1. Yrd.Doç.Dr. Çiğdem Kaspar
CLINICAL TRIALS
Yrd.Doç.Dr. Çiğdem Kaspar

2. A good clinical study starts with
a good question based on good hypothesis that is based on good and comprehensive review of the available evidence from pre-clinical and clinical data
Type of design depends on the question to be answered

3. CLINICAL TRIALS
Trial is from the Anglo–French trier, meaning to try. Broadly, it refers to the action or process of putting something to a test or proof.
Clinical is from clinic, from the French cliniqu´e and from the Greek klinike, and refers to the practice of caring for the sick at the bedside. Hence, narrowly, a clinical trial is the action or process of putting something to a test or proof at the bedside of the sick. However, broadly it refers to any testing done on human beings for the sake of determining the value of a treatment for the sick or for preventing disease or sickness.
Clinical Trials are prospective studies.

4. CLINICAL TRIALS Clinical trials are clinical investigations.
They have evolved with different meanings by different individuals and organizations at different times.
For example, Meinert (1986) indicates that a clinical trial is a research activity that involves administration of a test treatment to some experimental unit in order to evaluate the treatment. Meinert (1986) also defines a clinical trial as a planned experiment designed to assess the efficacy of a treatment in humans by comparing the outcomes in a group of patients treated with the test treatment with those observed in a comparable group of patients receiving a control treatment, where patients in both groups are enrolled, treated, and followed over the same timeperiod. This definition indicates that a clinical trial is used to evaluate the effectiveness of a treatment.
Piantadosi (1997) simply defined a clinical trial as an experimental testing medical treatment on human subject.
On the other hand, Spilker (1991) considers clinical trials as a subset of clinical studies that evaluate investigational medicines in phases I, II,and III, the clinical studies being the class of all scientific approaches to evaluate medical disease preventions, diagnostic techniques, and treatments.
Three important key words in these definitions of clinical trials are experimental unit, treatment, and evaluation of the treatment.

5. CLINICAL TRIALS Experimental Unit
An experimental unit is usually referred to as a subject from a targeted population under study. Therefore the experimental unit is usually used to specify the intended study population to which the results of the study are inferenced.
Treatment
In clinical trials a treatment can be a placebo or any combinations of a new pharmaceutical identity (e.g., a compound or drug), a new diet, a surgical procedure, a diagnostic test, a medial device, a health education program, or no treatment. For example, in the Physician’s Health Study, one treatment arm is a combination of low-dose aspirin and beta carotene.
Evaluation
In his definition of clinical trials, Meinert (1986) emphasizes the evaluation of efficacy of a test treatment. It, however, should be noted that the assessment of safety of an intervention such as adverse experiences, elevation of certain laboratory parameters, or change in findings of physical examination after administration of the treatment is at least as important as that of efficacy.

6. CLINICAL TRIALS

7. CLINICAL TRIALS
1)Prevention trials test new approaches, such as medications, vitamins, or other
supplements, that doctors believe may lower the risk of developing a certain type of
cancer. Most prevention trials are conducted with healthy people who have not had
cancer.
2) Screening trials study ways to detect cancer earlier. They are often conducted to
determine whether finding cancer before it causes symptoms decreases the chance of
dying from the disease. These trials involve people who do not have any symptoms
of cancer.
3) Diagnostic trials study tests or procedures that could be used to identify cancer more
accurately. Diagnostic trials usually include people who have signs or symptoms of
4) Treatment trials are conducted with people who have cancer. They are designed to
answer specific questions about, and evaluate the effectiveness of, a new treatment or
a new way of using a standard treatment. These trials test many types of treatments,
such as new drugs, vaccines, new approaches to surgery or radiation therapy, or new
combinations of treatments.
5) Quality-of-life (also called supportive care) trials explore ways to improve the
comfort and quality of life of cancer patients and cancer survivors. These trials may
study ways to help people who are experiencing nausea, vomiting, sleep disorders,
depression, or other effects from cancer or its treatment.
6) Genetics studies are sometimes part of another cancer clinical trial. The genetics
component of the trial may focus on how genetic makeup can affect detection,
diagnosis, or response to cancer treatment.

