Q&A - Questions to the PEC

Here, we discuss questions that have been put to the Project Ethics Council by scientists working on the project. They cover a broad spectrum of issues.

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'?

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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 3^rd 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 2^nd and 3^rd 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 1^st 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 2^nd 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.

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