Adverse effects of slimming drug orlistat were underreported

Adobe Spark (5)A new study comparing the protocols, clinical study reports (CSRs) and published papers on anti-obesity drug orlistat, has revealed a disparity in how adverse events were summarised and reported (Schroll et al, 2016).

Orlistat, which is manufactured by pharmaceutical company Roche, was approved by the European Medicines Agency (EMA) in 1998 but, along with other slimming drugs, has since encountered regulatory barriers. Nearly all slimming pills (but not orlistat) have been withdrawn from European markets because of harms.

Researchers at the Nordic Cochrane Centre in Copenhagen used a Freedom of Information Act request to the EMA to acquire the CSRs, which describe the results of studies conducted as part of the application for marketing authorisation of the drug.

Seven randomised placebo controlled orlistat trials were included in the application for marketing authorisation for the drug, and involved a total of 4,225 participants. Adverse events outlined in the CSRs were then compared by the researchers to each corresponding published trial paper identified on PubMed.

It was revealed that due to post hoc filters, only 3–33% of the total number of investigator-reported adverse events from the trials were outlined in the publications, though six of seven papers stated that ‘all adverse events were recorded.’

The investigators noted that none of the protocols to investigators for reporting harms or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were ‘bothersome,’ a condition that was not specified in the protocol for two of the trials. Events falling under the bracket of bothersome included ‘fatty/oily stool,’ ‘liquid stools’ (which term the protocol suggested to be used instead of diarrhoea), ‘increased defaecation,’ ‘stools soft,’ ‘decreased defaecation,’ and ‘pellets.’ Results sections in the core reports of the CSRs often stated that most of the adverse events were considered unrelated to the drug and that they were generally mild to moderate. The many gastrointestinal adverse events were explained as part of the pharmacological effect of orlistat. The researchers suggested that since gastrointestinal complaints are normal in healthy people, this type of censoring might have made it more difficult to detect gastrointestinal adverse events caused by orlistat.

Additionally, serious adverse events were assessed by the researchers for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group.

The researchers also revealed that in one trial, both the number of adverse effects and the number of days with adverse effects in participants taking the drug were understated in the corresponding publication. While 1,318 adverse events were not listed or mentioned in the CSR itself, the researchers were able to identify them through manually counting individual adverse events reported in an appendix.

Overall, the analysis revealed that participants treated with orlistat had experienced almost twice as many days with adverse events as those treated with placebo (22.7 days versus 14.9 days). Additionally, it was noted that the adverse events that occurred in the orlistat group were more severe compared with the placebo group. However, none of this information was stated in the CSR or the corresponding published paper.

A statement issued by Roche said: ‘Since the 1990s, technology for analysing data has changed and society’s desire and expectations for access has increased and so our practices have evolved.

‘We understand and support calls for the pharmaceutical industry to be transparent about clinical trial results, this is why we expanded our policy in 2013 to better share data from clinical trials across Roche medicines.

‘Roche are now at the forefront of the data sharing movement and now release all clinical study reports, periodic safety reports and summary reports of clinical data for all licensed, terminated or discontinued medicines.’

Based on the characteristics of harms observed and reported in these trials, the researchers at the Nordic Cochrane Centre suggested that reports of harms include duration of adverse effects. They also suggested that systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

They highlight how even though publication bias is well covered in the medical literature, few studies have analysed clinical study reports. They argue that in the future this could be a very important source of information. Other studies have found that only a fraction of adverse events were reported in published papers compared to the CSRs. For example, a study carried out by the German government’s Institute for Quality and Efficiency in Health Care looked at the CSRs for treatments assessed over a 5-year period and found that CSRs contained more information on adverse events and treatment effects than was published in trial reports and journal articles (Wieseler et al, 2013).

As mentioned by Schroll et al (2016), their research emphasises the ‘need for detailed analysis plans for harms data.’

References:

Schroll JB, Penninga EI, Gøtzsche PC (2016) Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis. PLoS Med 13(8): e1002101. doi: 10.1371/journal.pmed.1002101

Wieseler B, Wolfram N, McGauran N et al (2013) Completeness of reporting of patient-relevant clinical trial outcomes: comparison of unpublished clinical study reports with publicly available data. PLoS Med 10(10): e1001526. doi: 10.1371/journal.pmed.1001526

Taken from Nurse Prescribing, published 13 October 2016.

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Do advanced paramedics have a role as independent prescribers?

adobe-spark-3The journey regarding the proposal to introduce independent prescribing by advanced paramedic practitioners has been one focused on patient safety and a strong case for need. The challenge for the profession has been to ensure it’s positioned to respond to any concerns, and that any changes to the law allowing prescribing are made on the basis that patients will benefit.

