About us without us

/by

About us without us.

Letter to AMEQUIS, the Evaluation Body appointed to evaluate the EU’s ERN system

From: Philippe Pakter
Date: 22 March 2023
Subject: ERN-Cranio – feedback

Dear AMEQUIS Evaluation Body,

Last Friday 17 March you and your colleagues from AMEQUIS, the Evaluation Body appointed by the European Commission, were kind enough to gather feedback from the patient representatives of ERN-Cranio.

During the meeting you asked about patient involvement in the development of Clinical Practice Guidelines.

ERN-Cranio recently produced EU Clinical Practice Guidelines for the rare disease, Pierre Robin Sequence. Concerning this EU-funded ERN-Cranio project:

  1. ERN-Cranio’s working group to create EU Guidelines for Pierre Robin Sequence included zero Pierre Robin Sequence patients.
  2. ERN-Cranio’s consensus vote on these EU Guidelines for Pierre Robin Sequence included zero Pierre Robin Sequence patients.

Zero Pierre Robin Sequence patients in the working group and zero Pierre Robin Sequence patients in the consensus vote for ERN-Cranio’s EU-funded Clinical Practice Guidelines for the rare disease, Pierre Robin Sequence.

This EU-funded document which ERN-Cranio produced fails to meet the minimum standards of the EU’s ERN system, which legally requires that such EU-funded materials be “patient-centered”. Zero and zero does not equal patient-centered.

I am writing on behalf of Pierre Robin Europe, as the organization’s chairman. We represent patients with the rare disease, Pierre Robin Sequence. In ERN-Cranio, we are the only patient representatives who represent patients with Pierre Robin Sequence. We, Pierre Robin Europe, have been a member of ERN-Cranio since 2018; thus we were officially admitted to ERN-Cranio several years before this Pierre Robin Sequence Guideline development project began. ERN-Cranio’s Coordinator, Dr. Irene Mathijssen, intentionally excluded us from this EU-funded Guideline Development Project. This raises several questions, including the following:

  • why did ERN-Cranio Coordinator Dr. Irene Mathijssen exclude us from this guideline development project when we are the only patient representatives in ERN-Cranio who represent Pierre Robin Sequence patients?
  • why did the highly respected Coordinator of another ERN who won the EURORDIS “Black Pearl” award for his outstanding contributions to the rare disease movement send an official letter of complaint to the German Health Minister concerning this particular ERN-Cranio Pierre Robin Sequence guideline development project?
  • how can the European Commission, which provided ERN-Cranio with 50,000 euros of direct funding for this Pierre Robin Sequence guideline development project, claim that it is “patient-centered”, when the working group had zero Pierre Robin Sequence patients, and the consensus vote had zero Pierre Robin Sequence patients?
  • what mechanism is in place in the EU’s ERN system to ensure accountability when an EU-funded project demonstrates this level of dysfunction?

[…]

We look forward to speaking with you. Thank you.

Kind regards,

Philippe Pakter
Chairman, Pierre Robin Europe: ERN-Cranio’s official patient organization for Pierre Robin Sequence
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

ERN-Cranio’s EU Clinical Practice Guidelines for Pierre Robin Sequence

/by

When EU Guidelines for a rare disease are officially rejected by the EU’s top two experts on that rare disease, then the EU Guidelines are nonviable.

 

Wednesday 30 March 2022

From: Philippe Pakter
Date: Wednesday 30 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Irene Mathijssen
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Dr. Irene Mathijssen, Coordinator, ERN-Cranio,

Yesterday I asked an ERN-Cranio physician to share with me the final version of ERN-Cranio’s EU Clinical Practice Guidelines for Pierre Robin Sequence, because neither you nor your colleagues gave me access to these files. I went straight to the chapter on first line treatments. I read the following.

“Clinicians and many families will be aware of the general recommendation for infants is to be nursed in the supine position to reduce the risk of sudden death infant syndrome (SIDS), however, prone positioning is widely accepted and effective in up to approximately three-quarter of the RS patients. Close monitoring of O2 saturation should prevent SIDS… Positioning treatment is easily taught and there are few harms associated with this intervention although escalation of care must occur in non-responders.”

Our understanding of evidence-based medicine is that it involves a careful review of the medical literature in order to evaluate the benefits and harms of various interventions, according to objective criteria. Objective criteria in the context of Pierre Robin Sequence is polysomnography, the gold standard for objectively measuring the severity of upper airway obstruction among Pierre Robin Sequence babies.

Concerning benefits: these ERN-Cranio EU Guidelines recommend prone positioning as a first line treatment, based on the claim that prone positioning is “effective in up to approximately three-quarter of the RS patients”. However, a 2021 systematic review study published by the international Pierre Robin Sequence consensus movement – international Pierre Robin Sequence experts from all over the world – stated the following: “Three studies used PSG to estimate the effect of prone positioning and demonstrated that it did not completely resolve OSA in the majority of infants.” Thus, the number of evidence-based studies which actually relied on PSG to objectively gauge the benefits of prone positioning is extremely low – and in these studies, prone positioning failed to resolve OSA in the majority of cases.

Concerning harms: these ERN-Cranio EU Guidelines recommend prone positioning based on the claim that “there are few harms associated with this intervention”. However, according to a landmark paper on SIDS published in the Lancet (“Sudden unexplained infant death in 20 regions in Europe: case control study”), prone sleeping increases a baby’s risk of SIDS by over 13 times. Once again, ERN-Cranio’s EU Guidelines: “there are few harms associated with this intervention”; and the Lancet: a 13 times increase in the risk of SIDS.

ERN-Cranio’s EU Guidelines state that “Close monitoring of O2 saturation should prevent SIDS”. No evidence at all is provided in support of this statement – and it gets worse. This close monitoring of O2 saturation which “should” prevent SIDS is entirely optional: “Consider positioning therapy (either prone or lateral positioning with or without a saturation monitor) as first-line to relieve mandibular-related OSA or UAO”.

The benefits of the intervention are exaggerated; the risks are minimized; contradictory studies are omitted outright – and, for good measure, these Guidelines engage in sheer speculation (monitoring “should” prevent SIDS). Dr. Irene Mathijssen, as Coordinator of ERN-Cranio, you accepted EU funds on the basis that you would produce evidence-based Guidelines of care for the EU. We and others – including some of the most internationally renowned Pierre Robin Sequence experts in the world – believe that this is not evidence-based medicine. What other critical evidence is distorted or omitted, how many other unsupported statements and recommendations might be found, scattered throughout this document?

In a June 2021 letter we warned Dr. Andrzej Rys, Director, European Commission DG SANTE, and Prof. Till Voigtländer, Co-chair of the ERN Board of Member States, that this is exactly what would happen, and this would be the inevitable result, of an allegedly “EU” Guideline development project for a rare disease which intentionally excluded the EU’s top two experts in that rare disease. When an allegedly “patient-centered” Guideline working group included not a single Pierre Robin Sequence patient or parent – not one single Pierre Robin Sequence patient or parent – a shocking situation which continues to this day. “It is expected that all stakeholders should strive to adhere to the recommendations set out in this Chapter”. We who represent the ultimate stakeholders, babies suffering from this life-threatening rare disease, reject this document.

It has been brought to our attention that your hospital, Erasmus Rotterdam Medical Center, and the Great Ormond Street Hospital in London, may be bound together in a relationship with a certain American body, ICHOM, involving common financial and funding interests. This pre-existing relationship between Erasmus Rotterdam MC, and the Great Ormond Street Hospital in London, potentially creates the impression of a perceived conflict of interest. Erasmus Rotterdam MC, which is in charge of ERN-Cranio, favored the Great Ormond Street Hospital, and included the Great Ormond Street Hospital in this EU project – in spite of the fact that the Great Ormond Street Hospital is not a member of ERN-Cranio. At the very same time, Erasmus Rotterdam MC excluded the EU’s top two experts on this rare disease, on the exact same basis – that they were not members of ERN-Cranio. We will ask the research oversight boards to investigate this matter, because if the EU’s top two experts on this rare disease had not been arbitrarily excluded from this EU project by Erasmus Rotterdam MC, then the “final version” of this “EU” Guideline we are discussing today would be a higher quality document.

As ERN-Cranio’s official ePAG patient organization representing Pierre Robin Sequence patients, we request an invitation and link to participate in the upcoming discussion scheduled for 31 March 2022 concerning this EU document which was produced about us, without us.

Best regards,

Philippe Pakter
Chairman, Pierre Robin Europe: ERN-Cranio’s official patient organization for Pierre Robin Sequence
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

Friday 18 March 2022

From: Philippe Pakter
Date: Friday 18 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Irene Mathijssen
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Dr. Irene Mathijssen, Coordinator, ERN-Cranio,

You have released the final version of the EU Clinical Practice Guidelines for Pierre Robin Sequence.

The EU’s top two experts on Pierre Robin Sequence, Prof. Dr. Christian Poets at the Tübingen University Hospital, and Prof. Dr. Corstiaan Breugem at Amsterdam University Medical Center, have both formally rejected them.

When EU Guidelines for a rare disease are officially rejected by the EU’s top two experts on that rare disease, then the EU Guidelines are nonviable.

As ERN-Cranio’s Coordinator you may now be considering the option of moving forward anyway and rushing to publication, over the serious critiques of your internationally respected colleagues – Prof. Dr. Corstiaan Breugem, Prof. Dr. Siegmar Reinert, Prof. Dr. Christian Poets, Prof. Dr. Bernd Koos, and others. The ERN Coordinator is responsible for the way this project has been managed; in the same way you will be held responsible for what comes next. My colleagues and I are in touch with various Dutch and international bodies, including formal research oversight boards. They will receive a copy of this email and they will consider a number of issues, including the following.

