EUROPEAN SURVEILLANCE NETWORK TO MONITOR THE LONG TERM EFFECTIVENESS AND SAFETY OF SYSTEMIC AGENTS IN THE TREATMENT OF PSORIASIS DRAFT PROTOCOL VERSION: JUNE 2007 OBJECTIVES The main objective is to establish a network of independent European population registries, in order to perform coordinated post-marketing surveillance studies aimed at monitoring the effectiveness and safety of systemic agents, including biologicals (i.e. Tumor Necrosis Factor alpha, TNF- alpha, and T cell targeted molecules), in the treatment of psoriasis.
The network will achieve a critical mass of data through the development of a common
methodological platform allowing collaborative analyses, enabling the conduct of
investigations that would not be feasible in a single country registry. In principle, a
wide range of analyses would be possible, including:
Investigation of the clinical effectiveness of systemic treatments for psoriasis, in a
Identification of prognostic factors that can help in predicting the response to
Monitoring of adverse effects of systemic treatments, with particular attention to
long-term and rare adverse events, including infections, lymphomas and other cancers.
Once the network has been established, it may be extended, with relative ease, to the
monitoring of new therapeutic agents introduced in the future, and serve as a model
for pharmacoepidemiology and independent post marketing surveillance in Europe.
Moreover, the establishment of durable connections within a multidisciplinary group of
European investigators sharing resources and activities may enable the nesting of
biological studies within an epidemiological framework and the mounting of
independent pragmatic randomised clinical trials to assess the advantages of different
BACKGROUND AND RATIONALE
The prevalence of psoriasis in Europe is about 2-3%, and about 10-20% of affected
patients have severe or complicated disease (Naldi, 2005). Thus, it is estimated that out
of 815 million people in Europe (year 2000), 1.6 to 4.8 million persons suffer from
severe psoriasis, a condition that has a dramatic impact on the quality of life of
A genetic component in psoriasis is simply suggested by the fact that about one third of
affected individuals reports a family history of the disease. In recent decades, a number
of genetic loci have been associated with psoriasis and specific steps in disease
development have been clarified. Physical traumas, acute infections, use of selected
drugs (e.g. lithium salts) and stressful events can be triggering factors, and cigarette
smoking and high body mass index are well recognized risk factors.
The treatment of psoriasis has long been based on laborious topical treatments that
could assure, at most, a short term clearance of the lesions. Better control of disease
activity could be obtained by more recently introduced treatment options, such as UVB
phototherapy, PUVA therapy, methotrexate, ciclosporin and, in German speaking
countries, of fumaric acid derivatives. However, the safety profile of these treatments is
less than optimal, and they have thus been reserved to the treatment of moderate to
In more recent years, a number of molecules which specifically target steps deemed to
play a crucial role in the inflammatory process of psoriasis have been developed with
the expectation of offering a more effective and less toxic treatment for psoriasis (Stern
2003). The molecules which are collectively named as “biologicals” since they are
derived from live organisms or their products, include at this time agents that modulate
T cell functions by acting on co-stimulatory molecules, e.g., efalizumab or alefacept and
antagonists of the proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha),
e.g., infliximab and etanercept. Infliximab, etanercept and efalizumab, have recently
entered the European market being registered by the European Agency on Medications
(EMEA) for "treatment of moderate to severe plaque psoriasis in adults who do not
respond or present contraindications or intolerance to other systemic therapies,
including cyclosporine, methotrexate or PUVA therapy". Paradoxically, such an
indication is not supported by firm evidence from available pre-registration clinical
trials, where moderate to severe psoriatic patients were included without any
consideration of previous response to conventional systemic agents. This may translate
into patients treated with biological agents in Europe, who have a higher co-morbidty
rate or are clinically more complex than patients studied in pre-registration trials.
The clinical experience on the use of biological treatments in dermatology is limited.
Efficacy has been evaluated only in the context of placebo controlled randomized
clinical trials lasting for no longer than 24 weeks.
