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Highlights of the December 2007 meeting of the American Society of Health-System Pharmacists in Las Vegas included biosimilars, medication errors, stress and survey results
Laurence A Goldberg
Biological products, including monoclonal antibodies, blood derivatives and vaccines, differ from traditional drugs in many ways, according to James Hoffman (medication outcomes coordinator, St Jude Children’s Research Hospital, Memphis, Tennessee, USA). They are large molecules, have complex production processes and are usually administered parenterally. Potential immunogenicity is always a concern and complex analytical methods are often required.
In the USA, the use of biological products has increased at a rate of 20% per year in some areas. The patents for many biological products are now nearing expiry and the arrival of new “post-patent” or “follow-on” biologicals is anticipated. These are now described as “biosimilar” products because they are intended to achieve the same therapeutic effect as the original product but may be manufactured using a different process. Replicating the innovator’s process may be impossible because parts of it could be patent-protected, Dr Hoffman explained.
There are still many unanswered questions about biosimilars; these include the approval pathway, safety issues, interchangeability and cost. It is estimated that biosimilars could be 25–30% cheaper than innovator products, Dr Hoffman said.
In Europe, the patents on some biological products have already expired and guidelines for the development and approval of biosimilar products have been published by the European Medicines Evaluation Agency (EMEA; see Resources). Roger Tredree (visiting professor, Kingston University, London, UK) explained that guidance is now available for insulins, growth hormones, granulocyte colony-stimulating factors (G-CSF) and erythropoietin, and guidance for beta-interferon will follow soon.
Each biotechnology-derived protein is defined by its production process. The equipment, raw materials and process parameters all contribute to the characteristics of the final product. Thus, a biologicals licence includes the product, the process (with in-process control specifications) and the facility (with technical and operational specifications), Professor Tredree said. Even small changes in the manufacturing process can change the product and so comparability of the final product (with a reference product) has to be demonstrated.
Simple changes to biological products can result in unpredictable immunological consequences, Professor Tredree said. A good example was the change in the formulation of Eprex SC (a subcutaneous form of erythropoietin). When albumin was removed from the formulation a number of cases of pure red cell aplasia occurred. This was related to the formation of neutralising antibodies to erythropoietin. Eprex SC was then withdrawn for renal anaemia in most countries.
In January 2006 the EMEA approved the first biosimilar growth hormone product, Omnitrope (Sandoz). For growth hormones, the EMEA requires clinical studies comparing the new product with a reference product and 12-month immunogenicity data before authorisation can be granted. Currently several biosimilar growth hormone products are authorised in the EU and the EMEA guidelines appear to be both implementable and realistic.
Therapeutic interchange – that is, switching to a product that produces the same clinical outcome, with the agreement of the prescriber – is likely to be an important consideration with biosimilar products. In south London four similar erythropoiesis-stimulating agents were available and a therapeutic tendering exercise was undertaken. Two companies were eventually awarded contracts. The overall discount was about 70% and the estimated annual saving to the local health economy will be about £5m. The success of this exercise was heavily dependent on agreement with the prescribers and appropriate clinical control, Professor Tredree emphasised.
Pharmacosurveillance of medication errors in the neonatal intensive care unit
Most potential medication errors are picked up by clerks, pharmacists, nurses or parents before administration, according to John Chuo (director, neonatal intensive care unit, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA), but the importance of the pharmacovigilance team cannot be overstated. The core members of the team are a “4C” champion (correct culture, correct medicine, correct patient, correct administration), a physician, a nurse and a pharmacist, while the invited members include a respiratory therapist, a laboratory technician, a hospital administrator, a lecturer and a patient representative. The pharmacovigilance team reports directly to the neonatal intensive care unit (NICU) leadership team and it receives reports and communicates responses to the NICU staff. The surveillance process consists of a number of stages: data filtering, collection of more data, single case assessment, technical checks, case series, interpretation and communication.
Dr Chuo went on to discuss the barriers to the reporting of incidents. The “blame culture” still persists in many hospitals and this needs to change fairly quickly if progress is to be made. Lack of leadership and inappropriate delegation of ultimate responsibility plays a part along with statutory professional rules relating to reporting of errors. In addition, there is some ambiguity as to what needs to be reported. The importance to the physician of positive feedback immediately after an error has been identified cannot be overstated.
Large numbers of reports require appropriate data management. Common file structures enable data mapping to be carried out, which in turn helps to identify clustering of similar events. However, the data are often incomplete and a pharmacist is employed to go through each report filling in missing data and clarifying ambiguous information. This “data cleansing” is an essential part of the data management process.
