Subcutaneous monoclonal antibodies are replacing traditional intravenous biotherapeutics and this switch offers opportunities to remodel cancer services through the advantages that subcutaneous formulations confer
Fiona MacLean MSc IPres MRPharmS
Lead Clinical Pharmacist,
NHS Greater Glasgow and Clyde,
Email: [email protected]
Intravenous (IV) monoclonal antibodies for the treatment of cancer were introduced into clinical practice in the late 1990s and are recognised as standards of care for both solid tumours and haematological malignancies.1 Systemic anticancer therapy takes many forms (Table 1) and an era of subcutaneous (SC) biotherapeutic formulations for some established IV monoclonal antibodies (mAbs), notably trastuzumab and rituximab has been entered. Trials have established non-inferiority between SC and IV, so why not switch to SC?2 There are a number of operational and logistical factors that need to be considered when planning a formulation switch and this review will describe the planning and implementation of SC mAbs in a Scottish health board.
Horizon scanning and addition to Health Board Formulary
Awareness of pipeline products and new formulations is central to successful and timely implementation of medicines. Horizon scanning is a major function of the Scottish Medicines Consortium (SMC) and clinicians can request access to the horizon scanning report, Forward Look, which provides details of medicines with the potential to have a moderate to high financial or service impact. Cancer care pharmacists also engage with the pharmaceutical industry and tumour group Managed Clinical Networks in forward planning for new medicines. Health board-level meetings take place to predict and assess the impact within the individual boards.
If a medicine is accepted for use within NHS Scotland then it will be added to the Health Board Formulary. Local cancer specialists and tumour teams are required to support the inclusion of the medicine and there should be a role for it within existing clinical practice. A treatment protocol is required supported with budget impact analysis and identification of any service implications. This is summarised in Table 2.
SC mAbs – a prospective evaluation
Horizon scanning flagged the development of SC trastuzumab. It was recognised that service planning was needed in advance of a positive SMC decision. In 2012, a pharmacy pre-registration project was undertaken to prospectively audit the switch from IV mABs to SC.3 The focus of this project was on trastuzumab; however, the processes and learning is applicable to any mAb. Operational, logistical and financial implications of SC trastuzumab were considered.
The main decision-makers were identified as:
- Scottish Medicines Consortium
- Tumour teams – clinicians and nurses
- Regional Prescribing Advisory Group
- Area Drugs and Therapeutic Committee
- Cancer therapeutics group.
Operational and logistical implications
A positive recommendation from the SMC is required before a medicine can be added to the Formulary. The trastuzumab SC advice was published in 2013.4 The medicine requires a clinical champion and the breast cancer team were engaged with the evaluation and were very keen to switch to the SC product. The treatment protocol was revised and presented to the Regional Prescribing Advisory Group for approval.
Pharmacy had a number of factors to consider and it was recognised that the new formulation offered an opportunity for remodelling delivery of anticancer therapy. IV trastuzumab is administered as an infusion over 30–90 minutes and a loading dose based on body weight is required for the first dose. A period of observation is recommended post-infusion.
By contrast, with SC trastuzumab there is no loading dose and every dose is fixed at 600mg. The SC product is a 5ml solution for injection, which requires to be drawn up into a syringe for administration. This is performed by a trained nurse. A self-injector device will be available in the future. The SC injection is administered over two to five minutes. Patients do not need an IV access devices (cannula, port, IV line) and it could be argued that specialist chemotherapy-trained nurses are not needed for SC injections. Do patients even need to attend cancer daybed units?
To explore new ways of working, pharmacy undertook staff interviews, issued a questionnaire to nurses and prepared a process map describing IV trastuzumab administration (‘the now’) and a predictive process map of SC administration (‘the future’).
The barriers to implementation (Table 3) were considered and were addressed by seeking answers to a series of questions.
Pharmacy asked a number of questions:
- When will the drug be available? What are the time lines?
- Are we contracted to pre-filled trastuzumab bags for a fixed time period? NHS Scotland purchase many ‘ready-to-use’ parenteral anticancer medicines including trastuzumab. It was therefore essential to understand if there was a contractual obligation in place.
- Is there enough space to store SC formulation? Is the IV bag a similar size to the SC package?
- Is there a private area for SC administration? This is an important consideration as SC is administered into the thigh and cannot be given through clothing. In some clinical areas, infection control requirements have meant that curtains are not permitted. How do you offer patient privacy?
