Questions received

Here, we discuss questions that have been submitted to the Project Ethics Council. Anybody can ask the Council to consider an ethical question related to trials in neuromuscular disorders, please click the 'ask a question' link to do so.

1.   Research with industry
2.   Steroids in clinical trials
3.   Decision making
4.   Protection of minors versus medical need in clinical trials
5.   How to I find out about trial regulations in my home country?
6.   Carrying patients over from one trial phase to another
7.   How do I advise a patient who wants to travel abroad for stem cell 'treatment'?
8.   Can I guarantee a place on a clinical trial for my child by paying for it?
9.   Industry’s requests to the Global Database and Database of the Centre for Clinical Trials
10. The representation of the patient voice within the governance structure of TREAT-NMD
11. Self-medication via the internet

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The following are the final responses to questions posed to the PEC.

1. Research with Industry

Q1: “I would like the ethics council to consider the relationship of the network with industry in terms of decisions to offer the tools of the network to particular companies for trials and how we might want to protect our own position and not compromise relationships with multiple companies. So for example company X comes to talk to us about a DMD trial. They want access to registries and trial centres. Company Y has a similar compound. Can we work with both companies? And if so: on what basis? How do we protect ourselves, the patients and the individual companies?”

A1: Fruitful relationships with industry should not be jeopardised by adopting either a too restrictive approach or by a failure to safeguard the genuine interests of industry partners, however there should be no exclusive preference shown to one particular company. There is a need to be open and honest with industry, noting the need for transparency without compromising commercially sensitive information.

Patient registries should be open to access by industry partners and researchers. Patient and parent groups hope that this will enable the best therapies to be developed. The Steering Committee for the registries ought to act as an intermediary to ensure ethical access to and use of data.

Industrial partners should be reassured that there is a governance system in place and the PEC suggests a statement of principles could be developed to give to partners which outlines TREAT-NMD accountability regarding the relationship it has with them. We need them to know that TREAT-NMD is addressing accountability and is transparent.

Therefore how TREAT-NMD relates to industry will be important particularly for safeguarding future relationships but this must not be at the price of weakening the interests of patients.

PEC is willing to co-operate in developing a statement of principles (in conjunction with the GB) stating, for example, that whatever commitments are made to companies will not be disclosed nor will we disclose who we have given data to. TREAT-NMD is the custodian of the data and patients consented to multiple uses of the data (i.e. industry are not given sole use of data). The aim is to allow industry to make maximal beneficial use of data without compromising the rights and interests of the patients. A necessary degree of confidentiality will be required to protect commercial interests but this does not preclude dealing with industrial partners in an open, honest and transparent way.

The broad principles identified by the PEC

1. Consent – support for the importance of high quality information and the principles of consent
2. Open access, transparency with companies (possibly in dialogue with industry partners as to what is reasonable)
3. Independent advice / scrutiny – available to patients
4. Confidentiality - respecting the interests of industry on matters of commercial sensitivity
5. Any arrangements/ partnerships with industry should be least restrictive of individual rights (of patient participants). There was further discussion on this and related issue both here and at the 3rd PEC meeting – see the minutes for detail.

2. Steroids in Clinical Trials

Q2: “Steroids are now accepted as standard treatment (although there are some small pockets of resistance) but steroids are also recognised as a confounding factor in assessing efficacy of new molecules. Is it therefore ethical to have trials where the boys are not on steroids?

There are a number of possible scenarios:

* Withdrawal of steroids on entry to the trial
* Utilise steroid naïve populations only
* Withdraw from the trial if steroids were indicated."

A2: There was wide discussion of this question at the 2nd and 3rd PEC meeting which is not detailed in the following conclusions:

1. Since steroid use has become an international standard therapy it would be wrong to withdraw a beneficial treatment for research purposes.
2. However not all patients have been exposed to steroids and therefore this information ought to be collated on the patient registries in the hope that a naïve population could be identified (although this raises the dilemma of why patients haven’t been offered a standard treatment).
3. Generally it was considered beyond the scope of the PEC to advise on trial design.

3. Decision-Making

Q3: “One matter the PEC might want to discuss is through what mechanisms we can ensure that the treatment trials being organised through TREAT-NMD will all be scientifically sound and promising, and safe, and that not too many at a time are offered the same patients. I know we have toxicology people and all that, but I would just like to have it clarified where the decisions will be taken, based on what, in what order, and by whom. Is it, for example, ok for industrial representatives to be among the decision-makers?”

A3: The PEC decided that the 1st set of concerns were outside the remit of the PEC as there is a responsibility for chief investigators to ensure that there is peer review and ethical approval for research. The 2nd concern is dealt with in our statement of principles (see response to question 1) and it is agreed that it is not appropriate for industrial representatives to be part of the decision making process due to conflict of interest.