  • In developing these PRS Guidelines, Erasmus MC intentionally excluded the EU’s top two experts on this rare disease: Prof. Dr. Corstiaan Breugem, and Prof. Dr. Christian Poets. Prof. Dr. Corstiaan Breugem organized the world’s first international PRS consensus meeting, thereby launching the international PRS consensus movement; he has also published more research on PRS than any physician we know of in the world today.
  • Erasmus MC also excluded Prof. Dr. Christian Poets, of the Tübingen University Hospital, who manages the multidisciplinary team of highly specialized experts which administers a breakthrough PRS treatment, the Tübingen Palatal Plate. The Tübingen Palatal Plate has been adopted by Stanford University, and by Harvard University – with training and support from Prof. Dr. Christian Poets and his team.
  • Although Erasmus MC excluded these two world-class PRS experts from this EU-funded PRS Guideline development project, Erasmus MC is not itself an Orphanet Center of Expertise for PRS, which makes the exclusion of the EU’s top two PRS experts even more troubling.
  • ERN-Cranio, in order to justify the exclusion of these two world-class PRS experts from this PRS Guidelines project, stated in writing that “we are not allowed to involve centers outside the ERN CRANIO network”. There is no such rule. Furthermore Erasmus MC’s Dr. Eppo Wolvius, who made this statement, knew when writing it that the Great Ormond Street Hospital, which is “outside the ERN CRANIO network”, was involved in this project – because he and others at Erasmus MC were working on the Guidelines alongside the Great Ormond Street Hospital physicians. Openness and transparency are absolutely vital for high quality research; arbitrary decision making based on relationships and politics make it impossible to achieve top quality research results.
  • In September we received a letter from the Dutch Ministry of Health indicating that ERN-Cranio had informed the Dutch Ministry that these top two PRS experts were now a part of this PRS Guideline development project. Nevertheless in November 2021, when ERN-Cranio organized a meeting in Rotterdam to discuss these PRS Guidelines, Prof. Dr. Corstiaan Breugem and Prof. Dr. Christian Poets were both excluded. Prof. Dr. Corstiaan Breugem, whose PRS research volume exceeds that of any living PRS expert, is based in Amsterdam. Thus ERN-Cranio excluded from this important PRS Guideline development meeting a PRS expert with incomparable PRS research experience, who was located only 80 kilometers away.
  • Under additional pressure from the Dutch Ministry of Health, ERN-Cranio finally permitted these two experts to provide written feedback on the draft document which ERN-Cranio had produced without them. In our 13 December 2021 letter to the German Health Minister Dr. Karl Lauterbach, we described some of the serious serious flaws, medical inaccuracies, misinterpreted research, unsupported conclusions, overlooked medical studies, and multiple forms of bias, which the Tübingen University Hospital identified in ERN-Cranio’s late 2021 draft.
  • From the perspective of research quality, the key question is this: what did ERN-Cranio do with this feedback? ERN-Cranio largely ignored it. After reviewing the most recent draft of these PRS Guidelines, the final version, the Tübingen University Hospital indicated the following. “Most of our comments submitted on Nov 4 were not included in the set of documents the Rotterdam team created… They were apparently largely treated as if non-existing.” Once again this is PRS knowledge and expertise submitted by a world-class PRS Center of Expertise, the Tübingen University Hospital, which has achieved a medical breakthrough in PRS care, a breakthrough which has been adopted by Stanford and Harvard. Top quality evidence-based research requires at a bare minimum that all scientific evidence is considered – particularly if the evidence is presented by an internationally recognized expert.
  • The Dutch Ministry of Health asked Erasmus MC if they were including PRS patients in the Guideline Development Group. The response from ERN-Cranio was to bring in Mr. Gareth Davies. Mr. Gareth Davies is a very dear man, but he represents patients with cleft lip/cleft palate. The goal of this project however was to develop Guidelines of care for PRS. There is a stark difference between cleft lip/cleft palate, and PRS – a complex heterogeneous rare disease characterized by high morbidity, high mortality, and a high level of associated conditions.
  • ERN-Cranio has an official patient group representing PRS patients; it is called Pierre Robin Europe. Starting in April 2021 Pierre Robin Europe raised valid, serious questions about the way this research project was being managed. Our most serious concern was the exclusion from the PRS Guideline development group of the EU’s top two PRS experts. Pierre Robin Europe also protested the fact that there were zero patients in the Guideline Development Group. ERN-Cranio responded to the valid concerns we had raised by excluding us completely, and in our place using a substitute who does not represent patients suffering from this complex life-threatening rare disease. ERN-Cranio excluded Pierre Robin Europe from every single meeting which has ever been held in relation to these PRS Guidelines. We at Pierre Robin Europe have not had the opportunity to interact with a single healthcare provider in the Guideline Development Group. Many, perhaps most of the healthcare providers in the Guideline Development Group do not know that we exist. We, ERN-Cranio’s official patient organization representing the PRS rare disease community, were not involved in the discussion of the scope of these PRS Guidelines. We were not involved in the discussion of the clinical questions which the Guidelines would address. We were not permitted to share our perspective on the relative importance of the clinical questions. We were not given the chance to rate the importance of outcomes. A local Dutch company called Qualicura was hired to provide training for the members of the Guideline Development Group, training which was paid for by the EU; we were not told that such training was taking place. We were not invited to the November 2021 meeting in Rotterdam to discuss these Guidelines. We were not even sent a copy of the final version of these EU Guidelines. We are not on the Guideline Development Group’s email recipient list. We are ERN-Cranio’s one and only PRS patient organisation, and ERN-Cranio excluded us altogether. Quality research is absolutely impossible when those who raise valid questions, or who present dissenting views, are marginalized or excluded.
  • The highly respected Coordinator of another ERN, after learning how this project in ERN-Cranio was being managed, signed an official letter of complaint to Prof. Dr. Karl Lauterbach, the German Health Minister, a fact which can be confirmed through the Minister’s office.

The EU’s European Reference Networks are legally mandated to produce evidence-based patient-centered rare disease Guidelines of care, drawing upon the top rare disease experts in the EU. ERN-Cranio had all the resources it needed to produce outstanding PRS Guidelines. In support of this work, the European Commission spent approximately 4,000,000 Euros of EU taxpayer money (Tender N° SANTE/2018/B3/030) to create an official EU Methodology for the ERNs to use when developing Clinical Practice Guidelines for the EU’s rare disease community. The European Commission spent 100,000 Euros of EU taxpayer money (Tender N° SANTE/2017/B3/083) to hire a contractor to develop templates and documents for the ERNs. The European Commission DG SANTE informed us, Pierre Robin Europe, in a letter dated 1 October 2021 (Ref. Ares(2021)5983971), that the European Commission spent an additional 50,000 Euros of EU taxpayer money to provide ERN-Cranio with direct financial support, for this PRS Guideline development project. The financial resources were available. The necessary infrastructure and tools were available. Most importantly, the EU’s top two PRS experts were available – and they were ready, willing, able, and eager to contribute. So too was Pierre Robin Europe, ERN-Cranio’s official PRS patient organisation. In spite of the promising opportunity and abundant resources, this project has failed. The failure is managerial in nature, and the responsibility falls upon the Coordinator of ERN-Cranio. A formal, fully open and transparent investigation will follow.

Kind regards,

Philippe Pakter
Chairman, Pierre Robin Europe: ERN-Cranio’s official patient organization for Pierre Robin Sequence
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

From: Dr. Corstiaan Breugem
Date: Saturday 12 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Eppo Wolvius; Mr. Gareth Davies
CC: Dr. Irene Mathijssen; All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Eppo,

I would like to congratulate you and your team for doing a lot of work.

When I support a Guideline, I make sure I support something that we can always comply to. It should not be the “ideal” world, but it should be practical and achievable, based on the current literature or include experts in the field. If I do not follow the guideline, there should be a good reason, and this should not happen regularly. Last year I gave you reasons why I think this current guideline is not a practical guideline. It does also not include some relevant literature.

We were given the opportunity to give suggestions in October 2021. I see that many have not been included. My pediatricians for instance say that it is not practical to say that everybody should have a “PSG” before and after palatoplasties and pharyngoplasties. We work in a National reference centre for Robin sequence and see many patients. This is just not practical. Also simply saying a “PSG” is not enough. What criteria do we agree upon are safe to do surgery. Do we really need a PSG in every patient before and after surgery. Maybe in an ideal world. What other ways eg questionnaires, lab test are more practical and should performed, before we suggest doing a PSG in everybody. We feel that suggestions are made in this guideline that are not in reality with what can be achieved in practical care.

I also have a problem with the name “European Guideline”. The European Reference Network includes specialized centers in Europe and is not representative of the whole of Europe. I think at the most, you can call this a ERN Guideline. I am unsure if the ERN has the authority to call this a European Guideline because no National Cleft Association has been involved in the development of this guideline.

Although I see that you and your team have incorporated a lot of effort in this guideline, I am sorry to say, but we cannot support this in its current form.

Best wishes

Corstiaan

Kind regards

Prof. dr. Corstiaan Breugem (MD PhD)
Professor in Plastic and Reconstructive Surgery
Head Pediatric Plastic Surgery
President Dutch Cleft Palate Craniofacial Association
Vice-president European Cleft Palate Craniofacial Association

Department of Plastic Reconstructive and Hand Surgery
Amsterdam UMC, Emma Children’s Hospital
Location AMC, University of Amsterdam|
Room J1A. 210 | Meibergdreef 9, 1105 AZ Amsterdam
The Netherlands

 

 

 

From: Prof. Dr. Christian Poets
Date: Wednesday 2 March 2022
Subject: Rejection of request for final approval of the ERN Guideline on Robin-Sequence
To: Dr. Eppo Wolvius
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Eppo,

Thank you for sending the latest version of this guideline. After careful consideration, the Tuebingen team came to the conclusion that we have to reject this guideline in its present form. Please find our reasons for this decision outlined in the enclosed letter and in our annotations to chapters 1&2 (also enclosed).

We look forward to hearing from you.

Kind regards,

Prof. Christian F. Poets, M.D.
Medical Director
Dept. of Neonatology | Children’s Hospital
Calwerstraße 7 | 72076 Tübingen

Letter to German Health Minister, 13 December 2021

/by

Letter to German Health Minister, 13 December 2021

13 December 2021
Prof. Dr. Karl Lauterbach MdB, Bundesgesundheitsminister
Deutscher Bundestag
Platz der Republik 1
11011 Berlin
Germany

Re: OFFICIAL COMPLAINT: ERN-Cranio; EU Clinical Practice Guidelines for Pierre Robin Sequence

Dear Prof. Dr. Karl Lauterbach, Federal Minister of Health,

We are writing to you with an official complaint concerning ERN-Cranio, which is managed by a Dutch healthcare provider, Erasmus Rotterdam Medical Center, and the EU Clinical Practice Guidelines which ERN-Cranio is allegedly producing for the rare disease, Pierre Robin Sequence. For the sake of EU babies born with this complex and life-threatening rare disease, we urgently request your immediate intervention in this time sensitive matter. We ask that you immediately contact the Dutch Minister of Health, Hugo de Jonge, and call upon the Dutch Minister (1) to immediately suspend all activities on this EU-funded project, which has been grossly mismanaged by Erasmus Rotterdam; and (2) start the project once again, this time including Germany’s top Pierre Robin Sequence Center of Expertise at the Tübingen University Hospital, and also including German patients, all of whom were unjustifiably excluded, in violation of EU rules.

Prof. Dr. Karl Lauterbach, Federal Minister of Health, as this is a matter of ongoing urgency, we would welcome the opportunity to meet with you or your advisors in Berlin or elsewhere to discuss this complaint in person. We look forward to hearing from you. Thank you.

Introduction
The EU’s European Reference Network (ERN) system was designed to represent the best of the best of Europe’s rare disease experts, across the entire EU. This year one of the ERNs, ERN-Cranio, launched a project to create official EU Clinical Practice Guidelines for the treatment of babies suffering from a life-threatening rare disease called Pierre Robin Sequence. These EU Clinical Practice Guidelines will be the first international medical guidelines ever produced for this complex rare disease. They will therefore have a significant impact on Pierre Robin Sequence babies for many years to come, and on the medical care these babies receive.

We, Pierre Robin Europe, are an official rare disease patient advocacy organization, an ePAG representative, in ERN-Cranio. We have served in this capacity since 2018. Our duty in ERN-Cranio is to promote the interests of babies suffering from the life-threatening rare disease, Pierre Robin Sequence. We have watched with increasing concern as this EU-funded project has been managed in a way which we believe violates EU rules, scientific rigor – a view shared by two leading international experts on this rare disease – and once again in an opinion held strongly by respected outside observers, common sense – based on ERN-Cranio’s arbitrary decision to exclude from the drafting group Europe’s two most respected Orphanet Centers of Expertise for this rare disease. Of the two Orphanet Pierre Robin Sequence Centers of Expertise which have been excluded, one is the Center of Expertise located in der Universitätsklinikum Tübingen, the Tübingen University Hospital.

