Download IND Annual Reporting at a Glance

IND Annual Reporting at a Glance
Kristi Wiser, Quintiles, Inc., Kansas City, MO
ABSTRACT
INTRODUCTION
An Investigational New Drug (IND) Application is a request
for authorization from the Food and Drug Administration
(FDA) to administer an investigational drug or biological
product to humans. During a new drug’s early
development, the sponsor’s primary goal is to determine if
the product is reasonably safe for initial use in humans.
An IND Annual Report is required to be submitted in yearly
intervals within 60 days of the anniversary date of the IND
effective date. This report is required annually until the
final Clinical Study Report for studies filed under the IND
has been submitted to the FDA or the IND has been
withdrawn. Some of the IND Annual Report required
information includes a brief summary status of each study
in progress or completed during the previous year and the
safety of the drug as defined by adverse event tables and
listings. A more complete description of the process for
developing an IND Annual Report is found in the poster.
IND Annual Reporting (IAR)
Phase
Test
Population
Chemistry
Laboratory
Screening
Enzymes
Cell
Cultures
Tissues
Small
animals
Preclinical
Animals
(>1species)
Phase 1
I
N
D
S
U
B
M
I
S
S
I
O
N
Figure 1: Overview of U.S. Drug Development Process
20-100
healthy
volunteers
G
G
G
G
G
What does IND mean?
When is an IND initiated?
How does an IND fit into drug development?
What is required in an IAR?
Where does Statistical Programming fit in the IAR
process?
CHARACTERIZATION
Investigational New Drug (IND)
Once the preclinical stages including the required short
term animal studies have been completed, the drug is
ready to be moved into human testing. Before this can
happen permission for human research must be obtained
by submitting an IND application to the FDA. An IND
application is a request for authorization from the Food
and Drug Administration (FDA) to administer an
investigational drug or biological product to humans. The
following table outlines the drug development process and
defines where an IND fits into this process.
Phase 2
100-300
patient
volunteers
Phase 3
1000-3000
patient
volunteers
N
D
A
S
U
B
M
I
S
S
I
O
N
FDA
Review
Product
Release
Evaluate:
Manufacturing
Safety &
effectiveness
data
Distribution
Proposed
labeling
Advertising
Education
Safety reporting
Phase 4 studies
IND ANNUAL REPORT (IAR)
before the report is due to the FDA. This notification
defines the reporting period and all studies to be included.
Within 60 days of the anniversary date that the IND went
into effect, a sponsor is required to submit a brief report of
the progress of the investigation. This takes place
annually until the final Clinical Study Report (CSR) for
studies filed to the IND have been submitted to the FDA or
until the IND has been withdrawn. Foreign studies
involving the same drug that are not being conducted in
the U. S. are not required to be submitted to the IND. This
brief report concentrates on the safety of the drug and is
known as the IND Annual Report (IAR). The following
section will define the required sections included in an
IAR.
IAR SECTIONS
Section 1: Individual Study Information
G Status of each study in progress or completed
during the previous year
G Subject recruitment including total number of
subjects planned, enrolled (including screen
failures), completed, withdrawn and active in
study
G Demographics tabulated by age group, gender
and race
Section 2: Summary Information:
G AE Incidence tables by preferred term, system
organ class and decreasing frequency
G Listing of Expedites (unexpected SAEs related to
the study drug that does not appear in the
investigator brochure) in the past year
G Listing of subjects who died
G Listing of subjects who withdrew from the study
due to an adverse event
G New Information on Drug Actions
G Pre-Clinical Summary
G Manufacturing Changes
G Microbiological Changes
Section 3: General investigative plan for next year
G Rationale
G Indications
G General Plan
G Planned Trials/Expected Subject Recruitment
G Anticipated Risks of Particular Severity
Section 4: Investigator Brochure
Section 5: Phase I protocol modifications made
Section 6: Summary of foreign marketing experience
Section 7: Outstanding business
Components of sections 1 and 2 are generally produced
by Statistical Programming/Biostatistics and the following
is written from that perspective.
