Medicines reconciliation of biologics on a primary care clinical system

In the broadest sense of the word, ‘biologics’ are not anything new at all. Biologics have been defined by the American Food and Drug Agency (FDA, 2019) as being ‘composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources – human, animal, or microorganism – and may be produced by biotechnology methods and other cutting-edge technologies’. Using this definition products such as insulins, erthyropoetins and pancreatin, which are both well-established and frequently prescribed medicines, can be included. For the purposes of this article however, the term ‘biologics’ will refer to a paraphrased version of the latter part of the FDA (2019) definition ie ‘organic based medicines manufactured using new technology, which includes biotechnology’. The term ‘new’ in this context is highly subjective, given the rate of advancements in medicine, particularly in this 21^st century. What might be new at the time of writing this article may not be new by the time this article is read. That said, ‘biologics’ (using this paraphrased definition) includes (but is not limited to) the following:

• Tumour necrosis factor (TNF) antagonists – colloquially known as the ‘mabs’ eg infliximab, ustekinumab, adalimumab etc
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors – eg alirocumab and evolocumab, licensed and approved by National Institute for Health and Care Excellence (NICE) for primary hyperlipidaemia and mixed dyslipidaemia (eMC, 2020a, b)
• Genetically modified amino acids eg Teriparatide (licensed for the treatment of osteoporosis) which is manufactured from the common bacterium Escherichia coli, e.coli (eMC, 2020c)
• Selective immunoglobin binding monoclonal antibodies such as omalizumab licensed for use in eosinophilic asthma (eMC, 2020d)

This article focuses on biologics used in non-cancer indications, though of note, biologics have been used in COVID-19, with toculizumab (Veiga et al, 2021) and also with sarilumab (NICE, 2021).

Clarification of biologic and non-biologic medicines

DMARDs (Disease Modifying Anti-Rheumatic Drugs) such as methotrexate, azathioprine and leflunomide, licensed in dermatological, gastrointestinal and rheumatic conditions are not strictly biologics. Kinase inhibitors such baricitinib and tofacitinib also like DMARDs produce an immune response as part of their pharmacodynamics, they are not biologics, these are called non-biological DMARDs.

The process for medicines reconciliation for DMARDs would be the same as the process for biologics, however the focus of this article and the associated quality improvement project is on biologics.

Biosimilars

No discussion of biologics would be complete without discussing biosimilars also. Biosimilars have been described as a ‘medicine which has been shown not to have any clinically meaningful differences from the originator medicine in terms of quality, safety and efficacy’ (NHS England, 2021). Unlike generic versions of proprietary drugs (eg atorvastatin for Lipitor), biosimilars are medicines that resemble biologics (though are not structurally identical) but do share the same amino acid sequence. Examples of biosimilars include Amgevita and Remisma, which are biosimilars of the originator biologics Humira (Adalimumab) and Remicade (Infliximab) respectively. Though there are differences in brand names, biosimilars and biologics are not interchangeable therefore careful prescribing and transcribing is warranted due to clinical and cost reasons.

Due to the similarities of biosimilars to the originator biologic no changes in efficacy are expected, though patients would need to be consulted with before any switch from a biologic to a biosimilar.

In the 2018/2019 financial year, the cost-saving to NHS for the use biosimilars prescribed for clinically appropriate patients was £109 668 408 for adalimumab and £31 964 413 for infliximab (NHS England, 2019).

Due to their non-biological make-up, DMARDs, JAK inhibitors and biosimilars are not strictly biologics; however, much of the principles of prescribing and clinical use are the same.

Biologic formulations

At the time of writing, biologics were restricted to intravenous and subcutaneous formulations. The development of oral biologics have yet to materialise on to the UK market. The prospects and implications of oral biologics have recently been discussed in national pharmaceutical press (Mantaj and Vllasaliu, 2020). Oral formulation would be much less invasive than parenteral and reduce the risk injection site reactions (which carry a risk of infection). The convenience that comes with the freedom of oral administration coupled with the clinic space and staffing requirements that would be negated would be helpful to off-set the cost impact prescribing budgets. In a local healthcare economy, all biologics are rated as ‘RED’ (ie for secondary care prescribing only) by the Greater Manchester Medicines Management Group (GMMMG, 2021) with no current consultation running for biologics to be rated as appropriate to be prescribed in primary care (with or without a shared care agreement).

Biologic immunosuppression

The immunosuppression that can occur when patients are treated with these biologics can have significant clinical consequences. In a drug safety alert in April 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) warned of immunizing patients who are immunosuppressed with a Yellow Fever vaccine (gov.uk, 2019). This was the result of two reports of a fatal adverse reaction to a Yellow Fever vaccine, which is a live vaccine. Another example of a live vaccine is the herpes zoster also known as Shingles.

