Unlicensed And Off Label Medicines Health And Social Care Essay

Generally, UK medicines must have a marketing authorisation granted by the MHRA. An unlicensed medicine does not have a marketing authorisation. Off-label use of a medicine occurs when a medicine is used outside of its licence terms. Potential implications can arise when unlicensed and off-label medicines are used in practice(1). Currently, little is known about how NHS hospital trusts manage these medicines.

Aim

To determine how NHS hospital trusts in the North West region manage unlicensed and off-label medicines in clinical practice.

Objectives

To develop and distribute a questionnaire in North West NHS trusts to determine whether guidelines are implemented for managing these medicines.

To conduct a literature review to identify online hospital policies.

To qualitatively analyse the content of hospital policies.

Methodology

A questionnaire was developed and piloted in 3 hospitals, then sent via email to contact pharmacists working in 13 North West hospital trusts between February-March 2013. A literature search was conducted between September-December 2012, to identify online UK hospital guidance. Policies were qualitatively analysed and results were inputted into Microsoft Excel.

Results

The questionnaire response rate was 77%, and the literature search identified 13 policies. Fewer hospitals had policies for off-label (40%) compared to unlicensed medicines (90%). Off-label medicines were relatively common within mental health; however the difficulty in identifying these medicines was highlighted. Informing patients was largely the prescriber’s responsibility; and 65% of hospitals had developed patient leaflets.

Conclusion

The similarity between policies highlights a possibility for future integration. Using patient leaflets is recommended to help patients understand their treatment. The poor awareness of off-label medicines means hospitals may benefit from implementing systems to overcome this. It is recommended that all hospitals consider auditing these medicines. The importance of this research is highlighted by the fact that these medicines directly impact patient care.

Part 1. Introduction

1.1 Unlicensed and Off-label Medicines

The regulation of medicines in the UK is controlled by the Medicines and Healthcare products Regulatory Agency (MHRA). A marketing authorisation, also known as a licence, is granted if the MHRA is satisfied that a medicine demonstrates adequate safety and efficacy, and achieves a certain standard of quality from the manufacturing process. Generally medicines must be granted with a marketing authorisation in order to be prescribed and administered in the UK. This marketing authorisation lists the clinical indications under which that medicine is licensed for use(2).

Licensed medicines should be used whenever possible; however situations may arise in practice whereby a licensed medicine cannot meet the clinical needs of a patient. In these circumstances, a prescriber may legally prescribe a medicine for an indication that falls outside of the terms of its marketing authorisation, if considered to be in the patient’s best interests. This is known as use of a medicine off-label(2). Prescribers must rely on any published evidence, local protocols and personal experience to justify the off-label use of a medicine. It has been acknowledged that potential implications surrounding safety, liability and efficacy can arise when off-label medicines are used in practice(1). Off-label medicine use is more common in particular patient groups including children, neonates and pregnant women, who are unlikely to be included in clinical trials. Off-label drug use can involve administration of a licensed drug for an alternative indication, to a patient not covered in the licence, via an alternative route, at an alternative dose, as an alternative formulation or administration despite cautionary warnings.

A prescriber may wish to administer a medicine which does not hold a UK marketing authorisation for any indication, otherwise known as an unlicensed medicine. This may involve the procurement of such a medicine from a "specials" manufacturer, importation from abroad or its extemporaneous preparation, however additional implications surrounding quality and availability may arise as a result(2).

1.1.1 Safety

The final stages of the drug licensing process involve the stringent testing of a drug in clinical trials to determine its safety. A marketing authorisation is granted after a drug has demonstrated it is sufficiently safe for use in the intended patient population for the treatment of specific indications. It is therefore understandable that potential safety implications can arise for the patient, if a drug is used outside of its marketing authorisation or indeed without a marketing authorisation(2).

Mason et al (2012) conducted a narrative review of the literature regarding adverse drug reactions in children in relation to off-label and unlicensed drug use(3). The search resulted in identification of seven studies which were included in the review. Although several studies found a relationship exists between unlicensed and off-label medicines and the increased risk of adverse drug reactions, the review concluded that a lack of clarity remains(3). The study acknowledged that the major limiting factors of these studies were the population sizes used; extrapolation of these findings to apply them to a wider population was not considered appropriate. More research and the use of more representative population samples are necessary to establish clear conclusions(3).

Pharmacists often have to manipulate ingredients by a method of extemporaneous preparation, in order to manufacture appropriate medicines to meet a patient’s needs when no equivalent licensed alternative exists. It has also been recognised that adverse reactions can occur as a result of excipients which can be added to the formulation during extemporaneous preparation, and not necessarily to the drug alone. Co-solvents are frequently added to liquid extemporaneous formulations to improve the solubility of poorly water-soluble compounds. Adverse reactions have been known to occur against the co-solvent propylene glycol; its use is cautioned in paediatric extemporaneous formulations due to the 11.9 hour increase in half life when metabolised in children compared to adults(1). Glycerol is also sometimes incorporated into formulations for the similar purpose of improving formulation stability and for its sweet taste(1). However diarrhoea and dehydration have been reported following its administration to patients(1). Furthermore, toxicity has been reported when ethanol has been used as another co-solvent, due to some patients experiencing an idiosyncratic reaction to alcohol(1).