PROCESS FOR PRODUCING COMPONENTS OF
SECTIONS 1 AND 2 OF AN IAR
The sponsor’s Regulatory Affairs Coordinator will send
notification of a pending IND annual report 120 days
Table 1 Demographics for
The first step the statistical programmer takes is to notify
the data coordinator(s) or clinical manager that is
responsible for one or more of the studies. After receiving
this notice the data coordinator(s) or clinical manager
needs to identify the status of each study (database
finalized, ongoing, outsourced, etc.).
If the study was reported in the previous IAR as finalized
(database closed) then verification needs to made as to
whether there has been any changes or modifications to
the database in the past year. If the study was finalized in
the past year, the database to be used for reporting must
be identified.
For ongoing studies that will not be closed by the date the
database is due for reporting, a plan needs to be set into
place to provide the data needed by the due date. The
data needs to be as clean as possible (adverse events,
demographics, informed consent, dosing dates, treatment
data) and all adverse events need to be coded if possible.
When the data is clean and coded, a snapshot (copy) of
the data will be taken and used to report the ongoing
study. It is very important for the data coordinator or
clinical manager to identify the dictionary being used to
code the adverse events for each study. It is possible for
one IAR to have studies coded to multiple dictionaries.
Producing tables and listings for ongoing studies can be
challenging. Not only can adverse events be uncoded at
the cutoff date, but there can also be missing dates
needed to make specific determinations or subjects not
included in a dataset because the specific case report
form data has not been received or entered. Ongoing
studies can be problematic when reporting on blinded
data. The remedy is to report the frequencies of adverse
events in one column titled “Blinded Med” or “Double
Blind Med” until the study is finalized and the data is
unblinded.
After the data specifications are in process, the existence
of a project team developing the Clinical Study Report
(CSR) needs to be determined. Perhaps
tables and listings have been produced that could be used
in the IAR. If tables and listings are available, this
eliminates duplicate work and also allows the data to be
provided in the same format to the FDA as in the CSR.
If no CSR tables or listings have been produced then the
programmer or biostatistician responsible for the IAR will
need to produce the required tables and listings. Once the
tables, listings and memo (defines studies included and
any special instructions) are complete the report is then
sent to the sponsor’s Regulatory Affairs coordinator and
other responsible individuals.
The following are examples tables. The first table is
included in section 1 of the IAR and the remainder of the
tables are included in section 2.
Protocol XXXXXXXXX
--------------------------------------|
|
|
|-------------------------------+-----|
|AGE (years)
|0 – 15
|
11|
|
|---------------+-----|
|
|16 - 64
| 199|
|
|---------------+-----|
