February 2013: “Clinical trials on Alzheimer’s disease: update on recent trial results and the new regulatory framework”
Sirpa Pietikäinen, MEP (Finland) and Member of the European Alliance, opened the lunch debate by highlighting how Alzheimer Europe's lunch debates have proved to be a good way to exchange opinions, learn about research and policy developments, and discuss how best we can move forward in tackling dementia. She said that new codes of conduct and principles for guidelines for people with memory disabling diseases have just been approved and that the codes include specific rights which people with memory disabling diseases have to be a part of society and to make decisions.
Ms Pietikainen emphasised the importance which clinical trials have in addressing the challenge of dementia, the need for further EU research to be conducted and the importance ethical considerations have in research. Whilst introducing the speakers, she invited the audience to reflect on how vulnerable groups can be protected when clinical trials are carried out.
Medicines for Alzheimer's disease
Prof. Alexander Kurz, Professor of Psychiatry and Head of the Centre for Cognitive Disorders at the Department of Psychiatry and Psychotherapy of Technische Universitat, Munich, Germany, presented "New medicines for Alzheimer's disease? Disappointing results and hopes for the future.
A pathological cascade of events
Prof. Kurz explained the changes which occur in the brain of someone who has Alzheimer's disease and illustrated the difference between the brain of a healthy individual and that of an individual with Alzheimer’s disease by highlighting the presence of beta amyloid (Aβ). Prof. Kurz explained that beta amyloid is accumulated in the brain when there is an imbalance between the production and clearance of the protein. This results in the aggregation of beta amyloid and, in turn, in the formation of plaques. The consequence of this is that a complex pathological cascade of events begins. The beta amyloid aggregation causes the aggregation of a second protein, tau, resulting in energy dysfunction and then in nerve cell dysfunction. If nerve cells die, some parts of the brain become atrophic and it is at this point that clinical symptoms become evident. Some components of this cascade are visible outside of the brain. For example, the levels of tau increase in the spinal fluid.
Approaches to tackling Alzheimer’s disease
Different approaches are currently researched to combat this process. They aim to target the aggregation of beta amyloid by inhibiting its production, enhancing its clearance, prohibiting its re-entry into the brain, inhibiting plaque formation or stimulating certain enzymes in the brain which reverse the process.
Pharmacological strategies which directly remove beta amyloid from the brain have also been tried. He explained that some have not been successful and cited the use of gamma inhibitors which were discontinued due to the lack of efficacy.
On the other hand, Prof. Kurz said that some trials involving compounds which remove beta amyloid from the brain are proving to be promising. He explained that this removal can be achieved by using the brain’s own immunological machinery in one of two ways: (i) By active immunisation where beta amyloid fragments together with an immune stimulate are injected into the blood stream. The body responds by producing antibodies against beta amyloid which bind to them, flag them and stimulate cells known as “macrophages” in the brain (which recognise something is wrong) to eat up and degrade the flagged amyloid fragments. (ii) By passive immunisation where preformed synthetic antibodies against Aβ are injected. Some of these enter the brain, bind and flag beta amyloid and the macrophage eats it up.
Prof. Kurz highlighted a study (AN1792) in which an active immunisation treatment aimed to prevent the progression from mild dementia to advanced dementia. It showed that the biological effect was dramatic as beta amyloid had been cleared out of the brain. However, when cognitive ability and daily living abilities were compared to the placebo group there was no significant difference and there was no clinical effect. This led to the trial being stopped after an average of two injections. Even when individuals participated for longer and were followed for up to six to eight years, it did not prevent participants reaching the advanced stage of dementia.
He also presented a highly publicised passive immunisation trial using bapineuzumab. Prof. Kurz explained that this was the most expensive clinical trial ever conducted in Alzheimer’s disease. After 78 weeks of treatment it showed that the amyloid had gone from the brain. However, there were side effects. The discrepancy between the biological and clinical effects reflected the findings of the active immunisation trials in that there was no significant difference between the clinical results of the placebo group and the group receiving the passive immunisation.
However, another passive immunisation study which used solanezumab (LY20662430) has been more encouraging as it is the first time that a slowing of disease progression has been shown by the drug working.