With a few exceptions (e.g., PUVA therapy), medium to long term safety data derived
from observational studies of systemic agents used in psoriasis are lacking. As far as
biological agents are concerned, pharmaceutical companies are committed to set up
phase 4 post-marketing programmes. However, these programmes do not seem to
address the crucial issue of obtaining comparative safety data in a timely fashion and
reliable estimates of rare events, as indicated by the examples below concerning
studies planned for US approved biologicals (Stern, 2005):
Efalizumab - due 3/31/2014
5–year surveillance study of patients who have received at least one dose of the drug
Alefacept - due 7/31/2010
After 2 years (March 2005), 657 enrolled
Etanercept – due 9/30/2013
2500 patients, not previously treated with etanercept
The potential for rare but severe delayed adverse events of biological agents, such as
severe systemic infections and selected cancers (e.g., lymphomas) has been suggested
based on theoretical considerations and case reports (Hochberg et al 2005). More
alarmingly, a systematic review using data from randomized controlled studies on the
efficacy of anti-TNF antibody therapy (infliximab and adalimumab) in rheumatoid
arthritis based on 3493 actively treated patients and 1512 patients who received
placebo, found an increased risk of serious infections and a dose-dependent increased
risk of malignancies, mostly lymphomas and basal cell carcinomas of the skin, in
actively treated patients (Bongartz et al, 2006).
The study of the safety profile of systemic agents for the treatment of psoriasis is
hampered by the fact that the risk factors for psoriasis are common to several other
diseases, including several cancer types, that the disease itself may influence the risk of
developing cancer or other severe diseases, and that generally, prior therapies may
also lead to adverse effects. Thus, disentangling the effects due to biological agents
from those due to shared risk factors, the disease itself or the effects of prior therapies
is complex and only carefully designed studies, with large numbers of patients and
entailing the collaboration of several experts from various disciplines (dermatologists,
pharmacologists, epidemiologists, statisticians etc.) can provide useful information on
the safety profile of biological agents. Moreover, even a national registry might not be
able to provide meaningful information on rare adverse events in a reasonable time
Registries of biological treatments for psoriasis (and – for some registries – for other
conditions, such as rheumatoid arthritis) have been established or are being activated
in different European countries (Smith et al 2005, Schimtt-Egenolf 2007, Psocare 2004).
Given the recent introduction of biological agents in the treatment of psoriasis, the
registries have started very recently, or are in the process of being set up. There is
hence a unique opportunity to establish a network to allow collaboration between the
different independent registries, in order to organize data collection in a fashion that
will allow an easy pooling of data, as well as develop shared resources and activities
with the aim of avoiding duplication of effort, maximising efficiency and sharing and
Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid
arthritis and the risk of serious infections and malignancies. JAMA 2006;295:2275-85.
Hochberg MC, Lebwohl MG, Plevy SE, et al. The benefit/risk profile of TNF-blocking
agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819-36.
Naldi L. Epidemiology of psoriasis. Curr Drug Targets Inflamm Allergy. 2004;3:121-8.
Psocare. Valutazione degli esiti dei trattamenti per la psoriasi in Italia. BIF 2004;XI (5-
Schimtt-Egenolf M. PsoReg – The Swedish Registry for systemic psoriasis treatment.
Schimtt-Egenolf M. Psoriasis therapy in real life: the need for registries. Dermatology
Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists guidelines
for use of biological interventions in psoriasis 2005. Br J Dermatol. 2005;153:486-97.
Stern RS. Psoriasis therapy. Out with the old in with the new? Presentation at the
symposium Evidence, guidelines and practical use of systemic psoriasis therapies.
Stern RS. A promising step forward in psoriasis therapy. JAMA 2003;290:3133-5.
IMPLEMENTATION PLAN General outline of the project
The project is composed of the following components:
A survey of national registries of systemic treatments for psoriasis in Europe and
establishment of an international collaboration;
Implementation of study procedures to merge selected national data into an
international database to be regularly updated;
Conduct of analyses to assess specific safety issues for systemic agents used in
psoriasis, including biological agents, with particular attention to rare and/or late
events, e.g., infections, cancers, and interaction with other treatments and risk factors;
Conduct of analyses to assess the comparative value of different systemic agents for
the treatment of psoriasis and to assess prognostic factors for disease response and
An International Coordinating Committee will be established including
representatives of national registries and, in some instances, national
pharmacovigilance centres. The Coordinating Committee will be responsible for the
overall monitoring of the project, including the definition of working groups on specific
issues, the definition of data management and analysis, the approval of reports and
published papers, privacy and ethical issues.
