Download Clinical Trials

Basic
& Clinical Evaluation of New Drugs
Mayyada Wazaify, PhD
Brain Massage!
The development and testing process required to bring a drug to market
DRUG DISCOVERY
• Most new drugs or drug products are discovered or
developed through one or more of six approaches
:
1. Identification or elucidation of a new drug target .
2. Rational drug design of a new drug based on an understanding
of biologic mechanisms, drug receptor structure, and drug
structure
3. Chemical modification of a known molecule
DRUG DISCOVERY
4. Screening for biologic activity of large numbers of
natural products, banks of previously discovered
chemical entities, and large libraries of peptides,
nucleic acids, and other organic molecules
5. Biotechnology and cloning using genes to produce
peptides and proteins.
6. Combinations of known drugs to obtain additive or
synergistic effects or a repositioning of a known drug
for a new therapeutic use.
Evaluation in Humans
• The need for careful design and execution is
based on three major confounding factors
inherent in the study of any therapeutic
measure-pharmacologic or
nonpharmacologic-in humans
Evaluation in Humans
• Confounding Factors in Clinical Trials
1.Variable natural history of most diseases
(eg, spontaneous neoplasm remission) – to avoid
errors, a crossover design is used
2. Presence of other diseases & risk factors (eg, life
style) – to avoid errors, crossover design and valid
methods of randomization are used
3. Subject & observer bias (placebo response) - to
avoid, single-blind and double-blind design are used
Cross Over Design
Randomization
The Food & Drug Administration (FDA)
• The FDA is the administrative body that oversees
the drug evaluation process in the USA and
grants approval for marketing of new drug
products.
Jordan Food and Drug Administration
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JFDA Established in 2004
Clinical Trials Unit (CTU)
The Clinical Research Law established in 2001
Seven Contract Research Organizations (CROs)
19 IRB, 12 of which are active
PRECLINICAL SAFETY & TOXICITY TESTING
to correctly define the limiting toxicities of
drugs and the therapeutic index comparing
benefits and risks of a new drug
the most essential part of the new drug
development process
PRECLINICAL SAFETY & TOXICITY TESTING
•
The goals of preclinical toxicity studies
include:
1. identifying potential human toxicities;
2. designing tests to further define the toxic
mechanisms; and
3. predicting the specific and the most relevant
toxicities to be monitored in clinical trials
• "no-effect" dose: the maximum dose at which a
specified toxic effect is not seen
• The minimum lethal dose: the smallest dose that is
observed to kill any experimental animal
• The median lethal dose (LD50)-the dose that kills
approximately 50% of the animals..
• These doses are used to calculate the initial dose to be
tried in humans, usually taken as one hundredth to one
tenth of the no-effect dose in animals.
Clinical Trials
•
Once a drug is judged ready to be studied in humans, a
Notice of Claimed Investigational Exemption for a New
Drug (IND) must be filed with the FDA
•
IND contains:
(1) information on the composition and source of the drug,
(2) chemical and manufacturing information,
(3) all data from animal studies,
(4) proposed clinical plans and protocols,
(5) the names and credentials of physicians who will conduct the
clinical trials, and
(6) a compilation of the key data relevant to study the drug in
man made available to investigators and their institutional
review boards.
Clinical Trials
• Testing in humans is begun after sufficient acute &
subacute animal toxicity studies have been completed
• Chronic safety testing in animals is done concurrently
with clinical trials
• Usually 4-6 years of clinical testing
• Ethical principles: Declaration of Helsinki, 1966
• Approval of: sponsoring organization, FDA (in Jordan:
JFDA), interdisciplinary institutional review board at
facility
Clinical Trials
• Phase I:
- observes the effect of drug as a function of
dosage
- small number of healthy volunteers(25-50)
- In some cases (cancer, AIDS, ie drugs with
expected toxicity), patients with disease are
used rather than normal volunteers
- Nonblind (open)
- Detect safety & pharmacokinetics
- Done in research centers by clinical
pharmacologists
Clinical Trials
• Phase II:
- Drug studied in patients with the target
disease to determine efficacy
- Number of patients is 100-200
- Usually single-blind design with a placebo &
positive control
- Detects broader range of toxicities
- Done in special clinical centers (eg, university
clinics)
Clinical Trials
Phase III
-
Larger number of patients (e.g. Thousands)
Further study of safety & efficacy
Double-blind & crossover techniques
Investigators are specialists in disease being treated
If results meet expectations: application is made for
permission to market the agent (NDA-new drug
application)
- FDA review of NDA may take up to 3 years
Clinical Trials
• For serious diseases, the FDA may permit
extensive but controlled marketing of a new
drug before phase 3 studies are completed;
• For life threatening disease, it may permit
controlled marketing even before phase 2
studies have been completed;
• Once approval to market the drug has been
obtained, phase 4 begins…
Clinical Trials
• Phase IV (post-marketing)
- Constitutes monitoring the safety of the new drug
under actual conditions of use in large numbers of
patients
- Some rare toxicities are revealed (low incidence)
Orphan drugs:
• drugs for rare diseases. Difficult to research, develop
and market. FDA provides special assistance & grants
for research of such drugs.
• 120 orphan drugs are approved for 82 rare diseases
since 1983.
• Generic drug: a drug product that is produced
by any pharmaceutical company after the
patent of the originator drug is expired.
In Jordan
Year
2002
2003
2004
2005
2006
2007
No. of Clinical
Study protocols
submitted
6
5
5
2
3
10
No. of Clinical Study
protocols approved
1
3
3
2
2
9