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Laurence A Goldberg FRPharmS
An improved understanding of medication prescribing errors would be helpful in the design of error prevention strategies, according to Darren Ashcroft (Professor of Pharmacoepidemiology, Manchester University, United Kingdom). He described how the EQUIP study had examined prescribing errors and the underlying reasons in 20 hospitals in the UK.1 For the study, all newly prescribed or written inpatient medication orders were checked for errors by hospital pharmacists for a seven-day period. More than 124,000 prescriptions were checked corresponding to about 26,000 patients. The mean error rate was 8.8% and error rates were highest amongst the most junior grades of doctors. About 2% of the errors were potentially lethal, involving failures to check on allergies or prescribing medicines that were contraindicated. Some 5% of errors were serious and 53% were potentially significant. Errors occurred most commonly at admission and typically involved unintentional omission of medicines.
The causes of prescribing errors were investigated by in-depth interviews of Foundation Year 1 trainee doctors. Both critical incident analysis and questioning about prescribing education and training were used in the interviews. Of the 85 critical incidents analysed, slips, lapses and rule-based mistakes accounted for the majority and knowledge-based errors accounted for about a quarter. A number of contributory factors were identified including high workload, tiredness, lack of support and advice, unfamiliar drug charts and sometimes unfamiliar patients.
Commenting on a knowledge-based error, one junior doctor said that he knew he should have looked it up but he was afraid of looking stupid in front of others.
Turning to the way in which prescribing skills are learned, Professor Ashcroft said that most junior doctors “picked it up as they went along”, with little formal training. Interviewees commented that there were few opportunities to practise prescribing in advance and that little of their training was concerned with the practical aspects of prescribing. Pharmacology teaching helped them to know about medicines but not about how to prescribe them, they said. It was also apparent to the researchers that many errors were made but junior doctors received little feedback to help them improve their performance. Junior doctors thought that errors were probably identified and rectified by someone else and that they were only told about errors that caused serious problems. This situation meant that opportunities for learning were missed, said Professor Ashcroft.
In conclusion, Professor Ashcroft said that the risks of prescribing errors remain high and emphasised the importance of continuing education and feedback both in medical schools and in the workplace. He underlined the multifactorial nature of prescribing errors and said that this research showed that doctors relied upon others, particularly pharmacists and nurses, and expect safety mechanisms to start automatically when errors are made.
Pharmacy has undergone considerable changes as pharmacists shifted from the role of apothecaries to patient-centred care givers, said Sophie Savornin (Senior Consultant, Semio, Grenoble, France). Now that pharmacists are being asked to take on a growing role in helping patients to make the best use of their medicines, an understanding of change management processes is vitally important, she continued. If correctly managed, change projects could unify departments and improve morale and productivity. Mme Savornin recommended that process mapping should be undertaken to provide a ‘customer vision’ of the organisation. This provides a clear picture of all the processes involved and helps managers and staff identify the opportunities for improvement.
We need to acknowledge and embrace being human if we are to reduce the frequency of human errors in parenteral treatment, according to Arpan Guha (Consultant, Critical Care and Anaesthesia, Royal Liverpool University Hospital, UK) speaking at a satellite symposium sponsored by B Braun Medical. Slips and lapses are unintended errors that can occur as a result of inattention or distractions whereas mistakes and violations are often the result of a decision, for example to take a short cut, he explained. In one study, human factors were estimated to account for 66% of errors in anaesthetic practice. Another study showed that accidental interchange of syringes was one of the commonest errors. Such errors were usually attributed to inattention, haste, drug labelling or distraction. The majority of errors in critical care involved drugs with a high potential of serious consequences, according to a Canadian study. The error rates were 17.4% in high-dependency areas and 38% in intensive care. Although they fell substantially when timing errors were removed, timing of treatment can be critical in these areas, said Dr Guha. Another study had shown that medication errors accounted for 78% of serious errors in intensive care units.
Traditionally, error reduction initiatives have focused on systems but a greater emphasis on human factors could be helpful, suggested Dr Guha. However, the attitudes of doctors and nurses can be a barrier to success in error reduction schemes. A study of doctors and airline pilots showed that doctors generally believed that they performed effectively when fatigued whereas the majority of pilots believed that their performance was impaired. A study of nurses’ views had shown that beliefs such as, “if it is not my fault, it is not an error” and “if you can put it right, it is not an error”. In the face of such ingrained beliefs, exhortations to follow safe procedures do not work, said Dr Guha.
Task analysis research offers an insight into the ways in which errors occur. In a series of 100 simulated anaphylaxis scenarios, healthcare practitioners made errors in 42, 21 of which involved medication. Most commonly these were ‘wrong route’ or ‘wrong dose’ errors, due to drawing up the wrong dose (for example whole ampoule instead of dose required) or failure to check dose and route. Relying on recall rather than following a standard operating procedure (SOP) was a big factor in errors, he noted. However, another study had shown that healthcare staff are often unable to follow SOPs in highly stressed situations.
The value of simulation-based training was illustrated by a study that compared the impact of didactic and simulation-based training for critical care nurses on medication error rates. After simulation-based training the error rate in the coronary care unit fell from 30.8% to 4.0% and was sustained. However the error rate in the medical intensive care unit (didactic group) did not change and subsequently rose.
Dr Guha concluded that understanding of the reasons for human errors is needed and comprehensive solutions are required rather than “one-off, knee-jerk solutions”.
