Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment

Collection summary

Background

Like all dementias, Alzheimer’s Disease is an important global public health problem.

Immunoglobulins, traditionally used to prevent or treat infectious diseases have been recently used for other non-communicable conditions including rare neurological diseases.

We report on reviews of the evidence of use and effect of immunoglobulins for Alzheimer’s Disease and Mild Cognitive Impairment.

The existence and significance of Mild Cognitive Impairment are still debated

Results                                                                             

Health Problem and Current Use of the Technology (CUR)

Alzheimer’s Disease is an important public health problem, like all dementias. The existence and significance of Mild Cognitive Impairment are still debated

Description and technical characteristics of technology (TEC)

Immunoglobulins have been tradionatioally used for passive immunisation against  infectious diseases, although in the last decades their use has expanded to include blood disorders, rare neurological disorders and cancer. Safety of the technology (SAF)

Effectiveness of the technology (EFF)

Despite several placebo controlled trials having been carried out and completed and some being underway so far there is no evidence of either positive or negative impact  of IVIG on Alzheimer’s Disease or Mild Cognitive Impairment.

 Costs and economic evaluation (ECO)

In the absence of any discernible difference against placebo, no estimates of a trade-off between costs and benefits can be made at present.

Ethical aspects of the technology (ETH)

The only foreseeable ethical aspect which could be raised by the granting of a MA are the effects of industrial production on the limited supply of blood products used to treat other conditions such as clotting disorders.

Organisational aspects of the technology (ORG)

In the absence of any discernible difference against placebo, no estimates of organisational impact  can be made at present

Social aspects of the technology (SOC)

In the absence of any discernible difference against placebo the social aspects cannot be defined

Legal aspects of the technology (LEG)

In the absence of any discernible difference against placebo the legal aspects cannot be defined

Discussion

The data gathered and synthetized in this Core HTA show that at present there is little evidence of any effect (positive or negative) of IVIG on Alzheimer’s Disease  and Mild Cognitive Impairment. Although the evidence base is still small and several trials are still to be completed or reported, the persisting speculative nature of the pathogenesis of dementia and consequent mechanism of action of any biological product suggest that investment in research of causation might be a better priority.

This is the second of our three JA2 scheduled pilot projects. We have experienced several hitherto unforeseen difficulties during the development of the project.

The first  problem was related to the aftermath of choice of topic. There is little doubt that dementias are an important topic but we were also aware of the potential demands on plasma derivatives for the manufacture of IVIG. This would have a major influence in a delicately balanced market with many highly motivated patient organisations. Choice of an inert comparator, although dictated by the early phase of experimentation of AD IVIG, was also not a traditional choice in any HTA activity and much discussed. The choice has left unresolved disagreements.

The pre-Market Authorisation Application (MAA) nature of the intervention being assessed also meant that many trials were ongoing or unpublished, even if completed. This carried many implications which added to the difficulties. Data were either not available or were made available indirectly on registers such as clinicaltrials.gov after our manufacturer enquires drew a blank. Register “publication” took place in the autumn of 2014, long after completion of our primary searches in February 2014. Although data were quantitatively plentiful, they lacked detailed description of methods and a full study protocol which made its very inclusion and interpretation contentious. The difficulties came to a head with two distinct points of view regarding the inclusion of data after the main search had taken place. Some investigators were worried about risk of bias being introduced in the assessment, others thought the importance of reporting the largest trial ever conducted (yet inexplicably unpublished two years from completion) to be paramount.

To manage the problems, Coordination asked the Editorial Team for guidance. The Team, made up of all PIs, decided to allow inclusion of the register data. However, to minimize the risk of introducing bias by secondary searching (i.e. post primary search in February 2014) of only two domains, the Team recommended the conduct of an update search for all other domains to coincide with the date of the secondary search of registers. Although the secondary search did not identify any new additional evidence, it generated additional work, further delay and dissatisfaction with the composition of the Team as all members of the domains on which the discussion centered wanted a say.

Several positive points arise from this experience. First, it is clear that the management infrastructure and input were insufficient to deal with the complexity and novelty of the work. Second, few members of the team had experience in dealing with what were essentially unpublished data. Third, the topic proved to be a good testing ground for dealing with unexpected problems. The experience gained should be reflected in future procedures.

Closing Remarks

The Core Model is not intended to provide a cookbook solution to all problems but to suggest a way in which information can be assembled and structured, and to facilitate its local adaptation. The information is assembled around the nine domains, each with several result cards in which questions and possible answers are reported.