ERN-Cranio: excluding the EU’s top experts in this rare disease
Prof. Dr. Christian Poets, Head of the Department of Neonatology at the Tübingen University Hospital, can confirm that ERN-Cranio has excluded Tübingen’s world class Pierre Robin Sequence Center of Expertise from this EU Guideline drafting project. Almost one year ago, Prof. Dr. Poets approached Dr. Irene Mathijssen, the Coordinator of ERN-Cranio at Erasmus Rotterdam Medical Center, spoke with her by telephone, and expressed Tubingen’s strong interest in joining the Guideline Development Group. Dr. Mathijssen would not permit Tübingen to join.

Dr. Mathijssen’s pretext for excluding the Tübingen University Hospital was that the EU Methodology which governs the creation of ERN Guidelines only permits members of an ERN to be included in an ERN’s Guideline Development Group. In fact, the EU Methodology contains no such rule. The EU Methodology states, in Handbook 4, Section 3.1, that the Guideline Development Group can include healthcare professionals who are members of the ERN, as well as healthcare professionals who are not members of the ERN.

Dr. Holm Graessner, the Coordinator of the European Reference Network for Rare Neurological Diseases (ERN-RND), Managing Director of the Center for Rare Diseases (ZSE) Tübingen, and Head of the research management unit of the Institute of Medical Genetics and Applied Genomics at the Tübingen University Hospital, can confirm that this rule in the EU Methodology which ERN-Cranio has invoked – which supposedly prohibits healthcare professionals who are not in an ERN from joining an ERN’s Guideline Development Group – does not in fact exist. The ERN system was built because rare disease knowledge is scarce; thus there exists an urgent need for European countries to pool resources and knowledge about each rare disease. It would make no sense whatsoever for the EU Methodology to prohibit world-class Orphanet Centers of Expertise in the EU from joining a Guideline Development Group, simply because they were not members of the ERN. And indeed, the EU Methodology contains no such rule.

Not only is Erasmus Rotterdam’s ERN-Cranio Coordinator Dr. Irene Mathijssen invoking a rule in the EU Methodology, when no such rule exists, but while Dr. Mathijssen is invoking this non-existent rule to exclude Tübingen, she has, at precisely the same moment, included in the Guideline Development Group the Great Ormond Street Hospital – and the Great Ormond Street Hospital is not a member of the ERN. As confirmed in writing by Dr. Mathijssen, the Great Ormond Street Hospital, which is not a member of ERN-Cranio, has played a leading role in this EU Guideline Development Project. How can the EU Methodology’s non-existent rule, which supposedly bars non-ERN healthcare professionals from participating in a Guideline Development Group, apply to Tübingen… but not apply to the Great Ormond Street Hospital? What we do know for certain is that Dr. Mathijssen’s hospital, Erasmus Rotterdam, has a relationship with the Great Ormond Street Hospital – they are friendly with one another. It is difficult to avoid the impression that Dr. Mathijssen and Erasmus Rotterdam have been running this EU-funded ERN Guideline development project based on relationships and politics, rather than on experience and expertise.

Making matters worse, Dr. Mathijssen and Erasmus Rotterdam, rather than honestly and openly admitting to errors in judgment, have instead engaged in an ongoing pattern of obfuscation and outright misrepresentation – not only with us, but also with their own government, the Dutch Ministry of Health. To take one example: on 15 September 2021 we received a letter from the Dutch Ministry of Health, which had been in contact with ERN-Cranio concerning these EU Guidelines. The Dutch Ministry of Health told us in this 15 September letter that according to ERN-Cranio, the Tübingen University Hospital was indeed involved in this EU Guideline development project. Not only was Tübingen involved, but Tübingen had even provided ERN-Cranio with feedback on a draft.

In reality, Tübingen (1) was absolutely not involved; and (2) the feedback which Tübingen tried to give to Erasmus Rotterdam was outright rejected, by Erasmus Rotterdam. On 8 September 2021, two days after the Tübingen University Hospital provided Erasmus Rotterdam with 17 pages of meticulously detailed scientific feedback on ERN-Cranio’s draft EU Guidelines for Pierre Robin Sequence – which had been written without Tübingen – Dr. Eppo Wolvius, of Erasmus Rotterdam, wrote the following message:
—–

“Unexpectedly, I received a feedback form with comments on the RS Guideline from Prof. Poets, Tubingen. I am very surprised to receive these comments from a clinician outside the Steering Group of this Guideline initiated by the ERN CRANIO. Prof Poets informed me the draft was sent to him by Philippe Pakter. Maybe Philippe Pakter received the draft from you and therefore, I am sending you this mail. Please note that at this stage we are not allowed to involve centers outside the ERN CRANIO network.”

—–
Erasmus Rotterdam’s claim that “we are not allowed to involve centers outside the ERN CRANIO network” was false on multiple levels. First of all, the EU Methodology contains no such rule. Second of all, Dr. Eppo Wolvius of Erasmus Rotterdam knew very well when writing this statement that the Great Ormond Street Hospital was involved in this ERN CRANIO project, because Dr. Wolvius was working on the Guidelines alongside the Great Ormond Street Hospital physicians – and yet the Great Ormond Street Hospital is “outside the ERN CRANIO network.”

—–
Concerning the feedback itself, which Erasmus Rotterdam rejected: in the 17 pages of feedback the Tübingen University Hospital identified serious flaws, medical inaccuracies, misinterpreted research, unsupported conclusions, overlooked medical studies, and multiple forms of bias, in ERN-Cranio’s draft Guidelines.

Concerning bias in particular: in the feedback which Tübingen tried, unsuccessfully, to submit to Erasmus Rotterdam, Tübingen specifically protested the fact that ERN-Cranio’s draft Guidelines reflect a bias in favor of surgical interventions. Indeed ERN-Cranio actually states in their draft Guidelines that “The guideline steering group was chaired by a maxillofacial surgeon” and that “The guideline steering group consisted of eight professionals specialised in maxillofacial surgery and plastic surgery.” A bias toward surgery was inevitable.

This bias toward surgery constitutes a particularly grave defect in ERN-Cranio’s work, because while not all physicians agree on treatment strategies, virtually everyone agrees that surgery on newborn babies should only be performed when clinically necessary. The safe and medically proven Tübingen Palatal Plate treatment presents in the majority of cases a completely viable non-surgical alternative, which safely resolves the life-threatening upper airway obstruction associated with this rare disease. Nevertheless, Erasmus Rotterdam not only excluded the Tübingen University Hospital from the Guideline Development Group, but ERN-Cranio’s Coordinator Dr. Mathijssen, a surgeon, and Dr. Wolvius, a surgeon, would not even accept Tübingen’s feedback. It is worth adding here that while the draft Guidelines prepared by ERN-Cranio place an emphasis on surgical interventions, the clinical evidence demonstrating the efficacy and safety of the non-surgical Tübingen Palatal Plate treatment is actually stronger than the evidence in favor of surgery. Indeed the only Pierre Robin Sequence treatment which has ever been subjected to a controlled trial is the breakthrough non-surgical Tübingen Palatal Plate treatment developed by the Tübingen University Hospital.

Another form of bias which Tübingen protested in their feedback, which Erasmus Rotterdam refused to accept, concerned the following. According to ERN-Cranio’s draft, “Experts on each topic of the guideline were consulted to review the chapters and write recommendations.” What follows is a list of the 10 professionals who wrote the recommendations for these Guidelines. Every single one of the 10 professionals who wrote the all-important recommendations for these “EU” Guidelines come from the exact same country: the Netherlands. These are supposed to be Guidelines for the EU, not Guidelines for Holland. As Tübingen pointed out in their feedback, “It will automatically result in a strong bias if all experts invited are from only one country!”

And yet another form of bias which the Tübingen University Hospital specifically protested in their 17 pages of feedback – which Erasmus Rotterdam refused to accept – concerned the astonishing fact that as part of this EU-funded project’s patient survey for these EU Guidelines, patients from the EU’s largest Member State, Germany, were completely left out. This will be discussed in further detail below.

Most rare diseases lack an approved treatment or cure. The Tübingen Palatal Plate represents an exception, a shining hope: a safe, highly effective, economical rare disease treatment, developed right here in the EU. Stanford University has already adopted the Tübingen Palatal Plate treatment. Below is a photo of Dr. HyeRan Choo, Clinical Assistant Professor of Plastic and Reconstructive Surgery at Stanford University School of Medicine. Dr. Choo is holding a Tübingen Palatal Plate, which she and her colleagues learned how to produce and administer thanks to training from the Tübingen University Hospital:

Dr. HyeRan Choo with a Tübingen Palatal Plate at Stanford

The American baby who received this particular Tübingen Palatal Plate at Stanford was able to safely avoid painful and risky surgery – labioglossopexy, and mandibular distraction osteogenesis. The mother wrote that “I truly believe this intervention needs to be shared with everyone with PRS.” With genuine excitement and hope, the mother described the treatment as “an incredible noninvasive option with great results. My daughter has only used the device 5 days and you can already see a vast improvement. Please reach out if you would like more information!!”

Soon, Harvard too will adopt the Tübingen Palatal Plate. This reflects well on the EU in general, and on German medicine in particular. Nobody in the international community of Pierre Robin Sequence experts questions the fact that the Tübingen University Hospital is one of the world’s foremost leaders in Pierre Robin Sequence treatment and research. And yet Erasmus Rotterdam, which Orphanet does not recognize as a Pierre Robin Sequence Center of Expertise, refused to even consider what Tübingen had to say about the many serious shortcomings in ERN-Cranio’s work.

Another example of Erasmus Rotterdam’s pattern of obfuscation and misrepresentation is the following. We recently received another letter from the Dutch Ministry of Health concerning these Guidelines, dated 30 November 2021. In this 30 November letter, the Dutch Ministry of Health indicates that according to Erasmus Rotterdam, the Guideline Development Group includes the following healthcare providers:

“Helsinki University Hospital, Vall d’Hebron Barcelona, Santa Maria Hospital Lisboa, Karolinska Hospital, Vicenza San Bortolo Hospital, Uppsala University Hospital, 12 de Octubre University Hospital Madrid, San Gerardo Hospital Monza, Hôpital Universitaire Necker, UMC Utrecht and Erasmus MC Rotterdam.”

The one healthcare provider which is missing from this list is the Great Ormond Street Hospital. Why did the Great Ormond Street Hospital suddenly disappear, when Erasmus Rotterdam’s Coordinator, Dr. Mathijssen, repeatedly confirmed that the Great Ormond Street Hospital is playing a leading role in this EU-funded project? We believe that the Great Ormond Street Hospital suddenly disappeared because the Great Ormond Street Hospital’s involvement in this project makes it unquestionably clear that Dr. Mathijssen and Erasmus Rotterdam have been managing this EU-funded project in an arbitrary and discriminatory manner.

Relationships, professional competition and politics are a known aspect of healthcare, just as they are a part of every other professional sector. However when they take hold of an important and sensitive EU-funded project to the extent that we see here, where the EU’s top two Pierre Robin Sequence Centers of Expertise are unjustifiably excluded from drafting EU Guidelines of care for this particular rare disease, then something must be done.
—–
ERN-Cranio: excluding patients from the Guideline Development Group
In 2020 I was invited to submit an article to the Elsevier medical journal, “Seminars in Fetal & Neonatal Medicine.” One of the physicians who reviewed a draft of this rare disease patient perspective article wrote the following:

“Thanks, Philippe – this is tremendous and it emphasises the need or should I say absolute imperative that we obtain and heed the patient / parent perspective in the approach to rare diseases. This certainly provides aspects that we do not read about in the textbooks.”