The Department of Health produces an authoritative guide to all things related to vaccinations titled ‘Immunisation against infectious disease’. This guide is known more commonly as ‘The Green Book’ for obvious reasons. Contained in chapter 6 (Contraindications and special considerations) of the Green Book is the following statement ‘patients who have had a biologic in the last 12 months prior to the anticipated date… should not receive a live vaccine unless a specialist has deemed the benefits to outweigh the risks’ (gov.uk, 2017)

One of the criteria for the shielding of people defined on medical grounds as extremely vulnerable from COVID-19 included those people ‘on immunosuppression therapies sufficient to significantly increase risk of infection’ (gov.uk, 2021c). Given the licensed indications for biologics and their mechanism of action, many people prescribed biologics would be shielded based on this criterion alone. At the time of writing (pre-COVID-19), the immune status of this patient cohort arguably did not have such implications on anxiety, employment, social mobility as it has done since COVID-19 and its effects have impacted all our lives The importance of accurate medicines reconciliation of biologics could now said to have major life implications for relevant patients.

The motivation for this quality improvement stemmed from a root cause analysis of a near-miss prescribing event – an event self-reported by a GP. Following a joint GP and nurse visit to a care home to administer a shingles vaccine, the clinical system (EMIS) had no record on the medication screen that this patient was prescribed a biologic and therefore the shingles vaccine – a live vaccine – was contraindicated. The patient did not receive the vaccination and did not come to any harm.

In order to identify patients where an error such as the one just mentioned may occur, Clinical Commissioning Group (CCG) colleagues in the contracts team (who deal with invoices for high cost drugs) provided pseudo-anonymised data of patients registered with a GP within the borough who had been prescribed a biologic in the most recently financial quarter. This was for a clear purpose of increasing safety with the aim of ensuring that these biologics were reconciled appropriately on the patients' primary care health records.

Methods

The methodology for this quality improvement project began at the point when the patient prescribed the biologic from secondary care was identified. The next step was to reconcile the biologic on the patient's primary care records in such a way that the biologic would be easily identifiable on the patient record, but distinct from the rest of the patient's medication. The activity was to build a search and auto-report on the primary care clinical system to cross reference with the information from the high cost drug report.

This done by cross referencing the clinical READ codes related to the licensed indications of the biologics as clinical codes (eg rheumatoid arthritis, ankylosing spondioylilits, ulcerative colitis etc) with the month/year of birth of each patient.

This search criteria and pseudo-anonimised report was then shared with pharmacists and pharmacy technicians linked to each practice to identify the relevant patients and reconcile their biologic medicine to their primary care records. Data to each practice/clinical pharmacist/pharmacy technician was shared and a senior clinical pharmacist acted as the single data handler. 32 practices within in the CCG were contacted about this quality improvement project via either their practice manager, CCG employed clinical pharmacists or CCG employed pharmacy technician.

Results

In total, 16 practices completed the quality improvement project and submitted data before the agreed deadline. The remaining 15 practices that were contacted either did not respond to the request to participate in the quality improvement project, or responded in some capacity but did not submit any data. Any data submitted after the agreed deadline or incomplete data received from a practice was excluded. All of the medicines reconciliation was either completed by the CCG employed clinical pharmacists or CCG employed pharmacy technician. The outcomes were that in 16 practices from five different primary care networks (PCNs), 273 biologics were identified for medicines reconciliation. Of those 273 biologics, 30% (n=81) were already reconciled appropriately on the relevant patient primary care medical records. The remaining 70% (n= 192) were reconciled by the pharmacist or pharmacist technician working at the relevant practice. The most frequently occurring drugs for reconciling were

• Adalimumab for a range of indications including arthritic, psoriatic and gastrointestinal diseases in both adults and children)
• Infliximab - for Crohn's Disease and Ulcerative Colitis
• Darbepoetin alfa for patients with end-stage renal failure
• Etanercept for arthritic and psoriatic conditions. A small number of non-biologic high-cost medicines were identified as well (n=11) in the high-cost drug report given by the CCG's business analyst. These were included in the results on the basis that the principles of medicines reconciliation and patient safety are the exactly the same. The 11 other drugs were compromised from the following
• Alitretinion: for the treatment-resistant severe chronic hand eczema or predominantly hyperkeratotic eczema
• Somatropin: a growth hormone treatment
• Riluzole: licensed as a life extender for patients with amyotrophic lateral sclerosis (ALS)
• Romiplostin: an antihaemorrhagic that increases platelet production
• Dimethyl Fumarate: an immunomodulatory drug with a positive NICE technical appraisals for treating relapsing-remitting multiple sclerosis (NICE, 2014) and psoriasis (NICE, 2017).

