IMD WATCH
PRESCRIBING CHALLENGES IN METABOLIC DISEASE - FOCUS ON PKU Suzanne Ford NSPKU Dietitian for Adults Suzanne Ford is a Metabolic Dietitian working with Adults at North Bristol NHS Trust and also for the National Society of Phenylketonuria).
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In metabolic disorders of protein metabolism, e.g. Maple Syrup Urine Disease, Tyrosinaemia Type 2 and homocystinuria, dietary treatment via a low-protein diet and precursor-free protein substitutes are a key part of treatment. Specialist dietary products on prescription are often necessary to achieve best clinical and patient outcomes - this is also true of phenylketonuria (PKU). The NHS is the only provider of prescribable products in the Home Countries of England, Scotland, Wales and Northern Ireland, and when a dietary product achieves Advisory Committee on Borderline Substances (ACBS) approval, there is an expectation from patients and clinicians, that these products will then become available on prescription via general practitioners across the UK and that access will be according to clinical need. In England, GPs operate Clinical Commissioning Groups (CCGs), of which there are 207, accounting for two thirds of NHS England’s total budget or £73.6 billion in 2017-2018. Each CCG is responsible for the health of a population ranging from under 100,000 to 900,000, although their average population is about a quarter of a million people. NHS England Manual for Prescribed Specialised Services 2017/18 sets out the responsibilities of CCGs towards treatment of people with metabolic diseases under the heading What Clinical Commissioning Groups (CCGs) commission: CCGs, via GPs, are responsible for the ongoing prescription of all specialist dietary products for patients with IMD (inherited metabolic diseases), once initiated by the (Metabolic) Centre. The NSPKU helpline, from enquiries and countless discussions with dietitians, reveals that some CCGs do not provide unfettered access to prescribable products to patients with PKU and there are many points in the
process of prescription and dispensing and delivery of products where undesirable treatment interruptions can occur. TREATMENT OF PKU - WHAT DO PATIENTS NEED?
PKU is treated with a very low-protein diet necessitating specialist low-protein products to provide energy and variety. A protein substitute providing amino acids without the phenylalanine (Phe) neurotoxic to people with PKU is an essential requirement.2 Currently in the UK, there is no pharmaceutical treatment available (although available in 24 other European countries as well as in the USA). The European Guidelines for Diagnosis and Management of PKU published in The Lancet in 2017 state that stricter blood Phe control is needed than was previously thought.3 The diet for people with PKU needs to be more rigorously applied than ever before; the guidelines also state that diet for life is needed, based on a significant body of evidence describing poor neurological outcomes if treatment is stopped. COMPLICATIONS AND CONSEQUENCES OF UNDER TREATMENT OF PKU
The rationale for PKU treatment is to achieve strict blood control to prevent any brain damage or impairment in children,4-7 and avoid the reduced life chances via reductions in IQ, which are seen currently when children with PKU are compared to their non-PKU siblings.8-9 www.NHDmag.com March 2018 - Issue 132
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Ready to drink
Lowest volume‡
Lowest calorie^
Spoonable option
LIFE WITH PKU DON’T LET ANYTHING STOP YOU ^ PKU Lophlex Powder is the lowest calorie protein substitute, per 20 PE portion, for patients aged 8 years onwards. ‡ PKU Lophlex Powder is the lowest volume powder protein substitute for 20 PE available for use. The PKU Lophlex range are Foods for Special Medical Purposes used in the dietary management of PKU and must be used under medical supervision of a Healthcare Professional. This information is intended for Healthcare Professionals only.
The specialist low-protein products are needed to provide variety to children and adults, as their products are neither available in supermarkets, nor in health food shops in the way that gluten-free products now are. The accumulated evidence is now clear that adults with uncontrolled blood phenylalanine levels are compromised in their executive function, their mental health and their psychosocial outcomes.10-14 PROTEIN SUBSTITUTE USE IN PKU
Protein substitutes are essential when a very low Phe diet is prescribed. They provide protein/ nitrogen when micronutrient requirements must be met and support good blood phenylalanine control.15,16 The products should be taken at least three times daily, every day of a patient’s life, following diagnosis and, thus, a range of palatable products are essential.17,18 A reminder: the nutrients being substituted are macro as well as micronutrients, thus daily doses of substitutes are high, e.g. 80 tablets per day for a 55kg woman. Evidence tells us that this is the most burdensome aspect of the diet and that if patients are without protein substitutes, or are under treated with it, many nutritional deficiencies emerge, such as osteoporosis, B12 deficiency anaemia and protein deficiency. There have been considerable efforts in the last 30 years to develop these products to aid optimum safety, tolerance efficacy and palatability. Most protein substitute products contain micronutrients and, more recently, have added docosahexaenoic acid - for use in pregnancy as well as for infants and children.19 Finally, but very importantly, as well as reducing protein or micronutrient deficiencies, the protein substitutes provide protection (through provision of amino acids) against high blood phenylalanine levels by reducing catabolism and promoting anabolism.