|
|>= 65
| 101|
|---------------+---------------+-----|
|GENDER
|Male
| 124|
|
|---------------+-----|
|
|Female
| 187|
|---------------+---------------+-----|
|RACE
|White
| 170|
|
|---------------+-----|
|
|Black
|
81|
|
|---------------+-----|
|
|Asian/Oriental |
43|
|
|---------------+-----|
|
|Multiracial
|
17|
---------------------------------------
IND ANNUAL REPORT
pref02t.lst 20DEC01
Table 2.1
INCIDENCE (FREQUENCY) TABLE OF ADVERSE EVENT PREFERRED TERMS
FOR FINALIZED PROTOCOL XXXXXXXXX
___________________________________________________________________________
ADVERSE EVENT
PLACEBO
ACTIVE
DRUG
N=133
N=130_____
CODED TERM
N
PCT
N
PCT
___________________________________________________________________________
UPPER RESPIRATORY INFECTION
32 24.1%
33 25.4%
DIARRHEA
18 13.5%
39 22.3%
NAUSEA
15 11.3%
21 16.2%
HEADACHE
11
8.3%
17 13.1%
INFECTION
7
5.3%
14 10.8%
RASH
11
8.3%
13 10.0%
DIZZINESS
7
5.3%
11
8.5%
COUGH INCREASED
7
5.3%
11
8.5%
BLURRED VISION
3
2.3%
10
7.7%
DYSPEPSIA
6
4.5%
9
6.9%
ACCIDENTAL INJURY
9
6.8%
8
6.2%
ALOPECIA
5
3.8%
8
6.2%
SINUSITIS
7
5.3%
7
5.4%
HYPERGLYCEMIA
8
6.0%
6
4.6%
HYPERTENSION
4
3.0%
6
4.6%
GASTROINTESTINAL DISORDER
2
1.5%
6
4.6%
LIVER FUNCTION TEST ABNORMAL
2
1.5%
5
3.8%
VOMITING
5
3.8%
3
2.3%
ASTHENIA
4
3.0%
3
2.3%
NEUROPATHY
4
3.0%
3
2.3%
RHINITIS
3
2.3%
3
2.3%
ABDOMINAL PAIN
9
6.8%
2
1.5%
__________________________________________________________________________
PATIENTS WITH ONE OR MORE ADVERSE EVENTS
119 89.5%
117 90.0%
ADVERSE EVENTS FOR THIS TABLE ARE CODED USING THE HARTS DICTIONARY.
IND ANNUAL REPORT
body02t.lst 20DEC01
Table 2.2
INCIDENCE (FREQUENCY) TABLE OF ADVERSE EVENT PREFERRED TERMS
WITHIN EACH BODY SYSTEM FOR FINALIZED PROTOCOL XXXXXXXXX
___________________________________________________________________________
ADVERSE EVENT
PLACEBO
ACTIVE
DRUG
N=133
N=130
BODY SYSTEM
____________ ____________
CODED TERM
N
PCT
N
PCT
___________________________________________________________________________
DIGESTIVE SYSTEM
51 38.3%
70 53.8%
DIARRHEA
18 13.5%
27 20.8%
NAUSEA
11
8.3%
14 10.8%
GASTROENTERITIS
3
2.3%
10
7.7%
DYSPEPSIA
4
3.0%
9
6.9%
GASTROINTESTINAL DISORDER
2
1.5%
6
4.6%
LIVER FUNCTION TEST ABNORMAL
2
1.5%
5
3.8%
VOMITING
5
3.8%
3
2.3%
MOUTH ULCERATION
3
2.3%
3
2.3%
SORE THROAT
1
0.8%
3
2.3%
GASTROINTESTINAL PAIN
2
1.5%
2
1.5%
SORE MOUTH
2
1.5%
2
1.5%
ULCERATIVE STOMATITIS
0
0.0%
2
1.5%
STOMATITIS
3
2.3%
1
0.8%
GASTRITIS
2
1.5%
1
0.8%
COLITIS
0
0.0%
1
0.8%
CONSTIPATION
0
0.0%
1
0.8%
CHOLECYSTITIS
0
0.0%
1
0.8%
FLATULENCE
0
0.0%
1
0.8%
GASTROINTESTINAL PAIN
0
0.0%
1
0.8%
HEMORRHOIDS
0
0.0%
1
0.8%
INTESTINAL OBSTRUCTION
0
0.0%
1
0.8%
APHTHOUS STOMATITIS
0
0.0%
1
0.8%
ANOREXIA
0
0.0%
1
0.8%
TENESMUS
0
0.0%
1
0.8%
TONGUE DISORDER
0
0.0%
1
0.8%
ANOREXIA
2
1.5%
0
0.0%
LIVER DAMAGE
1
0.8%
0
0.0%
HALITOSIS
1
0.8%
0
0.0%
RESPIRATORY SYSTEM
44 33.1%
41 31.5%
UPPER RESPIRATORY INFECTION
35 26.3%
29 22.3%
COUGH INCREASED
7
5.3%
11
8.5%
APENA
5
3.8%
4
3.1%
___________________________________________________________________________
PATIENTS WITH ONE OR MORE ADVERSE EVENTS
119 89.5%
117 90.0%
ADVERSE EVENTS FOR THIS TABLE ARE CODED USING THE HARTS DICTIONARY.