Dr Chuo concluded by saying that the pharmacovigilance team must have influence over governance. It has to be multidisciplinary, and work to defined processes, and needs to overcome organisational culture challenges.
Mary C Binghay (paediatric clinical specialist, Shady Grove Adventist Hospital, Rockville, Maryland, USA) discussed the pharmacy strategies to improve medication safety in the 30-bed NICU. Initially, a multidisciplinary team was set up to evaluate the risks in the medication use process, to create a culture of safety and to create a strategic plan for incorporating best practices for improved medication safety in the NICU. The first strategy was to begin dispensing unit-dose oral and IV medications. This was consistent with best practice but had increased pharmacy staffing requirements. A pharmacy double-check process for all NICU medication orders was established. This again is consistent with best practice and it increases accountability and safety awareness. Pharmacists have now become involved in NICU nursing orientation and training. This has led to improved communication with nurses and consistency of practice. A computerised programme for TPN orders has standardised the process and this has reduced the number of TPN queries raised.
The introduction of “smart” IV pumps making use of standard concentrations of IV medicines and protocols has reduced medication errors, Dr Binghay said. The unit has recently improved the order entry process by developing protocol templates and an antibiotic dose calculator. This has reduced the number of queries relating to illegibly written orders and dosing problems. Finally, the implementation of point-of-care barcoding and electronic medication administration records (eMARs) has now closed the loop.
Dr Binghay believes that in addition to improving the safety of the patients in the NICU, at least two hours per day are saved by pharmacy personnel in not having to deal with clarification issues.
Post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) is usually related to trauma and has a lifetime prevalence of 7–14% in the USA, according to John Spollen (deputy associate chief of staff for mental health, Central Arkansas Veterans Health System, Little Rock, Arkansas, USA). It is now the fifth most common psychiatric disorder and is twice as likely to affect women as men (10–14% vs 5–6%), he continued.
Most people who are exposed to traumatic events do not develop PTSD. Those who experience interpersonal violence, such as rape, torture, assault or combat, are more likely to develop PTSD than people who experience accidents or natural disasters. Among women the most common causes are rape and molestation or assault; among men combat and witnessing violent events are the most common.
The diagnosis was based on the presence of a set of features, Dr Spollen said. First there had to be significant trauma – something that caused an emotional reaction – and then a typical triad of symptoms. These are re-experiencing (through nightmares or flashbacks), avoidance or numbing (the loss of normal emotions) and hyperarousal (“being very jumpy”, inability to concentrate).
One theory about PTSD draws on classical fear conditioning. This says that an unconditional stimulus causes an unconditional response (such as increased heart rate). Subsequently, events similar to the unconditional stimulus can act as conditioned stimuli and elicit conditioned responses such as anxiety or flashbacks. For example, a convoy driver in Iraq had been in a traffic jam surrounded by a crowd of people when a bomb exploded nearby. The brain sees a pattern – people, traffic, travelling slowly and intense fear. The natural immediate response is normal, but it is not normal when crowds, slow-moving traffic or fireworks elicit the same response, Dr Spollen explained.
People with PTSD are more likely to have coexisting substance-misuse problems, for example with alcohol or drugs, than non-PTSD sufferers, explained Sheila Botts (assistant professor, University of Kentucky College of Pharmacy and Clinical Pharmacy Specialist, Lexington Veterans Affairs Medical Center, Kentucky, USA).
When drug treatment is indicated for PTSD the first-line treatment is selective serotonin reuptake inhibitors (SSRIs). This is the only class of drugs with FDA approval for PTSD, Dr Potts pointed out. Overall, SSRIs have moderate efficacy in the acute treatment of chronic PTSD. Sertraline, paroxetine and fluoxetine are efficacious in civilian trauma – typically women with histories of sexual or physical abuse.
Fluoxetine is effective in combat-related trauma in one of two studies and sertraline appears to be effective for the prevention of relapse. All agents are well tolerated.
National survey findings
Patient safety goals set by the Joint Commission (the accrediting body for hospitals in the USA) appear to be exerting a significant positive influence on developments in practice. The 2007 survey showed that in nearly 80% of hospitals there is pharmacy involvement in the development and implementation of the medication reconciliation process (the process of comparing a patient’s medication orders to all of the medications that the patient has been taking).
The number of hospitals performing an annual assessment of processes for compounding sterile medications has almost doubled (up to 67.5% from 35.7%). Finally, 76.2% of hospitals reported that at least 95% of medication orders are reviewed by a pharmacist before the first dose is administered, up from 45.7% in 2004. ■
European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance. London: EMEA; 2006. Available online at: www.emea.europa.eu/pdfs/human/biosimilar/9452805en.pdf