(Prof. Dr. Peter A. Mossey, Professor and Personal Chair of Craniofacial Development & Dentofacial Orthopaeds, the University of Dundee; Associate Dean for Research; Director of WHO Collaborating Centre for Craniofacial Anomalies and Technology Transfer)

This rare disease patient perspective article which I submitted to Seminars in Fetal & Neonatal Medicine passed peer review and was published on 17 September 2021. Elsevier’s CEO, Ms. Kumsal Bayazit, was so impressed with the quality of the article that she personally waived the $4,100 Gold Open Access fee which Elsevier normally charges for Open Access in this particular medical journal; she also emailed me the following message:

“I am so very grateful you took the time and made the effort to write the paper from a rare disease patient and parent perspective. As you state it is critical that the vantage points and experiences of patients and parents are included in the literature to improve care and treatment.

…

My very best wishes to Lysiane and if I can be of any further assistance, please feel free to reach out to me.

Best regards,

Kumsal

Kumsal Bayazit
Chief Executive Officer
Elsevier”

Research makes it unquestionably clear that meaningful patient involvement in guideline development improves the quality of the final product:

“It has been shown that involvement of patients in guideline development improves the quality of guidelines and associated patient education materials and is particularly important when considering preference-sensitive decisions, for which patient preferences take priority when considering the benefits and harms of treatment options… Further challenges to patient involvement include ‘tokenistic’ involvement rather than routine integration of the patient voice, lack of support to help patients understand medical terminology, resistance from some health professionals, and a lack of resources.”

(Providing a Framework for Meaningful Patient Involvement in Clinical Practice Guideline Development and Implementation. Björkqvist, Josefine et al., European Urology Focus, Volume 7, Issue 5, 947 – 950.)

Unfortunately, ERN-Cranio’s coordinator Dr. Irene Mathijssen, in addition to excluding the Tübingen University Hospital from the Guideline Development Group, also excluded patients from the Guideline Development Group. Once again: ERN-Cranio’s EU Guideline Development Group included exactly zero patients.

The EU Methodology which governs the creation of EU Clinical Practice Guidelines for the ERN system absolutely requires that patients be included in the Guideline Development Group. The EU Methodology specifically identifies patients as one of the “four key constituents” of the Guideline Development Group. From the official EU Methodology, Handbook 4, Section 3.1:

The EU Methodology which governs the creation of EU Clinical Practice Guidelines for the ERN system absolutely requires that patients be included in the Guideline Development Group.

On 21 July 2021 a conference call was held with Dr. Mathijssen, a representative from Pierre Robin Europe, a representative from EURORDIS, and ERN-Cranio’s two Project Managers, to discuss the fact that ERN-Cranio had included no patients whatsoever in the Guideline Development Group for this EU Guideline development project. Various pretexts were given for the failure to include one single patient in the Guideline Development Group. One of the pretexts was that the EU Methodology was not yet available when ERN-Cranio began the project. Here are the facts.

Concerning the EU Methodology, the European Commission DG SANTE indicated to Pierre Robin Europe, in writing, in a letter dated 1 October 2021 (Ref. Ares(2021)5983971), that “The documents were initially distributed to all ERN coordinators in February 2021 in electronic format.” Once again, all ERN coordinators in all 24 of the ERNs received the EU Methodology in February. In a separate message, ERN-Cranio Project Manager Renée de Ruiter informed Pierre Robin Europe, in writing, in an email dated 14 July 2021, that ERN-Cranio launched this Guideline development project in February 2021.

Furthermore, in the European Commission DG SANTE’s abovementioned letter (Ref. Ares(2021)5983971), DG SANTE indicated that the European Commission was providing ERN-Cranio with €50.000  of financial support to develop these EU Clinical Practice Guidelines for Pierre Robin Sequence. We believe that ERN-Cranio channeled some portion or all of these EU funds to a private Dutch subcontractor named Qualicura (Emmastraat 2A, 4811 AG Breda, The Netherlands), in exchange for Qualicura’s assistance. If ERN-Cranio Coordinator Dr. Mathijssen did not have the time to read Handbook 4 of the EU Methodology governing the creation of EU Clinical Practice Guidelines for the ERN system, then she could have simply instructed the local Dutch subcontractor, Qualicura, to read it. After all, ERN-Cranio’s delegated duty is to produce EU Guidelines for the EU’s ERN system – not local Dutch guidelines based on local Dutch standards.

—–
To summarize: in February 2021, ERN-Cranio’s clinicians began working on these EU Guidelines. In September 2021 the work was done, the ERN-Cranio clinicians had completed the assignment and written the document – about us, without us. But now we, the patients, the ultimate stakeholders, were permitted to take a look. Now we were permitted to provide comments, and this opportunity to provide comments on this document which we had not been allowed to participate in or contribute to in any way, at all, would presumably make the document “patient-centered.” Indeed in this document which we were now permitted to comment on in September, the ERN-Cranio clinicians had included the following proud declaration: “Since the guideline will be developed for patients and parents of patients, the patient perspective will be of major importance in this guideline.” It would be difficult to conjure up a more offensive example of base hypocrisy.

We sent the following feedback to Erasmus Rotterdam’s Dr. Eppo Wolvius:

“Stichting Pierre Robin Europe, ERN-Cranio’s official ePAG patient organization for Pierre Robin Sequence patients since 2018, believes this EU-funded project to develop Clinical Practice Guidelines for Pierre Robin Sequence (1) should be restarted from the beginning, and (2) should be run in accordance with the EU’s official ERN Methodology located at https://ern-ithaca.eu/documentation/guidelines/#ern-guidelines-methodological-handbook and (3) should include in the Guideline Development Group the EU’s top Pierre Robin Sequence Centers of Expertise. Our Board has formally concluded that accepting anything less would constitute a profound betrayal of the interests of the rare disease patients we are mandated to represent. Our 30 June 2021 letter to the Board of Member States, attached, and our 7 September 2021 letter to the European Commission/DG SANTE, attached, explain the many reasons for our position.”

Nobody from ERN-Cranio’s Guideline Development Group responded to our feedback. Dr. Eppo Wolvius did not even acknowledge receipt. We did not exist in February 2021, when the clinicians began working on this document, and we still didn’t exist in September 2021, when we were finally permitted to see what the clinicians had written, and present our justifiable grievances.

On Tuesday evening, 23 November 2021, Dr. Mathijssen called me, the director of Pierre Robin Europe, by telephone. During this telephone call, Dr. Mathijssen explained to me that although ERN-Cranio had not included any patients in the Guideline Development Group, ERN-Cranio had sent out a survey to patients.

First of all, Pierre Robin Europe, ERN-Cranio’s official ePAG patient organization for Pierre Robin Sequence since 2018, was not given any opportunity whatsoever to help create this patient survey. We were not even given the chance to look at the survey, before the survey was sent out. Apparently it never occurred to Dr. Mathijssen that ERN-Cranio’s official ePAG patient organization for Pierre Robin Sequence might want to see the Pierre Robin Sequence patient survey which the clinicians were going to send out, to patients. However, it gets worse.

The patient survey, which Pierre Robin Europe was not permitted to produce, or comment on, or even see, was sent out to patients by the Pierre Robin Sequence Centers of Expertise which were included in the Guideline Development Group. Thus, the survey was distributed to a specific subset of Pierre Robin Sequence patients: Pierre Robin Sequence patients who were fortunate enough to be in contact with a Pierre Robin Sequence Center of Expertise. If a patient had not been in contact with a Pierre Robin Sequence Center of Expertise, then there would be no way for them to access this survey.

Many, perhaps the majority, of poor patient outcomes arise in situations where a patient with a rare disease is unable to receive treatment at a Center of Expertise for that rare disease or complex condition. Based on the method which ERN-Cranio employed to distribute this survey, few if any of these patients would be reached, and none of their experiences or perspectives would be recorded. This is ironic, because the patient survey which the ERN-Cranio clinicians created – without us, the patients – was coordinated around the obstacles which patients encountered in the organization of Pierre Robin Sequence care, the difficulties they faced concerning the treatment plan, and organizational problems.

If ERN-Cranio had included Pierre Robin Europe, ERN-Cranio’s official ePAG patient organization for Pierre Robin Sequence, or indeed any patients at all, in the Guideline Development Group, as required by the EU Methodology, then we would have pointed out this serious sampling flaw. We would have offered to distribute the survey within our own patient community, using our international Pierre Robin Sequence patient network, thereby reaching patients who never reached a Center of Expertise. This would have enabled ERN-Cranio clinicians to obtain precious information on the most serious difficulties and obstacles patients faced, and thoughts from patients themselves on how such challenges might be addressed and resolved. This did not happen. And yet, it once again gets even worse.

Germany and German patients erased from Europe
Dr. Mathijssen stated during the 23 November 2021 telephone call that “it is very important to include all these various opinions and various experiences that people have in different countries, which differ a lot.” Therefore ERN-Cranio translated the patient survey into 8 European languages. The patient survey was even translated into Finnish, which is spoken in an EU Member State with a relatively low population of 5.5 million, and therefore an exceedingly small population of Pierre Robin Sequence patients.

However, there was one major EU language which the patient survey was not translated into: ERN-Cranio’s “EU” patient survey was not translated into German.

Germany has, by a very wide margin, the highest population of any Member State in the entire European Union, approximately 83 million people. We can safely assume that Germany has a far higher Pierre Robin Sequence patient population than any other country in Europe. For obvious reasons it would have made more sense to translate this survey into German, rather than translating it into Finnish or Portuguese. However ERN-Cranio, in defiance of financial prudence and common sense, decided that translating the survey into German was unnecessary.

Furthermore Dr. Mathijssen confirmed during this 23 November 2021 telephone call that this patient survey was not distributed to one single patient in the entire country of Germany. Germany’s entire Pierre Robin Sequence patient population, the largest Pierre Robin Sequence patient population in all of Europe, was completely left out.

These are supposed to be EU Guidelines for the European Union as a whole. Based on limited EU budgets, EU surveys should always be translated, first and foremost, into the major EU languages. This includes German. Furthermore, the ERN system is financed by the EU, and Germany’s financial contribution to the EU is far greater than the financial contribution of any other country in Europe. Based on the most basic notions of fairness and good faith, Germany should not be excluded from such EU projects. However, what is more shocking than anything else is that ERN-Cranio’s Coordinator, Dr. Mathijssen, who herself admitted that the various experiences people have in different countries “differ a lot,” thought that it was perfectly acceptable to run this EU project without including one single German healthcare provider, or one single German patient. ERN-Cranio simply removed the entire country of Germany, and Germany’s entire Pierre Robin Sequence patient population, from the map.

During the 23 November 2021 telephone call with Dr. Mathijssen I pointed out that in Germany, Pierre Robin Sequence babies can receive a highly specialised treatment which is not offered anywhere else in the entire European Union – the safe, medically proven, non-surgical, and cost-effective Tübingen Palatal Plate treatment. The Tübingen Palatal Plate treatment has now been adopted by Stanford University, which underwent training by the Tübingen University Hospital. The Tübingen Palatal Plate will soon also be administered by Harvard/Boston Children’s Hospital, which is currently undergoing training by the Tübingen University Hospital. And yet not one single Pierre Robin Sequence patient in Germany who received this breakthrough German treatment had the opportunity to fill out ERN-Cranio’s “EU” patient survey, or even learn of the existence of this “EU” survey.

