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Randomized controlled trial

From Wikipedia, the free encyclopedia

Flowchart of four phases (enrollment, intervention allocation, follow-up, and data analysis) of a parallel randomized trial of
two groups, modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement[1]

A randomized controlled trial (RCT) is a type of scientific experiment most commonly used in testing
the efficacy or effectiveness ofhealthcare services (such as medicine ornursing) or health technologies (such
aspharmaceuticals, medical devices orsurgery). The key distinguishing feature of the usual RCT is that study
subjects, after assessment of eligibility and recruitment, but before the intervention to be studied begins, are
randomly allocated to receive one or other of the alternative treatments under study. Random allocation in real
trials is complex, but conceptually, the process is like tossing a coin. After randomization, the two (or more)
groups of subjects are followed up in exactly the same way, and the only differences between the care they
receive, for example, in terms of procedures, tests, outpatient visits, follow-up calls etc. should be those
intrinsic to the treatments being compared. The most important advantage of proper randomization is that it
minimises allocation bias, balancing both known and unknown prognostic factors, in the assignment of
treatments."[2]

The terms "RCT" and randomized trial are often used synonymously, but some authors distinguish between
"RCTs" which compare treatment groups with control groups not receiving treatment (as in aplacebo-controlled
study), and "randomized trials" which can compare multiple treatment groups with each other.[3] RCTs are
sometimes known as randomized control trials.[4] RCTs are also calledrandomized clinical
trials or randomized controlled clinical trials when they concern clinical research[5][6][7]; however, RCTs are
also employed in other research areas such as criminology,education, social work and international
development.

Contents
[hide]

• 1 History

• 2 Ethics

• 3 Classifications of RCTs

o 3.1 By study design

o 3.2 By outcome of interest (efficacy vs. effectiveness)

o 3.3 By hypothesis (superiority vs. noninferiority vs.

equivalence)

• 4 Randomization

o 4.1 Randomization procedures

 4.1.1 Simple randomization

 4.1.2 Restricted randomization

 4.1.3 Adaptive

o 4.2 Allocation concealment

• 5 Blinding

• 6 Analysis of data from RCTs

• 7 Reporting of RCT results

• 8 Advantages

• 9 Disadvantages

o 9.1 Limitations of external validity

 o 9.2 Costs

o 9.3 Relative importance of RCTs and observational

studies

o 9.4 Difficulty in studying rare events

o 9.5 Difficulty in studying outcomes in distant future

o 9.6 Pro-industry findings in industry-funded RCTs

o 9.7 Therapeutic misconception

o 9.8 Statistical error

o 9.9 Cultural effects

• 10 RCTs in criminology, education, and international

development

o 10.1 Criminology

o 10.2 Education

o 10.3 International development

• 11 See also

• 12 References

• 13 Further reading

• 14 External links

[edit]History

The earliest controlled experiments in agriculture research, leading to the development of randomized
controlled trials, were due to Charles Darwin who compared the growth of cross versus self- fertilized plants
(Darwin, 1876). Darwin asked Francis Galton to analyze the data from his experiments. R.A. Fisher later
argued that Galton's analysis was unsatisfactory and that the Student t-test can be used to test if there were
significant differences in heights of the two types of plants (Fisher, 1935). Fisher also underscored the need for
randomization in agricultural experiments. However, as suggested byAlok Bhargava (Bhargava, 2008), Darwin
was influenced to some degree by path-breaking experiments in physical sciences due to Michael
Faraday (e.g. Faraday, 1991).

While it is claimed that the first published RCT was a 1948 paper entitled "Streptomycin treatment of
pulmonary tuberculosis", the early agriculture experiments date back to Neyman (1923) and Fisher's work in
the 1920s. (Medical Research Council investigation).[8][9][10] One of the authors of that paper was Austin
Bradford Hill, who is credited as having conceived the modern RCT.[11] However, a recent paper which looked
at early RCT use in social and educational intervention studies rather than medical studies found reports of
RCT being used as early as 1928.[12]

By the late 20th century, RCTs had become the "gold standard" for "rational therapeutics" in medicine.[13] As of
2004, more than 150,000 RCTs were in the Cochrane Library.[11] To improve the reporting of RCTs in the
medical literature, an international group of scientists and editors publishedConsolidated Standards of
Reporting Trials (CONSORT) Statements in 1996, 2001, and 2010 which have become widely accepted.[1][2]