4. Protection of Minors versus Medical Needs in Clinical Trials

Q4: "[…] My problem is that the 'Human Ethics Committee' limits the participation of Duchenne Muscular Dystrophy patients in clinical trials of myoblast transplantation to those of 18 years and older. This decision is based on a Quebec law limiting the participation of minors in clinical trials. Their point of view is that if there are DMD patients of the age of 18 and above, the trials should include those. The problem is that there are not many adult DMD patients. Also, they tend to be severely handicapped at that age, and it is difficult to recruit patients that can still move one or both wrists. Furthermore, the myoblast transplantation has less chance to produce a significant increase of strength because muscle fibers of adult DMD patients are largely replaced by fat and connective tissue, and thus the myoblasts have less chance to fuse with existing muscle fibers. What we have here is a Catch 22: If I cannot demonstrate significant gain of strength in these older DMD patients, the ethics committee will not allow me to do a clinical trial with younger patients.

The ethics committee does not allow the participation of young patient because the allogeneic transplantation of myoblasts requires immunosuppression with tacrolimus for 6 months in the case of a clinical trial. This immunosuppression is required although myoblasts are transplanted in only one muscle and may thus increase the strength of only that muscle. However, I think that if strength increase is observed in that muscle the immunosuppression should be maintained and myoblasts should be transplanted in other muscles. Again, I think that I have to proof first that I can increase the strength of one muscle before transplanting myoblasts in several muscles. The problem is that the immunosuppression with tacrolimus increases the risk of cancer, nephrotoxicity, mneurotoxicity etc. The alternative to immunosuppression is to transplant patients' own genetically modified myoblasts. This can be done only in very young patients as myoblasts do not proliferate from the age of 5. Thus, it is almost impossible to conduct this clinical trial and to develop a treatment with the present ethical restriction!"

A4: Many thanks for the detail of this difficult dilemma. Of course I am not familiar with the specific Quebec law - is there an English version I can access? What would be useful to consider is whether there is scope for interpetation of the law according to particular circumstances (for example is there a body, such as an ethics committee/board, empowered to make such an interpretation?). In my experience, laws are not always specific in detail - the point is it would be useful to know just how prescriptive the law is in order to consider how a particular argument might be developed. I am very familiar with the UK research ethics context and here I think it would be possible to develop an argument that the research could only be done using a certain group of children and that the research would not be against their interests BUT the associated risks must be low - which may not be the case for the research you describe. I will consult a lawyer colleague who has a specialist interest in children and health and seek her opinion also.

5. Trial Regulations in Different Countries

Q5: "I am working as a researcher on a trial which involves a number of countries in the European Community. How can I find out more information about the different regulations?"

A5: Check the TREAT-NMD Regulatory Affairs Database here.

6. Carrying Patients Over from One Trial Phase to Another

Q6: "Is it ethical to carry patients over from one clinical trial phase to another or should a new cohort of patients be recruited for each phase? This may be a problem for studies which have a limited number of patients available. Is there a benefit to studying the same cohort of patients in different phases, eg: to compare results? Timelines may be longer than expected at the start of the trial resulting in the boys being 'too old' when the Phase III trial comes around. There are cost implications - using the same patients reduces the overall cost."

A6: Discussants agreed that there was no general ethical answer to the question whether to carry patients over from one phase to the next. An adequate response to this question would always be to a large extent ‘question specific’, ‘disease specific’, ‘intervention specific’, and (always) "protocol specific". The particular features of the case will tell whether a patient would have an increased risk or any other additional burden from being kept in the cohort for a next-phase study. In addition if it was feasible and safe there ought to be the provision of appropriate information together with a new informed consent for subjects, with an emphasis on the right to withdraw from the study.

Risk of harm: scientific and clinical considerations: Some research approaches would rule out using the same cohort for different trials. For example some gene therapy approaches because the subjects would already have been exposed to the vector with the risk of provoking an immune response.

Ethical considerations: This is an important question particularly in the context of rare diseases where there may be a limited research population from which to draw a sample. One of the ethical concerns for restricted populations is that of "over research" - although this is a rather vague concept one can unpack this in terms of additional risk, vulnerability and potential exploitation. There is a real danger of creating a "Catch 22" where a population qualifies for inclusion in research by virtue of having a rare disease but is at the same time disqualified from research on the grounds of (the risk of) "over research". There may also be a further case on what might be called social or moral grounds that whilst it may not be scientifically necessary to use the same cohort it is fair and respectful (e.g. of autonomy) to do so only where there is little or no risk. For example in the Prosensa trial the boys participating in the first phase which was an IM trial only had the burden while for the next groups (systemic) there was the potential for benefit.