A survey is not a substitute for a patient, or for any living human being. If meaningful diversity and inclusion could be achieved by sending out a survey, then there would be very few women or persons of color in EU governments or corporate boards. Instead of inclusion, the men in such positions would simply send out surveys. However for ERN-Cranio, even sending out one survey, to one German patient, proved to be too much.

When I asked Dr. Mathijssen how ERN-Cranio’s patient survey could achieve adequate coverage of EU patient experience, when it completely omitted the most populous Member State in all of Europe, Dr. Mathijssen replied that ERN-Cranio’s Guideline Development Group achieved German coverage through their literature review, which included medical studies published by the Tübingen University Hospital. Thus, ERN-Cranio can ignore the EU Methodology, which clearly requires patients in the Guideline Development Group, by instead sending out a survey; and in fact, even if it doesn’t send out a survey – not even one survey was sent out to a single one of Germany’s 83 million citizens and residents – that too is perfectly OK, because the “patient experience” can simply be extrapolated from clinical research, which is produced not by patients but by clinicians. Thus, according to Dr. Mathijssen’s logic, the EU’s ERN system can produce patient centered EU Guidelines without involving any patients or any patient surveys at all.

Dr. Mathijssen insisted during our 23 November 2021 phone call that ERN-Cranio’s EU Clinical Practice Guidelines for Pierre Robin Sequence conforms to the EU Methodology, and that ERN-Cranio’s performance on this project represents the “gold standard” of the EU’s ERN system. These were Dr. Mathijssen’s words: the “gold standard.” It is impossible to reconcile Dr. Mathijssen’s vision of this situation with objective reality.

Since early September 2021, we in Pierre Robin Europe, ERN-Cranio’s official Pierre Robin Sequence patient organization since 2018, have insisted that this EU Guideline development project for Pierre Robin Sequence be restarted from the very beginning. This EU-funded initiative must be relaunched and carried out as it should be carried out, in accordance with the EU rules, the official EU ERN Methodology – which the EU paid for, and distributed, to every single ERN in the entire ERN system. As ERN-Ithaca has rightfully pointed out, the EU Methodology “is an important step forward of the ERN CPG programme and a key element and tool for the work of the ERNs in the production, adaptation, adoption and appraisal of the different guidelines and technical sub-products, to be used for now on by all the ERNs. The methodology will ensure the quality and standardisation of the CPG and CDST produced and used by the ERNs, the backbone of the process of the diagnosis and treatment of patients suffering of rare or low prevalence and complex diseases.” ERN-Cranio’s performance on these Guidelines, and Erasmus Rotterdam’s mismanagement of the project, represent an embarrassing low point for the EU’s ERN system. Who pays the price? Babies suffering from a life-threatening rare disease, who are being cheated out the top quality EU Clinical Practice Guidelines which they desperately need.

Attached to this letter please find:

1) 30 June 2021 letter we sent to the Dutch Health Minister

This 30 June 2021 letter contains the most important facts, including the exclusion from the drafting group of the EU’s top two Centers of Expertise for Pierre Robin Sequence.

2) 7 September 2021 letter we sent to the Dutch Health Minister

In our 7 September 2021 letter to the Dutch Health Minister we demanded that this EU-funded initiative be relaunched and carried out as it should be carried out, in accordance with the EU rules, the official EU ERN Methodology, which the EU paid for, and distributed, to every single ERN in the entire ERN system.

3) the Dutch Ministry of Health’s response to us, 15 September 2021

In this 15 September 2021 letter from the Dutch Ministry of Health, the Dutch Ministry attempts to avoid responsibility for this matter, in spite of the fact that Erasmus Rotterdam’s conduct falls within the Dutch Ministry’s jurisdiction. The 15 September 2021 letter from the Dutch Ministry also contains a series of distortions and outright misrepresentations.

4) 30 September 2021 letter we sent to the Dutch Ministry of Health

In our 30 September 2021 letter we identified a series of factual and legal inaccuracies in the letter we received from the Dutch Ministry of Health on 15 September 2021.

5) 23 November 2021 letter we sent to Dr. Irene Mathijssen, Coordinator, ERN-Cranio

In this 23 November 2021 letter we inform Dr. Mathijssen that we have requested official intervention on the EU level.

On the evening of 23 November 2021, Dr. Mathijssen called me by telephone. We spoke about this situation involving the EU Guidelines for a little under 45 minutes.

6) 24 November 2021 letter we sent to Dr. Irene Mathijssen, Coordinator, ERN-Cranio

In this 24 November 2021 letter we sent to Dr. Mathijssen, we document our 23 November 2021 telephone call. During the 23 November 2021 telephone call, Dr. Mathijssen informed us that the Tübingen University Hospital had now been admitted to ERN-Cranio. Dr. Mathijssen said that since the Tübingen University Hospital was now a member of ERN-Cranio, the three healthcare providers which were in charge of this EU Guideline development project: Erasmus Rotterdam, Utrecht University Medical Center, and the Great Ormond Street Hospital – which is not a member of ERN-Cranio – would duly consider the Tübingen University Hospital’s 17 pages of feedback. Speaking on behalf of Pierre Robin Europe, the official ERN-Cranio ePAG patient organization for Pierre Robin Sequence, I made it clear to Dr. Mathijssen that this was not sufficient. The Tübingen University Hospital should have been included in the Guideline Development Group from the very beginning. The Tübingen University Hospital should have been involved in the discussion of the scope of these Guidelines. Tübingen should have been involved in the formulation of the clinical questions. Tübingen should have been involved in the discussion of the inclusion and exclusion criteria for selecting the relevant evidence. Tübingen should have been involved in the literature search and in the appraisal of the quality of the evidence. Tübingen should have been involved in the interpretation of the evidence, the construction of the recommendations, and the grading of the strength of the recommendations. The Tübingen University Hospital, one of the leading Pierre Robin Sequence Centers of Expertise in the entire world, should have been involved in the drafting of these EU Guidelines for Pierre Robin Sequence from day one, and it is an embarrassing scandal for the ERN system that they were senselessly kept out. Dr. Mathijssen’s belated assurance that she and her colleagues will now duly consider Tübingen’s feedback on a document which was produced completely without them is meaningless. At the end of this 24 November 2021 letter we sent to Dr. Mathijssen, we memorialize a proposal we had presented during the 23 November telephone call, as a possible way of moving forward. We proposed a conference call which would include Prof. Dr. Christian Poets of the Tübingen University Hospital, and another leading Pierre Robin Sequence expert, Prof. Dr. Corstiaan Breugem, who has probably published more medical studies on Pierre Robin Sequence than any other Pierre Robin Sequence expert in the world. At the end of our 23 November telephone call, Dr. Mathijssen solemnly promised that she would return to us with a response to our proposal “really soon.” Today is 13 December 2021; almost three full weeks have passed since our telephone call. Dr. Mathijssen has remained absolutely silent.

Additional material – my article, published in Seminars in Fetal and Neonatal Medicine

A parent’s view on the care of their baby with Robin sequence. Pakter, Philippe, Seminars in Fetal and Neonatal Medicine, Volume 26, Issue 6, 101288.

Conclusion
While ERN-Cranio’s Coordinator Dr. Irene Mathijssen and Erasmus Rotterdam are ultimately responsible for this dishonourable situation, which reflects so poorly on the EU’s ERN system, the Dutch Health Minister’s official inaction has played a pivotal role. The Dutch Ministry of Health’s ongoing justifications, rationalizations and misrepresentations have permitted Dr. Mathijssen to disregard our concerns, and to continue to “build facts on the ground,” with every passing month. Thus, when the issues which we in Pierre Robin Europe first raised in April of 2021 are finally discussed, the discussion will be meaningless, because the Guidelines will already be written. Perhaps this is the precise outcome which the Dutch Ministry of Health, Dr. Mathijssen, and Erasmus Rotterdam are looking to achieve.

For the sake of EU babies born with this complex and life-threatening rare disease, we urgently request your immediate intervention in this time sensitive matter. We ask that you immediately contact the Dutch Minister of Health, Hugo de Jonge, and call upon the Dutch Minister (1) to immediately suspend all activities on this EU-funded project, which has been grossly mismanaged by Erasmus Rotterdam; and (2) start the project once again, this time including Germany’s top Pierre Robin Sequence Center of Expertise at the Tübingen University Hospital, and also including German patients, all of whom were unjustifiably excluded, in violation of EU rules.

Prof. Dr. Karl Lauterbach, Federal Minister of Health, as this is a matter of ongoing urgency, we would welcome the opportunity to meet with you or your advisors in Berlin or elsewhere to discuss this complaint in person. We look forward to hearing from you. Thank you.

Kind regards,

Philippe Pakter

Pierre Robin Europe, chairman, pakter@pierrerobineurope.com
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law, the University of Geneva: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

Letter to Dutch Health Minister, 30 June 2021

/by

Letter to Dutch Health Minister, 30 June 2021

30 June 2021

Minister Tamara van Ark
Ministry of Health, Welfare and Sport
Postbus 20350
2500 EJ Den Haag
The Netherlands

Re: ERN-Cranio; Clinical Practice Guidelines for Pierre Robin Sequence/Syndrome

Dear Minister Tamara van Ark,

30 million rare disease patients here in Europe face profound hardships and daily challenges which most people could not even imagine. The European Reference Network (ERN) system was created to bring this community some measure of relief, by drawing upon the greatest rare disease experts throughout the EU. We at Stichting Pierre Robin Europe are members of Europe’s rare disease community; as part of our work, we advocate on behalf of newborn babies suffering from the rare disease, Pierre Robin Sequence / Pierre Robin Syndrome (PRS).

We are writing to you concerning ERN-Cranio, and the Clinical Practice Guidelines (CPGs) which ERN-Cranio is currently producing for PRS. These PRS CPGs will be the first international CPGs ever produced for this particular rare disease. They will therefore have a significant impact on PRS babies for years to come, and on the medical care these babies receive. We are writing to you to express serious concerns about the way this CPG project is being managed by Erasmus Rotterdam, where ERN-Cranio is based – and to formally request your official intervention. We will organize this letter under the following four headings, and provide further details below.

1. – Improper selection of healthcare providers in the Guideline Development Group

2. – Patients not included in the Guideline Development Group

3. – Efforts to address this situation amicably have failed

4. – The intervention we request

—–

1. – Improper selection of healthcare providers in the Guideline Development Group (GDG)

The Guideline Development Group (GDG) for this CPG project is composed of some number of healthcare providers. We are not sure how many healthcare providers are in the GDG, or who they are, because ERN-Cranio has not permitted us to be a part of the GDG; indeed in the GDG for this project there are no patients and no patient organizations at all, which violates the EU’s Aragon Health Sciences Methodological Handbooks & Toolkit for Clinical Practice Guidelines (the Methodology). What we do know is that among the healthcare providers which have been included in the GDG, there are three in particular who are leading the project. The three healthcare providers which are leading the project are: (1) Erasmus Rotterdam; (2) Utrecht UMC; and (3) the Great Ormond Street Hospital in London. We will address each of these below.