1.1.2 Efficacy

The use of an unlicensed or off-label medicine raises the issue of whether an equivalent pharmacological effect is achieved in comparison to a licensed alternative. Unlicensed preparations can include parenteral solutions which are reformulated for oral administration. Parenteral drugs are often administered via this route to avoid degradation by stomach acid. However when reformulated this way, the extent of drug release can be highly variable and bioavailability can therefore be affected. This can lead to uncertainty as to the overall efficacy of the drug(1).

Oral administration is sometimes inappropriate however; this commonly arises when a patient is intubated with a naso-gastric tube. Off-label use of a drug can occur when an oral capsule is opened and its contents are administered via these tubes. It has been acknowledged that aggregation of granules contained within these capsules can lead to subsequent blockage of the tube. This leads to concerns surrounding the extent, if any, of drug absorption and its subsequent pharmacological effect(1).

1.1.3 Quality

Extemporaneous preparations, as previously discussed, can give rise to other implications. It has been acknowledged that quality issues can arise when oral liquids are prepared, as their physical, chemical and microbiological stability and subsequent expiry date is unknown(1). Flavourings may be added to suspensions to improve palatability, and colourings to aid compliance. However this can cause sediments to form which may not be completely dispersed upon shaking(1). When solid oral dosage forms are added to liquids, this can modify the pH of the resulting formulation and lead to precipitation and degradation(1). In the manufacture of topical preparations, the process of mixing together creams or ointments can lead to incompatibilities and decreased stability as a result(1). When preparing solid oral dosage forms, a certain level of precision is needed for cutting tablets, which often leads to an inaccurate dose. The quality of these subsequent formulations is debatable; these medicines may never have been subjected to the analysis or quality control procedures that occurs during the drug licensing process(4).

The facilities available in pharmacy departments for extemporaneous preparations can also compromise the quality of formulations, as the equipment used by pharmacists may not necessarily be sterile(1). It has been acknowledged that calculations used in extemporaneous compounding may be incorrect, as can the ingredients and quantities selected(1). The Royal Pharmaceutical Society has released guidance for pharmacists on extemporaneous preparations; its most recent guidance was published in June 2011(5). The document includes information about crushing solid dosage forms and advice when dealing with "specials"(5). In 2010 the "Handbook of Extemporaneous Preparations" was published, which describes the top 50 most commonly prepared extemporaneous formulations(6). The main aim of this publication was to ensure that good practice was implemented in NHS hospitals, yet the extent to which this handbook is used nationally is unknown. No national standardisation of extemporaneous practices means that pharmacists may not be accessing the same guidance, and preparations of varying standards may be dispensed to patients. Nationwide extemporaneous practice formularies are important to ensure formulation strengths, chemical stabilities and ingredient qualities are consistent(1).

1.1.4 Liability

Under the UK Medicines Act 1968, doctors may legally prescribe unlicensed and off label medicines, however such prescribing falls under their own professional responsibility(2). The General Medical Council (GMC) is a regulatory body which has published good practice guidelines for the prescribing of such medicines for doctors. These guidelines state that doctors are legally responsible for using these medicines and that a reliable evidence base must support their use, and adequate records kept(7).

Despite previous plans by the GMC to remove this statement, guidelines also state that doctors must ensure that an alternative licensed medicine would not be appropriate. The GMC had considered recommending the use of unlicensed and off-label medicines to doctors if their cost was cheaper than the equivalent licensed alternative, yet such plans have been postponed(8).

1.2 Literature Review

This study aims to identify how unlicensed and off-label medicines are evaluated in clinical practice, and how implications which may arise from their use are subsequently managed. To serve as an introduction to this project, a literature review was therefore conducted to find background information from studies which focused on the problems in practice of prescribing and administering unlicensed and off-label medicines, as well as their use. This literature search was conducted between September-December 2012.

1.2.1.1 Search Strategy: Identification of Issues Surrounding the Use of Off-label and Unlicensed Medicines

This literature search aimed to identify studies evaluating the problems arising from the use of unlicensed and off-label medicines. The literature search began using Medline, a key data base for medical literature. To find articles the following keywords were used together with truncation symbols to allow for word variations. Searches were refined by combining keywords with the use of Boolean logic; specifically AND/OR. Terms were mapped to subject headings or index terms, if databases had this option.

medic* to search medication, medicine, medicines OR drug* to search drug, drugs

This search was combined with unlicensed OR/AND off-label OR/AND licence OR/AND authorisation

This returned 4067 results.

Four new searches were therefore conducted by combining each search above with the following line of keywords using AND. This refined searches when identifying specific aspects of unlicensed and off label medicine use.

safety OR side effect OR ADR OR error OR risk

quality OR quality control

efficacy OR effectiveness

supply OR availability

In addition, the database Embase was searched which has more of a European focus, as well as Cinahl using the same search technique as outlined above. Reference lists of articles were used to find other relevant studies. The Pharmaceutical Journal Online was also searched directly as it is not indexed by most databases.