- What is the capacity and capability of nurses for preparing the SC dose in the clinical area?
Clearly there are opportunities to redesign cancer services with the launch of SC mAbs. Decentralisation of mAb administration might be considered, especially in rural areas, to remove the need for patients to travel large distances to specialist centres. SC products lend themselves to homecare, outreach or community-led services, again, removing the need for travel to cancer centres and units.
Removal of the loading dose and observation period reduces the time in chair by hours (cycle 1) to about 50 minutes (cycle 3 onwards).5 Adjusting the nursing team skill mix is a feasible option as SC administration does not require an IV-chemotherapy-trained nurse. This would need local governance agreement.
For the pre-launch planning work, the actual cost for the SC product was not known, however, the indicative cost per SC fixed 600mg dose was that it would be similar to an IV dose for a 70kg patient. Trastuzumab is dose banded in NHS Scotland and a 70kg patient will receive a 399mg ready-to-use infusion. The electronic prescribing system was interrogated to determine the proportion of patients above 70kg and we found that more than 75% of patients with metastatic breast cancer were above 70kg. This fell to about 50% in the adjuvant setting. So, therefore, there is a considerable cost saving to be realised by switching to the SC formulation.
Handling of mAbs
A detailed review of handling of mAbs is out of the scope of this paper. Suffice to say, the nursing staff in the author’s hospital were satisfied with the risk assessments and agreed to draw up the required 5ml in the clinical area.
The risk assessment considered the following:6,7
- mAbs do not have acute toxic properties (for example, corrosive).
- No evidence of carcinogenicity or mutagenicity but no long-term studies.
- Developmental toxicity is not known, but mAbs can cross the placenta.
- Effects on fertility are not known.
- Sensitising properties – trastuzumab is humanised, low sensitising potential.
- Occupational exposure is dermal, inhalation or oral.
- Occupational exposure limits are not defined.
- Dermal: molecules >500Da will not penetrate the stratum corneum. mAbs are >140kDa. Unless skin is broken dermal uptake is unlikely.
- Inhalation: the high molecular weight reduces bioavailability by inhalation; passage into bloodstream from lungs is limited.
- Oral: mAbs are folded proteins, which are broken down by gut enzymes and inactivated; exposure will be minimal.
SC mAbs offer an opportunity to redesign cancer treatment services with the patient at the centre. Both patients and healthcare professionals prefer SC trastuzumab.8 Specialist administration is not required and SC has the potential to release capacity in cancer daybed units. There is a saving in both time and drug acquisition costs. SC mAbs remove the need for aseptic manipulation and lengthy infusions thus releasing time to care for both pharmacy and nursing staff. Future remodelling might consider community-supported mAb administration and patient self administration.
- Horizon scanning is key to implementation of new medicines.
- Use process mapping to understand local processes.
- Consult with and consider service users.
- Exploit new formulations to remodel services.
- Consider patient preference in strategic decision-making.
Sheila Doyle (NHS GGC pre-registration pharmacist, 2012–13) for the process maps.
- Buss N et al. Monoclonal antibody therapeutics: history and future. Curr Opin Pharmacol 2012;12:615–22.
- Ismael G et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012;13:869–78.
- Service impact from switching from intravenous to subcutaneous trastuzumab: A Prospective Evaluation. Pre-registration Audit 2012. Sheila Doyle, NHS Greater Glasgow and Clyde (on file).
- Trastuzumab 600mg/5ml solution for injection. Scottish Medicines Consortium Advice SMC 928/13. www.scottishmedicines.org.uk/files/advice/trastuzumab_Herceptin_FINAL_December_2013_for_website.pdf (accessed 10 July 2014).
- Pre-launch evaluation of potential service impacts from implementing Herceptin Subcutaneous. Roche Products Limited. September 2012.
- Halsen G, Kramer I. Assessing the risk to health care staff from long-term exposure to anticancer drugs – the case of monoclonal antibodies. J Oncol Pharm Pract 2011;17(1):68–80.
- Pan Birmingham Cancer Network. Guideline for the preparation or manipulation of monoclonal antibodies (MABs) and related compounds such as fusion proteins, used in the treatment of cancer. July 2012.
- Pivot X et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. 2013;14(10):962–70.