Clinical Trials

INTRODUCTION
 The preclinical trial “champions” are the “newborns” of clinical trial
 They must undergo another cycle of experimentation, just as
complex as and much more expensive than the previous one, this
time on the human species
 The term “clinical” is used to mean “on human subjects”
 Conventionally, Clinical trials of new treatments done in different
steps, called “phases”
 This is done in different phases in order to build up a greater
understanding of the new treatment, before it is approved or
recommended for routine use

INTRODUCTION…
 By convention, clinical trial is divided into four phases, indicated
with roman numerals I to IV
 Each new phase is designed to build on information discovered from
previous phases
 The pre-clinical phase occurs before the first phase of human testing
 During the pre-clinical phase, a drug is developed and then
evaluated in cells and animals to see its potential effect on the
human body

PHASE I TRIALS
 Phase I is the phase of clinical experimentation which starts with the
first administration of the drug to humans
 Traditionally it is carried out on healthy volunteers
 Main objectives of phase I:
 Obtain indications on the safety and tolerability of the drug over a
wide range of doses
 Study the pharmacokinetic properties of the drug in man
 If the phase I studies are performed on patients, instead of healthy
volunteers, a third objective is added:
 Obtain preliminary pharmacodynamic indications

 Normally a small (20-80) group of healthy volunteers will be selected
 This phase includes trials designed to assess the safety, tolerability,
pharmacokinetics, and Pharmacodynamics of a therapy
 These trials are almost always conducted in an inpatient clinic, where
the subject can be observed by full-time medical staff
 The subject is usually observed until several half-lives of the drug
have passed
 Phase I trials also normally include dose-ranging studies such that
doses for clinical use can be refined
 The tested range of doses will usually be a small fraction of the dose
that causes harm in animal testing

 Phase I trials most often include healthy volunteers, however there
are some circumstances when patients are used, such as with
oncology (cancer) and HIV drug trials
 In Phase I trials of new cancer drugs, for example, patients with
advanced (metastatic) cancer are used
 These trials are usually offered to patients who have had other types
of therapy and who have only few, if any, other treatment choices
 There are two specific kinds of Phase I trials
SAD – (Single Ascending Dose) studies are those in which groups of
three or six patients are given a small dose of the drug and observed
for a specific period of time
If they do not exhibit any adverse side effects, a new group of
patients is then given a higher dose. This is continued until
intolerable side effects start showing up, at which point the drug is
said to have reached the Maximum tolerated dose (MTD)

ALGORITHM FOR SINGLE DOSE ESCALATION

 MAD – (Multiple Ascending Dose) studies are conducted to better
understand the pharmacokinetics/pharmacodynamics of the drug
 In these studies, a group of patients receives a low dose of the drug
and the dose is subsequently escalated up to a predetermined level
 First in a small group of 20 to 25
 If safe  in a larger group of up to about 50 –75
 Samples (of blood, and other fluids) are collected at various time
points and analyzed to understand how the drug is processed within
the body
 Starting Dose can be calculated by different strategies:
1. Starting dose of a IND should be a small fraction – not more than
10 % of the predicted therapeutic dose

2. FDA guidance:
i. First, convert NOAEL (No Observed Adverse Effects Level)
from the toxicity studies to human equivalent dose (HED) on
the basis of body surface area
ii. Then select HED from the most appropriate species
iii. After that apply a safety factor (10 – fold) to give a Maximum
Recommended Starting Dose (MRSD)
iv. Finally, adjust the MRSD on the basis of the predicted
pharmacological action of the IND
 This approach is simple but has following limitations
 Emphasis is on selecting a dose with minimal risk of toxicity,
based on NOAEL, rather than selecting one with minimal
pharmacological activity in humans
 Also, the focus is on the dose of the IND rather than exposure

 An alternative or complementary method is to calculate the safe
starting dose based on the minimal anticipated biological effect
level (MABEL)
 If different methods give different estimates, the lowest value should
be taken and a margin of safety built into the actual starting dose
Increasing the dose:
 The number of subjects dosed on any one occasion, and the interval
between dosing individual subjects will depend on the IND, its route
of administration, and type of trial
 Ex.: only one subject must be given an active IND at the very first
administration of a higher – risk IND
 In contrast, if the IND is of low risk , subjects can be dosed on the
same occasion

