Rheumatoid Arthritis Clinical Trial
Official title:
Comparative Effectiveness and Safety of Biosimilar and Legacy Drugs
In Canada and worldwide there is a need for updated independent real-world comparative
effectiveness and safety data related to biologic drugs including biosimilar drugs.
Biosimilar drugs hold potential to improve access to needed therapies at reduced cost
enabling savings to be reallocated to other needs. However updated real-world evidence on
comparative effectiveness and safety of biosimilar drugs is lacking. Investigators aim to
demonstrate feasibility of creating network of clinical cohorts and other resources to
provide real-world information on use of biosimilar drugs in Canada.
The core revolves around clinical datasets but investigators will complement with other data
sources. Investigators will review data from National Prescription Drug Utilization
Information System database that contains prescription claims-level data collected from
publicly financed drug benefit programs in different provinces to conduct an environmental
scan of the use of biosimilars and respective legacy drugs and other anti-Tumor Necrosis
Factor agents covered by provincial drug plans from 2014-2017. Initial analysis will help to
confirm that use of biosimilars is lower than corresponding legacy drugs.
Biologic drugs are relatively new and expensive drugs; biosimilar medicines are similar to
original biologic drugs but cost less. If patients receive biosimilar drugs rather than
originator biologics healthcare systems may be able to save money. Those savings can be used
for other health care needs to benefit more Canadians. However investigators do not have
detailed information on safety and effectiveness of these biosimilar drugs. The aim of study
is to compare safety and effectiveness of biosimilar drugs to originator biologic drugs.
Investigators will study patients with inflammatory rheumatic diseases (RA and AS) and
Inflammatory Bowel Disease (CD and UC) and across Canada on these drugs. Primary focus is on
patients without history of biologic drug use but investigators will also study patients
switching to biosimilar drug from an originator biologic drug. Investigators will measure how
long patients stay on treatment, if patients require new treatment, if the patients' disease
control improves and occurrence of side effects such as infection that could be related to
these drugs.
Research question: What is the comparative effectiveness and safety of biosimilar drugs
versus the equivalent legacy drugs?
Primary aims:
To compare, in biologic-naive patients, new users of biosimilar drugs versus new users of the
equivalent legacy drugs:
1. Frequency of discontinuation of the initial therapy
2. Persistence on the initial therapy (time until drug discontinuation)
3. Frequency of patients starting or increasing prednisone or other immunosuppressive drugs
4. Frequency of and time to discontinuation of treatment due to ineffectiveness
5. Frequency of and time to clinical remission/induction of response
6. Frequency of and time to serious adverse events
Secondary aims
To describe in biologic-naïve patients, new users of biosimilar drugs or the equivalent
legacy drugs:
1. Change in disease activity over time
2. The frequency of, and time to, long-term outcomes (sustained remission, erosions in RA,
radiographic progression in AS, and endoscopic mucosal healing scores in CD and UC).
3. Change in quality of life measures over time
Exploratory aims:
1. To describe the above outcomes in patients switching from the legacy drug, to the
biosimilar.
2. To describe the above outcomes in patients switching from the biosimilar to the legacy
drug Investigators will be working with two types of cohorts; more specifically, new
cohorts collecting data prospectively and established cohorts that will share
retrospective and prospective data as per Data Transfer Agreements. Data from these
cohorts will be analyzed together.
Specific Outcomes
1. Discontinuation of initial therapy, measured as the number of patients who discontinued
the initial treatment during the follow-up period.
2. Persistence on the initial therapy, defined as the time in months from cohort entry
until drug discontinuation/switching.
3. Frequency of patients starting or increasing prednisone or other immunosuppressive drug.
4. Frequency of treatment failure, measured as the proportion of biosimilar or legacy drug
patients who discontinue treatment due to ineffectiveness during follow-up.
5. Time to treatment failure, measured in months from drug initiation until treatment
failure.
6. Frequency of clinical remission, measured by disease-specific measures including for RA,
the Disease Activity Score (DAS28), and Simple Disease Activity Index (SDAI); the
Spondylitis Disease Activity Score (ASDAS), the Assessment in SpondyloArthritis
International Society (ASAS) response criteria, Bath Ankylosing Spondylitis Functional
Index (BASFI), Stoke Ankylosing Spondylitis Spine Score (mSASSS) and Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) in AS; Crohn's Disease Activity Index
(CDAI), Harvey-Bradshaw Index (HBI) for CD and Mayo or Partial Mayo Score (PMS) for UC.
7. Serious adverse events (SAEs), measured as the proportion of patients in each group
presenting with an AE that is fatal or life-threatening, requiring or extending a
patient's hospitalization, resulting in persistent or significant disability or
incapacity, inducing a congenital anomaly or birth defect, or otherwise be considered
important by the physician.
8. Long-term outcomes: frequency of sustained remission, presence of erosions in RA and
radiographic progression in AS, and improvement or normalization of C-reactive protein
and fecal calprotectin.
9. Patient-reported change over time in the EuroQol-5D (EQ-5D), the Health Assessment
Questionnaire Disability Index (HAQ-DI), the Short Inflammatory Bowel Disease
Questionnaire (SIBDQ), Visual Analogue Scale (VAS) and the veterans RAND 12 (VR-12).