[edit]Ethics

Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about
the preferred treatment") common to clinical trials[14] has been applied to RCTs, the ethics of RCTs have special
considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs.[15] For another,
"collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention
is effective).[16] Finally, Zelen's design, which has been used for some RCTs, randomizes subjects before they
provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely
unethical "for most therapeutic trials."[17][18]

[edit]Classifications of RCTs
[edit]By study design
One way to classify RCTs is by study design. From most to least common in the medical literature, the major
categories of RCT study designs are[19]:

 Parallel-group – each participant is randomly assigned to a group, and all the

participants in the group receive (or do not receive) an intervention

 Crossover – over time, each participant receives (or does not receive) an
intervention in a random sequence

 Split-body – separate parts of the body of each participant (e.g., the left and
right sides of the face) are randomized to receive (or not receive) an
intervention

 Cluster – pre-existing groups of participants (e.g., villages, schools) are

randomly selected to receive (or not receive) an intervention

 Factorial – each participant is randomly assigned to a group that receives a

particular combination of interventions or non-interventions (e.g., group 1
receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y,
group 3 receives placebo X and vitamin Y, and group 4 receives placebo X
and placebo Y)
An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group
trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.[19]

[edit]By outcome of interest (efficacy vs. effectiveness)

RCTs can be classified as "explanatory" or "pragmatic."[20] Explanatory RCTs test efficacy in a research setting
with highly selected participants and under highly controlled conditions.[20] In contrast, pragmatic RCTs
test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in
this way, pragmatic RCTs can "inform decisions about practice."[20]

[edit]By hypothesis (superiority vs. noninferiority vs. equivalence)

Another classification of RCTs categorizes them as "superiority trials," "noninferiority trials," and "equivalence
trials," which differ in methodology and reporting.[21] Most RCTs are superiority trials, in which one intervention
is hypothesized to be superior to another in a statistically significant way.[21]Some RCTs are noninferiority trials
"to determine whether a new treatment is no worse than a reference treatment."[21] Other RCTs are equivalence
trials in which the hypothesis is that two interventions are indistinguishable from each other.[21]

[edit]Randomization

The advantages of proper randomization in RCTs include[22]:

 "It eliminates bias in treatment assignment," specifically selection

bias and confounding.

 "It facilitates blinding (masking) of the identity of treatments from

investigators, participants, and assessors."

 "It permits the use of probability theory to express the likelihood that any
difference in outcome between treatment groups merely indicates chance."

There are two processes involved in randomizing patients to different interventions. First is choosing
arandomization procedure to generate an unpredictable sequence of allocations; this may be a simple random
assignment of patients to any of the groups at equal probabilities, may be "restricted," or may be "adaptive." A
second and more practical issue is allocation concealment, which refers to the stringent precautions taken to
ensure that the group assignment of patients are not revealed prior to definitively allocating them to their
respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects
between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of
allocation concealment.[22]

[edit]Randomization procedures
An ideal randomization procedure would achieve the following goals[23]:
  Equal group sizes for adequate statistical power, especially in subgroup
analyses.

 Low selection bias. That is, the procedure should not allow an investigator
to predict the next subject's group assignment by examining which group has
been assigned the fewest subjects up to that point.

 Low probability of confounding (i.e., a low probability of "accidental

bias"[22][24]), which implies a balance in covariates across groups. If the
randomization procedure causes an imbalance in covariates related to the
outcome across groups, estimates of effect may be biased if not adjusted for
the covariates (which may be unmeasured and therefore impossible to adjust
for).

However, no single randomization procedure meets those goals in every circumstance, so researchers must
select a procedure for a given study based on its advantages and disadvantages.

[edit]Simple randomization

This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing."[22] Also known as
"complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However,
its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only
for RCTs with over 200 subjects.[25]

[edit]Restricted randomization

To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended.[25]The major
types of restricted randomization used in RCTs are:

 Permuted-block randomization or blocked randomization: a "block size"

and "allocation ratio" (number of subjects in one group versus the other group)
are specified, and subjects are allocated randomly within each block.[22] For
example, a block size of 6 and an allocation ratio of 2:1 would lead to random
assignment of 4 subjects to one group and 2 to the other. This type of
randomization can be combined with "stratified randomization", for example by
center in amulticenter trial, to "ensure good balance of participant
characteristics in each group."[2] A special case of permuted-block
randomization is random allocation, in which the entire sample is treated as
one block.[22] The major disadvantage of permuted-block randomization is that
even if the block sizes are large and randomly varied, the procedure can lead
 to selection bias.[23] Another disadvantage is that "proper" analysis of data
from permuted-block-randomized RCTs requires stratification by blocks.[25]