—–

1.1. – INCLUDED in the GDG: Erasmus Rotterdam
When drafting CPGs for a complex rare disease, the best available Centres of Expertise in Europe should be identified and brought in as members of the GDG. In the PRS CPG project, Erasmus Rotterdam is in the GDG, and is in fact one of the three healthcare providers which is leading the work. Erasmus Rotterdam is not one of Europe’s leading Centres of Expertise for PRS. Erasmus Rotterdam is not recognized as a PRS Centre of Expertise at all. Orphanet does not list Erasmus Rotterdam as a Centre of Expertise for PRS, and the Dutch Ministry of Health does not recognize Erasmus Rotterdam as a Centre of Expertise for PRS.

Erasmus Rotterdam is currently asking the Dutch Ministry of Health to accredit Erasmus Rotterdam as a Centre of Expertise PRS. In their application to the Dutch government they are asking the Dutch Ministry of Health to accredit Erasmus Rotterdam as a Centre of Expertise for both isolated Pierre Robin Sequence, ORPHA:718, and syndromic Pierre Robin Sequence, ORPHA:138044. As everybody in the rare disease community knows, rare disease patient volume is critical. This principle is so important that it is enshrined in the official Dutch law governing the Centre of Expertise accreditation procedure in the Netherlands:

“Het kandidaat ECZA adviseert aan, en behandelt voldoende patiënten om een bijdrage te kunnen leveren aan het verder ontwikkelen van kennis over de zeldzame aandoening en het verbeteren van de behandeling van een zeldzame aandoening. Het kandidaat ECZA moet bij een relevant percentage van het aantal bekende patiënten met de desbetreffende zeldzame aandoening in Nederland betrokken zijn in het zorgtraject.”

(“The candidate Centre of Expertise advises on, and treats enough patients to be able to contribute to the further development of knowledge about the rare disorder and to improve the treatment of the rare disorder. The Centre of Expertise candidate shall be involved in the care process in a relevant percentage of the number of known patients with the relevant rare disorder in the Netherlands.”)

At Erasmus Rotterdam, how many new ORPHA:718 isolated PRS patients were seen last year, meaning any and all new patients, ranging in age from newborn babies, all the way up to 18 years? Erasmus Rotterdam saw one isolated PRS patient.

Erasmus Rotterdam is also seeking accreditation as a Centre of Expertise for syndromic Pierre Robin Sequence, ORPHA:138044. How many new ORPHA:138044 syndromic PRS patients were seen last year, once again any new patients, ranging in age from newborn babies, all the way up to 18 years? Erasmus Rotterdam saw one syndromic PRS patient, again just one single patient.

These figures cannot be explained by COVID-19; during the same time period, the same Erasmus Rotterdam unit welcomed over 30 new cleft lip/cleft palate patients. Erasmus Rotterdam’s new patient volume for isolated PRS was just one patient, and for syndromic PRS was just one patient, and on the basis of this patient volume, which hovers just above zero, Erasmus Rotterdam seeks official accreditation from the Dutch Ministry of Health as a Centre of Expertise for this complex, heterogenous, life threatening rare disease.

In Erasmus Rotterdam’s application to the Dutch Ministry of Health requesting accreditation as a PRS Centre of Expertise, the application asks if there are any international CPGs for PRS, and if so, whether Erasmus Rotterdam contributed to them. In response Erasmus Rotterdam explains that PRS guidelines are being developed, and that Erasmus Rotterdam is the coordinating centre for this guideline development project. Thus: Erasmus Rotterdam has very low PRS patient volume, and is not a Centre of Expertise for PRS; therefore Erasmus Rotterdam should not be drafting CPGs for PRS. Nevertheless, Erasmus Rotterdam placed itself as the key healthcare provider in this PRS CPG drafting project. Then, after placing itself as the key healthcare provider in the PRS CPG drafting project, Erasmus Rotterdam, using circular logic, tells the Dutch government that this key role which Erasmus Rotterdam is playing is itself evidence of Erasmus Rotterdam’s PRS expertise, and therefore the Dutch Ministry of Health should officially accredit Erasmus Rotterdam as a Centre of Expertise for PRS.

Rare disease patients in the Netherlands are told that the official Dutch procedure for accrediting rare disease Centres of Expertise guards against “self-accreditation”. Self-accreditation should never be permitted, the Dutch Ministry of Health says, because self-accreditation leads to sub-optimal Centres of Expertise; sub-optimal Centres of Expertise lead, in turn, to sub-optimal ERNs. We agree with you.

While this particular situation involves the rare disease PRS, it nevertheless raises fundamental questions which apply to other rare diseases, other Centres of Expertise, and the ERN system in general. How many PRS Centres of Expertise does a small country like the Netherlands actually need? How many PRS Centres of Expertise would make the most sense, and provide the greatest healthcare benefit, to this very small rare disease patient population in the Netherlands? Finally, if every healthcare provider really is a PRS rare disease Centre of Expertise, as they claim, then why do we bother with the Orphanet “Centre of Expertise” designation – why should we even have an ERN system?

The reality is that ERN CPGs have profound consequences for actual living human beings. In this case the patients affected will be newborn babies with PRS. These newborn babies suffer from a life threatening rare disease which is characterized by significant morbidity, and significant mortality. In CPG development only the most highly qualified Centres of Expertise should be involved; CPG development is no place for on the job training, credential building exercises, or professional politics. Erasmus Rotterdam is without question a highly qualified Centre of Expertise for other rare diseases, but rare diseases are notoriously complex, and even deep expertise in one rare disease does not confer expertise in another. Erasmus Rotterdam is not a Centre of Expertise for PRS; this is an objective fact. Nevertheless ERN-Cranio’s Coordinator at Erasmus Rotterdam appointed Erasmus Rotterdam as the lead healthcare provider in this PRS CPG development project. At Stichting Pierre Robin Europe we have a legal duty to represent the interests of PRS babies, and we are gravely concerned about this state of affairs.

—–

1.2. – INCLUDED in the GDG: Utrecht UMC
As noted above, the PRS patient volume at Erasmus Rotterdam is very low. However in terms of population, the city of Rotterdam, which has approximately 650,000 people, is almost twice the size of the city of Utrecht, which has approximately 350,000 people. Once again for the purpose of developing highly specialised expertise in the treatment of any complex rare disease, especially a complex rare disease as heterogenous as PRS – at least half of PRS babies also suffer from an associated condition – patient volume is critical. If Erasmus Rotterdam’s PRS patient volume is already very low, with Rotterdam’s population of 650,000, then what can we expect of Utrecht UMC’s PRS patient volume, with Utrecht’s population of 350,000?

Even more importantly: what happened to Amsterdam? Rotterdam and Utrecht are two relatively small cities in the Netherlands, which is a relatively small EU Member State; Amsterdam’s population is by far the highest of any city in the Netherlands, and is substantially higher than the population of Rotterdam and Utrecht combined. Amsterdam UMC likely has higher PRS patient volumes than any other hospital in the Netherlands. Amsterdam UMC is indeed an Orphanet Centre of Expertise for PRS. Furthermore at Amsterdam UMC we find the most internationally recognized PRS expert in the Netherlands, Dr. Corstiaan Breugem. However, ERN-Cranio has kept Dr. Breugem and Amsterdam UMC completely out of this PRS CPG project. We will return to this subject of Amsterdam UMC shortly, after discussing the third leading healthcare provider in the GDG, the Great Ormond Street Hospital in London.

—–

1.3. – INCLUDED in the GDG: Great Ormond Street Hospital in London
The Great Ormond Street Hospital in London (GOSH London) is not a member of ERN-Cranio. Nevertheless GOSH London is in the GDG, and indeed they are playing a leading role in the development of these CPGs. On this subject, the following points must be considered.

GOSH London is not a member of ERN-Cranio. However, in order to be a member of a CPG project’s GDG, GOSH London does not have to be a member of ERN-Cranio. The EU’s Methodology makes it clear that the healthcare providers in the GDG can be healthcare providers which are in the ERN, as well as healthcare providers which are not in the ERN. As the Methodology explains, the GDG has four key constituents, one of which is healthcare professionals; these can be

“members of the corresponding European Reference Network (ERN) and, depending on the disease, any other professional, usually involved in the care of the patient with the rare condition”.

The Methodology does not require membership in an ERN to be a member of the ERN’s GDG for a CPG development project.

The goal is to produce the best possible CPGs. To produce the best possible CPGs, the ERNs must draw upon the most highly qualified rare disease Centres of Expertise in Europe. It is therefore fortunate that the Methodology does not require ERN membership as a condition for being a member of a CPG project’s GDG; it would bring no benefit to rare disease patients to exclude highly qualified rare disease Centres of Expertise, simply because they are not members of the ERN. Furthermore it is an unfortunate fact that not all of the ERN system’s members are Europe’s most highly qualified rare disease experts. As part of the 2017 launch of the ERN system, 953 healthcare providers across all of Europe applied to become members of the various ERNs. Of the 953 healthcare providers which applied to become members of the ERN system, 952 were accepted, an admission rate of 99.895%. When 953 healthcare providers declare themselves to be highly specialised rare disease experts, and only one single healthcare provider is rejected, with an admission rate of 99.895%, then we do not have a quality control procedure, we have a self-accreditation procedure.

In the EU’s ECA Special Report 7/2019, “EU actions for cross-border healthcare”, the EU’s European Court of Auditors (ECA) confirmed this. The ECA carefully studied the assessment procedure which was used when deciding which healthcare providers would become members of the ERN system. Based on their detailed analysis, the ECA came to the following conclusion: “The final outcome of the assessment process was that 952 Healthcare Providers out of the 953 that applied were accepted into the ERNs. We conclude in practice that this assessment process added limited value to the establishment of the ERNs.” For those outside of Europe, such ineptitude may draw a cynical smile. For us rare disease patients it was a catastrophe. We know how critical it is to have only the most highly qualified rare disease experts on board. We also know that it is significantly easier to permit underqualified healthcare providers to become members, than it is to slowly and painstakingly draw them out. In any case the Methodology permits GOSH London be a member of the GDG, even though GOSH London is not a member of ERN-Cranio. The only caveat here is that GOSH London is not in the EU, and this CPG project is an EU-funded project.

—–

1.4. – EXCLUDED from the GDG: Amsterdam UMC
Dr. Corstiaan Breugem of Amsterdam UMC is one of the leading Pierre Robin Sequence experts in the world (Prof. Dr. Corstiaan Breugem, Head of Pediatric Plastic Surgery at Amsterdam UMC, Emma Children’s Hospital; President of the Dutch Cleft Palate Craniofacial Association; Vice-President of the European Cleft Palate Craniofacial Association; c.c.breugem@amsterdamumc.nl). Based on his strong interest in Pierre Robin Sequence (PRS), which dates back many years, Dr. Breugem organized the world’s first International Consensus Meeting on Pierre Robin Sequence:
http://www.robinsequence.nl/sites/robinsequence/downloads/FinalProgram.pdf

The international PRS consensus movement which Dr. Breugem created and which he continues to develop represents only one aspect of the immense amount of work which Dr. Breugem has carried out on behalf of PRS babies. The volume of PRS studies which Dr. Breugem has authored/co-authored sets him apart from virtually any PRS expert not only in Europe but in the world. A PubMed search indicates that Dr. Breugem has authored/co-authored 27 papers on Robin Sequence. 27 papers is a remarkable body of research considering the fact that PRS is a rare disease; Stichting Pierre Robin Europe knows of no PRS expert who has published more:
https://bit.ly/breugem-prs

The EU Methodology states that when drafting CPGs, ERNs should be “using limited resources more efficiently by building on existing efforts”. In spite of Dr. Breugem’s existing efforts, which are basically incomparable, and influential, and long term, and in spite of Dr. Breugem’s unquestionably profound knowledge of this complex rare disease, ERN-Cranio has excluded Dr. Breugem from this PRS CPG development project’s GDG.