 Usually cost $ 0.1 million to $ 1 million
 Duration: From 3 month to 1 year
 Phase I study reveals no serious safety issues  Phase II studies
follow
 Success rate : 70 %
Facilities and Staff:
 Subjects – healthy or patient volunteers
 Medical Examinations – separate area for medical examination to
ensure privacy
 Beds – on wheels, adjustable for height and tilt and numbered for
individual trial subjects, enough aisles , curtain closed, lockers, over-
bed tables or trays
 Bed head services – power sockets for medical and other equipment,
adjustable lighting, nurse call button, which must be tested regularly

 Laundry services– to subjects who stay on the unit for long period
 Catering – prepared either by unit or by a subcontractor
- meal time and type of food depend on trial protocol
- low salt / high fat diet, involvement of dietician required
for some trials
- must follow the Food Safety Regulations
 Toilets and Bathrooms – enough toilets, wash basins , showers solely
for trial subjects with unlocking facility from outside in an
emergency
 Leisure areas in sight of trial staff – comfortable seats, television,
video, internet access, board games, news papers, magazines, books,
approved drinks such as decaffeinated coffee
 Staff rooms – facilities for dress change, lockers, dining room, toilets
and showers
 Access – entry to and exit from the premises should be controlled
and only authorized personnel should be allowed to the areas where
the trial subjects are studied

 Repairs, maintenance and cleaning – periodically ensured
 Medical equipments:
 Resuscitation equipment
 Medical examination equipment
 Equipment to monitor vital signs
 Electrocardiographs
 Equipment for processing biological samples
 Refrigerators and freezers
 Central monitoring system for continuous monitoring of
variables such as HR, BP, ECG, Temperature, Pulse Oximetry
 Alarm system when some thing goes out of control
 Particular persons should be in charge of equipments
 Consumables – adequate supplies of syringes, needles
 Crisis management – recovery plan for a disaster and plan to deal
with medical emergencies
Staff:
1. Physicians: qualified registered practitioners, at least one
physician must be present in unit

 All physicians must:
 Know the trial protocol and supporting documents
 Know and be able to manage the potentially
 Harmful effects of the IMP, non-IMP and trial procedures;
 Be well informed about the Clinical Trials
 Regulations, GCP, GMP, and the Declaration of Helsinki
 Be trained in medical emergency and resuscitation procedures
 Among the physicians
 One senior will act as medical director plays a major role and train
others
 One or more principal investigators depending on the size of the
unit
 Nursing staff – qualified and trained in GCP
 Scientific and technical staff
 Supporting staff
 Bank and agency staff
 Other specialists if required

 Staff training and development:
 Induction training
 Continuing training
Trial subjects
 Recruitment - paper or electronic data base who have given
willingness
- advertisement in media, notice boards
- by word or mouth
- referral from other doctor
 Monitoring over exposure – by counseling and warning in
information leaflet and concern form
 Special populations – women, children, elderly, vulnerable subjects,
patients
 Payments – never be related to risk, all information should be given
in the information leaflet
 Obtaining informed consent - as per GCP guidelines

 Timing of recruitment and screening – For Panel then for specific
trial after necessary screening
 Identification – ID cards with photograph of the subject
 Safety of the trial subjects – monitored through out the trial
 Follow – up – till the last dose of IND
Pharmacy :
 All units should have a designated pharmacy area
 IND should be stored in designated areas under specified conditions
 Adequate space for storing different INDs

PHASE II TRIALS…
• Phase II trials are useful in examining the potential effectiveness of an
intervention before embarking on a large, expensive phase III trial
• The aim is to obtain preliminary evidence on whether a new treatment
might be effective, i.e. whether it can influence a clinically important
outcome measure, such as mortality, or reduce the severity of a disease
• Sometimes phase II is itself divided into two “sub-phases”: IIa, for
proof of concept; IIb, for dose-finding
• The proof of concept studies (phase IIa) are particularly useful when
dealing with an innovative compound
• Their aim is to confirm in man the basic biological and
pharmacodynamic concepts concerning the mechanism of action of
the new drug
• Such concept, before phase II, is based only on “proofs” on in vitro and
animal models, generally with service formulations

PHASE II TRIALS…
• In a proof of concept study, the drug is put in the best conditions to
show efficacy
•only subjects with a “pure”, text book-like clinical picture are
included, while subjects with severe, atypical or mixed forms, as
well as those with concomitant diseases, are excluded
•The chosen dose is the highest that can be administered based on
phase I results
•The chosen pharmacodynamic model is validated and accepted
• Studies for the choice of the dose, commonly called dose-finding or
dose-ranging (phase IIb), have the main objective of selecting the dose
or the doses and the frequency of administration to be tested in phase
III
• Secondary objectives of such studies are to obtain information on the
pharmacodynamic and sometimes therapeutic activity of the drug
• When phase IIa is not carried out, they also serve as the proof of
concept.