Patient perspective: Many patients agree to participate in a clinical trial because they expect to receive an active medicine. Although this does not fit with the ethical basis of clinical trials it is a common position amongst patient subjects. This also suggests an argument from justice to include the same cohort throughout the various phases of the trial as they will then be more likely to receive an efficacious therapy. If it is not possible to do this for scientific or for clinical reasons then this fact must be emphasised as part of the informing process. The designers of clinical trials should be encouraged to consider the possible compassionate use of a trial drug for those patients who took part in the early phases. The Committee of Medical Journal Editors stated that the reason patients participate in clinical trials was purely ‘altruism’: i.e., to help future patients – not to help themselves. Surveys have indicated that patients join clinical trials largely because they are advised to by their doctors.

Suggested further action: It would be useful to suggest some ethical guidelines on establishing and using patient cohorts for clinical trials (in rare paediatric diseases). It would be useful to engage with the regulators such as EMEA and FDA as well as scientists, industry, and ethical experts to explore this important question. Do more work to provide appropriate advice about clinical trials which may contribute to creating good understanding and reasonable expectations regarding clinical trials. One approach would be to clarify the reasoning behind how patient cohorts are used in clinical trials. Further work on the therapeutic misunderstanding is also needed.

7. Unproven stem cell therapy

Q7: "A week or two ago one of my muscular dystrophy patients came to see me and urged me to contact a centre in China. He was quite excited because he was told that this centre offered a treatment for muscular dystrophy by injecting stem cells. He wanted to have my opinion before deciding to go over there."

"The treatment (6 stem cell perfusions over 25 days) costs 26,300 US dollars, excluding travel costs and food. Maybe you are aware of this practice. I had vaguely heard about it but this took my breath away. I don't know whether you are aware of this broad scale charlatanism operating in and from China. How do I advise my patient?"

A7: This is a highly topical and complex issue and one that raises questions about patient autonomy, paternalism, global governance, hope and hype regarding new biotechnologies. The following is a summary of the discussion and recommendations from the PEC.

There is no question that patients, or the parents of young patients are potential consumers within a globalised market. It is possible to buy “treatments” and “therapies” across borders and with disregard for national regulation and quality control. However caveat emptor (buyer beware), the ethics of the market place can not be the ethics of the clinic, since people as patients have specific vulnerabilities. When parents/patients buy products that are available direct-to-the-consumer, or travel directly to centres advertising “therapies” then they often act as if they are consumers and bypass the safeguard of consulting their usual clinician. This places them in a vulnerable position because the provider of “goods and services” does not have a fiduciary duty to protect the interests and welfare of the patient in the same way that their clinician does.

If things go wrong it would be extremely difficult to claim any legally enforceable duty of care against these providers. The universal duty of the clinician is to first do no harm, and to intend good but this moral order does not seem to apply to these questionable clinics. This is not to say that an informed parent/patient cannot make choices and decisions that are safe, appropriate and potentially beneficial. Rather there needs to be a balance between clinical paternalism and “consumer” autonomy.

A key basis of autonomy is knowledge: It is a necessary condition of an autonomous choice that parents/patients are able to judge the current state of knowledge. The potential for stem cell therapies is much hyped, apart from the use of haematopoietic stem cells in the cancer field, embryonic stem cell treatment has not yet been sufficiently scientifically tested anywhere in the world. Somatic stem cell therapy in the context of neuro-muscular disease is also at a very early stage of development.

Despite this some parents are using “stem cell treatment” for their children with neuro-muscular diseases , thinking that "it might work". The problem is that whilst some individuals may report some benefit, none of these clinics show scientifically validated measurement of improvement. In addition, no one has informed the patient of the potential negative effects of stem cell injections: probably all cells are quickly killed by the patient's immune system as no immune-suppressive agents are used. If immune-suppressive drugs are used, there is a risk that the stem cells will cause cancer as has been shown in immune-compromised mice. While patients/parents might be willing to take this risk, they should at least be informed about potential risks before the intervention is started.

Using an intervention where the risks are unknown or not made known, and without the evidence for benefit makes it impossible to make an informed choice. This is not informed consent but rather blind faith.

Where a parent makes such a decision for a child then the process is even more complicated. Of course parents will have the best interests of their child in mind but they will be unable to judge the child’s best interests if they do not have adequate information about the risks and benefits. It goes almost without saying that where parents are reckless in the choices they make then society has a duty to protect the interests of the vulnerable child. The concern for TREAT-NMD is not that parents are reckless but rather they are prey to mis-information from organisations that put commercial interest above those of patient safety and benefit. Therefore TREAT-NMD ought to aim to provide clear, accurate and up-to-date information on the status of novel therapies for neuro-muscular diseases.

Risk: Although risk is unavoidable when developing innovative therapies it is normally managed through carefully designed studies that aim to minimise risk, and the numbers exposed to such risk. It becomes impossible to evaluate risk when innovative therapies are given outside of such controlled circumstances and in the absence of a written protocol.

Patients should ask if the centre offering treatment is doing so through a carefully designed clinical trial, or by offering fully regulated and licensed therapies based on previous research. One of the tests of the credibility of a centre is the availability of research evidence supporting the treatment or trial published in peer reviewed journals.