Ministerial approval to take the proposal forward to the public consultation phase was granted by NHS England on 15 August 2014. The NHS England Allied Health Professions Medicines Project Team, in partnership with the College of Paramedics, developed a case of need for the proposal based on improving quality of care for patients. These improvements related to safety, clinical outcomes and experience, as well as the efficiency of service delivery, and value for money. Approval of the case of need was received from NHS England’s medical and nursing senior management teams in May 2014, and from the Department of Health non-medical prescribing board in July 2014.

Alongside the paramedic proposal, NHS England consulted on proposals to allow three other allied health professions to be able to prescribe or supply and administer medicines, as appropriate for their patients. These proposals were for independent prescribing by radiographers; supplementary prescribing by dietitians; and the use of exemptions within the Human Medicines Regulations 2012 by orthoptists.

At the time, Suzanne Rastrick, Chief Allied Health Professions Officer at NHS England, said:

‘Our proposals will allow patients to get the medicines they need without delay, instead of having to make separate appointments to see their doctor or GP.

‘Breaking down barriers in how care is provided between different parts of the NHS is key to the vision set out in the NHS Five Year Forward View.

‘Extension of prescribing and supply mechanisms for these four professions creates a more flexible workforce, able to innovate to provide services that are more responsive to the needs of patients, and reduce demand in other parts of the healthcare system.’

The public consultation opened on 26 February 2015 and ran for 12 weeks. As well as consulting on proposals for advanced paramedics to become independent prescribers of medicines across the UK, it also proposed that consideration be given to paramedic independent prescribers being allowed to mix licensed medicines prior to administration, and prescribe independently from a restricted list of controlled drugs. Anyone was welcome to respond, and feedback was received from members of the public, patients/patient representative groups, carers, voluntary organisations, health-care providers, commissioners, doctors, pharmacists, allied health professionals, nurses, regulators, non-medical prescribers and the Royal Colleges, as well as other representative bodies.

Why independent prescribing was not recommended

Following the close of the consultation, responses received were collated and analysed. The responses were considered by both the Commission on Human Medicines (CHM) and Medicines and Healthcare Products Regulatory Agency (MHRA), who felt unable to recommend independent prescribing for advanced paramedics at present.

The reasons for this decision were concerns over the wide range of conditions encountered by advanced paramedics and whether they could demonstrate evidence of adequate training and competency to diagnose the conditions that will be prescribed for. Additionally, there were notable concerns over the definition of an advanced paramedic practitioner, as this appears to vary between allied health professionals.

As a result, The CHM felt that independent prescribing might represent a risk to patient safety; for example, and in context with the lack of available evidence of competency at the time, if the wrong diagnosis was made and an inappropriate treatment was prescribed. They also felt that some of the examples cited to demonstrate a need for independent prescribing were not sufficiently robust.

Considering the possibility of independent prescribing

The College of Paramedics expressed disappointment that the CHM was unable to recommend independent prescribing for advanced paramedics at the present time, and has said it will continue its support and commitment to work with the project, and with NHS England this year to address the very legitimate comments made by the CHM. The college also said it would give regular updates to its members on the progress of the work.

Speaking on the possible future for independent prescribing by advanced paramedics, Andy Collen, medicines and prescribing project lead for the College of Paramedics, said:

‘We absolutely think that advanced paramedics have got a role as independent prescribers. The journey for any profession to undertake independent prescribing has to be done so with absolute rigour and consideration for patient safety. We need to provide reassurance that what is being proposed is going to benefit patients completely and that any risks are understood. Although it is disappointing, we absolutely welcome the feedback from CHM and we are continuing to work to answer the concerns the CHM have, and that is being supported by NHS England.’

Gerry Egan, chief executive officer of the College of Paramedics, said:

‘The College has a clear definition of the advanced paramedic role in terms of competencies and education and is working to make this the accepted definition both across the NHS and in the private health sector.

‘The College have no doubts advanced paramedics will deliver a massive benefit to patients in terms of delivering the right care at the right place and at the right time by the use of safe independent prescribing as part of integrated care systems.

‘The College remains totally committed to the proposal to introduce independent prescribing by advanced paramedics and looks forward to continuing supporting NHS England.’

Taken from Nurse Prescribing, published 9 September 2016.

Royal Pharmaceutical Society updates prescribing competency framework

Adobe Spark (1)The Royal Pharmaceutical Society (RPS, 2016) has published an update to the Competency Framework for all Prescribers to ensure health professionals prescribe safely and effectively.

Originally published in 2012, the framework was developed to offer a common set of competencies for prescribing, regardless of professional background. As a result, it is relevant to all prescribers, including doctors, pharmacists, nurses, dentists, physiotherapists, optometrists, radiographers, podiatrists and dietitians. However, the framework should be contextualised to reflect different areas of practice and levels of expertise.