OBJECTIVES
The primary objectives are to compare, in biologic-naive patients, new users of biosimilar
drugs versus new users of the equivalent legacy drugs:
1. Frequency of discontinuation of the initial therapy
2. Persistence (time until drug discontinuation) for the initial therapy
3. Frequency of patients starting or increasing prednisone or other immunosuppressive drugs
4. Frequency of and time to discontinuation of treatment due to ineffectiveness
5. Frequency of and time to
1. Induction and maintenance of response
2. Clinical remission and sustained clinical remission
6. Frequency of and time to serious adverse events.
Methods
Enrolment:
Investigators are working with pan-Canadian, prospective cohorts of patients with
inflammatory rheumatic diseases (rheumatoid arthritis, RA, and ankylosing spondylitis, AS)
and Inflammatory Bowel Disease (IBD) (Crohn's disease, CD, and Ulcerative Colitis, UC).
Cohort members eligible for our study are patients starting treatment with any biosimilar or
any legacy drug. Patients will be enrolled over an approximate 24 month-period and the
follow-up period will be up to four and a half years.
Patients will be followed for a maximum period of four and a half years for the study
including patients who permanently discontinue the biosimilar or equivalent legacy drug
treatment. Data for the study will be entered at enrolment and then approximately every 3
months in the first year of follow-up and then every 6 months thereafter up to 24 months. To
complement information collected by each cohort, patients' data obtained from administrative
health databases, including hospitalizations, physician billing, and prescription drugs will
also be collected. For those patients who reach the 24-month mark before the end of our study
(Dec. 2022), investigators will continue to collect data at yearly intervals (with a final
data collection at month 54) so that an exploratory analysis of outcomes beyond 24 months can
be done. Off protocol visits for patient reported increases in disease activity will occur as
clinically indicated, but no additional data are required for collection.
Statistical analysis
As mentioned earlier, the primary analyses will focus on biologic- naïve patients prior to
starting one of the drugs under study. Secondary analyses of non-biologic naïve patients will
be done, adjusting for number of prior biologics at baseline.
Baseline characteristics will be presented using descriptive statistics to compare the two
treatment groups. All continuous data will be expressed as the median (with range or
interquartile range, IQR) or mean (with standard deviation SD) when appropriate. Categorical
data will be presented as counts and percentages. Further descriptive comparisons of
follow-up data will include: mean and cumulative doses, augmentation/reduction of therapy,
and initiation or changes in the dose of prednisone and DMARDs/immunosuppressive agents.
In univariate analysis, groups will be compared in terms of frequency of treatment
discontinuation for any reason, treatment failure due to ineffectiveness, and the occurrence
of AEs including SAEs. Clinical remission, disease progression, and patient-reported outcomes
will be assessed at time points during follow-up. Disease damage will be assessed through
presence of erosions/radiographic progression in RA and AS, and specific surgeries (joint
replacements in AS and RA, abdominal surgery for CD and UC).
For the continuous variables, the change over time between the two groups will be analysed
using linear mixed models for repeated measures. Fixed effects of time will be estimated, and
diagnosis, sex and age will be included in the analysis as possible effect modifiers.
Kaplan-Meier curves will be used to compare time from cohort entry to: i) treatment
discontinuation/switching for any reason, ii) treatment failure due to ineffectiveness; iii)
first episode of clinical remission, iv) SAE v) disability. Additional Kaplan-Meier curves
will be plotted to compare time under sustained remission (from first remission until loss of
effectiveness).
Then the same outcomes will be assessed using multivariate survival analyses during
follow-up. In these analyses, the main exposure will be modeled as binary time-fixed
indicator of drug used at cohort entry, as well as time-dependent cumulative duration and
time-dependent cumulative dose of the biosimilar and the legacy drug. Survival analysis (Cox
regression model) will be conducted to evaluate the risk of any SAE during follow-up.
Separate Cox regression analysis will be conducted to evaluate the risk serious infection
(defined as those requiring a hospitalization, emergency visit, or intravenous antibiotics),
malignancies, and congestive heart failure, during the observational period. All models (for
effectiveness and safety analyses) will be adjusted for the baseline covariates: sex, age,
race/ethnicity, education, smoking, comorbidities, disease duration, disease activity,
non-biologic or biologic DMARDs drugs, steroids, NSAIDs and COXIBs.
KNOWLEDGE TRANSLATION (KT) PLAN The results of this project will be disseminated in part
through traditional methods of dissemination, such as publication in peer reviewed and open
access journals and abstracts submitted to national and international meetings. The advisory
committee will also advise on the development, implementation and progress of KT activities
in this project. Investigators will provide updates to Health Canada via the DSEN
coordinating office in two formats: quarterly interim reports and a final report. Through
quarterly interim reports investigators will share information on the status of the project,
provide early results from preliminary analysis, as well as inform DSEN about potential
modifications of project milestones and/or research protocols as needed. Investigators will
also provide a final report, and make use of DSEN contacts with policy makers to ensure that
results are adequately disseminated. Dissemination to a wide audience (researchers, policy
makers, and other stakeholders) at DSEN-sponsored workshops (such as those held in the
context of annual meetings of CADTH and the Canadian Association for Population Therapeutics
[CAPT]) may also be possible.
A novel element of our KT plan will be the presentation of the preliminary and final results
at stakeholder workshops. The presentation will help investigators gather information from a
wide range of stakeholders (patients, physicians, and policy makers) regarding reasons for
our results.
SUMMARY With this proof of concept project, investigators aim to demonstrate the feasibility
of creating a network of clinical cohorts and other resources to provide real-world
information on the use of biosimilar drugs in Canada. The core of the proposal revolves
around the clinical datasets, but as investigators will complement that with analyses of
national drug patterns using NPDUIS data. CAN-AIM is well-positioned to develop an effective
program of research and surveillance related to biologic and biosimilar drugs.
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