Database of UK recipients of pituitary-derived human growth hormone

University College London (UCL) requires access to NHS England data for the purpose of establishing two databases consisting of UK recipients of pituitary-derived human growth hormone.

The following is a summary of the aims provided by UCL:

Between 1959 and 1985, nearly 2000 individuals in the UK were treated with human growth hormone extracted from a gland in the brain (the pituitary gland) of people who had died. This treatment was called pituitary-derived growth hormone (also known as cadaveric growth hormone). The treatment was given for severe short stature, particularly if caused by growth hormone deficiency. It was given by several injections per week over months or years.

Some people who received this treatment went on develop a disease called iatrogenic Creutzfeldt-Jakob Disease (CJD). This occurred because some batches of pituitary-derived human growth hormone were contaminated with an abnormal form of one particular protein, called the prion protein, which went on to cause their disease. Recent research suggests that people who received pituitary-derived human growth hormone might also be at risk of a newly described disease, iatrogenic cerebral amyloid angiopathy. This is a disease associated with strokes caused by bleeding in the brain, as well as seizures (or fits) and cognitive changes. UCL believe this disease is caused by transmission of another abnormal protein, called amyloid-beta. We now know that pituitary-derived human growth hormone can also cause iatrogenic Alzheimer’s disease, which is also caused by transmission of amyloid-beta. It is possible that proteins other than amyloid-beta might also have been transmitted via pituitary derived human growth hormone, although there is no evidence that this has occurred in people yet. For these reasons, UCL are interested in monitoring the long-term health of people who were treated with pituitary-derived growth hormone, particularly with regard to neurological conditions caused by abnormal protein aggregates.

In order to better understand whether people who received pituitary-derived human growth hormone are at risk of neurological conditions other than iatrogenic CJD, the study team will create two research databases. Both of these use data from a pre-existing historical database currently held by UKHSA (the UK Health Security Agency) on behalf of DHSC (the Department of Health and Social Care).

1. “Surveillance Snapshot” Research Database

• This database will be used for the purpose of investigating whether people who received pituitary-derived human growth hormone have been affected by diseases caused by iatrogenic protein transmission, other than those caused by the prion protein, by:

i. Quantifying mortality due to neurological conditions (particularly stroke and dementia); comparison of mortality rates in those receiving high-risk preparations (i.e. those in which proteins associated with neurodegeneration have been found, such as Hartree-modified Wilhelmi preparations) vs others; review for dose effect

ii. Review of NHS hospital activity, including admissions, emergency attendances and outpatient appointments, for neurological symptoms and diagnoses; comparison of activity in those receiving high-risk preparations (e.g. Hartree-modified Wilhelmi) vs others; review for dose effect

- Only individuals based at the Medical Research Council Prion Unit at University College London (UCL) will be permitted to access to the “Surveillance Snapshot” database.

- The ”Surveillance Snapshot” database will not be used for any additional purposes, other than the purpose described above.

2. “Permission to contact” Research Database

• Demographics data will be used to create a new database of patients who consent to be contacted for future research studies.

- When the database is established and explicit consent obtained from individuals, external organisations may request access to the database.

- Subject to ethical approval and a Data Sharing Agreement (DSA) being in place between the requesting organisation and UCL, the requestor will be provided contact details (email address, phone number etc) of those individuals who provided explicit consent to be included in the database...

- The contact details shared, will have been provided through explicit consent by the individual who gave permission to be added to the “Permission to Contact” Database. No data sourced from NHS England can be requested or accessed by applying organisations.

- Once the Demographics has been used for the stated purpose, the “Permission to contact” database will no longer contain NHS England data. Non-respondents data will have been deleted and only details provided directly by consented participants will be held in this database.

The following NHS England Data will be accessed:

• Hospital Episode Statistics (HES) - Admitted Patient Care, Accident & Emergency and Outpatients – necessary for comparison between people who received high-risk growth hormone preparations (i.e. those in which proteins associated with neurodegeneration have been found, such as Hartree-modified Wilhelmi preparations). Also, necessary to review for dose effect (i.e. whether increasing number of treatments with high-risk preparations shows an association with neurological hospital episodes), if the number of events allows for this.

• Emergency Care Data Set (ECDS) – necessary for comparison between people who received high-risk growth hormone preparations (i.e. those in which proteins associated with neurodegeneration have been found, such as Hartree-modified Wilhelmi preparations). Also, necessary to review for dose effect (i.e. whether increasing number of treatments with high-risk preparations shows an association with neurological hospital episodes), if the number of events allows for this.

• Civil Registration Deaths – necessary for comparisons between people who received high-risk growth hormone preparations. Review for dose effect (i.e. whether increasing number of treatments with high-risk preparations shows an association with neurological mortality), if the number of events allows for this.

The HES/ECDS and Civil Registration Deaths data will be exclusively used in establishing the “Surveillance Snapshot” database and subsequently investigating the research question described above. The use of HES/ECDS and Civil Registration Deaths data is not permitted as part of establishing the “Permission to Contact” database.