8. CLINICAL TRIALS Basic Research Novel Compounds In-Vitro Screening
Isolated cells
& tissues
In-Vivo
Screening
In Animals
Safety
Testing
Drug
Licensing
& Release
Clinical
Trials I - III
In Humans

9. ClInIcal trIals (Any alternatIves)
In-Vitro Tests Can Show Whether:
A compound has the desired effect on isolated cells or tissues
There are adverse effects on those tissues
In-Vitro Tests Cannot Show Whether:
The desired effect will occur in a complete living system
There will be any adverse effects in a complete living system

10. CLINICAL TRIALS ClInIcal trIals (Any alternatIves) Animal Tests Can:
Suggest which drugs are likely to be effective in humans
Indicate which drugs may not be harmful in humans
Animal Tests Cannot:
Predict with absolute certainty what will happen in humans

11. CLINICAL TRIALS PHASE I PHASE II PHASE III PHASE IV
In a set of new regulations promulgated in 1987 and known as the IND Rewrite, the phases of clinical investigation adopted by the FDA since the late 1970s is generally divided into three phases (21 CFR ). These phases of clinical investigation are usually conducted sequentially but may overlap
PHASE I
PHASE II
PHASE III
PHASE IV

12. CLINICAL TRIALS .
Phase I clinical investigation provides an initial introduction of an investigational new drug to humans. The primary objectives of phase I clinical investigation are twofold. First, it is to determine the metabolism and pharmacologic activities of the drug in humans, the side effects associated with increasing doses, and early evidence on effectiveness. In addition it is to obtain sufficient information about the drug’s pharmacokinetics and pharmacological effects to permit the design of well-controlled and scientifically valid Phase II clinical studies. Thus phase I clinical investigation includes studies of drug metabolism, bioavailability, dose ranging, and multiple doses. Phase I clinical investigation usually involves 20 to 80 normal volunteer subjects or patients.
Phase II studies are the first controlled clinical studies of the drug, and they involve no more than several hundred patients. The primary objectives of phase II studies are not only to initially evaluate the effectiveness of a drug based on clinical endpoints for a particular indication or indications in patients with the disease or condition under study but also to determine the dosing ranges and doses for phase III studies and the common short-term side effects and risks associated with the drug. Although the clinical investigation usually involves no more than several hundred patients, expanded phase II clinical studies may involve up to several thousand patients.

13. CLINICAL TRIALS
Phase III studies are expanded controlled and uncontrolled trials. The primary objectives of phase III studies are not only to gather the additional information about effectiveness and safety needed to evaluate the overall benefit-risk relationship of the drug but also to provide an adequate basis for physician labeling.
Phase IV trials generally refer to studies performed after a drug is approved for marketing. The purpose for conducting phase IV studies is to elucidate further the incidence of adverse reactions and determine the effect of a drug on morbidity of mortality

14. Clinical Trials-Phases
Phase I - Does it hurt the Patient?
Usually in normal volunteers, small groups for safety testing
Phase II - Does it help the Patient?
On patients to confirm the effectiveness of the drug
Phase III - Is it any better?
Large groups of patients for statistical confirmation of effect and incidence of side-effects
Phase IV - Does it work in the community?
Post marketing studies. Fine tuning and new rare findings from a very large population

16. CLINICAL TRIALS
Bias
Since the accuracy of the clinical results is referred to as closeness to the true value, we measure any deviation from the true value. The deviation from the true value is considered as a bias.
In clinical trials, clinical scientists would make any attempt to avoid bias in order to ensure that the collected clinical results are accurate. It, however, should be noted that most biases are probably caused by human errors.
Clinical trials are usually planned, designed, executed, analyzed, and reported by a team that consists of clinical scientists from different disciplines to evaluate the effects of the treatments in a targeted population of human subjects. When there are such non negligible differences in human background, education, training, and opinions, it is extremely difficult to remain totally impartial to every aspect at all stages of a clinical trial.
Bias inevitably occurs. Where bias occurs, the true effects of the treatment cannot be accurately estimated from the collected data. Since it is almost impossible for a clinical trial to be free of any biases, it is crucial to identify any potential bias that may occur at every stage of a clinical trial.
Once the potential bias are identified, one can then implement some procedures such as blinding or randomization to minimize or eliminate the bias.

17. CLINICAL TRIALS
Sackett (1979) partitions a clinical trial (or research) into seven stages at which bias can occur. These seven stages are;
(1) in reading up on the field,
(2) in specifying and selecting the study sample,
(3) in executing the experimental maneuver,
(4) in measuring exposures and outcomes,
(5) in analyzing the data,
(6) in interpreting the analysis result, and
(7) in publishing the results.

