Aelip ends the year with sad news for all people affected by Lipodystrophy as well as for their families and people who give us all their support. "The Interministerial Commission on Drug Prices, held on 25 November, proposed to the Directorate General for the Common Portfolio of Services of the NHS and Pharmacy not to accept the allegations and not to include this drug in the pharmaceutical provision of the NHS, taking into account criteria of rationalisation of public spending and budgetary impact of the NHS". See pg. 34 and 35: https://www.mscbs.gob.es/profesionales/farmacia/pdf/20211210_ACUERDOS_CIPM_218.pdf
On 21 December 2021, AELIP received a reply from Patricia Lacruz informing us of the decision NOT TO INCLUDE the only drug approved for the treatment of lipodystrophies (Metreleptin, Myalepta) in the pharmaceutical provision of the NHS. After reading the response received, and the relevant assessment by our committee of experts, AELIP decided to respond in writing to the DIRECTORATE GENERAL FOR THE COMMON PORTFOLIO OF NHS SERVICES AND PHARMACY.
AELIP urges the Ministry of Health to include Metreleptin in the pharmaceutical provision of the NHS as the only authorised treatment in Europe for Lipodystrophy and to guarantee equal and equitable access to all patients who need it in the different autonomous communities of Spain.
The International Association of Lipodystrophy Patients and Families, AELIP, will continue to fight with your support until Metreleptin, the only authorised treatment for Lipodystrophy, is included in the Common Portfolio of Services of the NHS and Pharmacy.
We ask for your help and collaboration so that together we can achieve it!!!!
MINISTRY OF HEALTH
DIRECTORATE GENERAL FOR THE COMMON PORTFOLIO OF NHS AND PHARMACY SERVICES
A/A: Ms. Patricia Lacruz
The International Association of Lipodystrophy Families and Patients (AELIP) would like to continue to express our unease and concern, after reading the response received from the Directorate General for the Common Portfolio of NHS Services and Pharmacy on 21 December 2021, regarding the decision not to include the only medicine approved for the treatment of Lipodystrophy (Metreleptin, Myalepta) in the pharmaceutical provision of the NHS.
We will now proceed to analyse your response after the appropriate consultations with the Committee of Experts of AELIP and to transmit the documentation that accredits and supports each of the contributions that you send us, urging their review and informing that from AELIP we will defend the right to guarantee equal access to patients with lipodystrophy who require Metreleptin (Myalepta) to improve their quality of life, exercising for this, all the legal and juridical actions that may be appropriate.
From reading your letter in response to the one sent to you by our association, it is clear that the most relevant aspects have not been taken into account, as you reiterate the same arguments without answering the specific questions we ask you and that, we believe, we have the right to sue you as a public servant, in accordance with the right we have to act in the name and on behalf of AELIP.
In his current letter he reminds us again of what the treatment of lipodystrophies consists of, on our understanding that there is no need for this, since our association has a team of national and international medical experts in this type of rare disease who advise us (http://www.aelip.es/comite-expertosasesores-lipodistrofias.asp). We are therefore aware of the therapeutic management of lipodystrophies. We would like to express our dissatisfaction when it describes the treatment that should be established for these ailments because, in our opinion (after appropriate consultation with our committee of experts), it makes manifest errors. Thus, it is not correct to state that the use of thiazolidinediones could solve situations of poor metabolic control caused by severe insulin resistance in patients with lipodystrophy already treated with insulin. In this regard, according to international guidelines (1), it is often necessary to use concentrated insulin formulations such as U-500 in these cases, which you do not mention. The use of pioglitazone and other diabetes drugs such as iSGLT2 and/or aRGLP1 in lipodystrophy is well known to doctors, although unfortunately the published studies are few and far between and limited to a very small number of patients (few studies, reporting one or at most three cases). In any case, they are part of the conventional treatment of diabetes and in generalised lipodystrophies they are not usually sufficient and in partial lipodystrophies only sometimes (2-9). In addition, the international guidelines (1) specifically state in relation to glitazones: "Thiazolidinediones may improve metabolic complications in partial lipodystrophy, but should be used only with caution in generalized lipodystrophy. (Class IIb, Level B)". More surprising is the fact that in your considerations on the treatment of lipodystrophies you do not include the experts' position on the indication of metreleptin, as clearly indicated in the aforementioned guidelines: "In generalized lipodystrophy, metreleptin (with diet) is a first-line treatment for metabolic and endocrine abnormalities (Class I, Level B), and may be considered for prevention of these comorbidities in children. (Class IIb, Level C)" (1). We do not know why you have overlooked this aspect, which we consider to be of great importance, as it is the main subject of our demands. With regard to the treatment of dyslipidaemia in lipodystrophies, you again emphasise what is already known, albeit incompletely: statins and fibrates. As well as the importance of diet. And, for heaven's sake, there is no mention of the role of omega-3 fatty acids, which can also be beneficial. The point, Ms Lacruz, is that this approach in certain subtypes of lipodystrophies is not sufficient, as you should know if you had taken the trouble to consult the medical experts in these disorders (something that NICE did in the UK before approving your funding); These experts would explain to you the risk of some people with lipodystrophy developing acute, sometimes life-threatening pancreatitis when no combination of lipid-lowering drugs and diet can adequately control the extremely severe hypertriglyceridaemia they suffer from. Something you forgot to mention. As you forgot to mention, as we indicated in our previous article, that the number of cases of acute pancreatitis in the Spanish cohort treated with metreleptin was 0% compared to 42% before starting this treatment. Does this fact seem trivial to you? It must seem so to you because you do not even mention it in your letter.
