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When clinical trials arent enough
1. Postmarketing Studies
PHOTOGRAPHY: JIM SHIVE
Richard Gliklich
ILLUSTRATION: PAUL A. BELCI
When Clinical Trials
Aren’t Enough
Effectiveness and real-world data
underlie the global need for more
patient registries and standards.
P
atient registries have been gaining attention in Outcomes: A User’s Guide,6 to help guide registr y design
recent years as health care providers, payers, and and evaluation.
regulators have realized they can produce With these new principles of good practice, registries in
real-world data that more accurately depict the both pre- and postmarketing areas will have more potential to
safety, quality, performance, and effectiveness of provide data to support decision making. Paralleling these
drugs and devices. There has been a growing movement to efforts, so-called evidence hierarchies are also being recon-
raise the quality of observational research, including patient sidered, and the role of rigorous, high-quality observational
registries, so that it can be used for more purposes—from data for clinical and policy decision making is clearly chang-
labeling and advertising to regulator y submissions and ing. This article focuses on the impact of this process on
reimbursement decisions. unleashing the power of one type of observational program:
Recent efforts by several groups have brought forth important the patient registry.
guidelines and principles to develop or evaluate observational
study data. While in clinical trials, the CONSORT statement1 Multiple purposes
criteria have set the bar and standardized practice. However, A patient registry is “an organized system that uses observa-
for obser vational research there is not a single definitive tional study methods to collect uniform data (clinical and
document, but rather a series of publications and consensus other) to evaluate specified outcomes for a population defined
efforts that build on each other. These have included by a particular disease, condition or exposure, and that serves
publications such as: a predetermined scientific, clinical or policy purpose(s). The
• Guidelines for Good Pharmacoepidemiology Practices2 registry database is the file (or files) derived from the registry.”6
• Quality of Reporting of Observational Longitudinal Research3 As this definition notes, registries are observational, meaning
• Government guidance documents such as Guidance for they collect data as patients present for care, without prescribing
Industry: Good Pharmacovigilance Practices and Pharma- treatments or tests. This is the primary difference between a
coepidemiologic Assessment,4 Guidance for Industr y: registry and a clinical trial. In a registry, treatment decisions,
Establishing Pregnancy Exposure Registries5, and consensus visit schedules, and any tests/measurements are generally
statements from various working groups. left to the discretion of the provider; the registr y simply
In May 2007, the U.S. Deptartment of Health and Human obser ves as patients present for care. Registries also use
Ser vices’ Agency for Healthcare Research and Quality broad inclusion and exclusion criteria to produce data that is
released a handbook entitled Registries for Evaluating Patient generalizable to a wider population than trial data. In contrast,
2. Postmarketing Studies
clinical trials are controlled experiments designed to test a (and patients often have more comorbidities and concomitant
focused clinical hypothesis. They have strict inclusion and medicines than those included in the controlled setting of a
exclusion criteria that create homogenous patient groups, and clinical trial). While clinical trials are the best measure of efficacy,
treatment decisions are generally dictated by the protocol and registries provide strong evidence for effectiveness by observ-
randomization rather than by the practitioner. ing typical practice and including a broad patient population.
The design of clinical trials gives them strong internal While registries can ser ve many purposes and provide
validity, meaning that the data collected accurately reflects strong effectiveness data, decision-makers need to be able to
the truth about the population under study. In contrast, evaluate a registry in terms of the quality of the research and
registry data have strong external validity, or generalizability. evidence. The recent efforts described earlier have culmi-
Practitioners and payers, and even some regulatory agencies, nated in a far better understanding of what constitutes good
are beginning to view real-world data from registries favorably registry practices, such as confidence that the design, conduct,
because the limited inclusion/exclusion criteria mean that the and analysis of the registry protect against systematic errors
patients are more representative of usual practice and and errors in inference. Promoting consistent standards for
because estimates of the impact of treatment are more realistic. registr y design and evaluation will encourage the use of
Since registries are observing patients and not dictating patient registries as a way to provide evidence to support deci-
treatment, they can fulfill a wide variety of purposes. They can sion making. Widespread use of patient registries as a comple-
be used to conduct a prospective study of people who share a ment to clinical trials will provide benefits to patients, health
care providers, companies, payers, and even regulators.
Practitioners and payers, and even Patient and physician benefits
some regulatory agencies, are Registries can provide data on real world treatment choices
and outcomes for all types of patients. Clinical trial data may
beginning to view real-world data only provide limited evidence for treating patients with multiple
from registries favorably. or complex conditions or patients who are part of a sensitive
subgroup, such as pregnant women, children or the elderly. A
certain characteristic, such as product use or a procedure. registry can gather data on a broad patient population and
Examples include registries of patients who receive intravenous provide evidence to support treatment decisions for many
thrombolytics for heart attack or particular antiplatelet types of patients. Registries often include long-term follow-up
therapies after similar events. Registries can also focus on data, which can be particularly useful for patients with chronic
diseases. They can be particularly useful for tracking long-term conditions and for insight into long-term medication use. In
progression of chronic diseases, such as heart failure and cancer, some disease areas, particularly rare diseases, patient advo-
and rare diseases like Pompe disease and cystic fibrosis. cacy groups also promote participation in a registr y as a
Other registries provide a comparison of cases and controls means of increasing knowledge about the disease and promot-
to understand what differentiates them. These studies can be ing greater communication between patients and providers.