The way forward
Prof. Kurz considered the reasons behind the dramatic discrepancy found between the biological and clinical effects of the drugs. He suggested that one reason may be that the treatments are administered too late in the disease process. At the moment, the diagnosis of dementia is made at a point when a large part of the brain is already damaged. In order to overcome this problem, Prof. Kurz emphasised the importance of making a diagnosis at an earlier stage. He explained that in the case of Alzheimer’s disease, there are biomarkers (such indicators of Aβ deposition e.g. PiB PET and CSF Aβ markers) in place to help us diagnose it earlier. Prof. Kurz said that another possible limitation is the fact that the focus is on beta amyloid. This is because many people believe that it is central to the process of Alzheimer’s disease. However, he reflected that the reality maybe that beta amyloid is just one piece of a much bigger picture and suggested that we use a combination of pharmacological strategies to address not only beta amyloid aggregation but also the energy disruption, nerve cell loss and tau aggregation.
He concluded by saying that the development of new medications currently focuses on beta amyloid. Immunisation strategies to remove amyloid are the most advanced, have had impressive biological effects and recently have also had some clinical effects. However, the fact that treatment starts late in the disease lifecycle is a limitation as is the fact that beta amyloid may be one part of a far more complex scenario which we need to investigate further.
Charles Scerri and Heike von Lutzau-Hohlbein, respectively Honorary Secretary and Chair of Alzheimer Europe, asked for clarification regarding the progress of current anti-tau therapy. Prof. Kurz said that although some studies suggest it is not effective, there are some ongoing clinical trials which appear to suggest it is well tolerated. However, it is not possible to comment about clinical effects as the results are not due to be published until 2014.
The issue of screening was raised and Prof. Kurz said he believed that if there was a safe and effective drug available which could slow down Alzheimer’s disease, then screening would make sense. However, as we are not in a position to offer such a drug, he believed screening to be unreasonable in the current climate.
The proposal for an EU Regulation on Clinical Trials
Fabio D’Atri from the European Commission, Health and Consumers DG, Unit on Quality Safety and Efficacy of Medicinal products, presented an “Overview on the proposal for a Regulation on clinical trials”. He explained that the proposal for a Regulation was adopted by the European Commission in July 2012 and that it was now being discussed by the European Parliament and the Council.
At this stage of the procedure interested parties willing to suggest changes to the Commission proposal would have to approach a Member of the Parliament or their Member State in order to do so. A plenary vote at the European Parliament may be scheduled for later this year. Mr D’Atri said that a clinical trial is the “administering of a medicine on the basis of a protocol with the aim of exploring the characteristics of a medicine”. He also clarified that non-interventional trials (such as observational trials) and trials without medicinal products (such as a study on the best way to carry out surgery) will not be covered by the proposed Regulation.
To obtain an authorisation to carry out a clinical trial there must be a sponsor. The sponsor wanting to carry out a clinical trial must prepare a dossier. Mr D’Atri illustrated how under the current legal regime, a sponsor may carry out an international clinical trial. He or she will have to submit a different dossier to each of the Member States where he/she would like to conduct the trial. Currently, each Member State has different requirements about how the dossier should be composed. Furthermore, now each Member State gives its decision independently, even if a trial has to be conducted in several Member States. This situation is highly complex and it often results in the same application leading to the authorisation of different protocols in the different Member.States concerned by the trial.
Assessment of clinical trials
The Commission is proposing a new procedure so that a single set of common documents will need to be provided for assessment. A dedicated portal will be developed which will allow the sponsors to submit their dossier automatically to all Member States concerned by the trial. The new procedure defines issues which will be assessed jointly by the different Member States (part I) or assessed independently at national level (part II). Certain elements need to be already defined at the assessment stage such as a clear distinction on how a patient is recruited and the procedure for informed consent. In addition, a justification will be required if certain groups, such as older people or women, are excluded from a trial.
At the moment, the assessment procedure is carried out in parallel by a national competent authority and an ethics committee but the procedure and the tasks of these 2 bodies vary between Member States. In some countries ethics committees (in some Member States other names are used for these committees) assess the whole application, but this is not always the case. The proposal does not define which bodies should carry out the assessment and how they should share the tasks between themselves, but does require that areasonable number of people conduct the assessments, that the people involved are independent from the sponsor and investigator, that at least one lay-person is consulted and that the view of a patient is taken into account. These requirements may lead to some Member States having to change their internal organisations and working procedures. Unfortunately there has been the misunderstanding that the proposals will marginalise ethics committees and Mr D’Atri said that this is not the aim of the proposal.