Therefore another key indicator for the globalised patient consumer is to assess whether the intervention has, or is being, evaluated in a clinical trial. Making such a judgement requires specialised knowledge and good access to academic literature. This would be a very demanding task for most parents/patients and therefore imposes another restriction upon consumer autonomy.

Regulation: Another safeguard for the “consumer” is the reassurance that the intervention being offered is open to regulatory control. In many countries clinical trials are strictly regulated and monitored medicinal products must be rigorously tested and approved before they can be sold. These systems of regulation and oversight are a very strong safeguard for the patient and include adherence to internationally agreed ethical standards such as the Declaration of Helsinki, CIOMS/WHO Guidelines as well as compliance with national laws or regulations. Whilst countries such as China are taking the need for regulation very seriously it is fair to say that many countries have not yet achieved the standards that operate in Europe and thus pose an additional risk for the foreign consumer.

The Chinese authorities have issued guidelines to prevent bad clinical practice. Some information given at the BIONET media conference in London last autumn is very encouraging. The full version can be found here.

Conclusions: The TREAT-NMD Ethics Council would offer the following conclusions.

* Parents and patients should discuss any possible new treatment they are considering purchasing with their own doctor.
* They should seek the highest standard of evidence from centres offering “miracle cures” including a full explanation of risks and side-effects.
* They should be cautious of any claims to use new therapies such as “stem cells” and ask for evidence of the research underpinning such claims and not to take newspaper articles or patient testimony as evidence.
* TREAT-NMD should encourage legitimate partnerships with centres developing new therapies in order to share high standards and good practices in research and treatment.

TREAT-NMD has published further information and guidance on this issue here.

8. Can I guarantee a place on a clinical trial for my child by paying for it?

Q8: The Council has received three separate questions on the subject of paying for clinical trials. They are set out in full below but we have provided a single answer for these questions.

Q 8.1: Current plans for AON (Exon Skipping) Trials with Ambulatory boys who have Duchenne MD will not be conducted in the United States due to additional FDA requirements. The company planning these trials will instead conduct trials outside of the United States, primarily in the European Union. Is it possible for American boys/young men who have DMD and meet eligibility requirements to participate in these trials? I recently heard a European Center provided a family access to a trial after they paid a large sum of money to participate. What can families who wish to participate expect in additional costs to have their sons in a trial?

Q 8.2: I am interested in learning more about your exon skip study in Italy. I do not know the payment, but if I were able to pay, can an American child join? I heard something about this possibility. Please let me know what is the cost and who should receive the payments. I will do what I have to help my nephew to get treatment if you are opening the study for the US children. Most will do whatever is necessary to cure boys with Duchenne even if it means selling homes and moving. Thank you very much for this information.

Q 8.3: What would be the position of the Ethics Council in the case of a parent who decides to pay to ensure participation of his/her son to a clinical trial?

A8 Families who wish to pay for a place on a trial seem to have a serious misconception and unrealistic expectations about clinical trials. A trial is the therapeutic testing of a potential treatment for humans; it is not a treatment or a cure.

These questions have been asked by concerned parents/relatives and have been provoked by rumours that it is both possible, and indeed has happened, that parents have bought a place for a child on a clinical trial.

We understand that some parents will do anything to give their child a chance of a treatment or cure but we are concerned that parents may be vulnerable to misinformation and possible exploitation. The very idea of the possibility of buying a place on a clinical trial suggests a complete misunderstanding about the purposes of a trial and an unrealistic expectation about its outcome.

Trial regulations describe the drug as an ‘investigatory medicinal product’ or IMP. In addition a trial entails a certain level of risk for participants and is usually quite burdensome for participating patients and their families. So trials are not treatment; they are designed to test for toxicity and side effects and/or to demonstrate whether the drug will have the desired effect. They allow the collection of scientific data about a group, not about a single individual.

The trials that are currently ongoing are in Phase I/II or II/III, so these are both safety (I/II) and clinical (II/III) trials (see for more information). These early studies are conducted initially on a small number of patients in order to gain evidence of the risks, side-effects and possible benefits with a view to planning the dosing strategy for the next phase of study. As yet there is no conclusive evidence that exon skipping really works and is safe (which is why we need the trials to continue). While some of the trials that are at a later phase of testing are quite promising, the therapies are still in development and it is mistaken to see clinical trials as "treatments" or even "a cure". Of course it is hoped that the current trials will eventually result in an effective and safe treatment, but the trials are needed to confirm this.

It is very important that parents and patients are cautious about the claims made by some people about potential treatments. For example people claiming to be clinicians or researchers who ask for payment for treatments that are still being developed, are giving a very strong indication that the study is not research but a confidence trick and that their claims are false.