Survey of national registries
A survey of the organisation of registries of systemic treatments for psoriasis in
different European countries will be conducted. The person responsible for each
identified registry will be contacted and asked to complete a brief description of the
organisation of the national registry (number of employees, sources of support, storage
methodologies, entry criteria, variables collected and timing and modalities of follow up,
and the number of patients included annually). Those registries satisfying pre-defined
organisational criteria will be further contacted and asked to participate in the
international collaboration programme. An agreement to share selected data from the
registry in the international collaboration programme over a pre-defined time interval
should be signed by the registry manager.
Implementation of study procedures Entry criteria and follow-up The study population in the participating countries will consist of all the subjects with
active psoriasis who receive, for the first time in their life, at least one single dose of a
new systemic agent for psoriasis (the collection may be limited to biological agents in
some countries). Only patients recruited within the national registries will be considered
for inclusion. In addition, patients treated for rheumatological conditions by systemic
drugs may be considered for inclusion for specific comparative analyses.
Common definitions for variables such as "disease severity" and "response to
treatment" will be adopted. Uniform coding strategies should be better developed.
Internal consistency checks will be also defined.
Follow up procedures implemented in the context of the different national European
registries will be made as similar as possible. Active follow up (at least one contact per
year) with minimum loss to follow up (less than 20%) will be aimed for.
Definiton of the minimum set of variables to be merged Although each registry will decide independently on data collection and criteria for
patient enrolment, a minimum set of data to combine in an international database will
be defined in advance, as well as recruitment criteria and follow-up modalities.
The minimum set of variables to be shared among databases will include:
1. Patients’ socio-demographic characteristics (age, gender, profession, marital status) personal habits (smoking, alcohol consumption), anthropometric variables (weight and
2. Psoriasis and its characterization (date of reported onset, date of diagnosis, type of psoriasis, maximum extent), previous systemic treatments (for each treatment
modality, date of first exposure and date of the last exposure): in the case of
rheumatological conditions, similar data will be collected for disease characterization;
3. Selected co-morbidities (cardiovascular disease, systemic infections, cancer and their date of diagnosis);
4. Systemic treatment for psoriasis at entry (drug and dosage) and updates on systemic treatments for psoriasis during follow-up. In case of rheumatological
conditions, similar data will be collected on systemic treatment at entry and follow-up;
5. Diagnosis of selected diseases during follow up (date at diagnosis, diagnosed condition with particular attention to infections and cancer)
6. Any relevant suspected adverse event associated with treatment (date of diagnosis, kind of event)
7. Remissions and severe relapse of disease during follow-up Pooling of individual patient data from national registries At regular intervals, selected individual patient data will be extracted from national
registries and prepared in a standardized form. These data will be included in a
centralized database, under the control of the International Coordinating Committee,
with appropriate insurance of data confidentiality. Consistency checks of the data will
be performed and simple descriptive tables of the data collected will be prepared and
circulated among participants after each update.
General issues on analyses and statistical power Both internal and external comparisons can be made. Internal comparisons will
involve analyses of event occurrence in groups defined by different dosages/duration of
treatment and/or different drugs. External comparison, to be conducted with caution,
will be made by considering incidence rates in selected population samples. For rare
events such as cancer incidence, only marked increases of incidence (i.e., twice or
more) with respect to the general population could be detected by our system.
In general, the analyses will be split into different steps. A first phase will usually
consist of descriptive analyses. A further stage will consider simple univariate analyses.
Finally, in-depth analyses centered around specific questions and using more powerful
analytical methods, e.g., multivariate models, will be adopted.
Evaluation of the safety profile of systemic agents Eligible subjects: All the subjects available in the international database who have received at least one
single dose of a prescribed systemic agent for psoriasis or rheumatological conditions in
the participating countries will be eligible for the analyses of safety.
Outcome The primary outcome will be represented by selected adverse events. As far as
biological agents are concerned, those of primary interest include: systemic infections,
cancer diagnoses, and specific organ involvement or failure (cardiovascular, skin, liver,
Data collection Diagnoses will be reviewed by an International Safety Review Board. According to the
clinical diagnosis, additional information may be required with retrieval of information
from medical records, family doctors or directly from the patient.