After identification of papers, the following criterion was applied for inclusion of papers as follows:

Inclusion criteria

Off label use of medicine

Unlicensed medicine

NHS hospital pharmacy setting

All study types

Full papers and conference abstracts

Exclusion criteria

Non-NHS setting

Review papers

News-type articles

Non-English language

Table A in Appendix 1 summarises the studies included in this review.

1.2.1.2 Key Findings from Literature Review

Regarding the safety of unlicensed and off-label medicines, an important factor to consider is that the number of adverse reactions which occur may indeed be higher than those figures reported in studies. The studies identified in the literature review were mainly conducted within specialised areas including neonatology, intensive care and paediatrics. Patients in these areas of care may be perceived as bearing some degree of vulnerability, and may be unable to notify healthcare professionals of the adverse reactions they are suffering(9). However statistics which indicate the frequency of adverse reactions are also reliant upon healthcare professionals or patients actually reporting them(4). If patients in these areas of care are critically ill, the disturbances in their body’s metabolism and the likelihood that they are prescribed more drugs than the average patient, means they are more likely to experience an adverse drug reaction(10). However one study conducted in an intensive care unit acknowledges that critically ill patients in these settings are monitored more closely, and the likelihood of detecting an adverse drug reaction is therefore higher(8). These studies were all conducted in specialised medical areas which mean their results are not applicable to a wider population. This makes it difficult to assess whether unlicensed or off-label medicines are more frequently involved in adverse reactions.

One study was identified which specifically explored the potential implications surrounding the quality of these medicines when formulated in pharmacies(11). This study looked at the frequency of extemporaneous manufacture in pharmacy departments of seven UK paediatric hospitals over a 12 month period(11). The average number of formulations prepared extemporaneously was 1.5 items daily and 26.5% of preparations were unlicensed(11). During manufacture, the process of cutting and grinding tablets and subsequent dispersion into agents, was associated with the highest error risk due to an unknown bioavailability of the formulation(11). Although this study included several hospitals across the UK, it is unknown however whether these results are applicable to healthcare settings outside of paediatrics.

It has been reported that potential availability problems of unlicensed and off-label medicines in both primary and secondary care settings can occur(12). This may be an additional consideration prior to initiation of such treatments. One study highlighted the supply difficulties that occurred for paediatric patients who continue to take an unlicensed or off-label medicine post-discharge from Great Ormond Street Hospital for Children(12). Results showed that 12% of prescribed medicines were for an unlicensed or off-label drug, and 33% of carers described difficulties in obtaining these medicines following discharge(12). This study found that community pharmacies are often reluctant to store such medicines; in particular "specials" which have short shelf lives(12). Consequently they reported difficulty in locating an appropriate manufacturer to produce a suitable formulation(12). Another factor contributing to this problem was refusal of General Practitioners (GPs) to supply, on the basis of the high cost of these medicines, insufficient experience and information in this area, and lack of appropriate equipment to monitor the pharmacokinetics in patients upon administration(12). Healthcare professionals in hospitals must be aware of and consider potential problems in primary care when initiating such medicines; disruption of medical treatment is not ideal and in some cases can pose potentially life-threatening effects(12). However no studies were found regarding supply difficulties in other areas or including other patient groups.

To overcome potential availability problems, one study looked at whether medicines which were extemporaneously produced in one country were available as licensed preparations in Europe, North America or Australia(13). The results showed that 75% of the top twenty oral liquids, 75% of the top twenty capsules and 30% of the top twenty powders prepared extemporaneously in one country were available as licensed medicines in another country(13). This study looked at paediatric hospital pharmacies, and the results may not be applicable to all healthcare settings. Healthcare professionals in hospitals must consider all available options for obtaining medicines; the risks associated with importing a licensed medicine may be considered less than the risks associated with extemporaneous formulations. Licensed medicines are subjected to appropriate quality control procedures and use ingredients of an appropriate pharmacopoeial standard. Mutual cooperation between healthcare professionals and licensing authorities in various countries could potentially overcome these risks(13).

Several studies have aimed to identify the attitudes and experiences of healthcare professionals regarding unlicensed and off-label drugs and their efficacy. The limitations from these studies are the population samples used and the areas of practice. Mukattash et al aimed to identify the attitudes surrounding efficacy of unlicensed as well as off-label medicines by healthcare professionals working in sectors outside of paediatrics(14). A written questionnaire was distributed to community pharmacists, hospital consultants, paediatric nurses and randomly selected GPs across various sectors in Northern Ireland(14). Results revealed that 23.8% of respondents admitting to having experienced a treatment failure as a result of an unlicensed or off-label medicine, furthermore 87.9% expressed concerns about the efficacy of unlicensed and off-label medicines(14). The limitation of this study was that all healthcare professionals included were in Northern Ireland, it is unknown if perceptions are applicable to healthcare professionals in other locations.