PHASE II TRIALS…
Types of phase II trials:
• Single arm
• Single arm, two-stage design
• Randomized phase II with control arm
• Randomized phase II with several new treatment arms∗
• Randomized phase II with several new treatment arms, two-stage
design.∗
∗could include a control arm (standard treatment or placebo)

PHASE II TRIALS…
Single arm:
 The simplest design has only one arm: all subjects are given the
new intervention
 The advantage is that all resources, i.e. subjects and financial
costs, are concentrated on one group
Single arm, two-stage design:
 In a two-stage design, the intervention is first tested on a small
number of subjects, and the subjects are assessed at the end of
this stage
 If a certain number respond, the trial continues and a second
group of subjects is recruited, otherwise the trial stops: this is
referred to as a stopping rule
 Two-stage designs are useful when the new intervention might
have serious side-effects or is expensive, because only a few
subjects are given such a therapy
 A practical limitation is that after the first stage is reached,
centers probably need to stop recruiting further patients until the
initial assessment is made

PHASE II TRIALS…
Example of a two-stage phase II design
 The response rate for a new treatment should not be lower than 20%,
the rate associated with standard therapy
 The new intervention should have a response rate of at least 35%
 Using these estimates, 5% level of statistical significance and 80%
power produces the following design:
 Stage 1 : Recruit and treat 22 subjects
If ≥ 8 respond, continue trial to Stage 2 (treatment
might be effective enough)
If≤5 respond, stop trial early (treatment unlikely to be
effective enough)
 Stage 2 : Recruit a further 50 patients, to make 72 in total
If ≥ 25 respond consider further investigation
 However, the decision to continue to Stage 2 may hinge on the
response of only one or two subjects

PHASE II TRIALS…
 Suppose there are five responders during Stage 1, but there really is a
beneficial effect of the treatment
 If the stopping rule is strictly adhered to, an effective treatment
would not be studied further and future patients would not benefit
 The alternative is also possible. A truly ineffective treatment is
investigated further because a sufficient number of subjects
happened to show a response in Stage 1, though this is probably of
less importance
Randomized phase II trial with control arm:
 There are two trial groups; the new intervention and a control
(standard treatment or placebo)
 The control arm is often used when it is not well known how subjects
respond generally
 The results found in each arm are used to design the corresponding
arms in a phase III trial, in particular determining sample size
 This design also provides information on recruitment rates, subjects’
willingness to participate in a randomized study, and possible
logistical problems, all of which could help future studies

PHASE II TRIALS…
Randomized phase II trial with several intervention arms:
 Two or more new treatments could be examined simultaneously
 Each arm is designed as a single-arm study, and subjects are
randomized to the different groups, with the same advantages as
above
 One or more of the new treatments are identified that could be
investigated further
 This design is sometimes called ‘pick the winner’, though there is
not necessarily a single ‘winner’
 The primary intention is not to directly compare the results between
the new treatment arms
 Deciding which treatment should be taken further is determined in
the same way as with a single-arm phase II study, i.e. whether the
treatment response rate in each arm exceeds the expected response
associated with standard treatments
 This design could also include a control arm using standard
treatment or placebo

PHASE II TRIALS…
Randomized phase II trial with several intervention arms: two-stage
design
 This is an extension of the single-arm two-stage design
 At the first stage, a few subjects (specified by the sample size
calculation) are randomized to each of the new treatments
 An assessment of efficacy is made, and those treatments that seem
effective enough proceed to Stage 2, though not all will pass the first
stage (another form of ‘pick the winner’)
Choosing outcome measures
 Phase II studies should be conducted in a relatively short span of
time, and the main endpoint should be compatible with this, as well
as being clinically relevant
 Therefore, several surrogate endpoints (Cholesterol level, Blood
pressure, CD4 count) can be used
 Observed changes in a validated surrogate endpoint may indicate an
effect on a true endpoint. Similarly, if a new treatment appears to
have no effect on a surrogate marker, it is unlikely that it would have
an effect on a true endpoint

PHASE II TRIALS…
 There may be several endpoints because the aim is to have a
preliminary evaluation of the new intervention, and sufficient
information is needed to decide whether a larger phase III trial is
justified
Information needed to calculate sample size:
 Expected effect in the new intervention group
 The effect in patients given standard treatments (assumed to be
known with certainty)
 Significance level (usually 5%, at the one-sided level)
 Power (usually 80% or 90%).

