Tue, 18 Sep 2018

Autism Innovative Medicine Studies-2-Trials project FAQ

This post appeared first on the Participatory Autism Research Collective (PARC) blog.

Written by: Panda Mery

As so little information has been made available on 115 million euros Autism Innovative Medicine Studies-2-Trials (AIMS-2-Trials) research project, we suggested to Autistica to publish their project agreement. They didn’t. Using the access to information scheme of the Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU), we also requested a copy of the ‘Autism Innovative Medicine Studies-2‐Trials (AlMS-2-Trials) grant agreement and its appendices’. After extending its deadline, the IMI2 JU sent us a partly redacted copy of the grant agreement. The redactions are explained in a cover letter.

The grant agreement document, even redacted, weighs in at 19 MB and 664 pages. To help all those curious about this project to get a quick grasp on the project priorities, its ethical commitments and how it will involve autistic people, we are providing a summary in the form of a FAQ.

1. Will AIMS-2-Trials address the autism community’s priorities?

No.

‘Currently, there are no effective medical treatments for the core symptoms of ASD […] Our overall goal is to address these shortcomings by adopting a precision medicine approach to better target treatments to patients through the use of validated stratification biomarkers, and by testing novel or repurposed drugs in a highly trained European-wide clinical trials network for ASD that links to other international efforts’ (p. 165).

None of the top 10 autism community’s research priorities include ‘treatment for the core symptoms of ASD’.

2. Will AIMS-2-Trials really only target the core symptoms of ASD?

No, but mostly.

For instance, epilepsy is an important co-morbidity for autistic people that has a large impact on their quality of life and is likely well suited for a pharmaceutical intervention.

The grant agreement briefly acknowledges this: ‘We also specifically include younger populations, and target core symptoms that are relatively under investigated together with associated symptoms impacting on quality of life and mortality (e.g. epilepsy).’ (p. 184).

Searching for ‘epilepsy’ reveals that out of all the seven work packages, out of the 34 deliverables of Work Package 2 ‘Validation of stratification biomarkers’, only three deliverables are about epilepsy: 'D2.4-6 Epilepsy: First study subject approvals package completed (registered in WHO or ICMJE, Ethics approvals delivered to the IMI); Midterm recruitment report; Report on status of posting results’ (p. 117).

3. Has AIMS-2-Trials an ethics board?

Yes. Two ethics board are described.

The 'External Ethics Advisory Board (EEAB). The EEAB will report to the SSC [Study Steering Committee]. An external independent ethics advisor (Professor John Suckling) has been appointed to oversee, with impartiality, the ethical concerns involved in this research. He will chair the board and be supported by a Deputy Director (Prof. Dr. Marcella Rietschel, University of Heidelberg) and other relevant experts including Prof Dr Ulrike Schulze, Zentrum für Psychiatrie Baden-Würtemberg.’ (p. 198).

'Professor John Suckling, Chair of the Psychology Research Ethics Committee, University of Cambridge, has kindly agreed to lead this aspect of our work. Through regular (quarterly) meetings, the Ethics Board will ensure that our ethical approaches are consistent across work packages and across countries wherever appropriate; provide expert advice to the rest of the consortium on any specific ethical issues arising in particular studies; engage key experts to provide additional advice where necessary (e.g. new EU legislation as it arises); and develop strategies to explore the ethical implications of novel results as they emerge from the consortium (see below). Professor Suckling will ensure that the Ethics Board includes relevant independent expertise to monitor the ethics issues in this project and how they are handled. The Board will be consulted at least on the following points (inclusion of fetuses, infants at risk, imaging, animal models, genetic information, dedication, clinical trials and data protection). A report by the Ethics Board will be submitted as a deliverable at the end of each reporting period.’ (p. 309)

And the 'Data Monitoring and Ethics Board (DMEB). The DMEB will report to the SSC. There will be an independent DMEB that consists of a researcher/clinician with expertise in ASD, a statistical expert, and an ethical expert. The DMEB operates in accordance with a charter that follows the guidelines of the DAMOCLES study group for charters on clinical trial data monitoring committees [118]. The aim of the DMEB is to protect and serve the clinical study participants (especially re: safety) and to assist and advise the TSB [Trial Steering Board] as to protect the validity and credibility of the clinical study/trial. The DMEB will receive a summary report of the study progress every 6 months, and review the progress and accruing data of this trial and provide advice on the conduct of the trial to the TSB. To this purpose, the DMEB will meet face-2-face or by teleconference not later than within 6 months after the start of the study and thereafter every 4 months or more often if needed. The DMEB will support risk management and review incidents associated with data collection (including brain imaging) of vulnerable participants, as well as monitoring data curation and stewardship. This will run in parallel with the institutional Clinical Governance system which oversees clinical and radiological safety issues.’ (pp. 198 and 403).

4. Was ethics an overriding concern of AIMS-2-Trials?

No.