Regarding the specific rumours about the study in Italy conducted by UNIFE, the principal investigator of the study, Professor A Ferlini, who is also member of the TREAT-NMD Project Ethics Council (PEC) has sadly but firmly stated: “No-one is paying, has paid or will pay for entering a trial either spontaneous or sponsored in my institution”.

In addition, the Project Ethics Council wants to state categorically that it is unethical for any clinician or scientist to act in such a way. Such actions are also regarded as illegal in many countries:

Article 19 of European Clinical Trials Directive 2001/20/EC states:

Unless Member States have established precise conditions for exceptional circumstances, investigational medicinal products and, as the case may be, the devices used for their administration shall be made available free of charge by the sponsor.

Most EU countries will have legislation which reflects this directive. For example, The Clinical Trials Regulations of the UK state that the sponsor must provide (the investigatory medicinal product or trial drug) free of charge to subjects. The Italian legislation is regulated by the Istituto Superiore di Sanità, which has precise and detailed regulations for phase I/II trials, drug approval and patient’s rights including rules requiring that the drug under investigation must be free of charge to subjects. Similar requirements will be in place in all EU countries.

Another important reason why investigators are not allowed to take payments for trial participation is that it risks them being influenced by those who are paying. Trials should be based on robust and neutral science and there is the possibility that the scientific integrity of the trial could be weakened if the investigator was taking payment from someone involved in the trial. In addition, accepting payments would disregard the principle of equality required by the EU and the Declaration of Helsinki. Overall, anything which contributes unnecessarily to weakening the scientific design of a study is also unethical because it risks undermining the study and wasting the time and resources of the researchers and the other participants in the study.

It is important that rumours such as the one which has led to these questions are discussed openly and immediately clarified and qualified as unfounded. This should lead to greater scientific understanding and better relationships between scientists, clinicians and patients. The TREAT-NMD PEC provides a transparent and open mechanism whereby anyone can ask the Council to consider an ethical issue. All such questions and the answers are made publicly available via the TREAT-NMD website.

9. We would like to raise a concern for the PEC concerning industry’s requests to the Global Database and Database of the Centre for Clinical Trials. As Patient partners of "Industry" we would like to discuss the following issues:

We seek the PEC’s opinion on our claim that it should be a requirement that any industry partner who makes an enquiry of the patient registry ought to provide clear explanations of their decisions concerning eligibility for any planned clinical trials. Specifically an account should be given of the inclusion/exclusion criteria and the rationale for locating a trial in one place rather than another.

When we have attempted to gain this information from e.g. TROPHOS there has been no response. We would therefore like to make a strong recommendation that such information is disclosed but not go so far as to make it a condition of accessing the database.

In our opinion one of the aims of the collaboration in the database is also to provide information back to patients and therefore we do not think it unreasonable to have this information from industry.

Therefore there needs to be much clearer and comprehensive communication between those making an enquiry of the database and patient organizations about the nature of the enquiry and the recommendations of that enquiry. There needs to be an opportunity to challenge the way industry plans to roll out a clinical trial including its choice of location. We believe that patients from countries that will not be the location of a clinical trial still have the right to be included if they are willing to travel to the trial site. Country of residence should not be an acceptable exclusion criterion. TREAT-NMD should champion patients’ right to be included in a clinical trial. Although we accept that medical criteria for inclusion/exclusion are necessary they should nevertheless be explained.

Without a full explanation from industry about their trial strategy it is difficult to keep patient partners informed and it becomes difficult to justify asking people to collaborate with the registry if they believe that they are being unfairly prevented from having a chance to participate in a trial.

PEC Response:

The PEC has given the issues raised in this question considered thought. There are several aspects to the question and the PEC response is organised according to issue.

1. Communication between researchers/industry and patient organisations.
Industry and other researchers make an enquiry of the patient global registry as one of the initial stages in determining the feasibility of running a clinical trial or other study. All such requests follow an application process that is vetted and approved by the oversight committee which is itself comprised of representatives of patient organisations and national registries. The enquiry is itself part of the site selection process. The PEC broadly agrees that there should be an intention to be open and transparent at every stage of the process towards site selection but also accepts that there may be issues of commercial sensitivity which require some degree of confidentiality. The sustainability of the global registry requires that it serves a mutual benefit between patients and industry. If the conditions of access to the registry are too strict this may limit its usefulness and turn some potential partners away. It is possible to make some information publicly available about all enquiries to the global registry however the level of detail must be negotiated between the oversight committee and the person/organisation making the enquiry. In summary we are committed to transparency and open communication but if the conditions are too demanding or strict this might prove to be self-defeating for patients’ interests.