 Adaptive biased-coin randomization methods (of which urn

randomization is the most widely-known type): In these relatively uncommon
methods, the probability of being assigned to a group increases if the group is
over-represented and decreases if the group is under-represented.[22] The
methods are thought to be less affected by selection bias than permuted-block
randomization.[25]

[edit]Adaptive

At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently
than simple or restricted randomization:

 Covariate-adaptive randomization, of which one type is minimization: The

probability of being assigned to a group varies in order to minimize "covariate
imbalance."[25] Minimization is reported to have "supporters and detractors"[22];
because only the first subject's group assignment is truly chosen at random,
the method does not necessarily eliminate bias on unknown factors[2].

 Response-adaptive randomization, also known as outcome-adaptive

randomization: The probability of being assigned to a group increases if the
responses of the prior patients in the group were favorable.[25] Although
arguments have been made that this approach is more ethical than other
types of randomization when the probability that a treatment is effective or
ineffective increases during the course of an RCT, ethicists have not yet
studied the approach in detail.[26]

[edit]Allocation concealment
"Allocation concealment" (defined as "the procedure for protecting the randomisation process so that the
treatment to be allocated is not known before the patient is entered into the study") is considered desirable in
RCTs.[27] In practice, in taking care of individual patients, clinical investigators in RCTs often find it difficult to
maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices
to determine group assignments in order to dictate the assignment of their next patient.[22] Such practices
introduce selection bias and confounders (both of which should have minimized by randomization), thereby
possibly distorting the results of the study.[22]
Some standard methods of ensuring allocation concealment include sequentially-numbered, opaque, sealed
envelopes (SNOSE); sequentially-numbered containers; pharmacy controlled randomization; and central
randomization.[22] It is recommended that allocation concealment methods be included in an RCT's protocol,
and that the allocation concealment methods should be reported in detail in a publication of an RCT's results;
however, 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in
their publications, or both.[28] On the other hand, a 2008 study of 146 meta-analyses concluded that the results
of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if
the RCTs' outcomes were subjectiveas opposed to objective.[29]

[edit]Blinding

An RCT may be Blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or
outcome assessors from knowing which intervention was received."[29] Unlike allocation concealment, blinding
is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in
which active participation of the patient is necessary (e.g., physical therapy), participants cannot be blinded to
the intervention.

Traditionally, blinded RCTs have been classified as "single-blind," "double-blind," or "triple-blind"; however, in
2001 and 2006 two studies showed that these terms have different meanings for different people.[30][31] The
2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind," "double-
blind," and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after
assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."[2]

RCTs without blinding are referred to as "unblinded"[32], "open"[33], or (if the intervention is a medication) "open-
label"[34]. In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial
effects only if the RCTs' outcomes were subjective as opposed to objective[29]; for example, in an RCT of
treatments for multiple sclerosis, unblinded neurologists (but not blinded neurologists) felt that the treatments
were beneficial[35]. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still
desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of
outcomes."[20]

[edit]Analysis of data from RCTs

The types of statistical methods used in RCTs depend on the characteristics of the data and include:

 For dichotomous (binary) outcome data, logistic regression (e.g., to predict

sustained virological response after receipt of peginterferon alfa-
2a for hepatitis C[36]) and other methods can be used.
  For continuous outcome data, analysis of covariance (e.g., for changes in
blood lipid levels after receipt of atorvastatin after acute coronary syndrome[37])
tests the effects of predictor variables.

 For time-to-event outcome data that may be censored, survival

analysis (e.g., Kaplan–Meier estimators and Cox proportional hazards
models for time to coronary heart disease after receipt ofhormone
replacement therapy in menopause[38]) is appropriate.