Pharmacies should provide ready-to-use and ready-to-administer parenteral products as far as possible and this could involve a combination of commercially sourced and locally prepared items, Paul LeBrun (Head of Production, Central Hospital Pharmacy, The Hague, The Netherlands) told the audience. Errors with intravenous injections could be a nightmare, he acknowledged, and according to The Netherlands’ register of errors, intravenous doses accounted for 40% of all reported errors.
Working areas on wards are far from ideal for the preparation of parenteral drugs. In order to improve the situation we need to focus on the products and the processes for use, which are closely related, he said. Many products are presented in ampoules or vials and the error-prone processes of calculation, dilution and administration are unavoidable. The highest quality products are those that are made commercially, whereas those made on wards are of the lowest quality. Ready-to-use products are attractive because they eliminate many preparation steps. Ready-to-administer products are even better, he added.
A number of standardised products are now available such as norepinephrine 50mg in 50ml, midazolam and gentamicin injections. However, pharmacists will need to ensure that the use of standardised solutions does not introduce new problems associated with variable dosing. This could be important for products with narrow therapeutic indices such as gentamicin.
Pharmacy departments prepare a number of ready-to-administer products, often in preloaded syringes or elastomeric pump devices. Recognised advantages of pharmacy preparation include reduction in calculation errors and contamination with micro-organisms, said Dr LeBrun. However it is rarely possible for the pharmacy to take over preparation of all intravenous doses. One approach to this in The Netherlands had involved training ward staff. As a result of introducing good procedures, improved preparation environments and training, the contamination rates fell from 40% to less than 4%, he said.
Future developments in this area could include the introduction of robotic devices, which would be expected to improve safety. However, any future solution would need to be cost-effective, he concluded.
Interchangeability is a critical issue for biosimilars and when this is uncertain biological products are generally prescribed by brand name. An audience poll showed that 36% of pharmacists required both international non-proprietary names (INN) and brand names on prescriptions whereas 17% required only the INN. Speaking at a satellite symposium sponsored jointly by the Postgraduate Institute for Medicine and prIME Oncology, Jos Kosterink (Head of Hospital and Clinical Pharmacy, University Medical Centre, Groningen, The Netherlands) pointed out that biosimilars are derived from living organisms and they can carry pathogens from the donor organism. They are complex products that are often immunogenic and it can be difficult to predict responses. At present the biosimilars’ market is estimated to be worth $10 billion (€7 billion) and is set to increase considerably.
The INN system provides an internationally recognised way of identifying active substances that is unambiguous. It has worked well for traditional drug substances but the matter of classifying biosimilars now presents a “new and huge problem”, according to Jens Peter Kampmann (Consultant in Internal Medicine, Bispebjerg hospital, Copenhagen, Denmark). First it is important to understand the conventions that have been adopted for naming biological products. Parts of the name relate to the origin of the product, the source, the target and the disease to be treated. Antibody products all contain the stem, ‘mab’, before this syllables are added corresponding to source and disease. Thus, for example, abciximab is a monoclonal antibody for treatment of cardiovascular disease, denoted by ‘ci’, that is chimeric in origin, denoted by ‘xi’ (see Table 1).
Experts now agree that biosimilars cannot be considered to be generic versions of the originator products because subtle differences can exist between them. When it comes to names, there is a difficulty in that the World Health Organization (WHO) has elected not to create a distinctive INN designation to identify biosimilars. Some argue that the same INN (as the originator) should be used because this would allow better identification of class effects. It would also make substitution easier. Others argue that a different INN should be assigned because this would prevent automatic substitution, enhance traceability and facilitate safety surveillance. Dr Kampmann concluded that, until the naming system for biosimilars is improved, brand names should be used in addition to the INN.
Unwanted immunogenicity is the biggest challenge for the approval of biosimilars, Meenu Wadwha (Head of Cytokines and Growth Factor Section in the Biotherapeutics Group, National Institute for Biological Standards and Control, UK) told the audience. All therapeutic proteins have the potential to induce an immune response but there can be considerable variation in the level of immune response even between biosimilars. The consequences of the immune reaction could be neutralising of the biological effect, adverse symptoms or nothing at all, she continued.
Unfortunately it is impossible to predict the incidence of unwanted immunogenicity, the characteristics of such an immune response or the clinical consequences. Furthermore, the value of ‘in silico’ (via computer simulation), in vitro or animal methods is uncertain and so human clinical data are needed. For this reason, a tiered approach has been developed that involves screening for anti-therapeutic binding antibodies, followed by confirmatory assays and then neutralisation assays to distinguish between neutralising and non-neutralising antibodies. It is then necessary to determine how the antibodies relate to clinical response. Comparative immunogenicity studies might also be needed to demonstrate whether immunogenicity varies between products. If the immunogenicity profiles of marketed biosimilar products are significantly different, they may be considered dissimilar, she commented.
At present the European Medicines Agency (EMA) permits extrapolation to other indications if the mechanism of action is the same but this is a complex issue, explained Håkan Mellstedt (Professor of Oncologic Biotherapy, Karolinska Institute, Stockholm, Sweden). Ideally biosimilar manufacturers should provide information about which indications are extrapolated so that physicians, pharmacists and patients could make informed decisions, but this is not done at present, he continued. An example of this was erythropoietin. Cases of pure red cell aplasia (PRCA) emerged in 2003 after a change in formulation of a biosimilar. In 2009, PRCA again occurred when the product was administered subcutaneously instead of intravenously. The risk of PRCA is not a major problem in oncology where its use will be short term in immunosuppressed patients. If it is used on a long-term basis for other indications then PRCA would have serious consequences. Extrapolation across disease indications may put patients at risk, he concluded.