Post marketing surveillance & outsourcing BA and BE to CRO By Pratik Shinde, Mpharm, University department of Pharmaceutical science, Nagpur

1. Post marketing surveillance
Outsourcing BA and BE to CRO
GUIDED BY
PROF. NITIN PADOLE
UDPS NAGPUR
PREPARED BY
Mr. Pratik P. Shinde
M.Pharm 1st year
UDPS NAGPUR

2. INDEX
1. INTRODUCTION
2. POST MARKETING SURVEILLANCE
3. METHOD OF PMS
4. Outsourcing BA and BE to CRO
5. BIOAVAILABILITY
6. BIOEQUIVALENCE
7. CRO (Contract Research Organisation)
8. CRO Qualification
9. Final Report Content And Format
10. REFERNCE

3. PHASE IV = POST MARKETING SURVEILLANCE
1

4. POST-MARKETING SURVEILLANCE
• No fixed duration/Patient population
• Starts immediately after marketing
• Report all ADRs
• Help to detect
– Rare ADRs
– Drug interaction
– Also new uses for drugs[sometimes called Phase
V]. [3]
2

5. SOURCES OF PMS INFORMATION
• The following may be considered as sources of
information, some source are proactive and some
are reactive.
1. Expert user groups(“ focus groups‟‟)
2. Customer surveys.
3. Customer complaints and warranty claims
4. Post CE-market clinical trials.
5. Literature reviews.
6. Device tracking/implant registries.
7. User reaction during training programmers.
8. The media. [1]
3

6. BENEFITS
• Detection of manufacturing
problems
• improvement of medical
device quality
• verification of risk analysis
• intelligence of long-term
performance
• chronic complications
• performance trends
• The manufacturer assessed
the complaints and deemed
them statistically significant.
• Feedback on indications for
use, instructions for use.
• training required for users;
use with other devices.
• customer satisfaction .
• market performance and
sustainability.
• identification of incident
reports
• A manufacturer of
intraocular lenses collected
numerous complaints from
users about broken lenses.
• performance in different
user populations [1]
4

7. METHODS OF SURVEILLANCE
Thus, four types of studies are generally used
to identify drugs effects:
1. Controlled clinical trials,
2. Spontaneous or voluntary recording
3. Cohort studies
4. Case control studies [3]
5

8. Controlled clinical trials Spontaneous or voluntary reporting
 To minimize bias through such
method as randomization and
“double-blinding‟.
 Directly monitor patients for the
duration of studies.
 For evaluating a drugs efficacy and
safety.
 They are often costly.
 By physician and other health
provider & hospital may to alert FDA
and pharmaceutical firms to
possible adverse effects of drugs.
Cohort studies Case-control studies
 Studies follow a defined group of patient
for a period of time.
 Patient are not randomly assigned , &
there is no blinding.
 If adverse reaction occur. A second group
of patient with the same medical
condition , who are not taking the drug
and who may be receiving alternative
treatment.
 Case control studies identify patient
with the adverse effects to be
studied, and compare them with the
sample drawn from the same cohort
that gave rise to cases.
6

9. Outsourcing BA and BE to CRO
• Outsourcing is the business practice of hiring a
party outside a company to perform services and
create goods that traditionally were performed
in-house by the company’s own employees and
staff.
• Outsourcing is generally done to reduce the costs
and improving the efficient resources within a
company.
• Ex. Of outsourcing is bioavailability ,
bioequivalence [2]
7

10. Bioavailability
• It is defined as rate and amount of absorption of
unchanged drug from its dosage form.
1. Absolute Bioavailability
 Systemic availability of drug administered orally
which is determined in comparison to its intravenous
administration.
2. Relative Bioavailability
 Systemic availability of drug after oral administration
is compared with the oral std. of same drug. [2]
8

11. Bioequivalence
• It refers that the drug substance in two or more
identical dosage forms , reaches the systemic
circulation at the same rate and at same extent
• i.e. Their plasma conc. Time profiles will be identical
without significant statistical differences.
• There are four types of equivalence
1. Chemical equivalence
2. Pharmaceutical equivalence
3. Therapeutic equivalence [2]
9

12. Chemical
Equivalence
Pharmaceutical
Equivalence
Therapeutic
Equivalence
Two or more drug
products contains
the same labeled
chemical substances
as an active
ingredient in same
amount.
Two or more drug
products are same in
strength , quality,
purity, content
uniformity
,disintegration and
dissolution
characteristics.
This term indicates
that two or more
drug product
contains same
therapeutically active
ingredients elicit
identical
pharmacological
effects and can
control the disease
to same extent.
10

13. CRO (Contract Research Organisation)
• CRO is an organization that provide support to
the pharmaceutical, biotechnology and
medical devices industry in the form of
research services outsourced on a contract
basis.
• It offers various pharmaceutical research that
is essential for conducting clinical trials the
ICH technical requirements for registration of
pharmaceuticals for human use.
11

