Nearly 3000 participants attended the 15th Anniversary Congress of European Association of Hospital Pharmacists held in Nice, France in March 2010. The theme was pharmacotherapy hospital pharmacists advancing patient care
Laurence A Goldberg
About 75% of the costs of drug development are spent on failures but better design of early, non-clinical studies could decrease the high rate of attrition, Maria Beatriz da Silva Lima (professor of pharmacy, Lisbon University, Portugal) told the audience.
Clinical trials always involve an appropriate balance between safety and the acquisition of new information. The safety of trial subjects must be predicted before a study is undertaken but for “first in human” (FIH) studies this can be a problem as there will be no information on human safety. Pharmacological studies must address target and other effects and, in particular, the impact of therapeutic doses on systems essential for life such as the cardiovascular and central nervous systems. Pharmacokinetic investigations are important for understanding the fate of the drug. They must be undertaken in relevant species because it is necessary to know that the pharmacological response and metabolism are comparable with the effects likely to be seen in humans. Toxicology studies are also important for predicting human safety, she added.
The goals for non-clinical studies are to identify an initial safe dose and safety parameters for clinical monitoring. Many drugs fail because the non-clinical aspects are not properly explored, commented Professor da Silva Lima. Similarity between experimental models (species) and man is not enough-predictivity is needed. Factors that enhance predictivity include comparable pharmacology, kinetics and aspects of disease.
Concerning biopharmaceuticals, many subcellular elements are now targets for drug action. “The more depth we go into in a cell, the more specificity will emerge. Small differences can trigger big differences in responses and so biologics are designed to be as similar as possible to human molecules”, she said.
There is now considerable international pressure to avoid the use of primates. Instead, equivalent epitopes need to be identified, or if the clinical candidate does not work, homologous or genetically-modified targets (eg, the human receptor in an animal model) can be used. The same principles apply to biopharmaceuticals as to small molecules but biopharmaceuticals are in general human-specific, immunogenic and are metabolised through non-toxic pathways. Most of their toxicity comes from exaggerated pharmacodynamics, explained Professor da Silva Lima.
Safety, efficacy and toxicity are key reasons for the termination of early studies and toxicity is not reliably predicted by animal studies. Earlier human studies, specifically, “exploratory clinical trials” would reduce the attrition rate in drug development, said Professor da Silva Lima. Exploratory clinical trials involve limited human exposure in patients or volunteers but have no therapeutic intent and are not intended to examine clinical tolerability. They are intended to provide insight into the human pharmacology of the drug. A number of approaches have been identified by the European Medicines Evaluation Agency (EMEA) including microdosing, giving a single dose (sub-therapeutic or in the anticipated therapeutic dose range) and up to 14 days’ dosing at therapeutic level.
After the TeGenero case, in which human volunteers developed cytokine storm after receiving intravenous TGN 1412 at Parexel International Corporation’s Pharmacology Research Unit, Northwick Park Hospital, London, the Committee for Medicinal Products for Human Use (CHMP) introduced guidelines on risk mitigation in first-in-human clinical trials (See resources). In this case toxicity studies in the monkey model with a homologous receptor had not revealed any problems. The new guidelines brought in the concept of “minimum anticipated biological effect level” (MABEL) in addition to the “no observable adverse effect level” (NOAEL). Consideration should now be given to the use of MABEL rather than NOAEL for calculation of the dose for FIH studies, concluded Professor da Silva Lima.
SIRS reduced by filters
Particulate contamination of intravenous medicines contributes to the development of non-infectious systemic inflammatory response syndrome (SIRS) in ICU patients and this can be significantly reduced through the use of in-line filters. Speaking at a satellite symposium sponsored by B Braun Melsungen AG, Michael Sasse (head of paediatric intensive care unit, Medical University of Hannover, Germany) went on to explain how SIRS can affect up to 50% of patients in intensive care units, causing increases in morbidity, mortality and length of stay. It is a common problem after surgery, trauma and life-threatening events. Contrary to popular belief SIRS does not always have an infectious cause. In one survey 25% of deaths in intensive care were due to non-infectious SIRS.
