IN THE NAME OF GOD

Advanced Epidemiology

CHAPTER 8

Treatment

Treatment should be given “ not because they ought to work, but because they do

work”. L.H. Opie

Once the nature of a patient's illness has been established and its expected course predicted, the next question is, what can be done about it? Is there a treatment that improves the outcome of disease?

IDEAS AND EVIDENCE

6

Ideas about what might be a useful treatment arise from virtually any activity within medicine. Ideas are called hypotheses to the extent that are assertions about the natural world made for the purposes of empiric testing.

Other hypotheses about treatments have come from astute observations by clinicians.These observations are shared with their colleagues in case reports,which are detailed descriptions of a single case or just a few cases.

Ideas

:Example Amantadine Minoxidil Tamoxifen

Ideas about treatment, but more often prevention, have also come from epidemiologic studies of populations. Example:

-High-fiber diets-Fluoride

Some treatment effects are so prompt and powerful that their value is self-evident even without formal testing.

In contrast, many diseases, including most chronic diseases, involve treatments that

are considerably less dramatic .It is then necessary to put ideas about treatments to a formal test, through clinical research, because a variety of circumstances, such as coincidence, faulty comparisons, spontaneous changes in the course of disease, or wishful thinking, can obscure the true relationship between treatment and outcomes.

Testing Ideas

When knowledge of the pathogenesis of disease, based on work with laboratory models or physiologic studies in humans, has become extensive, it is tempting to predict effects in humans on this basis alone. However, relying solely on current understanding of mechanisms without testing ideas using strong clinical research on intact humans can lead to unpleasant surprises.

:ExampleSome strokes are caused by…

Clinical experience and tradition also need to be put to a test.

Therefore,It is almost always necessary to test therapeutic hypotheses by means of clinical research.

Treatment is any intervention, which may include prescribing drugs, performing surgery, or counseling, that is intended to improve the course of disease once it is established. Treatment is a special case of interventions in general that might be at any point in the natural history of disease ,from disease prevention to palliative care at the end of life.

STUDIES OF TREATMENT EFFECTS

In observational studies of interventions, investigators simply observe what happens to patients who for various reasons do or do not get exposed to an intervention

Experimental studies are a special kind of cohort study in which the conditions of study-that is, selection of treatment groups, nature of interventions, management during follow-up, and measurement of outcomes are specified by the investigator for the purpose of making unbiased comparisons

Observational and Experimental Studies Of Treatment Effects

The patients to be studied are first selected from a larger number of patients with the condition of interest. They are then divided, using randomization, into two groups (or more) of comparable Prognosis.one group,called the experimental group and other group,called a control group or comparison group.

RANDOMIZED CONTROLLED TRIALS

The main reason for structuring clinical trials in this way is to avoid bias (systematic error)

The validity of clinical trials depends on how well they have created equal distribution of all determinants of prognosis, other than the one being tested, in treated and control patients.

Clinical trials typically require patients to meet rigorous inclusion and exclusion criteria.

The usual inclusion criterion is that patients really do have the condition being studied.

patients in clinical trials are usually a highly selected, biased sample of all patients with the condition of interest.

Sampling

Because of the high degree of selection in trials, it may require considerable faith to generalize the results of clinical trials to ordinary practice settings

Large, simple trials are a way of overcoming the generalizability problem.

The intervention itself can be described in relation to three general characteristics: generalizability, complexity, and strength.

First, is the intervention one that is likely to be implemented in usual clinical practice?

Second, does the- intervention reflect a complexity that is normal for real-world treatment plans?

Third, is the intervention in question sufficiently different from alternative managements that it is reasonable to expect that the outcome will be affected?

Intervention

The value of a treatment can only be judged by comparing its results to those of some alternative course of action. No intervention. Do patients who are offered

the experimental treatment end up better off than those offered nothing at all?

Observation. Do treated patients do better than other patients who are simply observed?

Comparison groups

Placebo Treatment. Do treated patients do better than similar patients given a placebo an intervention intended to be indistinguishable from the active treatment (whether in physical appearance, color, taste, or smell) but which does not have a specific, known mechanism of action?

Usual Care. Do patients given the experimental treatment do better than those receiving usual care?

To study the effects of a clinical intervention free of other effects, the best way to allocate patients to treatment groups is by means of random allocation (randomization).

Random allocation of patients is preferable to other methods of allocation because only randomization has the ability to create truly comparable groups. All factors related to prognosis, whether or not they are known before the study takes place or have been measured, tend to be equally distributed in the comparison groups.

Allocating Treatment

To assess whether this kind of "bad luck" has occurred, authors of randomized controlled trials often present a table comparing the frequency of a variety of characteristics in the treated and control groups, especially those known to be related to outcome. These are called baseline characteristics because they are present before randomization and so should be equally distributed in the treatment groups.

Patients are gathered into groups (strata) having similar levels of a prognostic factor (such as age for most chronic disease) and are randomized separately within each stratum. This is a process called stratified randomization.

Some investigators do not favor stratified randomization

Not all patients in a clinical trial participate as originally planned.There are several reasons:

Patients Do Not Have the Disease Under StudyIt is sometimes necessary (both in clinical trials and in practice) to begin treatment before it is certain whether the patient actually has the disease for which the treatment is designed.