Then in your letter you refer to the requirements set by the EMA for marketing authorisation. We are well aware of them as they are published, but you do not answer a clear and extremely relevant question. However, you do not answer a clear and extremely relevant question: What are the differences between the criteria of the Spanish Ministry of Health and those of the EMA and the public health systems of Germany, France, Italy and the United Kingdom? Why do you omit to explain why these bodies failed to authorise marketing (in the case of the EMA) and public funding (in the case of the aforementioned countries) in order not to identify what you call therapeutic uncertainties? Are they less expert, perhaps? Are they less concerned about rationalising public spending, perhaps? Can you explain this to us, if you would be so kind, Mrs Lacruz? Because as citizens, we are puzzled by this lack of transparency. Why is this attitude so lacking in transparency?
He goes on in his letter to insist on what is already known: the differences in the indications depending on whether it is a question of generalised or partial lipodystrophy. It is in the data sheet, it is in the IPT. Thank you. But it is noteworthy that you yourself recognise, in a basic syllogism of Aristotelian logic, that at least for generalised lipodystrophy there is robust data when you say: "However, in partial lipodystrophy it is restricted to patients with failure to standard treatment, as no robust conclusions could be drawn...".
Your argument about morbidity and mortality and the potential beneficial effects of diet and conventional treatment is not correct according to the criteria of our expert panel. As already pointed out to you, and as you know as well as we do, the requirements for clinical trials on orphan drugs are not the same as those for drugs for common diseases. The argument that the beneficial effects of diet and conventional medication are not known does not fit with the pivotal studies, as most patients were already on conventional treatment (between 80-90% of patients with partial lipodystrophy (10) and between 50-80% in generalised lipodystrophy (11)) and in some cases it was possible to stop some of this treatment, or reduce doses. Specifically, the study by Brown et al. (11) indicates that 41% of patients were able to discontinue insulin treatment, 21.9% were able to discontinue oral antidiabetic treatment and 23.5% were able to discontinue lipid lowering drugs. From what source do you get, Mrs Lacruz, that the beneficial effect of conventional treatment could not be established: they were already on conventional treatment, and in quite a few cases it was possible to withdraw this treatment. And with regard to diet, we insist once again on what we indicated in our previous letter (and which you apparently ignored): "The drug's own data sheet indicates that metreleptin must be combined with diet. Any doctor with some experience with the drug will be able to tell you that without this association this drug is not as effective. But as noted above (12,13), metreleptin itself effectively reduces insulin resistance in controlled studies of intake.
I would also like to make it clear that our experts disagree with your statements on the efficacy in reducing morbidity and mortality by 65%. You, Ms Lacruz, question Cook's study on the grounds that it is a retrospective study and that further studies are needed. You argue that the study itself indicates that more studies are needed to evaluate the effect of the drug on morbidity and mortality (but this type of comment is very common in any scientific study: one should always be cautious), but does this discredit or detract from the validity of a study published in one of the most prestigious Endocrinology journals in the world, Or are you implying that the reviewers of this publication accepted a study with methodological flaws or results that did not correspond to the experimental design? Are you more expert than the experts to discredit a study that demonstrates a long-term benefit for patients? Are you asking for a prospective study on mortality? Mrs Lacruz, the least we ask for is seriousness and scientific soundness. Basically, you accept that the drug reduces mortality but you would like more cases to be included. You know perfectly well that survival studies are complex given that they have to be followed up over many years, and that in the case of rare diseases this is extremely difficult given the small number of patients and their geographical dispersion throughout the world. It is my understanding that you are wrongly applying common disease criteria to an orphan drug.
