2. The Drug Development Process
Each country has a regulatory body which governs the approval process
Drug must be proved to be Safe and Effective
Pre-Clinical testing (Laboratory and animals)
Clinical testing (Clinical trials in humans)
3. Clinical Trial
Give (new drug to a number of subjects and assess outcome
(uncontrolled)
Give new drug to one group and control to another group and assess outcome
(controlled clinical trial)
4. Clinical Trials: Major Questions
What happens to the drug in the body?
What happens to the body when given the drug?
Is the drug clinically effective?
Is the drug clinically safe / tolerable?
How should the drug be taken?
5. Concepts In Clinical Development
Pharmacokinetics (PK):
(Absorption, Distribution,
Metabolism, Elimination -
A.D.M.E.)
Pharmacodynamics (PD): (Effects
on Organs or Systems)
Evaluation or quantification of
what the body does to a drug
substance over time.
Evaluation or quantification of
what a drug substance does to
the body over time, and over
drug concentrations.
6. Concepts In Clinical Development
Efficacy
- A treatment is considered Ineffective unless Scientifically /
Clinically proven Efficacious.
Safety - A
treatment is considered Unsafe unless Scientifically / Clinically proven
Safe / Tolerated.
Key is risk / benefit ratio!
7. Standards Of Clinical Development
Key concepts in clinical trial design
Control: Active (positive)
Placebo (negative)
Others
Randomization: treatment assignment left to chance
Blinding: Double-Blind, Single Blind, Open
Parallel groups vs. cross-over vs. Others
(simultaneous)(sequential in time)
Dose titration vs. fixed dose
Stratification: balancing relevant subset of patients
8. Patient Control Groups: Why?
To provide a standard for comparison of new therapy
To eliminate positive bias toward new therapy, including
“placebo” effect.
To protect new therapy against negative bias concerning adverse
experiences.
To increase scientific and regulatory acceptance of study results
9. Placebo Effect
A real physiological effect caused by an inactive drug.
A placebo is a supposedly inert substance or ineffectual
technique originally used as a control in an experiment.
The nature of the effect is unknown, although it is does
demonstrate the power that an individual's belief can have on
their state and performance.
The belief or knowledge that one is being treated can itself have
an effect that confounds with the real effect of the treatment.
10. The History of Clinical Trials
First randomised controlled clinical trial
• 1948- First use of a randomised control group:
streptomycin treatment of pulmonary tuberculosis
• Treatments: streptomycin (antibiotic) versus bed rest
• Patients received streptomycin OR just bed rest at
random (randomised clinical trial)
• Outcome: streptomycin was effective
11. First double-blind randomised controlled clinical trial
1950 - investigated giving antihistamine treatment for the common
cold and placebo in a double-blind manner
Treatments: Antihistamine versus placebo
Neither patient nor doctor knew the treatment
Outcome: Antihistamine was not effective in curing common cold
The History of Clinical Trials
12. Development of New Drug - A High - Risk Undertaking
Time: 8 -12 years from discovery to market
Cost: average of $800-900 million
Success: 1 in 4000 compounds synthesized or 1 in 5 tested in humans reaches
the market
Return: 1 in 3 drugs reaching the market recaptures development costs
13. Major Stages of Drug Development – US FDA
Preclinical Testing
IND Application
Clinical Testing – Phase I
Clinical Testing – Phase II
Clinical Testing – Phase III
New Drug Application
Clinical Testing–Phase IV
14. Drug Development Process
Initial
Synthesis
Animal
Testing
I
N
D
A
P
P
L
I
C
A
T
I
O
N
Phase I
Phase II
Phase III
Phase IV
Adverse
Reaction
Reporting
Surveys/
Sampling
Testing
Inspections
Range 1-3 Yrs.
Avg:18 Mos.
FDA Time
30 Day
Safety Review
Range 2-10 Yrs.
Avg: 5 Yrs.
NDA
Submitted
NDA
Approved
Range 2 Mon – 7 Yrs.
Avg:24 Mos.
Average of Approximately 100 Months From Initial Synthesis to Approval of NDA
Treatment Use
Preclinical
Clinical NDA Review Post-Marketing
15. Preclinical Testing
Laboratory and Animal Testing is Done
Is compound safe in living organisms ?
Is compound biologically active?
If YES, file an IND Application
16. Clinical Testing – Phase I
Involves giving the drug to a small number of healthy volunteers
Determines the safety of the drug as well as the safe dosage range
Takes a year or less to complete
17. Clinical Testing – Phase II
Involves giving the drug to a large group (100-300) of patients who
have the disease that the drug is expected to treat
Purpose is twofold….
- Does the drug work in the disease population?
- At what dosage does the drug demonstrate efficacy?
Takes about 2 years to complete
18. Clinical Testing – Phase III
Involves administering the drug to a large number of patients (1000-
3000)
Purpose is to….
- Confirm earlier efficacy results
- Identify adverse events which occurs when the drug is
given to a larger population over a longer period of time
Takes about 3 years to complete
19. NDA – New Drug Application
If the results of all the previous testing is positive, then the
pharmaceutical company files an NDA
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 to review
20. Clinical Testing – Phase IV
Once the NDA is approved and the drug is available, post-marketing studies
are conducted to further confirm safety and efficacy during long-term use
Can include mail-in questionnaires and personal interviews
21. Good Science + Good Study Logistics
=
Good Clinical Development
• Regulatory authority satisfaction
• Public health protection
• Marketable product
24. Manager :
• Protocol review
• CRF development
• Authorization and database access
• Data validation document
• Approval of processes and procedures
• Oversight of all aspects of CDM
25. Paper studies and EDC
Data Tracking
• Logging of paper CRFs
• Tracking data through CDM process, e.g.
