data. “It is a core component when dealing with uncertainty in decision making”, said Professor Faber. Probability estimates for decision making must incorporate uncertainty due to natural variability and uncertainty due to lack of knowledge.

Turning to global perspectives of risk, Professor Faber said that mankind is exposed to a number of risks, including natural hazards (both terrestrial and extraterrestrial), technological risks, pandemics, disease and malnutrition, malevolence and war, economic instability, deterioration of infrastructure and human and organisational errors. “We are making a lot of mistakes and sometimes our decision-making processes do not appear to be rational”, he said. For example, the cost of saving one life by multiple vaccinations in developing countries was 100 Swiss francs, whereas the cost of saving one life by asbestos renovation was 109 Swiss francs – a sum that could have saved 10 million lives in developing countries.

Risks can be categorised into three types, explained Professor Faber.

Type 1 includes foreseeable, rare, large-scale ‘averaging’ events such as earthquakes or industrial accidents that lead to stable losses (of life). Type 2 events are described as ‘seepage’; they tend to occur continuously but at a level that passes largely unnoticed. These include medical and medication errors. Inefficient treatment of diseases and small mistakes or procedural errors can cause a few deaths here and there that can add up to very large numbers overall. Type 3 risks relate to unforeseeable events or very rare, highly-uncertain, large-scale events such as asteroid impacts or pandemics. Type 1 events are manageable through prevention measures and preparedness – it is possible to budget for them.

Type 2 events are subject to cognition biases. ‘Framing’ means that we tend to focus on disastrous and spectacular events that attract heavy media coverage. Even risk experts are susceptible to this, noted Professor Faber. We also tend to focus on hazards to which we have recently been exposed. Unfortunately, we fail to focus on the high probability events, which slowly but surely drain our resources or potentially lead us beyond the point of no return, he said. Type 3 events are partially manageable though control and mitigation – but only to the extent that the risk is realised.

The present situation with regard to global risk management is far from optimal and we neglect low-profile, technically uninteresting, high probability / marginally low consequence events. “It is disturbing that most important societal decision makers do not know the basics of decision-making theory”, said Professor Faber. There is a significant need for the development of best practices in risk‑informed decision making and risk assessment. In particular professionals in industry and public administration need this type of training.

It is becoming increasingly clear that we need to worry about sustainable development. Forecasts suggest that oil and gas will run out in about 40 years and climatic changes will impose further pressures. We need to use recyclable resources more efficiently and use fewer non-recyclable resources. In addition, we must ensure consistent and optimal societal decision making, reduce risk and maximise robustness in our systems. This will involve using the best knowledge and developing new technologies. It will be important to focus on the real losses and not the interesting issues, but the relevant issues. It may be necessary to take one step backwards and establish a holistic overview with regard to where the resources are disappearing before we decide to gain new knowledge, he suggested.