PHASE II TRIALS…
Summary :
 Phase II studies are a useful way of obtaining preliminary
information about a new intervention in a relatively small number of
subjects
 Subjects should be monitored closely, especially for side-effects
 Careful consideration should be given to interpreting the data from
randomized phase II studies that contain a control arm, particularly
if they produce positive results
 The decision to conduct a larger, confirmatory trial should depend
on several factors: efficacy, safety and feasibility
 ‘Positive’ results are used to underpin the justification for a larger
trial, thereby making such a trial more likely to be funded, and for it
to obtain approval from a regulatory authority and ethics committee
 Even if the data were negative, indicating that there is unlikely to be
a beneficial effect, it is useful to have this information because it
means valuable subjects and resources have not been wasted by
having a larger study.

PHASE III TRIALS…
Trial objectives:
 Comparing two interventions, A and B
(B could be the standard treatment, placebo or no intervention)
Superiority: A is more effective than B
Equivalence: A has a similar effect to B
Non-inferiority: A is not less effective than B
 ‘Effect’ is associated with any primary trial endpoint, such as death,
or occurrence or recurrence of a disorder
 Equivalence and non-inferiority trials are usually conducted when
the new intervention is expected to have fewer side-effects, be more
cost-effective or be more convenient to administer
 There are also bioequivalence drug trials, in which two forms of the
same drug, for example, produced using a new method or a different
formulation, are compared, rather than two different drugs

PHASE III TRIALS…
Trial Designs:

PHASE III TRIALS…
Trial Designs:
•A special case of a multi-arm study is a factorial design
•The above figure shows an example of a trial that evaluated folic acid
and a multi-vitamin combination for preventing neural tube defects
among pregnant women
• The following comparisons could be made:
B + D vs. A + C (is folic acid effective?)
C + D vs. A + B (are multivitamins effective?)
D vs. B (is folic acid + multivitamins better than folic acid
alone?)
D vs. C (is folic acid + multivitamins better than multivitamins
alone?)

PHASE III TRIALS…
Allocating individuals or groups of individuals to the trial groups:
 Most trials involve randomizing individual subjects to different arms,
and this is the preferable approach
 However, there are occasions when this is not practical, and groups of
subjects are randomized instead
Choosing outcome measures:
 There is some flexibility in the choice of outcome measures in phase
II studies, including surrogate endpoints
 This is done on the understanding that a subsequent, larger trial will
use a true endpoint
 In phase III trials the main outcome measure needs to be chosen
carefully and well defined so that the trial objectives are met, and the
results persuade health professionals to change practice
 The main endpoint should therefore ideally be an objective, rather
than a subjective measure
 Diagnosis by clinician is perhaps in between the previously
mentioned subjective and objective measures

PHASE III TRIALS…
Composite outcome measures:
 While some trial endpoints are associated with the occurrence of a
single event, others consist of several events combined into one
called a composite endpoint
 An example comes from trials of primary or secondary prevention of
cardiovascular disease that have evaluated statin therapy using an
endpoint with four components: fatal or non-fatal coronary heart
disease, or fatal or non-fatal stroke
 A limitation of composite endpoints is that a new intervention could
work for some but not all of the constituent events
Having several outcome measures (multiple endpoints):
 For many chronic diseases there could be a range of possible
endpoints and the temptation exists to include most or all of them in
a trial
 A new intervention may appear to work for some endpoints but not
others, making it difficult to interpret the results of the trial

PHASE III TRIALS…
 It may also be viewed as a ‘fishing expedition’, i.e. deliberately
choosing many endpoints in the hope that at least one will show an
effect
 Having multiple endpoints increases the chance of finding a
spurious effect, unless the sample size is increased
 Given these considerations, it is preferable to focus on one or two
primary endpoints, and stipulate at the start of the trial that these
will be used to determine whether practice should change
 The other endpoints should be treated as secondary outcome
measures, used to provide further information about the effect of the
intervention on the disorder
 If there are two or more primary endpoints the sample size
calculation and statistical analysis may need to allow for this