1. Completeness of CRFs
2. CRFs through data entry process
3. Data discrepancy forms DCF
26. Data Entry
• Entering data
• Changing data
• Developing CRF instructions
• Generating computerized or manual checks on a database to
check for missing, inconsistent, or illogical data
• Implementing the data discrepancy management process
27.
28. Case Report Form
• ..CRF
• Official clinical data-recording document or tool used in a
clinical study
RDC/RDE (Remote Data Capture,
Remote Data Entry)
PAPER
29. Purpose
• Collects relevant data in a specific format
•in accordance with the protocol
•compliance with regulatory requirements
• Allows for efficient and complete data
processing, analysis and reporting
• Facilitates the exchange of data across
projects and organizations esp. through
standardization
30. CRF Relationship to
Protocol
• Protocol determines what data should be
collected on the CRF
• All data must be collected on the CRF if
specified in the protocol
• Data that will not be analyzed should not
appear on the CRF
31. CRF Development
• Guidelines
• Collect data with all users in mind
• Collect data required by the regulatory
agencies
• Collect data outlined in the protocol
• Be clear and concise with your data
questions
• Avoid duplication
• Request minimal free text responses
32. CRF Development
• Guidelines (con’t)
• Provide units to ensure comparable values
• Provide instructions to reduce
misinterpretations
• Provide “choices” for each questions
•allows for computer summarization
• Use “None” and “Not done”
33. CRF Development
•Guidelines (con’t)
• Collect data in a fashion that:
•allows for the most efficient
computerization
•similar data to be collected across studies
• CRF book needs to be finalized and available
before an investigator starts enrolling patients
into a study
Take the time to get it right the first time
34. Three major parts:
Header
Safety related modules
Efficacy related modules
Module block of specific
questions
CRF module(s) make up a
single CRF page
CRF Book series of CRF pages
35. Header Information
• Key identifying Information
•MUST HAVES
• Study Number
• Site/Center Number
• Subject identification number
36. Creating Safety Modules
Usually come from a standard library
Select modules appropriate for your study
Keep safety analysis requirements in mind
Safety Modules usually include
Demographic
Adverse Events
Vital Signs
Medical History/Physical Exam
Concomitant Medications
Patient Disposition
37. Efficacy Modules
Designed for each therapeutic area based on the
protocol
Considered to be “unique” modules and can be
more difficult to develop
•Use existing examples from similar protocols where
applicable
•Consider developing a library of efficacy pages
Design modules following project standards for
data collection
38. Creating Efficacy Modules
Follow general CRF design guidelines
Use pages or modules from the therapeutic
library
Define diagnostics required
Include appropriate baseline
measurements
Repeat same battery of tests
Define and identify
•key efficacy endpoints
•additional tests for efficacy
39. Importance of Standard
CRFsPrepares the way for data exchange
Removes the need for mapping during data
exchange
Allows for consistent reporting across protocols,
across projects
Promotes monitoring and investigator staff
efficiency
Allows merging of data between studies
Provides increased efficiency in processing and
analysis of of clinical data
40. CRF Development
Process
CRF Designer
Reviewers
CRF Designer
CRF Book
•Drafts CRF from protocol
• CRF Review Meeting
• Comments back to designer
• Updates CRF to incl. comments
• Review and Sign off
• Coordinate printing and distribution
Site
41. CRF Development Process
Responsibility for CRF design can vary between
clinical research organizations (CRA, data
manager, specialty role)
• Include all efficacy and safety parameters
specified in the protocol using standards
libraries
• To collect ONLY data required by the
protocol
• Work with protocol grid/visit schedule
42. CRF Development Process
Interdisciplinary review is necessary
•each organization has its own process for
review/sign-off
•Should include relevant members of the
project team involved in conduct, analysis
and reporting of the trial
Begins
• As soon in the study prep process as possible
43. CRF Development Process
Review Team (example)
•Project Clinician
•Lead CRA
•Lead Statistician
•Lead Programmer
•Lead Data Manager
•Others
•Database Development, Dictionary Coding,
Standards
44. CRF Development Process
• After the CRF book is approved
• Initiate the process for printing
Note: the Protocol must be approved before
the CRF book is approved and printed
• After it is printed
• Stored according to organizational guidelines
• Printed and distributed to research sites
46. Poorly Designed CRF
Data not collected
Database may require modification
Data Entry process impeded
Need to edit data
Target dates are missed
Collected too much data – Wasted resources in
collection and processing
47. The Case Report Form
• How do we use it?
•Collect data from the investigational sites
•Helps project team and study site team
•Reminder to investigator to perform
specific evaluation
•CRA uses to verify protocol is being
followed and compare with source
documents
•Biometrics uses it to build database
structures, develop edit checks and
programming specs
48. The Case Report Form
• ...Used for
•Subject tracking
•Data analysis and reporting
•Reports to FDA on subject safety
•e.g.. APR
•Promotional materials
•New Drug Application submissions
•Support of labeling claims
•Articles in medical journals
49. Electronic CRFs
• The use of RDC is increasing
• In general, the concepts for the design of
electronic CRFs/RDC screens are the same as
covered for paper
• Electronic CRFs will impact the following:
• Review of CRF is different (screen review)
• No need to print and distribute paper
54. Demographics
DM001
***Manager Approval to Remove
Race and/or Ethnicity.
O
O
O
***If Informed Consent is the only Consent Date being
used in study REMOVE the Consent not given field.
O
