Uncontrolled Trials

• This design incorporates no control arm.

• This design is usually utilized to determine pharmacokinetic properties of a new drug
(Phase 1 trials).

Limitation:
• There is a threat of inherent bias and results are considered less valid than RCT.
• Another issue is use of this design in spontaneously resolving maladies that might
again overstate the effect
Illustrative example
In immunotherapy in warts, it is imperative to avoid an uncontrolled study. Warts can be
self-resolving and hence the efficacy of immunotherapy as opposed to the self-resolution
compromises the validity of the results
Control Arm Options in Controlled Trials
Controlled trials allow discrimination of the patient outcome from an outcome caused by
other factors (such as natural history or observer or patient expectation).

Choosing a right control at the right dose and right frequency is pivotal to trial success. The controls which can be used
are:
Placebo concurrent control – Placebo is a form of inert substance, or an intervention designed to simulate medical
therapy, without specificity for the condition being treated.
• The placebo must share the same appearance, frequency, and formulation as the active drug.
• Placebo control helps to discriminate outcomes due to intervention (new product) from outcomes due to other
factors.
• This design is used to demonstrate superiority or equivalence.
• This design must be adopted only when no effective treatment exits, and it will be deemed unethical to use a
placebo control if an effective standard of care exits.
• Placebo must only be used if no permanent harm (death or irreversible morbidity) accrues by delaying available
active treatment for the duration of the trial and is preferable for a minimal risk, short-term study

“No treatment” concurrent control – No intervention will be administered in control arm in this design. Study end
points must be objective in this design. The downsides are potential for observer bias and difficulty in blinding in this
design
Active treatment concurrent control – This design involves comparison of a new drug to a
standard drug or compare combination of new and standard therapies vis a vis standard
therapy alone.
• This design can be used to demonstrate equivalence, non-inferiority, and superiority.
• This design is most ethical whenever approved drugs are available for the disease under
study.
• The Declaration of Helsinki mandates the use of standard treatment as controls

Dose-comparison concurrent control – Different doses or regimens of same treatment are

used as active arm and control arm in this design.
• The purpose is to establish a relationship between dose and efficacy/safety of the
intervention.
• This design may include active and placebo groups also in addition to the different dose
groups.
• This design may be inefficient if the therapeutic range of the drug is not known
Historical control (external and non-concurrent) – Source of controls are external to the
present study and were treated at an earlier time (earlier therapeutic gold standard) or in a
different setting.
• The advantage of historical controls is in studying rare conditions where sample size
generation is difficult.
• The downside is that no randomization or blinding is possible in this design.
• A disadvantage is that the co-interventions evolve in due course of time thereby reducing
the comparability of the present intervention versus historic control.
• Another deficiency of this design is the difference between baseline characteristics of
subjects in trial arm versus historical arm.
For example, toxic epidermal necrolysis, where clinical outcomes in cyclosporine treated
patients can be compared with historical controls treated in the same center with IVIg in the
past.
Descriptive studies
Descriptive studies are observational studies which describe the patterns of disease occurrence
in relation to variables such as person, place and time.

• They are often the first step or initial enquiry into a new topic, event, disease or condition.
• Pure descriptive studies make no attempt to analyze the links between exposure and effect.
• They summarize patterns of disease or of disease determinants in terms of time, place and person. 
• They are usually based on mortality statistics and may examine patterns of death by age, sex, race or
ethnicity during specified time periods or in various countries.
• They describe a health outcome by different characteristics of a person (race, age, or sex, for example),
place (geographic location), and time (a specific year or a span of time). For example, the case fatality of
cholera in 1854 in London was 40% (John Snow, the cholera outbreak in London).
• The results are used to understand a population’s health status, generate hypotheses about the causes of
diseases, and inform program planning and evaluation. In other words, descriptive epidemiology
describes the distribution of disease.
 Types of Descriptive Studies

The types of descriptive studies include:

1. Case reports or case series
2. Correlational or ecologic studies
3. Cross-sectional studies
4. Prevalence surveys

• Descriptive studies that examine individuals can take the form of case reports (a report of
a single case of an unusual disease or association), case series (a description of several
similar cases)
• Descriptive studies that examine populations, or groups, as the unit of observation, are
known as ecological studies.
• cross-sectional studies collect data from many subjects at a single point in time
(longitudinal studies collect data repeatedly from the same subjects over time, often focusing
on a smaller group of individuals that are connected by a common trait.)
Descriptive vs analytical studies
Cross-sectional studies can be used for both analytical and descriptive purposes:
• An analytical study tries to answer how or why a certain outcome might occur.
• A descriptive study only summarizes said outcome using descriptive statistics.

Descriptive vs analytical
Example: studying child obesity.

A descriptive study might look at the prevalence of obesity in children, while an analytical
study might examine exercise and food habits in addition to obesity levels to explain why some
children are much more likely to be obese than others.
A case control study is a retrospective, observational study that compares two existing
groups.
Researchers form these groups based on the existence of a condition in the case group
and the lack of that condition in the control group.
They evaluate the differences in the histories between these two groups looking for 
factors that might cause a disease.
COHORT STUDIES
• These are the best method for determining the incidence and natural history of a
condition.
• The studies may be prospective or retrospective and sometimes two cohorts are
compared.
Prospective cohort studies
A group of people is chosen who do not have the outcome of interest (for example,
myocardial infarction). The investigator then measures a variety of variables that might be
relevant to the development of the condition. Over a period of time the people in the sample
are observed to see whether they develop the outcome of interest (that is, myocardial
infarction).
In single cohort studies those people who do not develop the outcome of interest are used as
internal controls.
Where two cohorts are used, one group has been exposed to or treated with the agent of
interest and the other has not, thereby acting as an external control.
Retrospective cohort studies
These use data already collected for other purposes.
The methodology is the same but the study is performed posthoc.
The cohort is “followed up” retrospectively. The study period may be many years but the time
to complete the study is only as long as it takes to collate and analyse the data.

Advantages and disadvantages

The use of cohorts is often mandatory as arandomised controlled trial may be unethical;
example: cannot deliberately expose people to cigarette smoke or asbestos. Thus research on
risk factors relies heavily on cohort studies. As cohort studies measure potential causes before
the outcome has occurred the study can demonstrate that these “causes” preceded