14. Reasons of Outsourcing
• Many of the larger pharmaceutical companies have in-house
capabilities for most, if not all, of these services.
• Unlike their larger counter parts, the smaller companies, virtual
firms and generic companies do not have the luxury of their own
dedicated clinical unit or full in-house capabilities and are required
to outsource their clinical trials, including bioavailability and
bioequivalence studies.
• Although generic companies have internal resources for product
development, manufacturing and release testing, they do not have
clinical and bioanalytical capabilities.
• Key elements necessary for success include the following:
1. Communication at all levels between the CRO and the
pharmaceutical company
2. Sensitivity to both the project specific requirements and timelines
3. flexibility to recognize and adjust to unexpected events throughout
the project timeline [2]
12

15. CRO Qualification
1. DUE DILIGENCE
– If the pharmaceutical firm has used the CRO in the past,
they should objectively evaluate their past experience with
this CRO.
– If the experience was good, the firm should identify those
components that were successful and insure that they are
used for their new study.
– However, caution should be exercised and due diligence
pursed if the new study requires a different subject
population or analytical technique
– EXAMPLE: A CRO may specialize in recruiting healthy male
and female volunteers, but may have difficulty in the
recruitment of postmenopausal females.[2]
13

16. • CLINICAL SITE QUALIFICATION
– The sponsor should conduct a site qualification visit. In
addition to a eGCP site audit, this evaluation should
include an assessment of the area in next slide.
• BIOANALYTICAL SITE QUALIFICATION
– Candidate CROs for bioanalytical laboratory work (for drug,
metabolite or biomakerassay) should also be assessed.
– The company audit should also include cGLP compliance
and an assessment of the laboratory’s inspection history.
Copies of the inspection history with all FDA 483s and
Establishment Inspection Reports should be reviewed.
– Laboratory project manager should be assessed for their
ability to coordinate all processes with client, clinic and
pharmacokinetic.
– Finally, the CRO should provide written documentation as
to the content of the final analytical report that should
contain additional project specific validation data to
support BA/BE study.
14

17. PHARMACOKINETIC SITE QUALIFICATION
• The pharmaceutical firm should also qualify the CRO site
(or department) that is responsible for PK and statistical
analyses and completion of the final integrated report.
During the pharmacokinetic site audit, following areas
should be assessed:
1. Qualification of pharmacokinetic and statistical personnel.
2. Validation of pharmacokinetic and statistical programs (usually
SAS)
3. Compliance with 21CFR(code of federal regulation) part 11. At
the time of this publication, full and complete compliance with
part 11 was not being enforced. However, the CRO should
have a written plan and timeline for bringing all post
laboratory functions into compliance. [2]
15

18. Final Report Content And Format
• Ideally, the development of an effective RFP and proposal
should begin with the outcomes in mind. That is, the focus
on the proposal should begin with the objective of a final
deliverable (the report) and should include a description of
the content and format of the final report.
• Final Written Report
1. CROs work with a large number of different clients; each client
often has their own report format preferences. Therefore, if
the RFP does not specifically address the report format, the
CRO often will make an assumption regarding the report
format.
2. This assumption may or may not be explicitly stated in the
resulting proposal. This assumption can make or break a
proposal because the report format assumes a number of
other important deliverables. [2]
16

19. Submission of Data and Reports
• To the FDA The FDA OGD currently requires ANDA applicants to
submit information from all BE studies conducted on the same
formulation of the drug product contained in an ANDA .
• In addition, they recommend that BE summary reports be
submitted in CTD format; OGD expects BE data to be submitted
using data summary tables consistent with CTD-formatted
applications; sample tables are available for download.
• The following tables are required for a BE review:
– Submission summary (or, alternatively, provide an electronic copy of
Form 356H)
– Summary of BA studies, which provides study reference numbers,
objectives, designs, treatments, and subjects as well as summary
statistics for pharmacokinetic parameters
17

20. • Summary of bioanalytical method validation data
• Summary of in vitro dissolution studies
• Summary of formulation data (qualitative and quantitative
composition)
• Demographic profile of subjects for each BE study
• Summary of adverse events for each study
• Bioanalytical reanalysis of study samples
• Study information for each study
• Product information with batch numbers and size, potency,
and content uniformity 277Outsourcing Bioavailability and
Bioequivalence Studies to CROs
• Summary of subject dropout information for each study
• Summary of protocol deviations [2]
18

21. X

22. REFERENCE
1. Borden E.K, The upjohn Co.,POST- MARKETING SURVEILLANCE OF
out patient drugs using a pharmacy-based registration system-
report of two studies, presented at the drug information
association Work shop, williamsburg va , DECEMBER 1981,
2. Gelenberg A.J., Post marketing surveillance – Perspective of
journal editor, National centre for biotechnology information,
national medicine library 10-32.
3. https://www.slideshare.net/DhanshreeBhattad/outsourcing-ba-
and-be-to-cro-195930022
4. https://www.slideshare.net/AmruthaJOSE4/3post-marketing-
surveillance-methods
5. WWW.GOOGLE.COM