IND ANNUAL REPORT
Table 2.3
death02t.lst 20DEC01
ADVERSE EVENT SUMMARY
CUMULATIVE LIST OF SUBJECTS/PATIENTS WHO DIED
____________________________________________________________________________________________________
PROTOCOL
DRUG RELATED
NUMBER
PATIENT
TREATMENT
PERIOD
CAUSE OF DEATH
ASSESSMENT
____________________________________________________________________________________________________
XXXXXXXXX
002007
PLACEBO
POST-TRT
CONGESTIVE HEART FAILURE NOT RELATED
004010
ACTIVE DRUG
ON-TRT
PNEUMONIA
NOT RELATED
____________________________________________________________________________________________________
IND ANNUAL REPORT
Table 2.4
discn02t.lst 20DEC01
ADVERSE EVENT SUMMARY
CUMULATIVE LIST OF SUBJECTS/PATIENTS WHO DROPPED OUT DUE TO ADVERSE EVENT
(RELATED & NON-RELATED) BASED ON ADVERSE EVENT FORM
___________________________________________________________________________________________________
PROTOCOL
TREATMENT
DRUG RELATED
NUMBER
PATIENT
CODED TERM
GROUP
ASSESSMENT
___________________________________________________________________________________________________
XXXXXXXXX
001016
002003
002004
002006
003006
003007
003011
003012
003016
003017
004008
004014
004024
005002
00500L
DIARRHEA
ACTIVE DRUG
RELATED
LIVER FUNCTION TEST ABNORMAL
ACTIVE DRUG
RELATED
PYOGENIC ARTHRITIS
PLACEBO
RELATED
INFECTION
PLACEBO
RELATED
HEADACHE
ACTIVE DRUG
RELATED
DIARRHEA
ACTIVE DRUG
RELATED
BONE DISORDER
PLACEBO
NOT RELATED
BACK PAIN
ACTIVE DRUG
RELATED
MACULOPAPULAR RASH
PLACEBO
RELATED
ASTHENIA
ACTIVE DRUG
RELATED
INTESTINAL OBSTRUCTION
ACTIVE DRUG
NOT RELATED
MACULOPAPULAR RASH
ACTIVE DRUG
RELATED
GASTROINTESTINAL HEMORRHAGE
ACTIVE DRUG
NOT RELATED
DIZZINESS
ACTIVE DRUG
RELATED
LYMPHOMA LIKE REACTION
PLACEBO
NOT RELATED
MULTI ORGAN FAILURE
PLACEBO
NOT RELATED
005012
LIVER FUNCTION TEST ABNORMAL
PLACEBO
RELATED
005013
RASH
ACTIVE DRUG
RELATED
005018
JOINT DISORDER
PLACEBO
NOT RELATED
006003
ASH
ACTIVE DRUG
RELATED
006007
BONE FRACTURE (NOT SPONTANEOUS)
ACTIVE DRUG
NOT RELATED
006009
HYPERTENSION
PLACEBO
RELATED
AUSEA
PLACEBO
RELATED
___________________________________________________________________________________________________
CONCLUSION
Producing an IND annual report does not have to be a
dreaded annual task if you are organized and have a
process in place. It is also important for the departments
involved to work together as a team.
REFERENCES
“Introduction to U.S. Drug Development”, Bill Wollberg,
Quintiles internal course, March 2000
“Investigational New Drug (IND) Application Process”,
http://www.fda.gov/cder/regulatory/applications/ind_pag_l.
htm
“Food and Drug Administration, HHS – Part 312.33 Annual
Reports”, Code of Federal Regulations
CONTACT INFORMATION
Kristi Wiser
Quintiles Inc.
P. O. Box 9708
Kansas City, MO 64134-0708
Email: [email protected]