18. CLINICAL TRIALS

19. CLINICAL TRIALS

20. CLINICAL TRIALS

21. CLINICAL TRIALS

22. CLINICAL TRIALS Variability
The reliability is referred to as the degree of the closeness (or precision) of the clinical results to the true value regarding the targeted patient population.
The reliability of a clinical trial is an assessment of the precision of the clinical trial which measures the degree of the closeness of the clinical results to the true value. Therefore the reliability of a clinical trial reflects the ability to repeat or reproduce similar clinical outcomes in the targeted patient population to which the clinical trial is inferred.
The higher precision a clinical trial has, the more likely the results will be reproducible.
The precision of a clinical trial can be characterized by the variability of an estimated treatment effect based on some clinical endpoints used for clinical evaluation of the trial. In practice, sample size and the variability of the primary clinical endpoint play an important role in determining the precision and reproducibility of the clinical trial.
The larger the sample size of the clinical trial is, the higher the precision and the more reliable the result will be. In clinical trials, however, the sample size is usually not large, and it cannot be increased indefinitely due to limited budget, resources, and often difficulty in patients recruitment. Indeed, the cost of achieving a desired precision can be extremely prohibitive. As an alternative, we can carefully define patient inclusion and exclusion criteria to reduce the variability of primary clinical endpoints and consequently reduce the cost.
Variations can be controlled by appropriate statistical designs, blocking, or stratification.
Their impact on the precision of the estimates for treatment effects may be eliminated through adequate statistical analyses.

23. CLINICAL TRIALS
to have an accurate and reliable assessment of the true efficacy and safety of a study medication, it is important to avoid bias and to minimize the variability of the primary clinical endpoint whenever possible

24. CLINICAL TRIALS BIas and VarIabIlIty
The clinical trial is considered to be the “gold standard” in clinical research
Clinical trials provide the ability to reduce bias and variability that can obscure the true effects of treatment
Bias  affects accuracy
Variability  affects precision

25. CLINICAL TRIALS CONFOUNDING AND INTERACTION
In clinical trials, confounding and interaction effects are the most common distortions in the evaluation of medication.
Confounding
In clinical trials, there are many sources of variation that have an impact on the primary clinical endpoints for evaluation relating to a certain new regimen or intervention.
Interaction
The objective of a statistical interaction investigation is to conclude whether the joint contribution of two or more factors is the same as the sum of the contributions from each factor when considered alone. The factors may be different drugs, different doses of two drugs, or some stratification variables such as severity of underlying disease, gender, or other important covariates.

26. CLINICAL TRIALS GOALS OF CLINICAL TRIALS
The ultimate goal of clinical research is to obtain an unbiased inference with possibly best precision in order to scientifically address the clinical questions regarding the study drug under investigation with respect to a target patient population.
Clinical Trials:
Provide stronger evidence of the effect (outcome) compared to observational designs, with maximum confidence and assurance
Yield more valid results, as variation is minimized and bias controlled
Determine whether experimental treatments are safe and effective under “controlled environments” (as opposed to “natural settings” in observational designs), especially when the margin of expected benefit is doubtful / narrow ( %)

27. CLINICAL TRIALS TARGET POPULATION AND PATIENT SELECTION
One of the primary objectives of a clinical trial is to provide an accurate and reliable clinical evaluation of a study drug for a target patient population with certain diseases.
In practice, statistical and clinical inference are usually drawn based on a representative sample (a group of patients to be enrolled in the trial) selected from the target patient population of the clinical trial.
A representative sample provides the clinician with the ability to generalize the findings of the study. Therefore, selecting patients for a clinical trial plays an important role to best answer the scientific and/or medical questions of interest regarding the study drug.

28. CLINICAL TRIALS Eligibility Criteria
In clinical trials a set of eligibility criteria is usually developed to define the target patient
population from which qualified (or eligible) patients can be recruited to enroll the studies.
Typically a set of eligibility criteria consists of a set of inclusion criteria and a set of exclusion criteria. The set of inclusion criteria is used to roughly outline the target patient population, while the set of exclusion criteria is used to fine-tune the target patient population by removing the expected sources of variabilities.
To be eligible for the intended study, patients must meet all the inclusion criteria. Patients meeting any of the exclusion criteria will be excluded from the study.
Eligibility criteria should be developed based on patient characteristics, diagnostic criteria, treatment duration, and the severity of the disease.

29. CLINICAL TRIALS

30. CLINICAL TRIALS Ethical Considerations
For many severely destructive diseases such as AIDS, Alzheimer’s disease, and cancer, it is unethical to include placebo concurrent control in a clinical trial where an effective alternative remedy is available. It, however, should be noted that the effectiveness and safety of a test agent can only be established by inclusion of a placebo concurrent control.
Ethical considerations will definitely affect the patient selection process.

