The document discusses the various phases of clinical drug trials. Phase 3 trials involve large patient populations of 500-3000 people across multiple sites to confirm the drug's safety, effectiveness, and appropriate dosage. Phase 4 trials occur after marketing approval and involve post-marketing surveillance and pharmacovigilance to monitor long-term safety and effectiveness in an even larger population under regular medical practice. The overall goal of clinical trials is to generate necessary data to allow regulatory approval and safe medical use of new drugs.
4. 1. To demonstrate the therapeutic efficacy
of the drug in a representative sample
of the patient population, generally by
means of at least two well-designed
and adequately performed independent
studies.
2. To demonstrate the safety and
tolerability of the drug in a sufficiently
large sample of the patient population,
by means of studies of sufficiently long
duration, compared to the intended
duration of the treatment in clinical
practice.
3. to gain additional information
regarding the effectiveness and safety
that is required to evaluate the overall
benefit-risk ratio
4
5. a larger patient population 500-3000
Multicentric
Length of study- 1 to 4 years
5
7. Objectives:
• To confirm safety and effectiveness of the drug
• Basis for marketing approval
• Active controlled studies
• Conducted in patients in whom the drug will be eventually
intended.
• Inclusion and exclusion criteria relatively relaxed
• Different dosages, schedules and combinations with other
drugs
7
8. • Different patient population ( Multicentre/ Multinational
trial )
• Also conducted in special group patients (e.g. elderly,
renally impaired, etc)
• Comparison PK/PD with current Gold Standard
8
9. Information obtained
• Definitive proof of efficacy
• Additional safety data in large patients
• Adverse effects with longer duration of treatment
• Information for package insert and labelling of
medicine
9
10. Objectives:
• Further explore dose-response relationship in different
stages of the disease and in combination with another
drug
• Clinical trial after regulatory submission of an NDA ( New
Drug Application ) but prior to approval and launch
• Supplement earlier trials, complete earlier trials, directs
towards new trials or phase IV evaluations
10
11. Difference between 3A and 3B
Phase 3 a Phase 3 b
• Trials carried out on a large number or in
a special category
• Regulatory requirement for NDA
• Generates data on safety and efficacy
• Extended trials of 3a after applying for
approval but before launch
• Also known as ‘ label expansion’
• To show the drug works for additional
types of patients/ diseases beyond the
original use for which the drug was
approved for marketing
• These may supplement or complete the
earlier trials or may be directed to Phase IV
11
12. End of Clinical Trial Activities
Sponsor: Expert Committee review of Efficacy, safety and potential
sales (Profit).
Go-No Go decision to file New Drug Application ( NDA) to the
competent authority of the concerned country (DCGI in India/FDA in
the US) for the approval of drug for marketing
Expert review by competent authority
Approval by competent authority
Drug marketed Phase IV begins 12
14. • The New Drug Application (NDA) is the vehicle
through which drug sponsors formally propose
that the DCGI ( in India) or FDA ( in the US)
approve a new pharmaceutical product for sale
and marketing
The goals of the NDA are to provide enough information to permit FDA/DCGI
reviewers to establish the following:
• Drug is safe and effective.
• Benefits outweigh the risks.
• Proposed labelling is appropriate
14
15. • NDA contains all of the information
gathered during preclinical to phase III
• NDA can be thousands of pages long
• Can take 2-3 years for FDA/DCGI to review
NDA used in India is called Form # 44:
Application for grant of permission to import or manufacture a new
Drug or to undertake clinical trial.
15
16. Contents:
• Full pre-clinical and
clinical testing
information
• Information of efficacy,
safety and marketing
status of the drug in
other countries
• Prescription, samples
and testing protocols,
• Product monograph,
labels, and cartons.