In Hannover, particulate contamination of intravenous fluids was identified as a factor that could trigger an inflammatory response. Infusion management and drug administration together account for 46% of error incidents in intensive care units, said Dr Sasse. Investigations in his department showed that the number of particles trapped on a filter was proportionate to the complexity of the intravenous regimen. Two important additional findings were that 45% of patients were receiving medicines, such as sodium nitroprusside or phenytoin that required administration through a separate line, and that central venous lines could undergo up to 100 manipulations per day. They concluded that an important source of particles is from precipitations that formed in the line when two incompatible drug solutions were allowed to mix. Typically this occurs when intravenous access is restricted to a few lines – a common situation in paediatric intensive care. Heavy precipitates can block filters and lead to loss of efficacy of the drugs. Precipitation can be avoided by strict infusion management but in practice this can be difficult to maintain, explained Dr Sasse.
In Dr Sasse’s hospital an infusion chart is used to indicate which drugs can safely be administered through central and peripheral lines. Staff also have access to a computerised programme for drug incompatibilities.
A randomised study of about 800 paediatric intensive care unit patients was conducted to compare the outcomes with and without in-line filters. Filters with pore sizes of 0.2 micrometers and 1.2 micrometers were used for aqueous solutions and for fat emulsions, respectively. The primary endpoints were severe complications (sepsis, SIRS, organ failure, thrombosis) and death. The results showed that the overall complication rate and the incidence of SIRS were significantly reduced in the filter group. Both organ dysfunction and the duration of mechanical ventilation were reduced. Importantly, the length of stay was reduced by nearly 22 hours on average, equivalent to a relative reduction of 23%. The researchers calculated that if in-line filters were used routinely, this would release 731 days of ICU time equivalent to an annual saving of 1.5 million Euros for their hospital.
Furthermore, the reduction in complications would also result in less expenditure on drugs, investigations and procedures and increase the operational capacity of the ICU. Shortening the length of stay in ICU is of high economic relevance, concluded Dr Sasse.
Urs Rickenbacher (consultant, Medius Ltd, Basel/Muttenz, Switzerland) described how the non ortho-phthalate plasticiser di(2-ethylhexyl) terephthalate (DEHT) improves the safety of medical tubing.
Medical devices made of PVC, such as administration sets and blood bags contain plasticisers. Ortho-phthalates like di(2-ethylhexyl) phthalate (DEHP) have been widely used but they can cause reproductive effects, endocrine disruption, testicular toxicity and liver cancers in animals. Animal experiments show that phthalates activate nuclear peroxisome proliferator-activated receptors. Humans are less sensitive to these effects than rodents but some studies have associated high monoester phthalate exposure with sperm damage and anti-androgenic effects in humans. Although the findings are believed to be inconclusive, DEHT has been tested as an alternative plasticiser. The results of a complete toxicological testing programme show that DEHT is safe to be used in medical devices and that biological effects which are of concern with DEHP like peroxisomal proliferation and reproductive effects did not occur.
Seamless pharmaceutical care
Seamless pharmaceutical care has been defined as, “the desirable continuity of care delivered to a patient in the healthcare system across the spectrum of caregivers and their environments”, Irene Krämer (director of the pharmacy department, Johannes Gutenberg University Medical Centre, Mainz, Germany) told the audience. Unfortunately, in real life there can be discontinuity of care at the times of admission to and discharge from hospital, with 30-50% of medicines being changed by the GP after discharge and a similar proportion not being taken by the patient.
It is now widely recognised that medicines reconciliation should take place at the point of admission, transfer, discharge or any other handover to another setting, service provider or level of care. The purpose of medicines reconciliation is to avoid medication discrepancies between the admission medication and medication at discharge from the hospital, explained Professor Krämer.
Seamless pharmaceutical care is needed because the current systems are fragmented and error-prone. In addition, increasing numbers of elderly patients, shorter hospital stays and a tendency for ad hoc discharges before patients or relatives are fully prepared all increase the risks of discrepancies in medicines.