PROTEIN SUBSTITUTE RANGE AND PRODUCT DEVELOPMENT IN PKU
The NSPKU firmly advocates for the widest range of protein substitutes to be available for patients with PKU. Patients’ clinical needs must be met, e.g. infancy, weaning, childhood, pregnancy, both higher and lower calorie formulae subject to growth needs.20 Pre-prepared liquid protein substitutes and formulae have some clinical advantages to powders and there is a variety of different presentations available to patients.21, 22 Protein substitute choices have recently expanded to include glycomacropeptide (GMP) powders and liquids. These are reported to have high levels of patient acceptability (reduced acidity compared to amino acids and also a lower osmolarity, so reducing osmolar effects on the gut). However, in some areas, GPs and CCG Exceptions Panels have declined to fund GMP products for PKU patients. Future development of better protein substitutes to improve acceptability and compliance is essential for better outcomes in PKU. The need for these products to be fully supported by prescribing bodies providing efficacy, safety and acceptability data, is unequivocal in PKU. LOW-PROTEIN PRODUCTS
The specialist low-protein products are needed to provide variety to children and adults, as their products are neither available in supermarkets, nor in health food shops in the way that gluten-free products now are. If these products are used insufficiently, then energy intake is compromised, and endogenous phenylalanine is released through catabolism, or the individual is hungry and is likely to eat higher protein food choices, resulting in loss of metabolic control. www.NHDmag.com March 2018 - Issue 132
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With the consolidation of evidence in the European Guidelines and acceptance that the PKU diet is for life, the reported frequency of interruption of the only treatment available is unacceptable. Scottish research (undertaken before glutenfree food prescription was questioned), outlines the negative experiences and obstructions which people with PKU have experienced when attempting to access prescribable low-protein products. Half of those surveyed had experienced comments on their prescription and 60% of the comments were negative.23 It is not uncommon for patients or parents to feel humiliated and frustrated by either the system, or by staff within primary care, and when no food is accessible, a hungry and uncontrolled patient is the result. The level of restrictions involved in this diet are such that it is not possible for most patients to maintain metabolic control without prescribable foods24 as hunger would be overwhelming. CURRENT BARRIERS TO METABOLIC PRESCRIPTIONS
Difficulties at prescriber level The first and main barrier is a lack of understanding within primary care about the needs of metabolic patients. Doctors, receptionists and prescribing administrators are often disbelieving of the number of items required by someone on a low-protein diet, because they do not understand: • the degree of protein restriction; • the presence of protein in starchy staples such as wheat and potatoes; • that prescribable low-protein products are not available in the supermarket in the same way that gluten-free products now are; • that protein substitutes are not all the same; palatability/acceptability is a factor in clinical effectiveness - unlike non-dietary prescriptions. CCGs, as with the rest of the NHS, are under financial pressure to make efficiency savings and use different approaches for this. For instance, some CCGs may circulate Quality Information Newsletters for Pharmacists 48
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and Prescribers in Primary Care (PrescQIPP) bulletins, outlining costs of PKU treatment and the evidence for it. Some CCGs use medicines optimization, or prescribing advisor dietitians, to search for PKU patients on the primary care databases and script scrutiny is undertaken in conjunction with a review of a PKU patient’s body mass index. The specialist metabolic dietitians may then be contacted to answer questions about the presence of cakes, biscuits, or carbohydrate-based items on the prescription list. It’s possible that these community dietitians are, along with GPs and pharmacists, unfamiliar with the degree of protein restriction faced by PKU patients. It is likely that the only information they will have received about PKU will have been as part of university training (likely minimal time assigned to it, due to the rarity). Some CCGs use formularies of the cheapest medications for common primary care medicines, such as anti-hypertensives for instance, and the CCG, may use software called ‘ScriptSwitch’ to identify for any given prescribable medicine, a cheaper alternative to the one inputted into the prescription system. This may be a very successful system for non-dietary medications, however, when dietary treatment adherence is closely linked to patient acceptability and choice, ScriptSwitch is likely to be inappropriate in leading to cost effective PKU treatment. With regards protein substitutes, the cost of the single item prescribed is relatively high and in some CCGs, this has triggered ‘Expensive Medicines’ processes for prescription approval, including, in more than one case, an Exceptions Panel or committee within the CCG declining (after original submission and appeal) to prescribe, or provide, the protein substitute requested. Some CCGs wish to develop formularies for metabolic products - this would curtail current treatment access and also future treatment development.
Possible solutions must all be considered for patient acceptability, clinical efficacy, clinician readiness and, of course, financial and administrative feasibility and long-term sustainability. Difficulties at dispensing stage Community pharmacies are local outlets who might make a rapport with patients they know well. However, we know from financial incentive and reimbursement structures that community pharmacies and pharmaceutical wholesalers are not the best outlets through which to have unusual small volume prescriptions dispensed. Monthly deliveries from metabolic companies themselves have been seen to be the answer throughout England. In the case of Scotland and Wales, free prescriptions have meant difficulties using some of the company delivery systems. Again, because of volumes, the reliability of even the company delivery systems has come under some question, as patients are left without products, face interrupted treatment, loss of metabolic control and the clinical sequelae thereof (irreversible brain damage in the case of young PKU patients). POTENTIAL SOLUTIONS
With the consolidation of evidence in the European Guidelines and acceptance that the PKU diet is for life, the reported frequency of interruption of the only treatment available is unacceptable. Possible solutions must all be considered for patient acceptability, clinical efficacy, clinician readiness and, of course, financial and administrative feasibility and longterm sustainability.
Could all metabolic dietitians become independent prescribers for instance? This might work in the long term, but senior managers would need to ensure that the ‘money follows the patient’ and the ramifications of a centre serving >30-40 CCGs for example, mean a large amount of cross checking, plus, the employment of script administrators in the metabolic centres might be necessary. Reworking the current home delivery system to become 100% gold standard would be ideal and a centralised one-stop-shop with online choice for patients in units of foods per month, might be the most patient-friendly and clinically effective system. However, would a centralised system be more vulnerable to cost and efficiency targets? Finally, is the ACBS system under scrutiny as a whole and is de-prescribing a consideration? There are many factors to consider. There may be opportunities and threats to treatment access inherent in any changes made; however, the current situation is extremely challenging. The NSPKU have a campaign underway to facilitate the PKU community, to gain improved treatment access. This is one issue to be considered closely. For better clinical outcomes and improved quality of life for metabolic patients, these challenges must be met head on. Watch this space.
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