Strikingly, you make no mention of our contributions on the beneficial effects of the drug, which are published in prestigious journals (J Clin Endocrinol Metab, J Hepatol, J Endocr Soc.) in terms of improvement in associated heart disease, hepatic steatosis or quality of life. As mentioned above, either you have not read it properly or you have intentionally left it out.
With regard to the cost of the drug, you state that it cannot be financed due to its high economic impact, and you argue this by referring to point d) of article 92.1 of the revised text of the Law on Guarantees and Rational Use of Medicines and Health Products. This point literally reads: "Rationalisation of public spending on pharmaceutical provision and budgetary impact on the National Health System". As these are indeterminate legal concepts, we understand that it is not possible to argue for non-financing on the basis of such a generic phrase. 1 of the aforementioned Law: a) Severity, duration and sequelae of the different pathologies for which they are indicated; b) Specific needs of certain groups; c) Therapeutic and social value of the medicine and its incremental clinical benefit taking into account its cost-effectiveness ratio; e) Existence of medicines or other therapeutic alternatives for the same conditions at a lower price or lower treatment cost; f) Degree of innovation of the medicine? Perhaps because the needs of patients with lipodystrophy and the benefits of treatment with metreleptin meet these criteria? Mrs Lacruz, we are neither minors nor do we lack skills or judgement. Therefore, do not treat us as such. In our previous letter we asked you to inform us of the economic impact of treating the small number of people who could be subsidised with metreleptin in Spain. And you have dismissed us with a reference to a Royal Decree. But we are convinced that you know this. Why this obscurantism? Perhaps because such an economic impact is probably derisory in relation to the overall pharmaceutical expenditure in the State? Is the price offered by the pharmaceutical company during these three years (EMA approval in 2018) not lower than what is currently paid as medication in special situations? Can you therefore answer these simple questions that we asked in the previous letter: Can you tell us the percentage impact of this expenditure on the total amount of pharmaceutical expenditure in Spain? Have you estimated what it could mean in terms of reduced medical care and other expenses arising from the comorbidities associated with this disorder if the disease follows its natural course? We believe that as free citizens we deserve to receive transparent information from the public administration.
In your last paragraph you open the door to a new negotiation with the pharmaceutical company in terms of reducing the price of the drug and that the conditions are more favourable for the Administration, accepting the possibility of incorporation into VALTERMED, but the decision of the meeting of the CIPM on 25 November was the denial of funding, something that we fail to understand since, without doubt and in the best case scenario, it will delay the prescription of this treatment to a (small) group of citizens who have not chosen to suffer from this type of ailment.
Today, 30 December, we have learned from the Ministry of Health website of the Minutes of the Interministerial Commission on Drug Prices held on 25 November 2021, in which it was agreed to propose to the Directorate General not to accept the allegations and therefore not to include this drug in the pharmaceutical provision of the NHS, taking into account the uncertainties regarding its therapeutic value and criteria of rationalisation of public spending and budgetary impact of the NHS. Strikingly, there is no mention in these minutes of what you told us a few days earlier: "Notwithstanding the above, the laboratory can request its inclusion again, which will allow for a new assessment. We are willing to continue working together with the incumbent laboratory to obtain more favourable conditions and a more appropriate price to reconsider the financing of metreleptin, as well as to support the generation of real-life evidence through the corporate information system VALTERMED". We remind you that your written response is a document with the letterhead of the Ministry of Health and with its digital signature, and therefore an official document. What were you trying to achieve with this last paragraph, to reassure us even though you know that the decision not to fund was already taken when you talk about "reconsidering the funding of metreleptin"?
Mrs Lacruz, we are aware that we are few in number, and as far as you and the members of the Interministerial Prices Commission are concerned, according to the content of your letter, which is almost entirely a rewritten copy of the first one, and of the minutes of the meeting held on 25 November, you care little about us. But however few we may be, we have the force of reason, which is scientific reason. We are the first to be interested in ensuring that all medicines approved to treat our health problems are backed by scientific evidence, and in this case it is not just us, but the international scientific community that considers that this drug reduces complications, improves quality of life and prolongs life expectancy in certain types of lipodystrophy. Do not put more obstacles, because others, in other countries around us, did not see them.
Therefore, from AELIP, we urge the Ministry and the pharmaceutical company to continue with the funding process and urgently reach an agreement that makes possible the Resolution of inclusion in the pharmaceutical provision of the NHS of the only drug approved for the treatment of lipodystrophies (Metreleptin, Myalepta).
Likewise, as president of AELIP, I place at your disposal all the means and resources available to us in the Association, which may be required on your part, in order to substantiate all of the above.
Totana, 30 December 2021
Naca Eulalia Perez de Tudela Canovas