The reasons for having a standardised but flexible content and layout are rooted in the way HTA is conducted in the EU and in the philosophy of the first EUnetHTA Joint Actions production experiment.

HTA is a complex multidisciplinary activity addressing a very complex reality – that of healthcare. Uniformly standardised evidence-based methods of conducting assessments for each domain do not exist1[1]. There are sometimes variations across and within Member States in how things are done and which aspects of the evaluation are privileged. This is especially so for the “softer” domains such as the ethical and social domains.

This pilot represents a useful lesson for methodological development in EUnetHTA Joint Action 2.

Collection methodology

Objective

To produce a Core Health Technology Assessment (HTA) assessing the effects of use of intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment based on the EUnetHTA Core Model and working within the a mixed Collaborative Model organisational framework.

Methods

The work was based on the HTA Core Model on pharmaceuticals (HTA Core Model Application for Pharmaceuticals version 2.0), which was developed during the EUnetHTA Joint Actions 1 and 2.

The first phase was the selection of the technology to be assessed using the Core Model; this phase was carried out through a three-step process that is described in our MSP.

Then a check of Partners’ availability to assume responsibility for taking the lead in one of the nine evaluation domains was carried out. At the same time, the nine domain teams were built-up in accordance with partners’ preferences and some general guidelines (see the MSP).

Finally the specific work plan was shared, according with the general WP4 3-year work plan and objectives. This specific work plan included the phases scheduled in the “HTA Core Model Handbook” (Production of Core HTAs and structured HTA information).

An editorial team was set up for discussion and major decisions on basic principles and solutions related to the content of core HTA. The editorial team was chaired by Tom Jefferson (Agenas) and included  all  primary investigators of the domains.

To allow collaboration between partners a draft protocol for Core Model use was agreed by the researchers involved. The research questions for each of the eight domains of the Core Model were formulated and the corresponding relevant assessment elements (AEs) were selected. The legal domain was included in the assessment.

The research strategy was carried out by Agenas with input from the other partners.

Evidence from published and manufacturer sources was identified, retrieved, assessed, and included according to pre-specified criteria, and summarised to answer each AE. Domain assessments were done by a single agency and by different investigators from different agencies, in a mixed organisational model.

The final text has not been proof read or copyedited.

Introduction to collection

This brief document provides background information on the preparation and development of the Core HTA on use of Intravenous immunoglobulins for Alzheimer’s disease including Mild Cognitive Impairment. The core HTA document was produced during the course of the second EUnetHTA Joint Action (JA2) 2012-2015.

The idea behind EUnetHTA’s Core Model is to provide a framework for structuring relevant HTA information while at the same time facilitating local use and adaptation of the information or guiding its production.

The Model is based on nine dimensions or “domains” of evaluation:

1. Health Problem and Current Use of the Technology (CUR)
2. Description and technical characteristics of technology (TEC)
3. Safety (SAF)
4. Effectiveness (EFF)
5. Costs and economic evaluation (ECO)
6. Ethical analysis (ETH)
7. Organisational aspects (ORG)
8. Social aspects (SOC)
9. Legal aspects

The Core Model application on pharmaceuticals was tested by assessing the effects of use of intravenous immunoglobuliuns for Alzheimer’s disease including Mild Cognitive Impairment. We produced a Core HTA structured as the eight documents that follow, one for each domain. The Legal Domain was not included in the used version of the Pharmaceuticals application but we produce it and add as appendix.

This Core HTA was prepared using a mixed Collaborative Model (COLMOD). Two different model of collaboration were tested during the first EUnetHTA Joint Action: in one, groups of researchers from different HTA Institutions produced the domain texts; in the other model, one of the national or sub-national HTA participating agencies took responsibility for the production of each domain. For the Core HTA on use of intravenous immunoglobuliuns for Alzheimer’s disease including Mild Cognitive Impairment, some domains were produced using the first collaborative model, while other domains were produced using the secondcollaborative model, with a lead agency. The experimental organisational model added an element of challenge but probably helped to forge strong links across participants.

In the next few months an intensive validation programme including interviews and consultations will elicit comments and feedback both from those who contributed to the Core HTA and from those who read a Core HTA for the first time. As scheduled in the 3-year work plan, the Core HTA will be sent to the Stakeholder Advisory Group (SAG) for feedback before the final Public Consultation, during which the Core HTA will be made publicly available.

The results from the Validation and SAG consultation should provide useful information to improve the product.

Scope