2. Should TREAT-NMD attempt to influence the selection of trial sites?
This is both an ethical and a practical question. The PEC acknowledges that there is a right that clinical trials relevant to NMDs should happen. However the PEC does not recognise that individual patients have the right to be in a clinical trial. The most important thing is that well designed clinical trials happen as quickly and as efficiently as possible. Not all patients can be in a clinical trial but all patients stand to benefit from well designed clinical trials because this either takes a promising compound one stage towards becoming commercially available or it filters out compounds that do not work or are dangerous. It must be noted that around 95% of potential drugs fail to get beyond Phase II clinical trials. A trial is not a treatment so it would be wrong to think in terms of patients’ rights to participate in a trial and to do so would be to fall into the therapeutic misconception.

Trial sites are chosen for a number of reasons and whilst it is the PEC’s view that companies should be as transparent as possible about these reasons, the picture is complex. The fact that a trial may utilise different sources of funding, and have to conform to different conditions of approval and indemnity within a certain country means it might not be possible to allow non-resident participants. For example, in the UK ethical approval and legal indemnity for trials is provided through the National Health Service and if there were sufficient participants for the trial in the UK, then recruitment would not be open to people in other countries.

3. Are their issues of equity and capacity building?
All contributors to the global patient registry should be treated fairly and equitably. The PEC recognises that there is an important benefit to patients and their families when they are able to make a personal contribution to advancing research by such activities as, providing data to the registries, managing registries and fund raising. Patients should not be unfairly prevented from participating in a clinical trial but neither is there an automatic right to participate.

There is of course scope for engaging industry partners in discussion about the potential for developing trial sites in countries that have been excluded for reasons other than numbers of eligible participants. Helping to develop the research capacity within a country may mean that such a country is likely to become a trial site in the future thus opening the opportunity for some patients to make a contribution to the research effort. However the PEC takes the view that although this is an important principle to explore with industry partners it would not be right to insist upon such actions as a condition of accessing the patient registries.

Summary of PEC opinion.

The PEC endorses the need for open and transparent communication between those accessing patient data via the registries and patient organisations. This point will be made to the Global Database Oversight Committee (TGDOC) with a view to considering the best options for taking the matter further. The PEC does not endorse the imposition of restrictive conditions which might prove to be counter-productive in for the global registry in its relations with industry and researchers.

The PEC does not agree that there is a right for patients to be involved in a clinical trial although it strongly endorses the right for clinical trials to happen in the most efficient and timely manner.

The PEC believes that in the interests of fairness and equity there should be effort to build the capacity for research to take place in every partner country. The PEC will raise this issue both with the TGDOC and with the TREAT-NMD Governing Board with a view to developing a strategy towards this end.

10. The representation of the patient voice within the governance structure of TREAT-NMD

Q10: "We (UPPMD) understand the purpose of the Ethics Council is to identify and examine ethical and social aspects in the context of TREAT- NMD. To that end, the Duchenne patient community is seeking your advice and opinion about how the patient voice should be represented within TREAT- NMD structure, to include both the governance structure as well as the Executive committee."

There was general agreement amongst PEC members that the question is important but also a complex one that touches on, amongst other things, issues of equity (fairness), the governance structure of the TREAT-NMD Alliance, and the challenge of facilitating the patient voice within that structure
There are two parts to this question:

1) The constitution (and by implication the function of) the Executive Committee of TREAT-NMD.

2) The way in which the structure of TREAT-NMD will facilitate the rights, interests and voice of the relevant patient organisation.

It was agreed amongst respondents that there must be appropriate and effective vehicles for facilitating the patient voice, but that this is not simply about the number of PO representatives. There must be both an executive committee that is fit for purpose, effective and efficient in executing its responsibilities as well as much wider mechanisms for facilitating the patient voice throughout the TREAT-NMD structure. It is impossible for the PEC to pluck an ideal solution to these questions out of thin air. However a number of valuable points have been suggested by PEC members contributing to this question.

It was acknowledged that platforms like TREAT-NMD are important as they allow POs a further reach and focus. Therefore it is critical in this phase of TREAT-NMD that it develops a structure that is synergistic with the aims and goals of POs, which must include a mechanism to collect, focused views and opinions of the broader PO membership. For example a system of surveys and feedback mechanisms will be needed as well as secondary groups to focus patient needs through the PO representatives on the TREAT-NMD board.

There was a strong consensus from respondents that there was scope for further reflection on the constitution of the Treat-NMD Alliance Executive Committee (EC) suggestions included:

  • Assuming that 25% of the (EC) is from POs perhaps 33% would be fairer (e.g. 4 POs, 4 clinicians and 4 researchers? - although perhaps fewer researchers is fairer, e.g. 4 PO, 2 researchers and 6 clinicians). There is a danger that if the EC should become too large it won't be a workable committee.
  • An equal representation from each (candidate member group) (i.e. 1/3 from each).
  • The Executive Committee should have an equal number of scientists, clinicians and patient representatives. Whether this should be 3-3-3 or 4-4-4 is for others to decide. I think that this equilibrium can be found in the TREAT-NMD Alliance charter statements.
  • EQUAL representation. 3-3-3, 4-4-4, or however it is decided. All voices at the table.
  • Whatever the formula for numbers of members it probably is unfair to fix the number for PO representatives and not for other members.