1.2.2.1 Search Strategy: Identification of Studies for the Management of Unlicensed and Off-label Medicines

Currently in the UK, the only national guidance to advise on the prescribing of unlicensed and off-label medicines are the twelve principles contained in the GMC’s Good Practice Guidance for Doctors(7). To aid the prescribing of these medicines, the National Institute for Health and Clinical Excellence (NICE) has occasionally recommended the off-label use of medicines in its clinical guidelines where no licensed alternative is available(15). In 2012, NICE Medicine and Prescribing Centre published its first evidence summaries for an off-label medicine(15). These publications summarise published evidence for selected unlicensed and off-label medicines and review information surrounding their efficacy and safety(15). These summaries do not constitute formal NICE guidance; instead they aim to support NHS formularies that hospitals have implemented and to aid prescribers with the decision making process(15). The means by which NHS healthcare practitioners procure, prescribe, supply and administer unlicensed and off-label medicines currently depends upon the individual NHS hospital trust in which that healthcare professional practices(2).

This project aims to identify the ways in which unlicensed and off-label medicines are managed in hospitals. The next step was to therefore identify studies focusing on the development and implementation of policies and guidelines for UK hospitals, for the handling of unlicensed and off-label medicines. This literature search was conducted between September – December 2012. The initial search was conducted again using the same databases as in Section 1.2.1.1, using the following search terms:

medic* to search medication, medicine, medicines OR drug* to search drug, drugs

AND unlicensed OR/AND off-label OR/AND licence OR/AND authorisation

guid* to search guidance, guideline, guidelines OR polic* to search policy, policies OR protocol OR audit

AND NHS OR United Kingdom OR England etc

AND hospital OR secondary care

AND pharm* to search pharmacist, pharmacists and pharmacy

The following inclusion criterion was applied:

Inclusion criteria

All publication types

Off label use of medicine

Unlicensed medicine

NHS hospital setting in the UK

Exclusion criteria

Non-NHS setting

Table B in Appendix 1 summarises the studies included in this review.

1.2.2.2 Key Findings from Literature Review

The internet search resulted in identification of 3 studies which described implementation of new schemes for the management of unlicensed medicines within the hospital. The first study summarises an audit which aimed to improve adherence to the hospital’s guidelines(16). The other two studies described measures which aimed to reduce pharmacy administration work, improve access to unlicensed medicines, and refine the classifications of unlicensed medicines as well as to ensure staff were aware of their risk(17, 18). Results of their long term effectiveness have not been published and there is no published evidence to indicate that other hospital settings have implemented similar schemes.

A lack of published studies means it is currently unknown how unlicensed and off-label medicines are evaluated in hospital settings, and whether any similarity exists regarding how implications in practice are managed. The importance of research in this area is highlighted by the fact that the use of unlicensed and off-label medicines can have a direct impact on patient care. Understanding how these NHS hospital trusts use unlicensed and off-label drugs may aid the movement towards greater standardisation of practice and potentially the production of national guidelines to guide NHS healthcare practitioners.

Part 2. Aims and Objectives

2.1 Aim

To determine how NHS hospital trusts in the North West region manage unlicensed and off-label medicines in clinical practice.

2.2 Objectives

A self-completion questionnaire was developed and distributed to NHS hospital trusts in the North West region to:

Determine whether hospitals in this region have implemented guidelines for managing and prescribing unlicensed and off-label medicines.

Establish whether unlicensed and off-label medicines are routinely assessed within the trust in accordance with any recommended guidance in place.

Determine whether patients and carers are informed by pharmacy staff that they are receiving an unlicensed or off-label medicine.

Documentary review of any policies returned with the questionnaire or identified from a literature review will:

Explore whether these developed guidelines differ between trusts in the key recommendations for initiation of unlicensed and off-label medicines.

Part 3. Methodology

3.1 Study Design

Firstly, a self-completion questionnaire was developed and sent to hospital pharmacists within NHS hospital trusts in the North West region, between February-March 2013. The questionnaire was used to collect quantitative and qualitative results. Qualitative data was generated following the review of hospital policies if returned with the questionnaire and from any additional comments that respondents wished to state about unlicensed and off-label medicines within their hospital. Secondly, a literature search was also conducted to identify any hospital policies for unlicensed and off-label medicines which had been published online.

3.2 Development of Questionnaire

The literature search, as outlined in Section 1.2.2.1, did not identify any studies which focused on guidelines for the management of unlicensed and off-label medicines. Consequently a self-completion questionnaire was developed which included questions investigating some key aspects surrounding the management of unlicensed and off-label medicines, which this study aimed to explore.

This self-completion questionnaire consisted largely of closed questions, including questions with multiple choice responses allowing for easier completion. This questionnaire was chosen as it allowed basic information to be collected to assess the types of guidance, if any, which existed in hospitals and for the subsequent review of these guidelines. Alternative approaches to collecting data, such as interviews with hospital pharmacists, would have provided qualitative insights into their perceptions of how unlicensed and off-label medicines are managed in each hospital. This however, would have proved too time consuming within the limitations of this study. A final open question was included however, whereby respondents could make additional comments about how these medicines are managed in their hospital, and it was requested that copies of any policies were also returned. A copy of the final questionnaire is found in Appendix 3.

3.2.1 Cover Page

The cover page presented the title, study aim and details of the investigator. It invited respondents to complete the questionnaire and included a statement that information provided would be treated anonymously. The questionnaire was kept short in length and an approximate completion time was given, with an aim of maximising the number of returned questionnaires.