Overview of the AIMS-2-Trials governance structure The Ethics requirements work package (WP7) was a late add-on to the agreement. The history of changes shows that ‘An Ethics WP has been added: WP7 with deliverables D7.1-8’ (p. 162). This change is listed as having been introduced in version 6 of that part of the agreement, which is dated 2018-06-13, just five days before the project’s launch press-release. ‘Figure 14 Overview of the AIMS-2-TRIALS governance structure’ still only shows six work packages (p. 197). WP7 is the only work package which still has no figure (‘N/A’) listed for its ‘total number of person-months allocated’ to it (p. 94).

All of the eight deliverables of WP7 (defined as GEN – Requirements No. 11 to 18) will be ‘Confidential only for members of the consortium (including the Commission Services)’ (pp. 147-148).

The second paragraph in a section on ethics explains the overall approach as: 'Any consideration of ethical issues has to be set in a context of the potential benefits and risks of the overall project. Undoubtedly, better options are needed for treating ASD. AIMS-2-TRIALS will address this issue using the latest techniques of animal and cellular models, genetics, proteomics, imaging and behavioural/cognitive phenotyping.’ (p. 309). That seems to indicate that the benefits and risks of the project may overrule any ethical concern.

(‘benefit’ is used on 30 pages, but with no clear definition, nor a list of what may be the benefits of AIMS-2-Trials for autistic people. For instance, here’s another use in the context of actions for investors: ‘the Actions include ‘Sensitize investors to AIMS-2-TRIALS potential benefit to patients and market opportunity, to support commercial ramp-up post regulatory clearance.’ p. 192).

The secrecy about the project’s approach to ethics goes further. Although the grant agreement mentions 'Activities raising ethical issues must comply with the ‘ethics requirements’ set out as deliverables in Annex 1.’ (p. 59), the covering letter to the redacted agreement explains 'the Annex 1 is withheld in its entirety considering that access to a redacted document would be meaningless;’ (I have requested a review of that redaction, and a response is due by 2018-10-05).

5. Will the ‘universities, research organisations, public bodies [and] non-profit groups’ involved receive any funding?

Yes.

The IMI will distribute 55 million and one euros to them. King's College London will receive 20 060 301 euros. The second largest recipient, Servicio Madrileno De Salud-Fibhug, will receive 5 502 025 euros. IMI2 has published the full list on its AIMS-2-Trials summary page. I’ve also updated the spreadsheet I had published earlier with this information.

6. Will the associated partners – Autism Speaks, Autistica and SFARI – receive any funding?

No, none of them will receive any of the IMI funding, however, they will receive benefits in kind.

The logos and mentions of Autism Speaks, Autistica and SFARI, as well as those of the Joint Undertaking and of the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the EU emblem must appear in ‘any dissemination of results (in any form, including electronic)’ (p. 54) and in ‘any communication activity related to the action (including in electronic form, via social media, etc.) and any infrastructure, equipment and major results funded by the grant’ (p. 62). And they ‘must have appropriate prominence.’

7. Will autistic people be involved?

Yes, a few though this is still to happen.

Some autistic persons will be invited to be part of an Autism Representatives Group (A-Reps) and a Patient Advisory Group (PAG); at most one autistic person from each EU country is to be invited to the A-Reps. Of course a few researchers from the organisations involved may also be autistic (at least one openly identifies as autistic).

‘To ensure full collaboration with the autism community, we will create an Autism Representatives Group (A-Reps), using Autistica’s DISCOVER Research Network, to ensure patient and public involvement (PPI) with autistic people, their families and relevant stake-holders (e.g. autism charities, autism-related professionals) across Europe. The A-Reps group will include representatives from EU countries (an autistic person/family member, and a charity/professional rep in each country).’ (p. 135).

'The PAG [Patient Advisory Group] will report to the SAB [Scientific Advisory Board]. It will consist of representatives from patient organisations and individuals with first hand knowledge of ASD. We have agreements from Autism Europe and Autistica, who will work together with our Autism Representatives Group (A-Reps) that includes representatives from the Catalonian Autism Society, Gautena society, Federation Autism Madrid, Dutch Autism Society, and the Phelan McDermid Syndrome Foundation. The PAG will provide a focus of expertise in patient experience, and offer a natural vehicle for patient engagement in the consortium’s activities. It will meet formally once a year as part of the General Assembly meetings.’ (p. 199).

Note that the organisations that will be represented on the ‘Patient Advisory Group’ are not autistic organisations.