16
17. • MAA-Marketing Authorization Application, IND-Investigational New Drug, CTA-Clinical Trial Authorization, DNA-Data Not Available.17
18. • In case of urgent need of therapy ( eg cancer
chemotherapy)
• For serious disease, or life threatening diseases
approval of controlled marketing of new drug
before phase 3 or even phase 2 is completed
18
19. Phase 4 and
Post Marketing Surveillance
The real test of the drug in real world
19
20. • Studies (other than routine surveillance) performed
after drug approval and are related to the approved
indication(s).
• These trials go beyond the prior demonstration of the
drug's safety, efficacy and dose definition
• Include additional drug-drug interaction(s), dose-
response or safety studies and trials designed to
support use under the approved indication(s)
20
21. • Pre-marketing phase are incomplete with regard to possible ADRs
• Number of patients one would need to observe to have a 95% chance of
detecting 1, 2, or 3 cases of adverse reaction
21
22. • New knowledge about a drug is obtained when doctors all over the
world use the drug in a wide spectrum of patients, with varied
ethnicity, various underlying diseases, and a range of concomitant
medication
• Additional knowledge about drugs comes from scientific, rather than
commercial interest, done by individual workers in universities and
research institutions which are possible only after the drug receives
regulatory approval and becomes commercially available
• Complements the efficacy data that results from a pre-marketing
randomized controlled trial (RCT).
22
23. • Pharmacoepidemiology
• Post marketing
surveillance
• Pharmacovigilance
• Pharmaco-economic
studies
• Case control
• Cohort
• Cross sectional
• Drug utilization
studies
• Meta analysis
• Patient registries
• Automated linkage
data
• Large simple trial
• Descriptive- case
reports, case series.
23
24. • PMS study is a non-interventional study requested by regulatory
authorities to verify the safety, tolerability and effectiveness of a
marketed drug in a particular population per the locally approved
label.
• Regulatory requirement in countries such as Japan and the
Philippines
• Open studies where unlike pre-marketing studies, no strict inclusion
& exclusion criteria, but governed by the permissible indications and
contra-indications of the drug as stated in prescribing information
25
25. • In India, PMS data used to be submitted to the Drugs Controller
General of India (DCGI) within 2 years of launch. Now Periodic Safety
Update Reports (PSURs) are filed at regular intervals
• PSUR are reports that provide an evaluation of the benefit-risk
balance of a medicine, submitted every six months for the first two
years after approval of the drug and for subsequent two years -
annually.
26
26. • Current worldwide
market authorization
status,
• Update of actions
taken for safety
reasons,
• Changes to reference
safety information,
• Estimated patient
exposure,
• Presentation of
individual case
histories, Studies,
• Other information,
• Overall safety
evaluation,
• Conclusion
PSUR should contain the following information:
27
27. Pharmacovigilance is the science and activities
relating to the Detection, Assessment,
Understanding and Prevention of adverse drug
reactions or any other possible drug related
problems.
In India, Pharmacovigilance activities are done under
Pharmacovigilance Program of India ( PVPI)
Indian Pharmacopoeia Commission (IPC) in an
autonomous institution of Ministry of Health and
Family Welfare, GOI, functions as National
Coordination Center for PvPI
28
28. • Initiated by GOI in July 2010
• Follows spontaneous reporting system for data
collection
• SPONTANEOUS REPORTING: All unsolicited reports of
suspected adverse events (AEs) from health care
professionals or consumers or pharmaceutical
companies, received by the regulatory authorities (
FDA, CDSCO,NCC, AMC etc)*
29
30. Changes to a drug’s label
Black-box warnings
Approval: new users/indications
Changes in a drug’s manufacturing
process
New CTs & analyses
(economic/efficacy/safety)
Drug withdrawals
31
31. • Clinical Endpoints.
• Practice based drug evaluation.
• Large and heterogeneous population.
• Long-term use.
• Pharmaco-economic considerations.
• Establishing methods of prescribing and
utilization.
• Meaningful role in drug development.
32
32. •No or little supervision.
•Fewer data collected from each patient.
•Non-compliance.
•Self-medication.
• Identification of new indications may promote
off-label use.