3.2.2 Sections 1 and 2 – Unlicensed Medicines and Off-label Medicines

Sections 1 and 2 investigated unlicensed and off-label medicines respectively, and equivalent questions were included in each section. These questions were initially grouped under the same section investigating both classes of medicines, but later separated after acknowledging that hospitals may have guidelines for one class of medicines and not the other.

The aim of these sections was to determine whether hospitals have policies implemented for the management of unlicensed and off-label medicines, the reason for implementation and to whom it applied. This section also determined whether unlicensed and off-label medicines were routinely audited in accordance with this guidance. A statement requesting that respondents attach any copies of policies with the returned questionnaire was repeated in each section.

3.2.3 Section 3 – Informal Procedures

It was acknowledged that hospitals may not have formal policies implemented for the management of unlicensed and off-label medicines, therefore this section of the questionnaire was developed to assess whether any unofficial procedures were followed instead.

To avoid ambiguity and varied interpretations of this question, an eight point checklist was developed whereby respondents were asked to tick all procedures which applied to their hospital. Key information was extrapolated from the NHS hospital policies identified from the literature search as detailed in section 3.5, to help formulate this checklist. Space was included should respondents wish to comment on any alternative informal procedures followed in their hospital, if not included on this checklist.

3.2.4 Section 4 – Informing Patients

This study was particularly interested in patients’ awareness and understanding of unlicensed and off-label medicines, when prescribed such treatments. This section of the questionnaire was developed after acknowledging that information about informing patients may not be incorporated into hospital policies. Therefore questions in this section addressed the role of pharmacy staff in confirming patients’ awareness, the information given to patients and in which form this information takes.

3.2.5 Additional Information and Comments

The final question was developed to allow respondents to detail any further information or comments they wished to make about the management of unlicensed and off-label medicines within their hospital. Completion of this section was optional, but was included to allow respondents to detail any additional management issues not anticipated by this questionnaire, and for the collection of further qualitative information.

A concluding statement thanked respondents for completing the questionnaire and gave details of the investigator if they wished for further information. The statement requesting that respondents attach copies of policies with the returned questionnaire was again repeated, to maximise the number of policies returned.

3.3 Piloting of Data Collection Tool

The questionnaire was initially piloted before the final collection of results. The aim of this pilot was to ensure this data collection tool fulfilled the aim of the study, and to establish whether questions were interpreted in the intended way. The pilot involved 3 hospital pharmacists in the North West region that were within the target group for the final study. This pilot study was conducted in December 2012, with the final questionnaire returned in February 2013. A questionnaire comments form was also distributed with the questionnaire to collect feedback on the ease of completion.

Following this pilot, some minor amendments were made to the questionnaire. Question 9 initially asked for respondents to provide details of any unofficial procedures followed in their hospital, should no formal policies exist. The pilot showed that one respondent interpreted this question as being too broad to answer. Consequently the checklist approach for answering this question was developed to avoid ambiguity, allowing respondents to tick all statements which apply and to list additional procedures as well. Secondly, only 2 hospitals attached policies despite all 3 hospitals indicating in the questionnaire that guidance existed. For this reason, the statement requesting that respondents attach copies of policies with the returned questionnaire was repeated several times and also outlined in a box as a reminder. Lastly, the pilot gave an indication of the approximate timescale to be expected when awaiting replies. The time constraints of the project meant that respondents were asked to return final questionnaires before the 15th March.

No major problems were identified regarding the context of questions or difficulties understanding the question sequence. Consequently the information collected in the pilot and in the final questionnaire did not differ, and these pilot results were therefore included in the final data analysis.

3.4 Questionnaire Distribution

Questionnaires were sent via email to contact pharmacists at selected NHS hospitals in the North West region. This region was chosen due to good communication links with these hospitals and due to proximity. Additionally written questionnaires were also distributed to hospital pharmacists in the North West region who were studying for a diploma in Clinical and Health Services Pharmacy, which aimed to maximise the number of returned questionnaires. NHS ethics approval was not required for this service evaluation. Questionnaires were returned via email or post. A total of 13 questionnaires were distributed, and a deadline of 15th March was set for replies.

3.5 Search Strategy: Identification of NHS Hospital Policies

A literature search was conducted to explore whether NHS hospitals in the UK had guidelines published for the management of unlicensed and off-label medicines. This would explore whether the guidelines implemented in North West hospitals differed from guidelines developed by hospitals elsewhere in the UK. This literature search was conducted between September – December 2012.

The same search strategy was conducted as detailed in Section 1.2.2.1, however little relevant information was found regarding NHS guidelines and policies. Therefore, the next approach was to search the wider internet with the following keywords to determine whether hospitals had posted online any guidelines that their NHS trust had developed. The following search terms were used:

unlicensed and off-label and drugs/medicines and hospital policies/guideline

The following inclusion criterion was applied:

Inclusion criteria

All publication types

Off label use of medicine

Unlicensed medicine

NHS hospital setting in the UK

Exclusion criteria

Non-NHS setting

The table in Appendix 2 summarise the 13 policies identified from this search, which were subsequently included in this data analysis.

3.6 Development of Data Analysis Tool

Questionnaire results were analysed using two spreadsheets on Microsoft Excel; the first for the analysis of questionnaire results and the second for the analysis of guidelines. Each hospital was labelled with a number to allow for cross referencing between spreadsheets.