8. What is this patient and public involvement (PPI) the A-Reps will participate to?

‘The PPI will focus on the following objectives of Task 1: We will (a) develop Clinical Guidelines for Autism across the EU; (b) produce a ‘Time for Change’ ten-point Public Health Autism Plan, (c) translate these into 6 main European languages for dissemination to national governments and clinicians, (d) present these to European decision-makers and the UN, working with MEPs... All work will take place in consultation with AE, A-Reps and the KCL Policy Institute. Research on comorbidities and precision medicine policy development will be disseminated via conference presentations at the Annual INSAR and ECNP Meetings, Autism Europe, through the AIMS-2-TRIALS Clinical Network, and via webinars and press releases in collaboration with WP1 and WP5.2-3. Outputs: Dissemination of evidences based [sic] results to policy makers and the public. [...]

A focus of outreach will be the Autism Representatives Group (including autistic individuals, parents/carers, special educators, clinicians and researchers from across Europe (based on Autistica’s Discover Network; https: //www.autistica.org.uk/our-research/discover-network). In addition, our collaborative effort with co-leads Autistica and Autism Europe and our new Autism Representatives Group will ensure that we include as many Autism Charities in our network as possible. A number of charities across Europe, including those affiliated with Autism Europe such as Aprenem Associacio per a la inclusio de persones amb Transtorn de |’Especter [sic] Autista, Gaurema [sic] (San Sebastian, Spain), Nuevo Horizonte, Phelan McDermid Syndrome Foundation and The Dutch Autism Society, have already agreed to be part of our network. These organisations will be working with us on dissemination and patient and public involvement workshops to receive input from and provide information to the community. This will assist in the effective dissemination of information on educational events, policy initiatives, and newsletters (involving news updates on research, policy, education and other relevant materials). All these efforts will also be available on the new website and through the collaborative dissemination strategy with Autistica, Autism Europe and other partners. We will ensure that feedback is provided to the autism community and other citizens on how these groups interact to provide example of collaborative efforts for other projects, using a framework set-up by Shaping Autism Research (http://www. shapingautismresearch.co.uk).' (pp. 135-136).

9. Are there really 48 participants?

Sort of!

In Attempting to lift the veil of secrecy over AIMS-2 we published the authoritative list of 48 participants we had received from IMI2. The AIMS-2-Trials summary page now lists a 49th organisation: Greater Glasgow Health Board. However it is listed separately as a ‘Third parties’ (despite the plural, there’s only one). It will receive 195 000 euros of IMI funding.

The grant agreement document mentions ‘Greater Glasgow and Clyde Health Board’ (p. 275). This explains why the AIMS-2-Trials press release includes a logo for NHS Greater Glasgow and Clyde.

Autistic power

If after having read this FAQ and perused the grant agreement, this is a research project you want to support contact AIMS-2-Trials with your offer of participation.

If however, you are shocked by the limited autistic involvement, the late ethical considerations, the track records of some of the partners, etc. and have lost faith in this research, you have some power according to none other than Simon Baron-Cohen (the University of Cambridge is receiving 2 808 025 euros in IMI funding): ‘A large part of that collaboration [for genetics research] is with the autism community. If that community loses faith in this research, then progress will slow down. […] I hope the autism community will be willing to trust researchers who nail their colours to the mast in this way.’

You can also contact your Member of the European Parliament.

Table of contents for the AlMS-2-Trials grant agreement document

To help with navigating the 664 pages of the grant agreement, here’s a reconstructed table of contents:

Section title

Pages

Grant agreement

1-88

Annex 1 – Research and Innovation action (Part A)

89-158

Terminology definitions

159-160

Research and innovation actions & innovation actions (Technical annex – Part B)

161-335

Clinical trials (Other annexes)

336-565

Annex 2 – Estimated budget for the action

566-568

Annex 2a – Additional information on the estimated budget

569-574

Annex 3 – Accession forms for beneficiaries

575-621

Annex 3a – Declaration on joint and several liability of linked third parties

622

Annex 4 – Model for the financial statements

623

Annex 5 – Model for the certificate on the financial statements

624-650

Annex 6 – Model for the certificate on the methodology

651-663

(Note that many pages of the document are locked for copying/pasting so some of the quotes have been copied using OCR and typos may have been introduced; though as indicated with [sic] some of the typos in the name of organisations are in the original.)

Related posts

Update 2018-10-05

I have received a response to my request to review the redactions made to the grant agreement I had received. The outcome of this review is that

Following this assessment, I am pleased to inform you that I have concluded that the part of Annex 1 of the Grant Agreement that relates to the ethics requirements may be partially disclosed, with some of its parts redacted based on Article 4(1) (b) of Regulation (EC) No 1049/2001 (protection of personal data).

Two documents were attached: the Ethics-related excerpt of ANNEX I of the AIMS-2-TRIALS Grant Agreement (partly redacted) and the Work Package 7, described in Annex 1 of the AIMS-2-TRIALS Grant Agreement.

In fact this information was already included in the redacted grant agreement that had been sent earlier. Some further redactions have been applied to the documents received today, but the documents have copy/paste enabled making it easier to quote from them. So no further analysis needed.

websiteblogblog archivenews feedfeedback