However it was also clear that the major concern was that the EC was able to carry out its function in providing strategic decisions for the Alliance that were informed by the interests of the stakeholders. To this end PEC members made a number of comments:

  • ‘It could be argued that the representation of POs (or clinicians, -or scientists) in the executive committee is not that important because these should all aim at the same goal and whoever is on the EC … should be efficient in reaching this common goal. However, at least in the beginning of the new TREAT-NMD, I would argue for an executive committee that builds on the above mentioned representation. The reason for this is both the importance of expertise from them all, and also to avoid any feeling of "some being more equal than others".’
  • There is no doubt that POs should be part of the EC – but whoever takes on that role is not there to ‘represent’ any one particular faction but they are there as an individual deemed experienced and able enough to take full membership of the EC and fulfil the terms and conditions of that membership, which may mean that they have to put aside some more individual interests for the greater good of the EC and the Alliance (this is true for all EC members).
  • The EC: ‘…should seek to operate on the basis of consensus as it would be absurd to have a dispute lead to a split between scientists, clinicians and patients’.
  • TREAT-NMD has been successful in representing various stakeholders in the NMD field and it should continue these good practices in particular ensuring transparency in the way that appointments are made to key committees.
  • ‘The organisation also has to talk to Regulatory and Governing bodies so we need to represent a community of patients, carers, clinicians and researchers to be able to lobby for funds and resources, it maybe that in some countries our patient organisations are very influential and can lobby but in the international community the same level of influence may not be possible unless we are representative of the community.
  • So together we are strong, divided we are seen as only one group or an aspect of care. TREAT-NMD has been a success as it has pulled together a number of groups into a platform for advancing care of NMD so we need to maintain this.’
  • It should be noted that not only PO representation/ participation but also patient participation should be encouraged and thus careful attention to the planning of meetings in terms of convenience and accessibility for those with limited mobility is needed.

Several members raised the point that it would be an advantage of having an EC member with professional executive experience, though it was acknowledged that this may be difficult to achieve with the financial constraints TREAT-NMD is facing. A possible solution might be to seek a nomination from someone with this experience/ expertise from the PO community, perhaps even funded by a PO.

It was also recognised that even if the number of PO places in the EC was changed it is quite challenging to select amongst POs ones that are indeed representative:

  • ‘POs for the diseases in most focus for TREAT-NMD so far, DMD and SMA, are likely to have a very good representation in the governing structure. How about POs for other neuromuscular diseases, e.g. congenital myopathies, FSHD, CMDs, CMT, myotonic dystrophy, LGMD etc? How are the interests of these best taken care of in the governing structure?’
  • ‘Patients with NMD are, like everybody else, different people with different life perspectives depending on who they are and at which stage of their lives they are.
  • As an example, there are a number of studies which show that parents of children with SMA and DMD boys would like to see the development of medical treatments, which can cure the disease (or alter the disease so that the boy will end up with a less severe form of the disease and thereby a change of personality/identity). Adults with DMD or SMA, on the contrary, want treatments which prolong life expectancy without altering their personality/ identity.
  • This is only one example, but I think it illustrates the need for more than just one person to represent the NMD patients. I also think it is important that such people be patient representatives who come from patient organizations. The reason for this is that they should be persons who not only represent themselves but who are also responsible for a group of stakeholders/patients.’

Several members noted the importance of learning from effective models and methods seen in other organisations. For example:

The European Medicines Agency has patients as full members of its major committees (e.g. Committee for Orphan Medicinal Products (COMP), the Paediatric Committee (PDCO) and the Committee for Advanced Therapies (CAT). As of July 2012, patients will also be members of the Pharmacovigilance and Risk Assessment Committee.)

It was felt that the EMA’s own rationale was something the TREAT-NMD Alliance could learn from:
“Recent analysis of the experience acquired so far to demonstrate that participation of patients in the scientific committees leads to increased transparency and trust in regulatory processes and develops mutual respect between regulators and the community of patients. It is also acknowledged that their contribution enriches the quality of the opinion given by the scientific committees. This positive experience confirms the importance for the Agency to continue supporting and facilitating patient contribution to the work of the committees.”

“Although experience has demonstrated that they very often contribute scientifically into the discussion, the added value of having patients and consumers in the scientific committees is to bring a unique and critical input based on their real-life experience of being affected by a disease and its current therapeutic environment. This element fills a gap which other committee members (so-called scientific experts) cannot fill, and which has proven necessary to achieve the best possible results within the regulatory process.

The role of patients in the scientific committees will therefore be the same as of any other member.