• Unregulated environment
33
33. • Pragmatic trial/ translational research
• Decision makers, whether patients, physicians or policy makers need to
know what they can expect from the available diagnostic or therapeutic
option when applied to day to day life ( external validity )
• should allow minimum constrains of usual practice of prescribing and using
medicine
• Explanatory trials seek to maximize the probability that the intervention
and not some other factor causes the study outcome ( internal validity)
• Pragmatic trials place a premium on external validity while maintaining as
much internal validity as possible
35
34. Select clinically relevant alternative
intervention to compare
Include a diverse population of study
participants
Recruit participants from
heterogeneous practice settings
Collect data on a broad range of health
outcomes
36
35. • Central drugs standard control organization directorate general of health
services ministry of health & family welfare govt. Of india,.
• Form 44 format at URL Form%2044.htm accessed on 21-02-2019.
• Schedule y at URL Schedule%20Y(ammended%20version)%20-
%20CDSCO.htm accessed on 21-02-2019
• New drug approval process in india by Dr. Harish Dureja at URL
New%20Drug%20Approval%20Process%20%20Regulatory%20View%20%2
0%20Pharmainfo.net.htm accessed on 21-02-2019
• Suvarna V. Phase IV of Drug Development. Perspect Clin Res. 2010;1(2):57-
60.
• Berkowitz Berry A. Development & Regulation of Drug .Katzung BG,
Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. 11th
ed.New York: Tata McGraw Hill; 2017.p67-75.
37
Generally, these are randomized , double blind and comparative trials conducted on a larger patient population (500-3000) by several physicians (usually specialists in treating the target disease).
Phase III studies are large multicentric studies involving a lot of time, money and manpower.
11.5 million to 53million dollars
Sponsor: Expert Committee review of Efficacy, safety and potential sales (Profit).
Go-No Go decision to file New Drug Application ( NDA) to the competent authority of the concerned country (DCGI in India/FDA in the US) for the approval of drug for marketing
Expert review by competent authority
Approval by competent authority
NCE marketed ….. Phase IV begins
for new drug substances discovered in India, clinical trials are required to be
carried out in India right from Phase I
for new drug substances discovered in countries other than India, Phase I data as required.
After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat
Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials
concurrently with other global trials for that drug. Phase III trials are required to be
conducted in India before permission to market the drug in India is granted;
Diff btw 3a and 3b
Diff btw 3a and 3b
Diff btw 3a and 3b
A lot of the additional knowledge about drugs comes from scientific, rather than commercial interest, done by individual workers in universities and research institutions which are possible only after the drug receives regulatory approval and becomes commercially available
New knowledge about a drug is obtained when doctors all over the world use the drug in a wide spectrum of patients, with varied ethnicity, various underlying diseases, and a range of concomitant medication
By the time of licensing, exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected;
A lot of the additional knowledge about drugs comes from scientific, rather than commercial interest, done by individual workers in universities and research institutions which are possible only after the drug receives regulatory approval and becomes commercially available
New knowledge about a drug is obtained when doctors all over the world use the drug in a wide spectrum of patients, with varied ethnicity, various underlying diseases, and a range of concomitant medication
By the time of licensing, exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected;
Such studies describe how a drug is marketed, prescribed, and used in a population, and how these factors
influence outcomes, including clinical, social, and economic outcomes
It is a hybrid between a randomized clinical trial and an observational study (e.g., cohort study). A large
number of participants are randomized to treatment groups, with follow-up per routine practice. Simple
refers to the effort of enrolling physicians and participants and the objective is to interfere with routine
practice as little as possibl
PSURs shall be submitted every six months for the first two years after approval of the drug is granted to the applicant. For subsequent two years - annually.
These are reports providing an evaluation of the benefit-risk balance of a medicine.
The information in PSURs helps to determine if there are new risks identified for a medicine or whether the balance of benefits and risks of a medicine has changed.
A black box warning is the strictest warning put in the labeling of prescription drugs or drug products by the Food and Drug Administration (FDA) when there is reasonable evidence of an association of a serious hazard with the drug.