Special provisions are given for the assessment of clinical trials which concern people with incapacity. In this case it is required that the assessment include people with expertise in the relevant disease and the patient population concerned or that advice is taken on the clinical, ethical and psychosocial questions in the field of the relevant disease and patient population concerned. In addition to the general rules concerning the protection of subjects participating in a trial, additional requirements are stipulated for incapacitated subjects. A definition of what constitutes an incapacitated subject is included and the specific provisions on the procedure for requesting their consent are addressed.
Mr D’Atri explained that there was much debate when discussing the current Directive back in 2001 on the issue of the protection of subjects involved in clinical trials. The new proposal broadly keeps the existing provisions. They have just been rearranged in order to make them clearer. Consent issues have been a big area of discussion and the Commission did not wish to modify the compromise agreement made back in 2001. Essentially, if a person is unable to give consent then consent must be gained by a legal representative. This has been strengthened through reference to the fact that incapacitated subjects should take part, as far as possible, in the consent procedure.
A completely new section regarding emergency situations (which may concern also incapacitated people) has been added to the proposed Regulation. Mr D’Atri explained that this section refers to those situations when a person is not able to give consent, for example when someone has a stroke. It is very important to develop new medicines to treat these conditions yet in that moment, if no one from the family is present what can be done? A possibility to waive the informed consent requirement is suggested although consent will have to be sought as soon as possible. In addition, in emergency situations the clinical trial has to impose only a minimal risk and minimal burden on the subject. There is some debate over this issue and the minimal risk/ burden requirement has been criticised for being too restrictive and not allowing clinical trials to be conducted in emergency situations.
Lastly, Mr D’Atri raised the issue of transparency. This is a big issue at the moment. Currently, applications are not available for public scrutiny and Member States do not necessarily disclose everything. The Commission has proposed to have a new portal where all submitted applications and all decisions by Member States are introduced, making them publically available.
The Commission has proposed that a summary of the trial results must be submitted to the portal one year after the conclusion of the trial and consequently be made publicly available. The Commission has recently published guidelines on the structure and content of this summary. Raw data are not being demanded but safety concerns will highlighted in the submitted summary of results. A discussion is currently underway in the European Parliament on various options for transparency on clinical trials results. The burden that the various options may place on independent searchers is also the subject of discussions as well as the timing of the publication of results and if results should be publicly available or available only on justified request.
Margrete Auken, MEP (Denmark), remarked that clinical trials are for the good of society and humanity. Therefore, she believed it to be unacceptable that anything may be hidden. She emphasised that there is a duty to the public to have information which is both fully transparent and in electronic form. Mr D’Atri highlighted that the provisions which are being proposed are already a big step towards increasing the transparency of clinical trials results. Prof. Kurz added that there can be issues for the sponsors in that if a study protocol from a sponsor is received, it usually has information on the product which is strictly confidential. If we were to say that the portal will automatically publicise all information then there is a likelihood that this will result in the sponsor not sharing their information about their products so freely. To overcome this, a solution could be to prepare a guidance document to define commercially confidential information and personal information.
Clarification was sought regarding the requirement that the summary of results has to be submitted one year after the end of a trail. The end of a trial is defined, normally, as the last visit of the last patient. Mr D’Atri explained that if such summary is not provided within one year after the end of a trial it would be for Member States to take the appropriate legal action.
The Commission will have to ensure that the proposed Regulation is correctly enforced by Member States. Helga Rohra, Chair of the European Working Group of People with Dementia (EWGPWD), asked why the view of only one patient should be taken into account and Sirpa Pietikainen asked whether an association could be part of a procedure of representation of rights for those patients who do not have the capacity to protect themselves.
Mr D’Atri explained that the proposal aimed at ensuring that at least one patient is involved in the assessment of a clinical trial application. Discussions ensued as to what constitutes a patient and what organisations may be able to represent them. It was felt that this would have to be assessed on a case by case basis. Sirpa Pietikäinen thanked the speakers and delegates for an interesting and informative debate. Heike von Lützau-Hohlbein thanked everyone for supporting the lunch debates and was delighted that MEPs Anneli Jaatteenmaki (Finland), Sirpa Pietikäinen (Finland) and Angelika Werthmann (Austria) had also given their support today. She closed the debate by emphasising the need to strike a balance between, on the one hand, enabling clinical trials to be done and, on the other, protecting the people who participate in them. She also highlighted the ethical aspects which need to be considered when conducting clinical trials in the field of dementia as people in the advanced stage of the disease are probably unable to give consent and this makes them vulnerable.
Last Updated: Monday 08 July 2013