Members take part in committee decisions and have equal voting capacity.“

Source: ‘The role of patients as members of the EMA Human Scientific Committees’ (14 December 2011)

The sentiment behind the EMA approach is echoed the Dutch Institution for Care and Medical Research (ZONMW) which states: ‘Care revolves around the people with a disease or disability. Without them there would be no need for research and care policy. It is important that the needs of these groups are the starting point for initiatives concerning them. There is a lot to win if their experience and expertise is utilized. People with (a) disabilities and diseases know what it means to have this condition. It means they will bring in a different (another) perspective to (than) caregivers, researchers or policymakers. Their questions and needs are based on their own experiences, interests and vision.’

However it was acknowledged that TREAT-NMD has already done much to put these values into practice and indeed had gained considerable experience in ensuring adequate patient representation. For example Thomas Sejerson comments that the question of "who represents the patients" has emerged in the context of developing care guidelines. Ideally there ought to be a structure allowing largest possible patient input into the development and updating of standards of care. The new description of work developed with Michael Rutgers for Standards of care added a task devoted to this ("Involving patients in developing and updating standards of care"). The idea and goal here is what we in Sweden would call "grass root democracy; a model that may be applicable in a wider context for future TREAT-NMD tasks, other than standards of care, in order to allow best possible direct interaction with patients. (Further details can be provided).

The PEC was reminded of the forthcoming, ENMC hosted workshop (15-16 June 2012) with the participation of a wide range of patient organizations. One of the aims will be to discuss how the patient organizations are best represented and how they represent the different points of view in the NMD group thus TREAT-NMD may benefit from the deliberations of this meeting.

Concluding summary:

This question from the UPPMD Executive has proved complex and challenging. There is no doubt that the PEC recognises the importance of patient representation in organisations like TREAT-NMD and the dual challenge faced by TREAT-NMD to foster patient representation and also ensure good governance of the Alliance.

This question from UPPMD to the PEC implies that the PEC response will be part of further deliberation on the issues within UPPMD. Thus it is clear from the discussion amongst PEC members that there is scope for further reflection on the issues of patient representation within TREAT-NMD.

On the particular matter of PO membership of the Executive Committee: it probably is advisable to suggest that there should be equitable representation from the stake holder groups with the proviso that all members of the EC recognise that individual interests must be seen as secondary to the aims and goals of the Alliance.

The PEC recognises that the EC may benefit from a member with professional executive experience and therefore the PEC would suggest that UPPMD consider whether they are in a position to nominate, and if successful support, such a candidate.

On the matter of ensuring that the patient voice is encouraged and facilitated throughout the Alliance then the PEC would encourage UPPMD to provide TREAT-NMD with advice and support regarding the good practices and approaches that have proven successful in the past.

Finally the PEC has faith that the TREAT-NMD Alliance has impeccable intentions to improve the treatment and care of people with NMDs. TREAT-NMD also has a very good track record of doing so. The PEC therefore encourages UPPMD to offer TREAT-NMD wise counsel and fraternal support in dealing with the challenges ahead.

11. Self-medication via the internet

Q11: I have been approached by a parent of one of my patients with a neuromuscular disorder (NMD).  The father had found that it’s possible to buy Ataluren (PTC 124) via an internet site and asked about the possibility of purchasing it to treat his child.

A: Ataluren is an investigational drug and not licenced for clinical use in NMDs as
Diane Goetz at PTC Therapeutics, the drug’s manufacturer, confirms:

“Ataluren (formerly PTC124) is an investigational new drug that is only available through clinical trials. It has not been approved for use by regulatory authorities in any country and thus cannot be legally purchased for human use.

Websites advertising PTC124 or ataluren for sale are not connected to PTC Therapeutics and the company does not know anything about the quality, purity, or safety of these products. It is also quite possible that the products being sold are not, in fact, ataluren.”

The company concerned is Selleckbio. In correspondence with us they stated that Ataluren,

“is a biochemical for research purposes only. It is not pharmaceutical grade or available in tablet form. We have many enquiries for Selleck products from patients trying to get access to potential new drug candidates. We have systems in place that ‘vets’ enquiries and prevents deliveries going to personal addresses.

We did have a statement on the website that indicated this, but are currently migrating to a new website, so haven’t kept this completely up to date. I have asked our web guys to get this statement back on our existing website and ensure it is on our new one.”

There has been some discussion about the availability of Ataluren on online forums for Duchenne Muscular Dystrophy and Cystic Fibrosis. Most people are adopting an appropriately cautious note.

The PEC’s position is that parents/patients should not attempt to purchase these products for the purposes of self-medication for the following reasons:

1. Clinical trials have not been concluded and the product is therefore potentially dangerous.
2. There is no guarantee regarding the quality of the product (even as to whether it is Ataluren or not)
3. The product is not supplied in a format for patient use

Though the PEC support efforts  to advance the study of potential treatments as rapidly and effectively as possible, chemicals which have not been tested as part of an approved clinical trial are potentially dangerous.

In addition, self-administration or administration to children of unapproved treatments is illegal in the majority of countries.

12 Apr 2017