Regardless of the statistical methods used, important considerations in the analysis of RCT data include:

 Whether a RCT should be stopped early due to interim results. For example,
RCTs may be stopped early if an intervention produces "larger than expected
benefit or harm," or if "investigators find evidence of no important difference
between experimental and control interventions."[2]

 The extent to which the groups can be analyzed exactly as they existed upon
randomization (i.e., whether a so-called "intention-to-treat analysis" is used). A
"pure" intention-to-treat analysis is "possible only when complete outcome
data are available" for all randomized subjects[39]; when some outcome data
are missing, options include analyzing only cases with known outcomes and
using imputed data[2]. Nevertheless, the more that analyses can include all
participants in the groups to which they were randomized, the less bias that an
RCT will be subject to.[2]

 Whether subgroup analysis should be performed. These are "often

discouraged" because multiple comparisons may produce false positive
findings that cannot be confirmed by other studies.[2]

[edit]Reporting of RCT results

The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting
RCTs."[40] The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually
randomised, two group, parallel trials" which are the most common type of RCT.[1] For other RCT study
designs, "CONSORT extensions" have been published.[1]

[edit]Advantages

RCTs are considered by most to be the most reliable form of scientific evidence in the hierarchy of
evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias.
Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct
of evidence-based medicine. Some examples of scientific organizations' considering RCTs or systematic
reviews of RCTs to be the highest-quality evidence available are:

 As of 1998, the National Health and Medical Research Council of Australia

designated "Level I" evidence as that "obtained from a systematic review of all
relevant randomised controlled trials" and "Level II" evidence as that "obtained
from at least one properly designed randomised controlled trial."[41]

 Since at least 2001, in making clinical practice guideline recommendations

the United States Preventive Services Task Force has considered both a
study's design and its internal validity as indicators of its quality.[42] It has
recognized "evidence obtained from at least one properly randomized
controlled trial" with good internal validity (i.e., a rating of "I-good") as the
highest quality evidence available to it.[42]

 The GRADE Working Group concluded in 2008 that "randomised trials

without important limitations constitute high quality evidence."[43]

 For issues involving "Therapy/Prevention, Aetiology/Harm," the Oxford

Centre for Evidence-based Medicine]] as of 2009 defined "Level 1a" evidence
as a systematic review of RCTs that are consistent with each other, and
"Level 1b" evidence as an "individual RCT (with narrow Confidence
Interval)."[44]

Notable RCTs with unexpected results that contributed to changes in clinical practice include:

 After Food and Drug Administration approval, the antiarrhythmic

agents flecainide and encainidecame to market in 1986 and 1987
respectively.[45] The non-randomized studies concerning the drugs were
characterized as "glowing"[46], and their sales increased to a combined total of
approximately 165,000 prescriptions per month in early 1989[45]. In that year,
however, a preliminary report of a RCT concluded that the two drugs
increased mortality.[47] Sales of the drugs then decreased.[45]

 Prior to 2002, based on observational studies, it was routine for physicians to

prescribe hormone replacement therapy for post-menopausal women to
prevent myocardial infarction.[46] In 2002 and 2004, however, published RCTs
from the Women's Health Initiative claimed that women taking hormone
replacement therapy with estrogen plus progestin had a higher rate of
myocardial infarctions than women on a placebo, and that estrogen-only
 hormone replacement therapy caused no reduction in the incidence of
coronary heart disease.[38][48] Possible explanations for the discrepancy
between the observational studies and the RCTs involved differences in
methodology, in the hormone regimens used, and in the populations studied.
[49][50]
The use of hormone replacement therapy decreased after publication of
the RCTs.[51]

[edit]Disadvantages

Many papers discuss the disadvantages of RCTs.[52][53] Among the most frequently-cited drawbacks are:

[edit]Limitations of external validity

The extent to which RCTs' results are applicable outside the RCTs varies; that is, RCTs' external validity may
be limited.[52][54] Factors that can affect RCTs' external validity include[54]:

 Where the RCT was performed (e.g., what works in one country may not
work in another)

 Characteristics of the patients (e.g., an RCT may include patients whose

prognosis is better than average, or may exclude "women, children, the
elderly, and those with common medical conditions"[55])

 Study procedures (e.g., in an RCT patients may receive intensive diagnostic

procedures and follow-up care difficult to achieve in the "real world")

 Outcome measures (e.g., RCTs may use composite measures infrequently

used in clinical practice)

 Incomplete reporting of adverse effects of interventions

[edit]Costs

RCTs can be expensive[53]; one study found 28 Phase III RCTs funded by the National Institute of Neurological
Disorders and Stroke prior to 2000 with a total cost of US$335 million[56], for a mean cost of US$12 million per
RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28
RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on
evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.[56]