To avoid any misunderstanding, we are not saying that Dr. Breugem and Amsterdam UMC, his Orphanet PRS Centre of Expertise, are not one of the three leading healthcare providers in the GDG (those are Erasmus Rotterdam, Utrecht UMC, and GOSH London). We are saying that Dr. Breugem and Amsterdam UMC are not members of the GDG at all. They are completely excluded, out altogether.

There is no possible justification for excluding this world class PRS expert, Dr. Corstiaan Breugem of Amsterdam UMC, from the GDG to develop CPGs for this complex rare disease. His absence is shocking. Dr. Breugem is one of Europe’s leading authorities on PRS; certainly no Dutch PRS expert has contributed more, or published as many studies, or tried harder, to move things forward for this highly vulnerable rare disease population. Apparently ERN-Cranio’s Coordinator at Erasmus Rotterdam – which is not a PRS Centre of Expertise – considers it natural to recruit into this EU-funded PRS CPG project a hospital which is not even in the EU – GOSH London – while at the same time excluding a world-renowned PRS expert and Orphanet PRS Centre of Expertise located just 80 kilometres away, in Amsterdam. How? Why? What good can possibly come of this? Once again, Stichting Pierre Robin Europe has a legal duty to represent the interests of PRS babies; we are gravely concerned. We find this situation incomprehensible.

—–

1.5. – EXCLUDED from the GDG: Tübingen University Hospital
Dr. Christian Poets is another internationally recognized PRS expert (Prof. Dr. Christian F. Poets, Department Head at the Tübingen University Hospital, Department of Neonatology; christian-f.poets@med.uni-tuebingen.de). Dr. Poets is with the Tübingen University Hospital in Germany, an Orphanet PRS Centre of Expertise. Dr. Poets manages the team which administers the highly specialised, medically proven, safe, non-surgical, cost-effective Tübingen Palatal Plate treatment. The Tübingen Palatal Plate was specifically developed to treat babies with this rare disease, PRS. Using the Tübingen Palatal Plate, the Tübingen University Hospital has successfully treated PRS babies from throughout Europe, Russia, even the United States of America. These babies were transported by ambulance and even flown in, from other countries, to Tübingen Germany, for the express purpose of receiving the highly specialised, medically proven, safe, non-surgical, and cost-effective PRS treatment, the Tübingen Palatal Plate.

Based on its medically proven ability to safely resolve the PRS baby’s life threatening breathing difficulties – without surgery – Stanford University has already adopted the Tübingen Palatal Plate treatment. Dr. Poets and his highly specialised multidisciplinary team of PRS experts in Tübingen provided Stanford with careful guidance, instruction and support.

Dr. Poets and his colleagues at the Tübingen University Hospital are now training experts at Harvard University how to offer the Tübingen Palatal Plate treatment to PRS babies at Harvard/Boston Children’s Hospital. The Tübingen Palatal Plate, which safely and effectively resolves the Pierre Robin Sequence baby’s breathing difficulties, without the need for painful surgery, represents a breakthrough in PRS care. It is having a considerable impact on international clinical practice by inspiring PRS experts everywhere, including PRS experts at the top research hospitals in the United States of America – Stanford and Harvard – to rethink longstanding PRS treatment practices.

In internationally peer-reviewed PRS research, Dr. Poets and the Tübingen University Hospital have played a leading role. Once again, the volume of papers authored/co-authored by Dr. Poets sets him apart from the overwhelming majority of international PRS experts. A PubMed search indicates that Dr. Poets has authored/co-authored no less than 19 papers on Robin Sequence, once again a remarkable body of research when one considers that PRS is a rare disease:
https://bit.ly/poets-prs

Furthermore the studies authored by Dr. Poets and his colleagues at the Tübingen University Hospital are evidence-based; they rely upon polysomnography to measure PRS upper airway obstruction both pre-treatment and post-treatment. Virtually everyone agrees on the importance of practicing evidence-based medicine, using objective criteria, and virtually everyone agrees that polysomnography is the gold standard for measuring the severity of upper airway obstruction in PRS babies. Nevertheless a substantial percentage of PRS studies simply ignore polysomnography altogether. Dr. Poets and his multidisciplinary team of highly specialised PRS experts at the Tübingen University Hospital, by consistently focusing on objective criteria, have raised the bar for evidence-based PRS research.

From the very beginning of the international PRS consensus movement launched by Dr. Breugem, Dr. Poets has played a leading role. The world’s Third International Consensus Meeting on Pierre Robin Sequence is being organized by Dr. Poets. It will take place in Tübingen Germany in 2022. It was supposed to take place in 2020, but it was delayed due to COVID-19:
https://robin-sequence.de/

Elsevier’s “Seminars in Fetal-Neonatal Medicine” decided to dedicate a full issue of their respected medical journal to PRS. Based on the Tübingen University Hospital’s world-renowned reputation for PRS treatment and research, Elsevier chose the Tübingen University Hospital to serve as guest editor for this upcoming PRS edition.

Thus: the Tübingen University Hospital, an Orphanet PRS Centre of Expertise, has high PRS patient volume; they routinely receive and successfully treat PRS babies from both inside and outside of Germany; they have produced an exceptionally high volume of high quality PRS research; they have played a fundamental and leading role in the international PRS consensus movement; they were selected to host the world’s Third International Consensus Meeting on Pierre Robin Sequence; they have shared their highly specialised breakthrough PRS treatment with Stanford and they are currently sharing it with Harvard; Elsevier publishing company chose them to serve as editors of the upcoming “Seminars in Fetal-Neonatal Medicine” edition which will be devoted to PRS… and yet ERN-Cranio decided that Dr. Poets / the Tübingen University Hospital must not be a member of the GDG.

To be clear, we are not saying that Dr. Poets and the Tübingen University Hospital are not one of the three leading healthcare providers in the GDG (Erasmus Rotterdam, Utrecht UMC, and GOSH London). We are saying that Dr. Poets and the Tübingen University Hospital are not in the GDG at all. They are absolutely out, just as Dr. Breugem and Amsterdam UMC are absolutely out.

When it comes to the pooling of the EU’s rare disease knowledge and expertise, the Atlantic Ocean separating Europe from the United States of America may prove itself to be more transversable than the internal borders separating different EU Member States. According to the 2011 Cross-border Healthcare Directive, the EU’s European Reference Networks for rare diseases are supposed to “help realise the potential of European cooperation regarding highly specialised healthcare for patients and for healthcare systems by exploiting innovations in medical science and health technologies.” By excluding the Tübingen University Hospital from the GDG, Erasmus Rotterdam, an official recipient of EU funds, may be violating the 2011 Directive, and turning the spirit of the ERN system on its head.

—–

2. – Patients excluded from Guideline Development Group

The EU’s Aragon Health Sciences Methodological Handbooks & Toolkit for Clinical Practice Guidelines (the Methodology) states that patients should be included in the Guideline Development Group (GDG) which creates CPGs. The Methodology states that the GDG has four key constituents, the second of which is patients:

“Composition of the Guideline Development Group.
The guideline development group (GDG) must be multidisciplinary, with representation of the expertise and views relevant to the particular needs of the guideline. Although it is likely that one professional group may dominate, comprehensive stakeholder involvement is as important to the development of guidelines for rare diseases as it is for common diseases… The GDG has four key constituents:

1) Healthcare professionals…
2) Patients…”
…

The EU Methodology lists “Patients” as the second most important constituent in the GDG. The AGREE II instrument, one of the world’s most widely employed and internationally validated grading systems for assessing the methodological quality of CPGs, also states that patients should be in the GDG, which AGREE II refers to as the “working group”.

In correspondence with ERN-Cranio’s Coordinator, Dr. Irene Mathijssen, Dr. Mathijssen confirmed that ERN-Cranio is bound to respect the Methodology. Dr. Mathijssen wrote that:

“As a rule, an ERN guideline is developed according to the official and mandatory scientific methodology supervised by a professional organisation.”

ERN-Cranio has permitted no patients, and no patient groups, in the GDG. This violates both the Methodology, and the AGREE II instrument.

The Methodology requires that patients be in the GDG; it is not enough for healthcare providers in the GDG to speak with patients, or reach out to patients. Patients must be in the GDG, they are one of the four key constituent members of the GDG. We, Stichting Pierre Robin Europe, and the other ePAG patient organization which ERN-Cranio committed to include in this work, have both been excluded from the GDG.

We estimate that this PRS CPG project began in late 2020. We cannot be certain. We have never been CC’d on any email sent out to the GDG’s members concerning this CPG development project. We have never been invited to any telephone conference call or video conference. We have not received a copy of the GDG’s agenda, or work schedule. We are not included in the GDG’s email recipient list.

We were not told about the initial meetings of the GDG. We do not know when the initial meetings took place – sometime last year, we guess. The Methodology emphasizes how important these first GDG meetings are:

“The first meeting of the GDG is very important because the operating rules are set up and the roles and functions of each member are defined. The first meeting can also generate the conditions for developing a good group dynamic… The second meeting can focus on agreeing the clinical questions, based on the scope.”

We were excluded from all of these initial meetings. And we never received any documents or minutes from these meetings. Also from the Methodology:

“Particular attention should be paid to the needs of the patients with rare diseases of the GDG when scheduling and organising meetings, as they may have ongoing health conditions that will impact their ability to engage.”

There was need for the GDG’s members to consider our schedules, because ERN-Cranio excluded us from the GDG altogether.

According to the Methodology, the GDG uses the initial meetings to discuss the clinical questions which the CPGs will address. What are the clinical questions which these CPGs will address? ERN-Cranio excluded us from the GDG, so we do not know. However according to the Methodology, we the patients should have been involved in this very important process, of defining the clinical questions:

“During the first meeting(s) of the GDG, the content experts (clinical experts, policy makers, etc.) and the patients and carers inform the development of the detailed clinical questions and may contribute additional questions. The list of clinical questions must be agreed by all GDG members.”

In the discussion and development of the clinical questions, we, Stichting Pierre Robin Europe, ERN-Cranio’s official ePAG patient organization for PRS, were supposed to share perspectives on patient outcomes: symptoms, adverse events, burdens, demands on caregivers, restrictions on lifestyle, quality of life… this did not happen.

The Methodology states that our agreement on the final list of clinical questions was required; “The list of clinical questions must be agreed by all GDG members.” Never mind the fact that we never agreed on the final list of the CPG’s clinical questions – we still do not even know what the clinical questions are.

In rating the importance of outcomes, our involvement as a patient organization was again necessary, as explained by the Methodology:

“Before starting an evidence review to answer a clinical question, the GDG should apply an initial rating to the importance of outcomes, according to GRADE methodology, in order to identify which outcomes of interest are both critical to decision-making and important to patients.”

All of these activities above were discussed by the GDG’s members, planned, carried out, and completed, without us, the patients. The patient’s experience, concerns, knowledge, values, preferences, goals, fears – everything the patient knows, wants, thinks, and feels – the patient perspective itself – was excluded.