Discussion

A mixed skill set and mixed familiarity with biologics of the pharmacy team, concurrent workload of pharmacists and pharmacy technicians competing with other tasks such as medication reviews, discharge reconciliation and prescribing queries resulted in lower than expected numbers of complete data sets being returned.

In day-to-day practice, medicines reconciliation from practices within the CCG are done by a range of clinical and non-clinical staff depending on the skill mix of each practice. These may include ‘medicines managers’, GPs, receptionists (with or without a working familiarity with specialist medications) and in some cases a pharmacy technician or pharmacist. As experts in all things medicine related, it could be argued that the pharmacy professionals in primary care should be the ones leading on (but necessarily solely responsible for) medicines reconciliation from secondary care into primary care. Regardless of who receives the clinic letters from secondary care mentioning biologics, secondary care could make it explicit on their letters to request primary care to add the biologic on to their primary records with a reason why, such as to increase patient safety and minimise risk of harm. In the absence of having computer systems in primary and secondary care that ‘talk’ to each other, this could be a positive interim step.

As the numbers of licensed and NICE approved biologics grows, it is important that medicines reconciliation of these drugs is not left only to the time of audits and quality improvement projects. One idea that has been suggested to increase the quality of medicines reconciliation of biologics was to add a question to a new patient screening template that is used by health care assistants. This (and other members of staff who undertake new patient checks) to ask if the newly-registered patient receives and medicines, injections or infusion from any hospital or other specialist clinic.

The practices that agreed to this quality improvement project reduced the risk of medicines reconciliation harm to their patients. Those practices that did not respond to the request did not benefit from this free intervention and no feedback was received regarding their non-engagement. Following the quality improvement project, a one-page prescribing alert was produced for all the practices within the borough highlighting the process and a case study of reconciling secondary issued medication on to a patient's primary care record. It is anticipated that when repeating this quality improvement in 12 months' time, there would be a greater response from practices as the original quality improvement project would then have been peer-reviewed and in the literature.

As an added qualitative value, this project enabled some of the pharmacists to invite patients for a medication review who might not have been otherwise been highlighted to have been invited for a review. These medication reviews include compliance checks, ascertaining of patient knowledge of medication and therapy, clinical examinations where appropriate, side-effect checking, safe prescribing checks, applying evidence, reviewing durations and indications, non-pharmacological advice and interventions e.g. smoking cessation, weight management and appropriate de-prescribing (NB not of the biologic but of other prescribed medications).

Flags to alert clinicians in primary care to the existence co-prescribed biologics do exist (depending on the biologic being reconciled in the first place) but with the plethora of alerts that exist (safety alerts, cost-effective alerts and other alerts) the term ‘alert fatigue’ – a desensitisation to safety alert on computer systems leading to non-response to such warnings – can be a real oxymoronic danger. A US systematic review (Patient Safety Network, 2019) showed that alert fatigue is common, the alerts themselves are moderately effective at best and that alert fatigue grows with increasing exposure, therefore the answer is not necessarily more alerts, but more targeted and specific alerts, such as the biologics' contraindication to a live vaccine only appears when a live vaccine is selected or when an excipient is problematic for a patient (allergy, sensitivity or otherwise) rather than at every instance of prescribing any item for a patient. A further consideration could be the ethical dilemmas that arise from the manufacturer of biologics. Given the increasing popularity of veganism, it is surely a matter of time until this becomes a bigger issue as biologics become more of mainstream medicine, a potential future put forward in a recent magazine editorial (Payne, 2019).

Biologics and veganism

Defined by the Vegan Society (Wunsch, 2020) as ‘a way of living which seeks to exclude, as far as is possible and practicable, all forms of exploitation of, and cruelty to, animals for food, clothing or any other purpose’. Veganism ought to be a consideration for medication review of biologics. The implications of prescribing decisions is beyond the scope this article but has been discussed elsewhere

In research published the estimated number of vegans quadrupled from during the time period of 2014 where there were 150 000 vegans to 600 000 vegans in 2018 (Wunsch, 2020). That 2018 figure equated to 1.16% of the then UK population. Even by being conservative to assume a similar trajectory, the number of vegans in the UK will surely increase. Sensitivity to food and non-food items sourced from animal sources contravenes the principle of veganism and therefore (in theory) that principle would apply to medicinal products and medicines just as much as food products and cosmetic products. Therefore, the fact that biologics such as and alirocumab (licensed for the treatment of hyperlipidaemia) are derived from Chinese hamster ovaries and are produced by using recombinant DNA technology (eMC, 2020) could be problematic for some vegans. Chinese Hamster ovaries have been shown to be part of a preferable method for protein synthesis (Hejanes and Ransohoff, 2018). A more comprehensive list of animal-derived medicines and pharmaceutical have been elsewhere (Queensland Department of Health, 2020)

