Study type

Study topic

Disease /health condition
Human medicinal product

Study type

Non-interventional study

Scope of the study

Assessment of risk minimisation measure implementation or effectiveness
Disease epidemiology
Drug utilisation
Effectiveness study (incl. comparative)
Method development or testing
Safety study (incl. comparative)

Data collection methods

Secondary data collection
Non-interventional study

Non-interventional study design

Cohort
Other

Non-interventional study design, other

External control arm study
Study drug and medical condition

Anatomical Therapeutic Chemical (ATC) code

(A10BH) Dipeptidyl peptidase 4 (DPP-4) inhibitors
(A10BK) Sodium-glucose co-transporter 2 (SGLT2) inhibitors
(J01) ANTIBACTERIALS FOR SYSTEMIC USE
(J01MA) Fluoroquinolones

Medical condition to be studied

Type 2 diabetes mellitus
Amyotrophic lateral sclerosis
Breast neoplasm

Additional medical condition(s)

Cardiac arrythmias, Peripheral neuropathies, Drug-induced liver injury, Cardiac failure, Sudden cardiac death
Population studied

Short description of the study population

The source population come from health registers for the entire adult population (≥18 years) in Denmark, Finland, and Portugal and from claims records of public health insurance providers in Germany (~90% of population). Populations studied vary by use case, see settings below.

Age groups

Adults (18 to < 46 years)
Adults (46 to < 65 years)
Adults (65 to < 75 years)
Adults (75 to < 85 years)
Adults (85 years and over)

Estimated number of subjects

88000000
Study design details

Study design

See study protocols.

Main study objective

The study develops tools & technologies for the effective analyses of real-world data (RWD) in regulatory decision-making & HTA based on four highly relevant uses cases along the pre-& post-authorisation steps of the product life cycle. Portugal, Finland, Denmark, & Germany provide routine care RWD.

Setting

Adult population (≥18 years unless otherwise specified).
Inpatient and outpatient data is used.

Setting varies by use case, in short:
1&2: a) persons diagnosed with incident primary breast cancer and external controls,
b) persons diagnosed with incident ALS and external controls,
3. persons with prescriptions of oral antibiotics,
4. persons with prescriptions of noninsulinic antidiabetes drugs (≥40 years).

Study period:
for use cases 1&2: 2000/2005/2008*-2021;
for use case 3: 2010-2021*;
for use case 4: 2012-2021*.

*depending on data availability

Comparators

Use case 3: fluoroquinolones compared to active comparators
Use case 4: SGLT-2 inhibitors compared to active comparators

Outcomes

For details, see protocols.

Use case 1&2: incidence, prevalence, survival time, mortality; further outcomes see protocol;

Use case 3: number of prescriptions, trends in user characteristics, sudden cardiac death or cardiac arrhythmia, sudden cardiac death, aortic aneurysm and dissection, acute toxic liver disease, polyneuropathy;

Use case 4: proportion of SGLT-2 inhibitor prescription/non-insulin antidiabetic prescriptions, change in user characteristics, hospital admission, heart failure diagnosis, mortality.

Data analysis plan

* Define a simplified common data model based on OMOP to harmonise metadata

Use Case (UC) 1

* Determine the population as well as rates of occurrence and outcome using the STROBE standards (Strengthening the Reporting of Observational studies in Epidemiology).

* Examine heterogeneity within the dataset, including coding practices in the four partners, representativeness etc.

UC 2

* Develop a workflow to subset and display RWD by user definable inclusion/exclusion criteria; workflow allows to display summary statistics and disease trajectories of selected patients.
* Construct synthetic and external control arms for RWD ALS patients (based on data from the ProACT database: https://ncri1.partners.org/ProACT) by implementing different propensity score matching algorithms from the literature
* Explore, whether one of the RCTs contained in ProACT can be emulated using RWD, depending on availability of treatments in data

UCs 3 and 4

* Drug utilisation study: description of outcomes:
UC 3: proportion of fluorquinolone (FQ) and comparison antibiotics prescriptions out of all oral antibiotic prescriptions, change in user characteristics;
UC 4: proportion of SGLT-2 inhibitors users and DPP-4 inhibitors users out of all non-insulin antidiabetic drug users, change in user characteristics

* Adverse drug reaction study concerning FQ use (UC 3) and effectiveness analysis concerning SGLT-2 inhibitor use (UC4):

· Use active comparator new user (ACNU) design,

· Derive propensity scores for ACNU design derived from pre-specified covariates using logistic regression,

· Fit IPT-weighted Cox regression (if assumptions are met) for the entire follow-up

· Outcomes:

- UC3: Sudden cardiac death and cardiac arrhythmia, aortic aneurysm and dissection, acute toxic liver diseases (drug-induced liver injury), polyneuropathy (drug-induced peripheral polyneuropathy)

- UC4: heart failure diagnosis, all-cause and cause-specific hospital admissions and mortality.