For the collection of comparative data other sources of information may be considered,
including routinely collected data (mortality data, hospital admissions), and Cancer
Data analysis Basic descriptive tables presenting numbers of events, ordered by type of disease and
therapeutic agent will be prepared at every update of the central database. Rates
(standardised by sex and age as appropriate) per 1,000 treated patients will be also
Subsequently, internal comparisons taking into consideration patients receiving
different systemic treatments will be conducted. According to the adverse event of
interest, various analytical methods may be evaluated. These may include longitudinal
analyses of patients’ cohorts, nested case-control studies, or case-crossover design (the
latter when dealing with acute events and frequent changes of therapies). In any case,
the observational nature of the study implies a careful consideration of possible sources
Comparisons with data from sources external to the international database may be also
considered. In countries/regions covered by cancer registries, standardized incidence
ratios for lymphomas and other cancers may be computed (i.e. the ratio between the
observed number of cases and the number expected using the sex and age specific
incidence data from the cancer registry). In areas not covered by cancer registries the
possibility of using national or local estimates of incidence will be investigated.
For severe infections, and other possible events of interest, observed and expected
hospitalization rates, using hospital admission data, may be considered. Other data
sources for the estimation of expected numbers of events e.g., published and grey
literature, ad hoc surveys etc. will also be investigated. Temporal relation between administration and outcome occurrence, dose-response
profiles, biologic plausibility, confounding effects of the disease itself, or other
treatments, or other potential confounding factors will be evaluated.
International Safety Review Board The steering committee will appoint an International Safety Review Board that will be in
charge of reviewing safety data and will help preparing periodic safety reports. This
committee will also be in charge of setting up procedures for the prompt identification
and investigation of unexpected alarming events.
Evaluation of the effectiveness of systemic agents for the treatment of psoriasis and prognostic factors Eligible subjects: All the subjects available in the overall database with a diagnosis of psoriasis who have
received at least one single dose of a prescribed systemic agent for psoriasis in the
participating countries will be eligible for effectiveness analysis.
Outcome Outcome variables will include overall assessment of response to treatment as judged
by patient and physician and changes in indicators of severity (e.g., PASI score).
In the long term, simple and cheap outcome measures applicable in all patients seem
to be preferable. These may include the number of patients in remission, the number of
major disease flare ups, survival within the originally administered therapy, switch to
another drug or drug withdrawal because of a lack of response.
Data collection The centralized database will provide data for the effectiveness analyses. Individual
registry data may contain different pieces of information concerning the outcomes of
interest. Standardisation will be attempted as much as possible.
Data analyses An overall description of the outcomes for each systemic agent will be regularly
prepared. Data will be initially stratified by age and sex, and then by several other
comparison of effectiveness between different agents
overall estimation of short term response rates in a general population setting, as
compared to the estimates derived from controlled clinical trials.
evaluation of the impact of the therapies in groups generally excluded from clinical
studies, eg. patients with multiple diseases, older subjects, etc
identification of prognostic factors for the response to the treatment
identification of groups of patients at higher risk of non response, complications and
The outcome of patients receiving different therapeutic regimens will be compared after
adjustment for the most important covariates (eg. age, sex, severity of disease, prior
treatments, etc). Univariate and multivariate analyses will be performed, also by means
of regression models for longitudinal data, including when needed, time-dependent
covariates. Given the observational nature of the study, specific attention will be
devoted to the investigation of possible sources of bias and the confounding effect of
The drugs involved are licensed in Europe for the use in psoriasis and are available on
the market. All the procedures involved in the different national registries should be
part of the usual care of the patients. Patient will be informed that his/her medical
records will be anonymously utilised for an international observational study and
consent obtained. For the identification of the case report forms only initials and date of
Dissemination of results
Results will be made available to the scientific community and, according to pre-defined
criteria, to the general public. Dissemination means may include:
presentation of data in a project’s website
collaboration with pharmacovigilance units in different countries and EMEA
collaboration with patients’ organizations.
Annex 2 - Survey of registries of systemic treatments for psoriasis in Europe Registry already established? Coverage of the Systemic treatment Modality of data collection registry considered Portugal
Waiting for an answer from the Direction of the Portuguese Group of Psoriasis
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