The first spreadsheet was developed with hospital numbers inserted as column headers against the question numbers from the questionnaire. Questionnaire responses were assigned letters to be entered into the spreadsheets, as shown in Appendix 3. Unanswered questions were left blank unless information could be extrapolated from the policy if returned from the hospital.

Following a review of the NHS hospital policies identified from the literature search in Section 3.5, key guidance which related to different management aspects of unlicensed and off-label medicines was extrapolated and formulated into a checklist, as shown in Appendix 4. The second spreadsheet was developed with hospital numbers inserted as column headers against numbers assigned to each checklist statement. Policies identified from the literature search and any policies returned from hospitals were qualitatively analysed, to assess whether guidance in this checklist was included. They were subsequently entered into the spreadsheet after analysing whether a statement was included in the policy, whether limited information was included in the policy, or whether it was not included in the policy at all, using the letters "Y", "L" or "N" respectively. To differentiate between those returned from the questionnaire and those identified from the internet search, policies were labelled with the letter "Q" or "I" respectively.

Quantitative data was analysed descriptively using frequency tables to calculate percentage statistics. Any additional comments made on the questionnaire about the management of unlicensed and off-label medicines, were analysed to identify any significant or recurring themes between hospitals.

Part 4. Results

4.1 Questionnaire Results

A total of 10 questionnaires were returned from different NHS hospital trusts in the North West region, achieving a response rate of 77%. The Microsoft Excel spreadsheet with the results of the questionnaire is in data sheet 1 of Appendix 5.

4.1.1 Unlicensed and Off-label Medicines Management

The majority of hospitals had policies implemented for unlicensed medicines, 5 of which applied to all healthcare professionals, 2 to pharmacy staff only and 2 to prescribers as well as pharmacy staff. The policy in 1 of these hospitals was currently under development; advice was currently being sought from the GMC as to what should be included within this unlicensed and off-label medicines policy. Of the 7 hospitals which had policies implemented for good practice, 2 of these were also implemented due to a specific incident which occurred within the hospital. The hospital with guidance currently under development, commented that audits for unlicensed medicines may be conducted after their policy had been ratified. Furthermore, 2 hospitals which did not conduct audits for unlicensed medicines commented that they believed these medicines should be audited.

A lower number of hospitals had policies for off-label medicines compared to unlicensed medicines, and the policy in 1 of these hospitals was currently under development. Of the 4 hospitals with policies, 3 applied to all healthcare professionals and 1 to prescribers and pharmacy staff. Audits were conducted in 1 of these hospitals for off-label medicines classified as high risk only, and 1 hospital commented that they believed audits for off-label medicines should be conducted.

N = Number of respondents

(Percentage total)

Unlicensed medicines

Off-label medicines

Guideline implemented

N=9 (90%)

N=4 (40%)

Guideline applies to pharmacy staff only

N=2 (20%)

N=0

Separate guidelines for other hospital staff

N=2 (20%)

N=0

Reason for implementing guideline:

Good practice

Specific incident

Not sure

Other

N=7 (70%)

N=2 (20%)

N=2 (20%)

N=0

N=3 (30%)

N=0

N=1 (10%)

N=0

Medicines are routinely audited

N=3 (30%)

N=1 (10%)

Last audit conducted:

Previous 6 months

Previous 12 months

More than 12 months

Not sure

N=0

N=3 (30%)

N=0

N=0

N=0

N=1 (10%)

N=0

N=0

Medicines are continuously monitored

N=4 (40%)

N=1 (10%)

Table 4.1.1: Table to show the questionnaire responses for unlicensed and off-label medicines management.

Additional comments were made by 4 hospitals highlighting the difficulty that exists when identifying medicines that are used off-label. A pharmacist working within a mental health specialist hospital commented: "Unless a pharmacist is directly involved within the multidisciplinary team then the pharmacy staff may not be aware it is an off-label use". Similarly, a pharmacist working within a cancer specialist hospital commented: "It is impractical to track off-label usage of drugs in the dispensary".

Additionally 2 hospitals, identified as mental health hospitals, commented on the low frequency use of unlicensed medicines within their trusts; 1 of these hospitals commented that currently only one unlicensed medicine was used and the other commented that they have very few, sometimes none used. Interestingly, 1 of these hospitals commented that off-label medicines were routinely used within their trust, particularly with the SSRI antidepressant drugs. This respondent commented: "This may be because all the medicines in a group are known to act the same way and it is purely licensing that differentiates, for example, SSRIs and anxiety".

4.1.2 Informal Procedures

A total of 7 hospitals had no guidance for unlicensed or off-label medicines; 1 hospital had no unlicensed or off-label medicines policy, 5 hospitals had no off label medicines policy and 1 hospital had guidance for unlicensed and off-label medicines currently under development. In the questionnaire, 6 of these 7 hospitals completed the following section on informal procedures which are alternatively followed.