used to evaluate safety, characterize adherence, and describe Health care providers similarly benefit from additional
off-label use. Finally, registries provide a means of gathering evidence on effectiveness and safety that is broadly applicable
data in areas where experimental research is impractical or to their patient populations. Registry data can provide practical
not feasible, such as in studies of compliance and adherence; information on how to treat a wide variety of patients, including
long-term follow-up studies; studies in special patient the sensitive subgroups rarely studied in clinical trials. Reg-
subgroups (e.g., pregnant women, the elderly, and children); istries also generate data to help characterize rare diseases
and when randomization to certain treatments is not ethical. and can promote information sharing among providers treat-
ing patients with such diseases. Additionally, in cases where a
Efficacy and effectiveness provider has only one or two patients with a particular condi-
The flexibility of registr y design and the wide number of tion, a registry can provide a way to learn more about the dis-
purposes that registries can serve has led to their growing ease and connect with other providers with similar patients.
popularity. Interest in registries has also increased as the focus By collecting data on treatment patterns and long-term
in evidence-based medicine has shifted from efficacy to effec- outcomes, registries can also provide evidence to support the
tiveness. Efficacy is the extent to which medical interventions development of treatment guidelines.
achieve health improvements under ideal circumstances—
essentially, does the intervention work? Effectiveness, on the A company perspective
other hand, is the extent to which medical inter ventions Registries offer companies a way to achieve clinical and
achieve health improvements in real practice settings. marketing goals, meet regulatory needs, and support other data
Effectiveness adds an additional hurdle for interventions: needs. Clinical goals of company-sponsored registries include
They must work in the real world, where providers must studying the effects of products designated for long-term use;
prescribe them correctly and patients must comply with therapy examining unanticipated beneficial effects that may lead to new
3. Postmarketing Studies
approved under an accelerated review process and fulfill post-
The ability to provide long-term marketing commitments. Some registries are required to fur-
data to support safety during ther study premarket safety signals or answer additional ques-
tions from the regulatory agency. In some cases, companies
real-world use is a strong benefit develop rollover safety registries as a way to continue to mon-
of patient registries. itor a population from a clinical trial for any long-term safety
signals. The ability to provide long-term data to support safety
indications or side effects that lead to labeling changes; and during real- world use is a strong benefit of registries and one
identifying best practices to achieve optimal outcomes. that is encouraging some companies to implement registries
A registry can support marketing goals, such as assisting in for new products as a proactive approach to risk management
market penetration; understanding utilization patterns and spe- in the current environment of heightened concerns.
cial patient subpopulations; further documenting safety or Payers and insurers are also beginning to appreciate the ben-
effectiveness; repositioning the product through different out- efits of registry data. These groups can use the practical com-
comes (e.g., quality of life and cost effectiveness) and develop- parative information on clinical effectiveness and safety from
ing relationships with providers. Data on cost effectiveness and registries to help them make better formulary and
comparative effectiveness can be useful in advocating for reimbursement decisions, including understanding the needs
national or private payer changes in coverage determinations. of sensitive subgroups. In some cases, payers have even requ-
Registries can also offer data for understanding a particular ested registry data to better evaluate the use of a new product
market by answering questions on what kind of patients use a or procedure in populations similar to their covered population.
product, what other treatments they use, how often and why The recent implementation of the coverage under evidence
they switch therapies, and what other co-morbidities they have. development7 program by the Centers for Medicare and Med-
Companies also turn to registries to meet regulator y icaid Services (CMS) is an example of how registries may be
needs. Registries can collect additional data for products used to determine reimbursement policies. In the case of
implantable cardioverter defibrillators (ICDs), when CMS
was asked to reconsider its prior coverage decision in 2004,
Canada, EU Exchange Safety Info
the agency determined that the new clinical trial evidence was
A new agreement between Canada and the Euro- not useful for determining the appropriateness of the proce-
pean Union will allow their respective regulatory dure for an elderly population. The median age in the trial pop-
experts to share confidential information, such as ulation was 60, but the median age of Medicare patients is 70
safety and authorization issues regarding products to 75. CMS also noted concerns about the expanding group of
on the market or in development. The European physician specialists inserting ICDs.
Commission (EC) and the European Medicines To gather data on these questions, CMS made an ICD
Agency (EMEA) struck this deal with the Health registry a condition of coverage for Medicare beneficiaries
Products and Food Branch of Health Canada at their and the results have been dramatic, with nearly 1500 hospitals
bilateral meeting on December 7 in Brussels, Bel- participating. Full participation in a registry as a requirement
gium. The confidentiality arrangements will enable for coverage for pharmaceutical and biologic products seems
earlier availability of information, helping authori- unlikely in the foreseeable future. However, the interest and
ties to better protect public health by improving value placed on such observational data by decision makers is
the safety and performance of medicines and allow- not, and more and more data of this type will be increasingly
ing speedier patient access to new treatments.
requested in reimbursement determinations.
Since Canada and the EU have a history of
More recently, regulatory groups have begun to consider
working together in the regulatory environment,
registry data in safety evaluations. Registries can meet regula-
this new collaboration will further previous
tory requirements for risk management plans and postmar-
efforts by encouraging the exchange of informa-
keting commitments. Some regulatory agencies have even
tion, which includes position papers and regula-
tory guidance documents, scientific advice on begun including observational data in their assessments of
product development, assessments of marketing requests for supplementary indication approval. The use of
authorization applications, and safety informa- registry data is likely to increase as more registries can pro-
tion on marketed medicines. vide data that meet the requirements for decision making.
To view the letters from Health Canada and the In addition, the current debate over products with safety
EC and EMEA concerning the confidentiality issues that were not detected until the product was being
arrangements, visit www.emea.europa.eu/pdfs/ widely used could result in an increase in the use of patient
general/direct/pr/confidentiality_canada.pdf and registries to study real-world product use. In the United
www.emea.europa.eu/pdfs/general/direct/pr/ States, a September 2006 report by the Institute of Medicine
confidentiality_EU_EMEA.pdf. — Samantha Etkin called for widespread changes in the way medications are
monitored and marketed after approval. Recommendations