PHASE III TRIALS…
Information needed to calculate sample size:
 Expected effect in the new intervention group
 Expected effect in the control (comparison) group
 Significance level (usually 5%, at the two-sided level∗)
 Power (usually 80% or 90%).
 ∗ One-sided if the trial objective is to examine whether the new
treatment is not worse than the control (i.e. non-inferiority), or that
it can only be better
Summary
 Phase III trials are considered the ‘gold standard’ for evaluating a
new intervention
 They should be designed to be sufficiently large to provide reliable
evidence
 The methods for estimating sample size depend on the type of
outcome measure, the trial objective and whether there are separate
groups of subjects, or subjects get all treatments

PHASE III TRIALS…
Method of sample-size calculation:
 To determine the method of sample-size calculation, one option
from each of the three following features should be chosen:
 The type of outcome measure used:
 Counting people
 Taking measurements on people
 Time-to-event data
 What is being sought when comparing the two interventions:
 Superiority
 Equivalence
 Non-inferiority
 Factorial (if looking for an interaction)
 Having separate patient groups or one group receives all
treatments:
 Parallel group
 Crossover (split-person).
 Several free or commercially available software are also available,
and statistical software packages have sample-size facilities

PHASE III TRIALS…
Registration Dossier:
 All the data generated on the drug must be summarized and
discussed in a logical and comprehensive way in the registration
dossier, to be submitted to the regulatory authorities as the basis of
the request for approval
 The dossier is divided into various sections, each corresponding to a
development area:
 Physico-chemical characteristics and pharmaceutical
formulation.
 Delivery device (if applicable)
 Production and quality control
 Toxicology
 Pharmacology
 Pharmacokinetics
 Clinical evidence
 With regard to the registration dossier, the ICH process concluded
with the approval of the “Common Technical Document” (CTD)

PHASE IV TRIALS…
 The expression phase IV is used to indicate the set of clinical studies
performed after the approval of a new drug within the approved
indication(s) and restrictions imposed by the Summary of Product
Characteristics
 It is important to stress the fact that studies performed after
approval, but on different indications or outside of the restrictions
imposed by the regulatory (for example, new dose strengths or
regimens, special populations, use with contraindicated
concomitant medications) are not phase IV studies
 They are phase I to III studies, generally part of a new development
process, which requires new pivotal studies and a new registration
dossier, in order to obtain approval for a broader population or range
of concomitant medications, a new indication or dosage, etc.
 Sometimes, a distinction is made between studies performed after
submission of the registration dossier, but before approval by
regulatory authorities, referred to as phase IIIb studies, and studies
performed entirely after approval, the proper phase IV studies

PHASE IV TRIALS…
 Phase IV studies can have many different aims, among which are the
following:
 Comparisons between the new treatment and frequently used current
treatments (in phase II and III, a maximum of one or two active
controls are tested, if at all, not rarely the only comparison being
with the placebo)
 Pharmaco-economic assessments, intended to extend the
information obtained in phase III
 Safety assessments via clinical trials and/or pharmaco-vigilance
studies
 The latter are large observational studies aimed at evaluating the
safety of the new treatment on samples of patients much larger
than those used in phase III and in a context much closer to the
reality of clinical practice
 Such studies are particularly useful for evaluating rare and/or
delayed adverse events, i.e. events appearing only after prolonged
exposure to treatment, which generally cannot be quantified in
the preregistration phase
 Pharmacodynamic assessments

PHASE IV TRIALS…
 Assessments on subgroups of the patient population for which
the treatment has been approved, for example, patients more
seriously affected or more at risk
 Since the drug is available on the market, phase IV studies can be
performed more easily by independent research groups, that is, not
linked directly or indirectly to the pharmaceutical company
producing the drug
 This is a very positive situation, because it allows for independent
verification of the efficacy and safety of a new drug
 On the other hand, we must warn against uncritical acceptance of
data generated by independent groups that contrast the conclusions
of studies performed by the sponsor

PHASE V TRIALS
 The purpose of Phase V research is to determine who benefits from
the treatment protocol and at what cost
 The costs and values are assessed in fiscal terms through cost
effectiveness studies and in societal terms through cost-benefit
analyses
 Phase V has different interpretations in different companies
 It can be defined as additional studies that will ultimately be
submitted to regulatory authorities for approval of new indications,
formulations etc.
 Such study protocols may therefore have all the complexity of Phase
II and III protocols

Clinical Trials

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