N = Number of respondents

(Percentage)

Medicines Management Committee (or similar) maintains a list of unlicensed/off-label medicines used within the hospital

N=4 (67%)

Medicines Management Committee (or similar) is alerted as to the use of a new unlicensed/off-label medicine within the hospital

N=3 (50%)

Request forms are completed to approve the use of new unlicensed/off-label medicines within the hospital

N=5 (83%)

Risk assessments are conducted for unlicensed/off label medicines used within the hospital

N=6 (100%)

Systems are in place (e.g. alerts on computer systems) to inform pharmacy staff as to the licence status of a medicine

N=2 (33%)

Pharmacy monitors and/or records the use of unlicensed/off-label medicines

N=6 (100%)

Pharmacy ensures prescribers are aware of the licence status and clinical implications of unlicensed/off-label medicines prior to use

N=5 (83%)

Pharmacy maintains a list of approved suppliers of unlicensed medicines

N=6 (100%)

Table 4.1.2: Table to show the questionnaire responses for informal procedures.

Additional comments about these informal procedures were made by 2 mental health hospitals. The first hospital commented that all unlicensed medicines are approved on a case by case basis due to the low number of unlicensed medicines used. Regarding off-label medicines they have a range of peer reviewed accepted treatments within the trust, when using a high risk off-label medicine all that is required is a second opinion from a doctor or pharmacist. This respondent commented: "This is a mental health trust where the use of certain medicines off label is standard practice in some conditions". The second hospital had guidance currently under development and made a similar reference to the relatively common use of medicines used off-label. The respondent stated: "We will have a list of common drugs used off label and will not expect any request forms for these if they are agreed by the Trust Medicines Management Group".

4.1.3 Informing Patients

Only 3 hospitals responded that pharmacy staff confirm patients’ awareness and understanding if they have been prescribed an unlicensed or off-label medicine, the same 3 hospitals answered that pharmacy staff also provide advice. Verbal advice was always given and a standard leaflet was used when available, in 1 of these hospitals.

N = Number of respondents

(Percentage total)

Pharmacy staff confirm patients’ awareness

N=3 (30%)

Pharmacy staff provide relevant advice

N=3 (30%)

Form in which this advice takes

Verbal

Standard leaflet

Other

N=2 (20%)

N=2 (20%)

N=0

Table 4.1.3: Table to show the questionnaire responses for informing patients.

Additional comments made about informing patients followed a similar theme; informing patients was seen as the prescriber’s role in 4 hospitals. This was because it is deemed impractical to track these medicines, particularly those used off-label, in the dispensary. One respondent commented: "I personally confirm patients’ awareness, but I cannot confirm that all pharmacists within the hospital do the same".

The hospital with an unlicensed and off-label medicines policy currently under development plans to develop standard leaflets and another hospital commented that they had a leaflet currently under development.

A mental health hospital whose pharmacy staff did not confirm patients’ awareness, commented that more work was needed within their policies on the patient information side. They also commented that there are occasions whereby patients may be detained and are consequently unable to consent to treatment; in these circumstances a second opinion from a doctor is required before treatment can commence.

4.2 Guideline Analysis

A total of 4 North West hospitals returned copies of their policies with the questionnaire; 2 applied to unlicensed medicines only and 2 applied to both unlicensed and off-label medicines. A total of 13 policies were identified from the literature search in Section 3.5; 7 policies included guidance for both unlicensed and off-label medicines, 5 for unlicensed medicines and 1 for off-label medicines only. The Microsoft Excel spreadsheet containing the documentary review of these policies is in data sheet 2 of Appendix 5.

4.2.1 Unlicensed Medicines Management

The majority of policies detailed risk assessments which were conducted for unlicensed medicines; 7 policies detailed a classification system whereby medicines were categorised into a specific risk category such as lower, intermediate or higher risk. A "traffic light system" was described in 4 policies dependent on the level of risk of the unlicensed medicine; in 2 of these policies this traffic light classification also controlled who was able to prescribe these medicines, and which medicines were suitable for transferred prescribing into primary care.

Within 2 policies the process of conducting risk assessments for unlicensed medicines was described as being the sole responsibility of the prescriber, without any involvement of the Drug and Therapeutics Committee (DTC) at any stage. The purpose of this was to help the prescriber decide whether to prescribe an unlicensed medicine or not.

N = Total number of policies

(Percentage of unlicensed medicine policies)

Hospital maintains a list of unlicensed medicines used within hospital

N=13 (81%)

Request forms are completed before use of a new unlicensed medicine

N=12 (81%)

Risk assessment processes are conducted for all unlicensed medicines

N=15 (94%)

Systems are implemented to inform make pharmacy staff aware it is an unlicensed medicine

N=4 (25%)

Pharmacy monitors and/or records the use of unlicensed medicines

N=12 (75%)

Pharmacy ensures prescribers are aware of the licence status of unlicensed medicines prior to use

N=12 (75%)

Designated Pharmacist is appointed who has overall responsibility for monitoring unlicensed medicines in the hospital

N=7 (44%)

Patients’ GPs are made aware of initiation of an unlicensed medicine

N=14 (88%)

Patients’ GPs must agree to continue to prescribe an unlicensed medicine

N=14 (88%)

Table 4.2.1: Table to show the number of policies containing checklist statements surrounding unlicensed medicines management.