• Demographics - necessary for contact of data subjects via GPs for informed consent to be a part of the "permission to contact" database. This dataset will be used exclusively in establishing the “Permission to Contact” database, these Data must not be used in establishing the “Surveillance Snapshot” database.

The level of the Data will be:

• Identifiable – necessary to confirm linkage accuracy in order to establish the “Permission to contact” research database.

The Data will be minimised as follows:

“Surveillance Snapshot” and “Permission to contact” database

• Limited to a study cohort consisting of all recipients of pituitary-derived human growth hormone between 1959 and 1985.

University College London (UCL) is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The funding comes from multiple sources. Current funders include:

• Alzheimer’s Research UK – Funding is in place until January 2026 .

• Stroke Association – Funding is in place until August 2026.

Funding to continue the work described will be sought on an ongoing basis.

The funders will have no ability to suppress or otherwise limit the publication of findings.

The UK Health Security Agency (UKHSA) is a processor acting under the instructions of UCL. UKHSA is Data Controller for the historical database containing details of recipients of pituitary-derived human growth hormone. UKHSA will extract identifiers for data linkage, and receive linked data from NHS England; they will then add variables of interest (relating to growth hormone administration, match certainty, study ID) and pseudonymise the dataset prior to transfer to UCL.

Amazon Web Services (AWS) is a processor acting under the instructions of UCL solely to host encrypted backup data from the Data Safe Haven.

Data will be accessed by:

• PHD students enrolled with UCL. Any student working with the Data held under this Data Sharing Agreement (DSA) must have completed relevant data protection and confidentiality training and are subject to UCL's policies on data protection and confidentiality. Any students accessing the Data will do so under the supervision of a substantive employee of UCL. UCL would be responsible and liable for any work carried out by students. These students would only work on the Data for the purposes described in this DSA.

• An individual holding an honorary contract under the supervision of a substantive employee of UCL for the purposes described in this DSA only. UCL must maintain records in a single location that cover the following details of each individual given access under an honorary contract:

o Their substantive employer;

o Their role in respect of the purpose for the processing specified in the DSA;

o The start date and end date of the duration in which the Data will be accessed by the individual under an honorary contract;

o The necessity for the Data to be accessed by the person(s) holding an honorary contract, instead of a substantive employee of an organisation named as controller or a processor in this DSA;

o Confirmation that an appropriate contract is in place which follows the relevant guidance and is countersigned by the substantive employer of the honorary contract holder.

A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above.

UCL have spoken to different groups of people who might be familiar with certain aspects of this lived experience; UCL are grateful for their help in designing this proposal.

• UCL discussed ethical considerations with a focus group, with participants from the CJD Support Network; attendees included a relative of a recipient of pituitary-derived human growth hormone who died of iatrogenic CJD; people “at risk” of developing CJD (genetic risk); people who had lost family members to CJD.

• The “Stroke Voices in Research” patient and carer group, coordinated by the Stroke Association, reviewed UCL's study materials for accessibility

• UCL received input from a recipients of pituitary-derived human growth hormone on this proposal and how it might be improved

UKHSA will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, and name) for the cohort to be linked with NHS England data.

NHS England will provide the relevant records from the HES, ECDS, Civil Registration Deaths and Demographics datasets to UKHSA. The Data will

• contain directly identifying data items including Names, NHS Number, Date of Birth, Postcode, Gender which are required to link to growth hormone data held by UKHSA, in order to establish the “Permission to contact” database.

The “Surveillance Snapshot” database will:

• contain no direct identifying data items but will contain a unique person ID which can be used to link the Data with other record level data already held by the recipient

UKHSA will extract a further subset of the Data (details of growth hormone administration including indication for administration, dates of treatment, batches administered; match flag) to generate a pseudonymised dataset, and will securely transfer this to UCL to perform analysis within the “Surveillance Snapshot” database.

For the “surveillance snapshot” database, all analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

The “permission to contact” database, which includes identifying details, will be stored in a separate database to the “surveillance snapshot” dataset. This will be used for the purpose of contact only. The identifiable data will be used to initiate contact with data subjects via their GP, to request their consent to be in the database. Data subject’s will be removed from the “Permission to Contact” database if a) They opt-out of being in the database, or b) Contact is attempted 3-times, and the data subject does not respond.

The Data will be stored on servers at University College London (UCL).

UCL stores Data on the Cloud provided by Amazon Web Services.

Data will be accessed onsite at UCL premises, and by authorised personnel via remote access.

UCL will confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

• Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

• Access controls granting users the minimum level of access required are in place;

• Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

• Multifactor authentication (MFA) is required for remote access;

• Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

• All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England at any time.

Data accessed by individuals with an honorary contract with UCL will act as an agent of UCL at all times under supervision from employees of UCL. Aside from these individuals, access is restricted to employees or agents of UCL.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will be linked at person record level with growth hormone data held by UKHSA on recipients of pituitary-derived human growth hormone with NHS England data. This linkage will be performed by UKHSA.