Healthcare systems differ in different European countries but the basic elements of seamless pharmaceutical care remain the same. It involves taking a medication history initially, assessing the appropriateness and accuracy of discharge medication and providing medication counselling and written information. Concerns about adherence difficulties should be identified and addressed and the reconciled medication list should be sent to the patient’s next health care provider. Finally, there should be a post-discharge follow-up telephone call to check that all is well and to resolve any medicines-related problems. In Professor Krämer’s hospital patients are given a printed personal medication plan that contains pictures of the tablets, dosing information and indications. She also described a project involving liver transplant patients. They receive full inpatient pharmaceutical care and at the time of discharge, the pharmacist not only counsels the patients but also liaises with their local pharmacists and provides them with a pharmaceutical care manual for liver transplant patients. One patient had commented, “I wish every patient could have this seamless pharmaceutical care. I really feel satisfied and safer with my immunosuppressive therapy.”
There are inevitably barriers to effective implementation of seamless pharmaceutical care, including insufficient time, lack of funding, logistical difficulties caused by unexpected discharges and lack of defined criteria for patient selection. There can also be poor communications between hospital and community pharmacists, data protection problems and technical difficulties. However, Professor Krämer recommended that hospital pharmacists should seize the initiative and “just do it”. “Make the commitment with or without desirable resources”, she said. Standards, guidelines and practice models could then be developed and features such as fees-for-service could be built in. “Collaboration between health care professionals is the heart of clinical pharmacy practice”, she concluded.
Robotic dispensing improves service quality
Pharmacists in the busy outpatient pharmacy at the Hotel Dieu hospital in Paris routinely counsel patients about complex treatment regimens including those for HIV, cancer and clinical trials. However, the outpatient consulting rooms are about 30 metres away from the main dispensary and without an automated delivery system the pharmacist would have to interrupt the consultation to collect the medicines. Speaking at a satellite symposium sponsored by ARX-Rowa, François Chast (head of the pharmacy, pharmacology and toxicology services, Hotel Dieu, Paris) described how an automated system had been designed to deliver dispensed medicines directly to the outpatient consulting rooms.
A dispensing robot (Rowa Speedcase) was installed and linked to the outpatient consulting rooms by pneumatic tubes. Given the distance involved, speed was a critical consideration, commented Professor Chast. It takes 12-19 seconds to deliver medicines from the robot to the consultation rooms. The most important outcome of this development has been that pharmacists now have more time to spend with patientsdiscussing treatment and answering questions, he said.
The Spanish Society of Hospital Pharmacists is committed to the introduction of technological advances as part of its ‘2020 project’ to improve the quality of pharmacy services and to increase patient safety, according to Ainhoa Aranguren (assistant director of pharmacy, University Hospital de la Princesa, Madrid, Spain). She recommended that automated dispensing should be used for individual doses for day cases, which, in her hospital comprise mainly cytotoxic agents, and for clinical trial products. Items that require special controls such as narcotics and blood derivatives would also benefit from the high level of control offered by automated dispensing.
A remote dispensing module would be ideal for out-of-hours supplies, repeat prescriptions for out-patients with chronic conditions and single doses for diagnostic tests.
Linking electronic prescribing with robotic dispensing can improve the quality of care that is delivered, David Miller (chief pharmacist, City Hospitals Sunderland NHS Foundation Trust, UK) told the audience. In his hospital an electronic prescribing system is linked to the pharmacy robot – a triple Rowa speedcase, with a built in labelling facility. Linking the two systems together eliminates the eight common dispensing errors that are reported in studies (incorrect labelling of patient name, directions, medicine name or strength, and supply of the incorrect medicine, strength, quantity or form), he emphasised. Pharmacists now authorise prescriptions on the ward and the items are automatically dispensed in the pharmacy. They also use the system to prepare discharge prescriptions on the ward. As a result workflow in the pharmacy department is better organised and dispensing work does not accumulate towards the end of the day.