Systems developed to alert pharmacy staff of an unlicensed medicine were described in just 4 policies; 2 hospitals ensured all prescriptions for unlicensed medicines were clearly endorsed, the other 2 had alerts on their computer systems within the dispensary.

4.2.2. Off label Medicines Management

Fewer processes for monitoring off-label medicines were detailed within policies, compared to those for monitoring unlicensed medicines. Just 3 policies included off-label medicines within their classification system whereby medicines were categorised into specific risk categories such as lower, intermediate or higher risk, and off-label medicines were included within the "traffic light system" in just 1 policy. Off-label medicines were stated as carrying the same risk as high risk unlicensed medicines in 1 policy, and were subsequently managed the same way.

The guidance developed within 1 setting, identified as a mental health hospital, contained very little detailed framework for managing off-label medicines. Off-label medicines were categorised into 2 levels; when using a level 1 medicine the guidance stated prescribers must follow any "authoritative guidance available", and monitor and document the efficacy of treatment. However for medicines within level 2, prescribers must additionally obtain a colleague’s second opinion, discuss their treatment decision with a multidisciplinary team and document this. The guidance stated that it was the prescriber’s responsibility to assess whether medicines fell into level 1 or 2, which subsequently affected which actions they followed.

N = Total number of policies

(Percentage of off-label medicine policies)

Hospital maintains a list of off-label medicines used within hospital

N=5 (50%)

Risk assessment processes are conducted for all off-label medicines

N=7 (70%)

Systems are implemented to make pharmacy staff aware it is an off-label medicine

N=0

Pharmacy monitors and/or records the use of off-label medicines

N=0

Patients’ GPs are made aware of initiation of an off-label medicine

N=8 (80%)

Patients’ GPs must agree to continue to prescribe an off-label medicine

N=8 (80%)

Table 4.2.2: Table to show the number of policies containing checklist statements surrounding off-label medicines management.

No systems were detailed in policies which make pharmacy staff aware of a medicine being used off-label; 1 policy stated that in order to identify an off-label medicine it must be looked up on the medicines reference list on their trust’s intranet.

Additionally, 5 hospitals had also developed off-label request forms which were required to be completed before the use of a new off-label medicine. Within 2 of these hospitals request forms were only required for high risk drugs, and in 1 policy it was acknowledged that their use within paediatrics was not feasible due to the number of off-label medicines used within this specialty. Policies in 3 hospitals explained that prescribers can apply for routinely used off-label medicines to be added to their trust’s formulary, if they have demonstrated a clear clinical benefit.

4.2.3. Availability

A total of 9 hospital policies acknowledged the potential difficulty that may occur for patients upon discharge when obtaining supplies of unlicensed medicines; these hospitals subsequently made arrangements for continuing supply. In the majority of policies, the responsibility for all procurement aspects of unlicensed medicines remained with the pharmacy department.

N = Total number of policies

(Percentage of unlicensed medicine policies)

Hospital makes arrangements for continuing supply of unlicensed medicines for patients post-discharge

N=9 (56%)

Pharmacy maintains a list of approved suppliers of unlicensed medicines

N=5 (31%)

Pharmacy department has responsibility for procurement of unlicensed medicines

N=11 (69%)

Pharmacy department maintains records of all purchased unlicensed medicines

N=10 (62%)

Table 4.2.3: Table to show the number of policies containing checklist statements surrounding availability.

4.2.4 Quality

All 4 policies implemented by North West hospitals prepared specifications for unlicensed medicines in conjunction with good quality control. It was stated in 3 of these policies that unlicensed medicines were assessed in conjunction with Quality Control North West, a regional NHS quality assurance service.

N = Total number of policies

(Percentage of unlicensed medicine policies)

Specifications for unlicensed medicines are prepared/assessed by pharmacy staff in conjunction with good quality control

N=9 (56%)

Limited information: 1 (6%)

Upon receipt of an unlicensed medicine, pharmacy staff must inspect medicine for any defects in quality

N=7 (44%)

Limited information: 2 (13%)

Certificates of analysis are obtained for unlicensed medicines

N=6 (38%)

Limited information: 2 (13%)

Table 4.2.4: Table to show the number of policies containing checklist statements surrounding quality.

It was highlighted in 6 policies that the pharmacist who ordered or prepared the unlicensed medicine was legally considered to be the manufacturer; consequently they were professionally accountable for any harm arising from the quality of the medicine.

Certificates of analysis were required to be obtained in 6 policies, 1 of these required certificates of analysis for high risk unlicensed medicines only. The 2 policies which contained limited information about this checklist point stated that the pharmacist ordering the unlicensed medicine must ensure that the product "complies with the product specification produced by the manufacturer".

4.2.5 Safety

The responsibility of pharmacy staff for ensuring that unlicensed and off-label medicines were only used when a licensed medicine was not available or appropriate was reiterated in a total of 12 (71%) policies. The same number of policies also detailed that all adverse drug reactions arising from the use of unlicensed and off-label medicines should legally be reported using the Yellow Card Reporting Scheme, to the MHRA. Adverse drug reactions from unlicensed and off-label medicines were required to be documented in patient’s medical notes in just 2 (12%) policies, both of which were in from North West hospitals.