In Part1 of “How are you doing?” the importance of PRO reports was explained as well as how important it was that aHUS patients in the Alexion aHUS Registry complied with the requirement to complete their PROs regularly.
In Part 2 the data about PRO compliance provided by the Alexion aHUS Registry was presented and analysed and it revealed that as the years thave gone by, newer patients are less likley to provide their Patient Reported Outcome (PRO) reports. A marked deterioration in compliance has been found which will have an impact on the quality of the Registry.
In Part 3 , some thoughts about neccessity for compliance action is discussed and what forms that might take, including any contributory action from aHUS patient organisation advocates.
It is a privilege for rare disease patients to have, and to be asked to join a Registry for their disease. The vast majority of rare diseases do not have registries. Then to be given the opportunity to represent others, who themselves cannot be enrolled, to get answers and raise awareness on their behalf is rewarding. No less so for aHUS patients.
In the 2016 aHUS alliance Global Poll, over 75% of aHUS patients said they were enrolled in ,or wanted to be enrolled in an aHUS registry. Most of other 25% were not sure if they were in one or not! Almost 95% of aHUS patients reported in the same Poll that they were either, already participating ,or, were prepared to participate in aHUS research. There has been an evident enthusiasm shown by aHUS patients for Registries and Research, so why would just over 20% of patients not meet their obligations when they get a change to contribute to aHUS research? Furthermore PRO non compliance rose even higher, to 40%, in the few countries still enrolling patients in 2018 and 2019.
Whilst there is a noble reason to participate, participants are not rewarded for their effort. There is no direct acknowledgement nor is little said to participants of what good has come from using their data. They are left in the dark while the Registry investigators tell their peers about what they researched and found. Perhaps with some token acknowledgement of patients at the bottom of articles patients will never see, often because the articles are behind paywalls. Whilst patients would not expect to be paid, perhaps it would be an encouragement if Alexion paid a sum for each completed PRO into a fund that could be used for the aHUS community. Pharma often use market research companies who offer rewards, maybe as much as $50, to patient participants for completing their questionnaires. Nearly 80% of new participants have completed PROs, nearly 2000 of each reports. At $15 per completed pair of PROs that could raise $30,000 for Alexion to use for the global aHUS community.
The procedural interface between the patient and data entry into the Registry database is at the patient’s hospital, which is paid to do it. Unless they miss an appointment, patients give PRO data to their hospital, if and when they are asked to do so on a visit to their hospital. Distribution of the patient questionnaires is the hospital’s responsibility and so is entering the PRO responses into the Registry database. It is a manual process things can go wrong. Patients cannot comply if they not been given forms, nor if completed forms are not entered into the database. That is down to hospital administrators. It may be that some administrators are not doing so. But whether it is down to patients or their hospitals, if PROs are missing it is perhaps better, from a data quality perspective, that it is random rather systematic in just some study sites.
It is most important that at the enrollment stage, and particularly when the first PROs are completed, that patients know what, and why, reports are to be completed and at what intervals. This is all done at the hospital but it is not clear what is actually said ( whether there is a script) and whether it is understood. But any failure in engagement at that stage could determine what happens going forward.
It is up to those managing the Registry Database database to prompt submission of outstanding reports, but there may be little resource for repeated prompts , nor any escalation or other action to ensure compliance by sites . It may be the case that at non compliant sites past practice can become routine and unalterable.
Alexion’s policy decision on recruitment has impacted on the time series data about enrollment . However it might have revealed what could be cultural differences in meeting PRO obligations. Potential recruitment in 2018 and 2019 was restricted to Belgian, French ,Polish and and South Korean patients. Reporting of initial patient outcomes by these patients has been considerably less than when aHUS patients from other countries were recruited.
It is not known whether this is down to one specific country, or all of them. If the latter it might well have been the case for those countries in previous years, although Poland and South Korea would have small patient cohorts and would have only joined in the later years.
What is not understood is why, when the number of newly recruited patients in those years is so few, that a perfomance comparable to 2012 was not attained.
That raises the question “What is an acceptable level of compliance?”. Clearly the higher the better. Acheiving 100% compliance might be an unrealistic goal, although it may well be that some patients and some study sites are consistently achieving that. What is acceptable might vary from registry to registry. Some might accept an 60 to 70% compliance performance.
Overall Alexions AHUS Registry has achieved just short of 80% compliance over 8 years. In the earlier years even higher levels were reached, In year 1 there was over 90% compliance, gold standard. So the Registry could benchmark against itself. There is always the thought that the value of the data about one person with an ultra rare disease is worth the data from thousands of those with very common diseases. So the aim should be to avoid as few valueable missing PROs by making every effort to capture each one and setting a gold standard target, and then strive for excellence.