Differences Arising After Randomization

When patients are enrolled in a study and later turn out not to have the index disease, there is a price to pay. The main disadvantage of this approach is the inefficiency of enrolling and gathering data on patients who do not contribute to the study’s results.

Compliance Compliance is the extent to which patients follow

medical advice. The term adherence may be preferable because it connotes a less subservient relationship between patient and doctor.

In clinical trials, patients are typically selected for their compliance. During a run-in period, in which placebo is given and compliance monitored, noncompliant patients can be detected and excluded before randomization.

Co-interventionsAfter randomization, patients may receive a variety of interventions other than the ones being studied

In some clinical trials, particularly those involving cancer, the outcomes of patients who initially improve after treatment (responders) are compared with outcomes in those who do not (nonresponders).

Comparispns of Responders to Nonresponders

Participants in a trial may change their behavior or reporting of outcomes in a systematic way if they are aware of which patients receive which treatment. One way to minimize this effect is by blinding

Masking is a more appropriate metaphor, but blinding is the time-honored term.

Blinding

First, those responsible for allocating patients to treatment groups should not know which treatment will be assigned next so that the knowledge does not allow them to break the randomization plan. Allocation concealment is a common term for this form of blinding .

Second, patients should be unaware of which treatment they are taking so that they cannot change their compliance or reporting of symptoms because of their knowledge of this information

Third, physicians who take care of patients in the study should not know which treatment each patient is on The terms single-blind (patients) and

double blind are sometimes used, but their meanings

are ambiguous . A trial in which there is no attempt at

blinding is called an open or in the case of drug trials, an open label trial.

In some trials, patients and doctors are asked whether they believe the patient is taking an active drug or placebo. Their answers provide objective evidence of whether efforts to mask patients were successful.

Assessment of outcome and how it can be affected by measurement bias has been discussed,as have the dangers of substituting intermediate outcomes for clinically important ones

Assessment of Outcome

The results of a randomized controlled trial can be analyzed and presented in two general ways: according to the treatment to which the patients were randomized or according to the one they actually received.

Trials analyzed in this way are called explanatory trials because they assess whether actually taking the treatments, rather than just being offered them,makes the difference.

INTENTION-TO-TREAT AND EXPLANATORY TRIALS

Clinical trials are also classified according to whether they describe the results of an intervention in ideal or real-world situations.

First, can treatment work under ideal circumstances? trials that answer this question are called efficacy trials.

Second, does treatment work under ordinary circumstances? Trials designed to answer this kind of question are called effectiveness trials.

EFFICACY AND EFFECTIVENESS

Clinical trial, involve pooling the experience of many patients who may be dissimilar, both to one another and to the patients to whom the trial results will be generalized.

Subgroups Patients in clinical trials can be sorted into

subgroups, each with a specific combination of characteristics, such as age, severity of disease, and comorbidity, that might affect outcome

TAILORING THE RESULTS OF TRIALS TO INDIVIDUAL PATIENTS

Trials of N=1Rigorous clinical trials, with proper attention to bias and chance, can be done with individual patients, one at a time. The method-called trials of N = 1 - is an improvement over the more informal process of trial and error that is time-honored in clinical practice. This method is useful when activity of

disease is unpredictable, response to treatment is prom pt, and there is no carryover effect from period to period.

N of 1 trials can be useful for guiding clinical decision making.

A treatment that is effective on the average may not work on an individual patient.

When managing an individual patient,it is useful to ask the following series of questions;

• Is the treatment known (by randomized controlled trial) to be efficacious for any patients?

• Is the treatment known to be effective, on the average, in patients like mine?

• Is the treatment working in my patient?• Are the benefits worth the discomforts and risks

(according to the patient's values and preferences)?

Effectiveness in Individual Patients

Randomized controlled trials are the gold standard of intervention studies.

There may not be enough patients with the disease of interest, at one time and place, to carry out a scientifically sound trial. This can be overcome by multicenter trials.

LIMITATION OF RANDOMIZED TRIALS

Comparisons Across Time and PlaceExperimental and control patients can be assembled from different time and places.

ALTERNATIVES TO RANDOMIZED TRIALS

The results of current treatment are sometimes compared to experience with similar patients in the past,called historical controls or nonconcurrent controls

Uncontrolled trials describe the course of disease in a single group of patients before and after exposure to an intervention. Another name for this design is a before-after study.

Uncontrolled Trials

The assumption of this approach is that any improvement observed after treatment is the result of treatment.This assumption may be unwarranted for the reasons described below.

• Unpredictable Clinical Course• Nonspecific Effects• Regression to the Mean• Predictable Improvement

Especially troubling is confounding by indication,which occurs,in the case of a drug,when whatever has made the dr prescribe a drug(the”indications”)is the cause of the observed outcome,not the drug itself.

OBSERVATIONAL STUDIES OFINTERVENTIONS

STANDARDS FOR REPORTINGRANDOMIZED CONTROLLED TRIALS

phase 1 trials are intended to identify a dose range that is well tolerated and safe(at least for high-frequency,severe side effects)and include very small numbers of patients(perhaps a dosen), without a control group.

PHASES OF STUDIES OF TREATMENT

phase 2 trials provide preliminary information on whether the drug is efficacious and the relationship between dose and efficacy

phase 3 trials are randomized trials and can provide definitive evidence of efficacy

and rates of common side effects.

Thank you!