Ash Soni, President of the RPS, said:

‘Both the number of medicines prescribed and the complexity of medicine regimens are increasing. The challenges associated with prescribing the right medicines and supporting patients to use them effectively should not be underestimated.

‘There’s lots of evidence to show that much needs to be done to improve the way we prescribe and support patients in effective medicines use. This guide will be invaluable and I’m delighted the RPS has coordinated the update.’

The initial framework was published by the National Prescribing Centre and the National Institute for Health and Care Excellence (NICE). For the update, the RPS was approached by NICE and Health Education England to carry out the work on behalf of all prescribing professions. Additionally, the RPS was asked to ensure the framework had UK-wide applicability.

A project steering group of prescribers across all professions and patients updated the framework. This involved a 6-week consultation of the draft policy, where hundreds of organisations and individuals responded.

The framework has been endorsed by the UK’s Chief Pharmaceutical Officers—Keith Ridge, Rose Marie Parr, Andrew Evans and Mark Timoney—who said:

‘The single competency framework provides a means for all prescribers to become equipped to support patients to achieve the best outcomes from their medicines.

‘This update will ensure individuals can continue to benefit from access to resources which help them continually improve their practice and work more effectively.

‘We commend the updated framework and encourage prescribers, professional bodies, education providers and regulators to use it to support their role in delivering safe and effective care.’

How the competencies are separated

The framework comprises 10 competencies split into two areas: the consultation and prescribing governance. Within each of these competency areas, statements describe the activity or outcomes that prescribers should be able to demonstrate.

The consultation

The first competency concerns assessing the patient. It promotes taking an appropriate medical, social and medication history, before undertaking an appropriate clinical assessment.

The second competency involves the prescriber considering the options for the patient. This includes both non-pharmacological and pharmacological approaches to treatment, and weighing up the risks and benefits to the patient of taking medicine.

The third competency is about reaching a shared decision with the patient/carer, so the patient/carer can make informed choices and agree on a plan that respects the patient’s preferences.

The fourth competency is the prescribing itself. The framework states the medicine should be prescribed only with ‘adequate, up-to-date awareness of its actions, indications, dose, contraindications, interactions, cautions, and unwanted effects.’ Where appropriate, medicines should be prescribed within relevant frameworks, such as local formularies or care pathways.

The fifth competency concerns providing information to the patient/carer about their medicines. This includes what the medicine is for, how to use it, possible unwanted effects and how to report them, and expected duration of treatment.

The sixth and final competency in the area of consultation is monitoring and reviewing. Here the prescriber should establish and maintain a plan for reviewing the patient’s treatment. The effectiveness of treatment and potential unwanted effects should be monitored.

Prescribing governance

The seventh competency, and first under the area of prescribing governance, concerns prescribing safely. It highlights that the prescriber should prescribe within their own scope of practice and recognise the limits of their own knowledge and skill.

The eighth competency comprises prescribing professionally, and ensuring the prescriber maintains confidence and competence to prescribe. This includes accepting personal responsibility for prescribing and understanding the legal and ethical implications.

The ninth competency focuses on improving prescribing practice through reflection. It also stresses the importance of acting on feedback and discussion.

The tenth and final competency involves prescribing as part of a multidisciplinary team to ensure continuity of care across care settings. Part of this concerns establishing relationships with other professionals based on understanding, trust and respect.

Putting the framework into practice

The framework can be used for a variety of reasons by prescribers to help them improve their performance and work more effectively. The following examples are highlighted in the framework:

  • To inform the design and delivery of education programmes; for example, through validation of educational sessions (including rationale for need) and as a framework to structure learning and assessment
  • To help health professionals prepare to prescribe and provide the basis for ongoing education and development programmes, continuous professional development and revalidation processes. For example, use as a framework for a portfolio to demonstrate competency in prescribing
  • To help prescribers identify strengths and areas for development through self-assessment, appraisal and as a way of structuring feedback from colleagues
  • To inform the development of education curricula and relevant accreditation of prescribing programmes for all prescribing professions
  • To provide professional organisations or specialist groups with a basis for the development of levels of prescribing competency; for example, from recently qualified prescriber through to advanced prescriber
  • To stimulate discussions around prescribing competencies and multidisciplinary skill mix at an organisational level
  • To inform organisational recruitment processes to help frame questions and benchmark candidates’prescribing experience
  • To inform the development of organisational systems and processes that support safe effective prescribing; for example, local clinical governance frameworks.

The RPS is liaising with the professional bodies and organisations of the other prescribing professions to encourage uptake of the framework, which will be reviewed again in July 2020.

References

Royal Pharmaceutical Society (2016) A Competency Framework for all Prescribers. http://www.rpharms.com/support-pdfs/prescribing-competencyframework.pdf (accessed 1 August 2016)

Taken from Nurse Prescribing, published 12 August 2016.