Overall responsibility for the data in the Registry is Alexion’s and the Registry’s governing committees. Each participating country has a nominated National Coordinator, each with their own hospital site participating in the Registry. National Coordinators are also in contact with the other hospital sites in their own country. Members of the Registry’s scientific advisory board are also based at hospital sites included in the Registry. There are now only 128 active study locations, of which only 65 potentially are still recruiting. Collectively there is a duty by all to ensure quantity and quality of data from those study locations , including data from PROs. For that duty to be discharged management information is essential. (More information about the Alexion Registry governance can be seen on its website using this LINK. )
But what can aHUS patient organisation advocates contribute?
aHUS patient organisations, whether at global or national level, cannot communicate directly with the patients enrolled in the Registry . The confidentiality of participating patients is paramount. It is probably not permitted ,nor practical, in a non interventional observational study to seek anonymous views and feedback from those patients who are participating through a patient poll distributed via their hospitals.
The only clue In the public domain for aHUS patient advocates about where the specific patient audience might be, is the list of hospital sites participating in the trial which is given on the ClinicalTrials.gov website. ( click HERE to see where the current active/recruiting hospital sites are ).
Even so, communication with patients at those sites can only be indirect and broadcasted via the channels that each patient organisatiion has set up both on line and in the social media.
Only one patient organisation has, for the past five years, consistently communicated information about the aHUS Registry to patients and repeatedly acknowledged and encouraged their participation – the aHUS alliance Global Action.
It is through aHUS Global Action that participants would have had the chance to become aware of what research has been published and what that research might have found. A study of the back content of Global Action’s website will reveal the numerous mentions of Alexion’s aHUS Registry ( and other registries). Global Action has featured articles by members of the Registry’s governance team to raise their profile with aHUS patients.
National aHUS patients organisations generally do not provide such formation to patients in their countries. Either because they cannot, or they are not motivated, to do so. There may not even be a national organisation in all of the countries falling within the scope of the Alexion aHUS Registry, or if there is, one with a large enough outreach.
Even if they were , collectively, existing aHUS patient organisations, cannot realististically outreach to all aHUS patients in that Registry, some but not all. The majority of aHUS patients, including many of those within the Registry, will have no contact with patient advocacy groups. This may be because they are not aware of such advocacy groups, or because they do not want to be aware. There will be little outreach about the Registry to aHUS patients in not just Poland and South Korea but also in Belgium and France. France is particularly important , given France’s dominant hospital sites and patient numbers in the Registry.
As things stand there may be little more that patient organisations can do to encourage the aHUS Registry cohort, who may be non compliant, to report their outcomes. Nor, if they are not being asked, to apply “pressure” on hospitals and “push” their PROs down the data “pipeline”. It may also be that patient organisation communication particularly by aHUS Global Action has reached those who are compliant and even encouraged them to be so. Global Action might have done all it can do but there may be something that national organisations could do if willing.
In the Global aHUS Poll in 2016, patients gave an opinion on their preferred method for supplying patient reported outcomes data to a registry. Athough some (14%) would prefer to continue to do it using paper versions during their hospital visit , 69% said they would prefer to do it, or would not object to doing it, online. An electronic version of the PROs could help raise compliance and assure patients’ participation. ePROs are something that should be considered in the 2020s. Even some of those preferring to complete PROs during a hospital visit could use a “gadget” whilst waiting in clinic, if safe space permits.
As a patient from Australia said on the aHUS alliance Facebook page last year:
“I get regular questionnaires/surveys to complete -but always sent via post – and they tend to get lost amongst all of my other paper work, hospital and Dr visits, medical bills etc . I’d be more likely to complete something on line”.
It would need investment by Alexion to provide a secure facility/application for use on all “gadgets” used by patients. Alexion has more than one Registry, so ePRO software etc costs could be shared if all use PROs.
The considerable challenges for implementing ePROs cannot be overstated. It would have to be done through the hospital sites. Migration from paper to technology would need a careful patient centred implementation process.
However the technology could help give prompts, immediate acknowledgement and gratitude to patients before and after each submission. Even news bites and info graphics about published research results could be added to keep participants up to date and feel valued. There may even be helpful direction to aHUS patient organisations for those unaware of them.
In conclusion, the data provided by Alexion’s aHUS Registry for aHUS Global Action’s research has shown:
Potential opprtunities for improvement include:
This study has been limited to the PRO reporting compliance of newly enrolled patients into the Registry. It has assumed uniform recruitment across each calendar and that its not skewed to the later months which might have distorted some calendar year results adversely.
In the long term ,however, it would be useful to know what the on going compliance by patients has been after their enrollment year and for that similar data for the cumulative PROs would be needed. It would also be helpful to know the distribution of non compliance across all active sites, including those not recruiting, so that more targeted action can be deployed to improve compliance.
aHUS patients have said that the impact of their disease matters to them and have expressed a support for Research and Registries to give them answers. Some of those answers will come collectively from patients themselves in the Alexion aHUS Registry. Full understanding will depend on their PRO data getting into the Registry and providing an informed patients’ voice answering “how are you all doing?”.
In Part 4 an example of how PRO data has been used by the Alexion aHUS Registry is discussed.