31. CLINICAL TRIALS Sample Size Estimation
For assessment of the effectiveness and safety of a study drug, a typical approach is first to show that the study drug is statistically significant from a placebo control.
If there is statistically significant difference, we then demonstrate that the trial has a high probability of correctly detecting a clinically meaningful difference.
The probability of correctly detecting a clinically meaningful difference is known as the (statistical) power of the trial.
In clinical trials, for a given significance level, we can increase the statistical power by increasing the sample size.
In practice, a pre-study power analysis for sample size estimation is usually performed to ensure that the intended trials have a desired power (e.g., 80%) for addressing the scientific/medical questions of interest.

32. How can we ensure comparabIlIty of treatment groups?
CLINICAL TRIALS
How can we ensure comparabIlIty of treatment groups?
We can not ensure comparability but randomization helps to balance all factors between treatment groups
If randomization “works” then groups will be similar in all aspects except for the treatment received

33. CLINICAL TRIALS RandomIzatIon
Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned
Simplest Case: each patient has the same chance of receiving any of the treatments under study
RandomIzatIon

34. Problem wIth SImple RandomIzatIon:
CLINICAL TRIALS
Problem wIth SImple RandomIzatIon:
May result in substantial imbalance in either
an important baseline factor and/or
the number of subjects assigned to each group
Solution: Use blocking and/or stratified randomization

35. CLINICAL TRIALS BlockIng Example:
If we have two treatment groups (A and B) equal allocation, and a block size of 4, random assignments would be chosen from the blocks
1) AABB 4) BABA
2) ABAB 5) BAAB
3) ABBA 6) BABA
Blocking ensures balance after every 4th assignment

36. StratIfIcatIon Example
CLINICAL TRIALS
StratIfIcatIon Example
To ensure balance on an important baseline factor, create strata and set up separate randomization schedules within each stratum
Example: if we want prevent an imbalance on age in an osteoporosis study, first create the strata “< 75 years” and “ 75 years”
then randomize within each stratum separately
Blocking should be also be used within each stratum

37. CLINICAL TRIALS BlIndIng
Masking the identity of the assigned interventions
Main goal: avoid potential bias caused by conscious or subconscious factors
Single blind: patient is blinded
Double blind: patient and assessing investigator are blinded
Triple blind: committee monitoring response variables (e.g.statistician) is also blinded

38. CLINICAL TRIALS How to BlInd To “blind” patients, can use a placebo
Examples
pill of same size, color, shape as treatment
sham operation (anesthesia and incision) for angina relief
sham device such as sham acupuncture

39. CLINICAL TRIALS General Study DesIgns
Many clinical trial study designs fall into the categories of parallel group, dose-ranging, cross-over and factorial designs
There are many other possible designs and variations on these designs
We will consider the general cases

40. CLINICAL TRIALS
Parallel group designs

41. CLINICAL TRIALS
Dose-Ranging Studies

42. CLINICAL TRIALS
Cross-Over Designs

43. CLINICAL TRIALS Cross-Over DesIgns
Subjects are randomized to sequences of treatments (A then B or B then A)
Uses the patient as his/her own control
Often a “wash-out” period (time between treatment periods) is used to avoid a “carry over” effect (the effect of treatment in the first period affecting outcomes in the second period)
Can have a cross-over design with more than 2 periods
Cross-Over DesIgns

44. CLINICAL TRIALS
Cross-Over DesIgns
Advantage: treatment comparison is only subject to within- subject variability not between-subject variability
 reduced sample sizes
Disadvantages:
strict assumption about carry-over effects
inappropriate for certain acute diseases (where a condition may be cured during the first period)
drop outs before second period

45. CLINICAL TRIALS
Cross-Over DesIgns
Appropriate for conditions that are expected to return to baseline levels at the beginning of the second period
Examples:
Treatment of chronic pain
Comparison of hearing aids for hearing loss
Mouth wash treatment for gingivitis

46. Factorial Designs
CLINICAL TRIALS

47. CLINICAL TRIALS
FactorIal DesIgns
Attempts to evaluate two interventions compared to a control in a single experiment (simplest case)
An important concept for these designs is interaction (sometimes called effect modification)
Interaction: The effect of treatment A differs depending upon the presence or absence of intervention B and vice-versa.

48. CLINICAL TRIALS FactorIal DesIgns Advantages: Disadvantages:
If no interaction, can perform two experiments with less patients than performing two separate experiments
Can examine interactions if this is of interest
Disadvantages:
Added complexity
potential for adverse effects due to “poly-pharmacy”