The “Permission to Contact” database will be linked to growth hormone data, to allocate priority for which data subjects are contacted first (via their GP).

Apart from this linkage, the data will not be linked with any other data.

Researchers from the MRC Prion Unit at UCL will analyse the pseudonymised data within the “Surveillance Snapshot” database for the purposes described above.

Researchers from the MRC Prion Unit at UCL will process the identifiable Demographics data in establishing the “Permission to Contact” database for the purposes described above.

The expected outputs of the processing will be:

• Submissions to peer reviewed journals; anticipated 1 or 2 articles, submitted 12 to 18 months following data receipt by UCL

• Presentations at patient and public engagement events, attended by a side range of stakeholders which might include: recipients of pituitary-derived human growth hormone, their families and carers; general public; representatives from government departments or bodies; relevant charities and funders

• Presentations at appropriate academic conferences.

• A database to be utilised as a resource for health research

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Workshops involving relevant stakeholders, including governmental officials and representatives (e.g. DHSC, UKHSA), advisory committees, charities and other research funders

• Social media

• Public events hosted by the MRC Prion Unit at a UCL open day, which will be attended by a wide range of stakeholders, including patients and carers, charities, researchers, MPs and public health specialists.

• Posters displayed at university research events and conferences

• Press/media engagement

• Reports aimed at recipients of pituitary-derived human growth hormone, their families and carers

UCL estimate that outputs will be produced 12 to 18 months after data receipt by UCL, with dissemination immediately thereafter (likely over a further 12 months).

The potential benefits of this database and subsequent research are:

• To confirm whether recipients of pituitary-derived human growth hormone are at risk of iatrogenic CAA, and if they are, to ensure they can be monitored and receive appropriate clinical care, including interventions that aim to reduce their future risk of stroke

• If recipients of pituitary-derived human growth hormone are at risk of developing iatrogenic CAA, the team intend to educate and update other clinical providers on this risk, so that at-risk individuals can receive relevant information (if they so wish) and care

• To review whether recipients of pituitary-derived human growth hormone are at risk of other neurological diseases caused by iatrogenic protein transmission

• To update public health bodies about these potential risks; it might be necessary to institute new public health measures (for example, relating to instrument sterilisation) in order to prevent future cases of disease

A great deal is unknown about how proteins other than the prion protein result in human disease via iatrogenic transmission; this includes knowledge of which proteins are able to do this in people and what the possible routes of iatrogenic exposure are. Our projects will provide knowledge for the risks associated with pituitary-derived growth hormone, a treatment which is known to have resulted in iatrogenic CJD previously. The “Surveillance Snapshot” research database will establish whether people who received this treatment are at increased risk of neurological disorders compared to the general population, and this information will be used to communicate risk to recipients. In some cases, there might be an opportunity to intervene; for example, if there is evidence of a higher incidence of early onset stroke due to CAA in recipients, the team might approach as yet asymptomatic individuals with advice on blood pressure management and avoidance of medications that increase bleeding risk, in order to reduce their future stroke risk.

Future research involving people in this cohort will be possible because of the “Permission to contact” research database, should people in this database chose to consent for this later work. Our planned studies include biomarkers studies to look for protein transmission, which might be subclinical; this will provide information on which proteins might have been transmitted in people via pituitary-derived growth hormone. For those that are symptomatic with neurological conditions, the team would offer detailed evaluations via our linked NHS services, as well as the option to participate in research studies to better characterise these newly described conditions and their natural history.

Cases of iatrogenic cerebral amyloid angiopathy and iatrogenic Alzheimer’s disease, caused by transmission of amyloid-beta protein, have now been reported. The team do not know the impact that this will have in the UK, in terms of how many people are likely to be exposed to amyloid-beta in the course of historical treatment, or what these causative treatments are. This work will help in specifically quantifying the risk associated with pituitary-derived growth hormone, a treatment which is known to have resulted in iatrogenic CJD previously. People who have received pituitary-derived growth hormone might be asked to take certain measures in the future to prevent further onward transmission. These projects will also contribute to a broader programme of work with additional public health impacts, including those relating to instrument sterilisation and whether current strategies are sufficient to prevent onward amyloid-beta transmission.

The team hope that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Our results are likely to be of interest to the public, and the team will continue to work closely with UCL Media Relations to encourage appropriate reporting of our results. The team will use focused workshops to communicate with policy-makers, governmental advisory bodies and public health officials, and engage with these stakeholders through our annual open day, which is also attended by patients and carers, charities and MPs. The team also plan to share results with patients and the public on social media, using short videos, illustrations, animations and other communication strategies to maximise accessibility and reach. This work is funded by charities (Alzheimer’s Research UK and the Stroke Association) who will also support dissemination of this work to a wide audience.

Yielded Benefits is not a requirement for new applications.