In a recent paper which ERN-Cranio’s Coordinator Dr. Irene Mathijssen co-authored, “European Reference Networks: challenges and opportunities”, one of the sections is titled “Patient-centeredness in ERNs”. It opens with:

“Increasing patient-centeredness is a general trend in healthcare, but in RD area, it is of special importance…”

Everybody already knows that patient-centeredness is important, and this is why it is built into the EU Methodology which the EU paid Aragon Health Sciences Institute to develop, for the EU’s ERN system, for the express purpose of creating ERN Clinical Practice Guidelines for rare diseases. The ERN Methodology explicitly requires that patients be members of the GDG, and that they be directly involved in the creation of an ERN’s CPGs from the very beginning of the CPG development process. ERN-Cranio has been running this CPG project now for three months, six months, nine months, we do not know how long; one of the physicians involved in this project indicates on his LinkedIn profile that he has been working on these ERN guidelines for PRS since September 2020, which was 10 months ago. Whenever it began, we have been excluded completely, in violation of the EU Methodology.

—–

3. – Efforts to address this situation amicably have failed

Our correspondence with ERN-Cranio demonstrates that we have tried to address these issues amicably, first by communicating directly with ERN-Cranio’s Coordinator, and then by asking outside parties to intervene. These efforts have failed; we will provide further details below.

Stichting Pierre Robin Europe has been an ePAG patient organization in ERN-Cranio since 2018. We received repeated assurances over the years that the CPG project would soon begin, and that we would be actively involved. In April 2021 Stichting Pierre Robin Europe received the following message from ERN-Cranio Project Manager Renée de Ruiter:

From: R. de Ruiter, r.deruiter.1@erasmusmc.nl
Date: Wed, Apr 21, 2021 at 2:32 PM
Subject: update ERN CRANIO guideline Robin Sequence
To: pakter@pierrerobineurope.com
Cc: O.K.C. Spivack, o.spivack@erasmusmc.nl

Dear Philippe,

I would like to inform you that ERN CRANIO has started the development of a European Guideline on Robin sequence. The project is led by Erasmus MC as ERN CRANIO coordinating centre and involves all ERN CRANIO expert centres for RS. As part of this process we will contact patients/families via the ERN CRANIO centres involved to identify bottlenecks in organization of care for patients with Robin sequence.

Best regards,

Renée de Ruiter
Project manager ERN CRANIO, Erasmus MC Rotterdam

The other ePAG patient organisation which ERN-Cranio promised on multiple occasions to include in this PRS CPG development project did not receive the above message at all; we had to forward the message to them.

The next day we sent a detailed message directly to ERN-Cranio’s Coordinator, expressing our concerns. That detailed message can be read in its entirety over here.

We found it disappointing that the patient’s role in this CPG development process was limited to providing feedback on one narrow and specific question: “bottlenecks” in care. As we explained to Dr. Mathijssen, “the email indicates that you plan to contact patients/families via the ERN-Cranio centres to identify bottlenecks in care. Bottlenecks in care – is this the limit of patient involvement in the development of these Guidelines, which are so critical for us, the patients? We are limited to commenting on bottlenecks, without being permitted to contribute anything meaningful or participate in any way to a discussion of THE CARE ITSELF? Have you no interest in Pierre Robin Sequence parental concerns, treatment preferences, goals, fears, patient perspectives on burden of care, quality of life, nothing of this sort, just bottlenecks?”

One week later we received a response from ERN-Cranio’s Coordinator, Dr. Irene Mathijssen:

From: I.M.J. Mathijssen <i.mathijssen@erasmusmc.nl>
Date: Thu, Apr 29, 2021 at 9:38 PM
Subject: RE: update ERN CRANIO guideline Robin Sequence
To: Philippe Pakter <pakter@pierrerobineurope.com>
Cc: R. de Ruiter <r.deruiter.1@erasmusmc.nl>, O.K.C. Spivack <o.spivack@erasmusmc.nl>, Anne-Laure Aslanian <anne-laure.aslanian@eurordis.org>, Neil Russell <russell@pierrerobineurope.com>

Dear Philippe,

For some time, the members of ERN CRANIO indicated an interest in developing a guideline on Robin sequence. It took a long time before it became clear that the EC guideline tender did not include finances to develop a guideline, but was mainly directed at training care providers in guideline development. To overcome this hurdle, we have obtained permission from the EC to reserve a part of the management-budget of ERN CRANIO to develop the Robin guideline.

As a rule, an ERN guideline is developed according to the official and mandatory scientific methodology supervised by a professional organisation. The same procedure was followed for the ERN guideline on craniofacial microsomia. As part of this procedure, patient input is requested via all participating ERN Centres with expertise in treating Robin sequence. This offers us a view on the bottlenecks that parents and patients encounter in the care per country. This is important given the different organisation of care for these patients per country. At present, we have collected nearly 100 responses.

Next to this, a systematic review of the literature is undertaken by the three leading Centres of London, Utrecht and Rotterdam. This will result in a draft version of the guideline that is open for comments to all ERN CRANIO members, including yourself.

Regards,

Irene Mathijssen, Aebele Mink van der Molen, Neil Bulstrode, Eppo Wolvius

Based on Dr. Mathijssen’s response, we now knew that the three healthcare providers which would be leading this PRS CPG project would be Erasmus Rotterdam, Utrecht UMC, and GOSH London. We did not know what other healthcare providers were involved. We still had no idea when the project began, and we could not understand why we were only finding out about it now. What was clear from this message was that this PRS CPG project was well underway. ERN-Cranio had excluded us from all of the work which the members of the GDG had already completed to determine the scope, develop the clinical questions, discuss patient outcomes, discuss the importance of these outcomes, discuss the work plan, and begin the research.

In the message above, ERN-Cranio’s Coordinator told us that we would be permitted to comment on the draft of the CPGs, once the draft had been written. When a draft document has been discussed, outlined, researched, and written, it achieves a momentum which makes it naturally resistant to change. Furthermore, permitting someone to provide feedback on a written draft is not the same thing as inviting that party in at the beginning of the process, so that they can actively and meaningfully contribute before the draft is written. In this context, active and meaningful participation means membership in the GDG – that is, the GDG whose members discuss the scope, develop the clinical questions, agree on the clinical questions, discuss patient outcomes, discuss the importance of those outcomes, discuss the work plan, go through all of these and other critical steps. ERN-Cranio excluded us from all of this.

At this point we reached out to the European Organisation for Rare Diseases (EURORDIS), to request mediation. After receiving our request for mediation, Ms. Inés Hernando, the EURORDIS ERN and Healthcare Director, contacted ERN-Cranio’s Coordinator. Shortly thereafter, Ms. Hernando provided us with the following report:

“I had a call earlier this week with Irene to share with her your request. She mentioned that she had replied to your email explaining that the ERN will follow a validated methodology for the development of the CPG.”

ERN-Cranio told Ms. Hernando of EURORDIS essentially the same thing that ERN-Cranio had already told us: ERN-Cranio is following the Methodology.

We then decided to approach a different ERN in the EU’s ERN system. We requested a conference call with the Coordinator; this ERN Coordinator, who was intimately familiar with the Methodology, confirmed that patients are supposed to be involved as active participants in the CPG development process from the very beginning, from day one.

Stichting Pierre Robin Europe is a Dutch stichting. Being legally based in the Netherlands, Stichting Pierre Robin Europe, in addition to being a member of EURORDIS, is also a member of Vereniging Samenwerkende Ouder en Patiëntenorganisaties (VSOP), the Dutch Patient Alliance for Rare and Genetic Diseases. We reached out to VSOP’s Director, Dr. Cor Oosterwijk. We explained that the top priority was to immediately involve, in the CPG development project’s GDG, two of the EU’s most highly respected Orphanet PRS Centres of Expertise, Amsterdam UMC, and the Tübingen University Hospital. We emphasized that these two Orphanet PRS Centres of Expertise should be included in the GDG before the draft CPGs were written – not after the draft CPGs were written, but before. The second priority was for ERN-Cranio to include patients as members of the GDG, as required by the EU Methodology. VSOP’s Director, Dr. Oosterwijk, contacted ERN-Cranio. ERN-Cranio’s Coordinator informed Dr. Oosterwijk that “the current procedure will not be changed”.

—–

4. – The intervention we request

Concerning healthcare providers: PRS babies need and are entitled to the very best CPGs possible. To produce the best possible CPGs, the GDG for this guideline development project must include the most highly qualified PRS experts in the EU. ERN-Cranio at Erasmus Rotterdam has completely excluded, from the GDG, two world class PRS experts, Dr. Corstiaan Breugem of Amsterdam UMC, and Dr. Christian Poets of the Tübingen University Hospital. There is no possible justification for this; their exclusion is astonishing. It almost appears as if they are being punished for their exceptional PRS expertise. Nothing good can come from their exclusion; absolutely no benefit can be gained by keeping them out. All Erasmus Rotterdam is doing by excluding them is compromising the quality of the PRS CPGs, at the expense of PRS babies. For the sake of PRS babies – not for the sake of the professionals involved, but simply for the sake of these PRS babies – Dr. Corstiaan Breugem of Amsterdam UMC, and Dr. Christian Poets of the Tübingen University Hospital, both highly respected EU Orphanet PRS Centres of Expertise, must immediately be brought in as members of this Pierre Robin Sequence CPG project’s GDG. Whatever regrettable reason Erasmus Rotterdam may have had for excluding these two world class experts, this is beside the point. The important thing now is to immediately bring both of them into the GDG, in order to produce the best possible CPGs for this complex rare disease.

Concerning patient representation: the EU Methodology states that patients should be included in an ERN’s CPG development project’s GDG from the very beginning. Patients should be full members of the GDG, in the room, sitting at the table, alongside the other GDG constituents. Stichting Pierre Robin Europe should immediately be brought in as a member of this Pierre Robin Sequence CPG development project’s GDG. When an email is sent out to members of the GDG, we as members of the GDG should receive the message. When a conference call is organized, we should be invited to participate in the conference call. When a video conference is scheduled, we should receive a link to the video conference. When an agenda is produced, we should receive a copy of the agenda. We must immediately be brought in as members of this PRS CPG development project’s GDG. This is not complicated or obscure. If you want to involve patients in healthcare, all you have to do is invite them in – not exclude them at every possible turn.

Minister Tamara van Ark, we are not asking for the opportunity to participate in the process of external review. We are not asking for the chance to provide feedback on work which the actual members of the GDG have already carried out. We seek inclusion in the GDG, and full recognition as members of the GDG, for ourselves – Stichting Pierre Robin Europe – and Dr. Breugem, and Dr. Poets. The Methodology makes it clear that being part of the external review group, and being an actual member of the GDG, are two separate and distinct things. Members of the GDG run the project, make the decisions, and do the work; they discuss and formulate and prioritize the questions, they carry out the research, and they draft the document. Members of the external review group come in after the fact. The GDG is under no obligation whatsoever to incorporate any of the feedback which the GDG receives from external reviewers; the GDG does not even have to respond to those who are providing the feedback, regardless of how serious the concerns may be. From the Methodology: “All external reviewers’ comments will be considered by the GDG who will ultimately decide whether they are incorporated or not… It is not necessary to respond to every single comment individually.” Once again we seek full and prompt inclusion as members of this CPG development project’s GDG.

Minister Tamara van Ark, as this is a matter of ongoing urgency – the work on these CPGs is already well underway – we would welcome the opportunity to meet with you in person in Den Haag or elsewhere to discuss this complaint in person. We look forward to hearing from you. Thank you.

Kind regards,

Philippe Pakter
Stichting Pierre Robin Europe, voorzitter
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties, The Dutch Patient Alliance for Rare and Genetic Diseases
PhD candidate, law, the University of Geneva: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”