[edit]Relative importance of RCTs and observational studies

Two studies published in The New England Journal of Medicine in 2000 found that observational studies and
RCTs overall produced similar results[57][58]. The authors of the 2000 findings cast doubt on the ideas that
"observational studies should not be used for defining evidence-based medical care" and that RCTs' results are
"evidence of the highest grade."[57][58] However, a 2001 study published inJournal of the American Medical
Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of
treatment effect are very common" between observational studies and RCTs.[59]

Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:

 If study designs are ranked by their potential for new discoveries,

then anecdotal evidence would be at the top of the list, followed by
observational studies, followed by RCTs.[60]

 RCTs may be unnecessary for treatments that have dramatic and rapid
effects relative to the expected stable or progressively worse natural course of
the condition treated.[52][61] One example is combination
chemotherapy including cisplatin for metastatic testicular cancer, which
increased the cure rate from 5% to 60% in a 1977 non-randomized study.[61][62]

[edit]Difficulty in studying rare events

Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and
uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large
sample sizes and may therefore best be assessed by observational studies.[52]

[edit]Difficulty in studying outcomes in distant future

It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.[52][53]

[edit]Pro-industry findings in industry-funded RCTs

Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as
opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986-
2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was
a correlation of industry sponsorship and positive study outcome.[63] A 2004 study of 1999-2001 RCTs
published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be
associated with statistically significant pro-industry findings."[64] One possible reason for the pro-industry results
in industry-funded published RCTs is publication bias.[64]

[edit]Therapeutic misconception
Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982
have documented that many RCT subjects believe that they are certain to receive treatment that is best for
them personally; that is, they do not understand the difference between research and treatment.[65][66] Further
research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".[66]
[edit]Statistical error
RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type
I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally
effective treatments significantly different.[67] Regarding Type II errors, despite the publication of a 1978 paper
noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the
negative results[68], by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely-reported
sample size calculations[69].

[edit]Cultural effects
The RCT method creates cultural effects that have not been well understood.[70] For example, patients with
terminal illness may attempt to join trials as a last ditch attempt at treatment, even when treatments are unlikely
to be successful.

[edit]RCTs in criminology, education, and international development

[edit]Criminology

A 2005 review found 83 randomized experiments in criminology published in 1982-2004, compared with only
35 published in 1957-1981.[71] The authors classified the studies they found into five categories: "policing",
"prevention", "corrections", "court", and "community".[71] Focusing only on offending behavior programs, Hollin
(2008) argued that RCTs may be difficult to implement (e.g., if an RCT required "passing sentences that would
randomly assign offenders to programmes") and therefore that experiments with quasi-experimental design are
still necessary.[72]

[edit]Education

RCTs have been used in evaluating a number of educational interventions. For example, a 2009 study
randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral
screening, classroom intervention, and parent training, and then measured the behavioral and academic
performance of their students.[73] Another 2009 study randomized classrooms for 678 first-grade children to
receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed
their academic outcomes through age 19.[74]

[edit]International development
RCTs are currently being used by a number of international development experts to measure the impact of
development interventions worldwide. Development economists at research organizations including Abdul Latif
Jameel Poverty Action Lab[75][76] and Innovations for Poverty Action[77] have used RCTs to measure the
effectiveness of poverty, health, and education programs in the developing world. While RCTs can be useful in
policy evaluation, it is necessary to exercise care in interpreting the results in social science settings. For
example, interventions can inadvertently induce socioeconomic and behavioral changes that can confound the
relationships (Bhargava, 2008).

For some development economists, the main benefit to using RCTs compared to other research methods is
that randomization guards against selection bias, a problem present in many current studies of development
policy. In one notable example of a cluster RCT in the field of development economics, Olken (2007)
randomized 608 villages in Indonesia in which roads were about to be built into six groups (no audit vs. audit,
and no invitations to accountability meetings vs. invitations to accountability meetings vs. invitations to
accountability meetings along with anonymous comment forms).[78] After estimating "missing expenditures" (a
measure of corruption), Olken concluded that government audits were more effective than "increasing
grassroots participation in monitoring" in reducing corruption.[78] However, similar conclusions can also be
reached by suitable modeling of the data from longitudinal studies. Overall, it is important in social sciences to
account for the intended as well as the unintended consequences of interventions for policy evaluations.