Medicines derived from animals is sure to be a more contentious issue as veganism is on the rise. Also, in the age of more explicit informed consent to for prescribing in a post Montgomery vs Lanarkshire (The Supreme Court, 2015), shared decision making and increased patient choice, there is an argument to be had for being upfront with the excipients and manufacturing process of biologics. At the moment, prescribing responsibility lies in almost exclusively in secondary care as biologic prescribing occurs predominantly (overwhelmingly so) in secondary care.

If a primary care pharmacist identifies a patient who is a vegan already prescribed a biologic, it would be prudent to inform the patient of the excipients and to liaise directly (via email or telephone) with the prescribers of the biologic. If the medicine was not a biologic, then the burden the responsibility would ultimately lie with the prescriber (whoever they may be). As with any potential medication issue, it would be good practice for the pharmacist to suggest clinical alternatives so that the prescriber can be well informed when making a shared decision with the patient.

In more recent news, Moderna have well-publicised and made explicit that their MHRA-approved COVID-19 vaccines does not contain any ingredients with animal origins (gov.uk 2021a), though it must be made clear that just like every licensed medicine and vaccine, these are tested on animals as part of the standard clinical trials criteria. The pros and cons of COVID-19 vaccinations in the context of veganism are beyond the scope of this article but have been discussed elsewhere. At the time of writing, the Moderna COVID-19 vaccine was the most recent to be approved in the UK (gov.uk, 2021b). Making the vegan nature of the Moderna vaccine explicit in its initial documentation may suggest that this could be an area of concern for patients (potentially based on frequently asked questions from patients and the public), hence the pro-active announcement.

Conclusion

As stated previously, patient safety is the foundation of this quality improvement project. Though biologics are predominantly prescribed and monitored in secondary care, the risks to the very same patients in primary care can be present if a biologic medicine is not accounted for. This article aims to expand the awareness of biologics in the context of medicines optimisation in the primary care arena with the direct purpose of reducing patient harm.

With the increasing numbers biologics being prescribed for patients in a wide range of conditions, naturally the need for accurate medicines reconciliation to maintain patient safety also increases. Given the acceleration of the number of biologic prescriptions it is surely a matter of time until biologics become commonplace – a thought put forward by Payne (2019). It is also conceivable that biologics could be prescribed in primary care in the not-too-distant future – given that some biologics like adalimumab are available as a subcutaneous formulation. At present, there would be some upskilling of primary care prescribers and perhaps shared care agreements in place in the interim in order for biologic prescribing in primary care to happen safely. However, until that point in primary care prescribing arrives, raising awareness in primary care of where biologics may be placed in a treatment pathway could still help to increase patient safety.

The need for thorough and accurate medication reconciliation is still warranted when taking in to account national statistics and this quality improvement project in particular. The fact that 70% (n= 192) of biologics in this project were not reconciled until an intervention by a pharmacy professional adds further weight to that claim to the positive value of pharmacy professionals in primary care.

The support that clinical pharmacists and pharmacy technicians give to practices can be an enabler towards more complete medications reconciliation, further medicines optimisation and ultimately greater patient safety.

The manufacturing process and the excipients of biologics may raise ethical dilemmas for patients therefore informing patients who might object to biologics on this basis prior to prescribing and as part of a routine medication review (as personal and societal ethics are liable to change as time passes) is of importance considering the patient and their wishes in a holistic manner.

Key Points

• Biologics are becoming more and more part of clinical treatment pathways and being approved by health authorities
• Whilst biologics are still prescribed in secondary predominantly, accurate medicines reconciliation in primary care plays a part in maintaining patient safety and medicines optimisation
• Knowing the excipients of medicines prescribed to patients who may have ethical objections has an importance in the light of explicit consent
• Utilising pharmacy staff for medicines reconciliation in primary care can result in more accurate medicines reconciliation and consequently patient safety.

CPD reflective questions

• How could you help to improve medicines reconciliation in the setting in which you work?
• How aware are you of newly-approved biologic treatments in your area of practice or for patients under your care?
• Considering your own scope of practice, how confident are you on the excipients of the medications you prescribe/advise/dispense which may pose ethical dilemmas for your patients?
• What one positive change can you make to your own practice having read this article?