outsourcing BA and BE to CRO

1. OUTSOURCING TO BA &BE IN CRO
MANOJ R
M.PHARM 1ST SEMESTER
DEPT OF PHARMACEUTICS
NANDHA COLLEGE OF PHARMACY
ERODE-52
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2. What is Outsourcing?
 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.
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3. Bioavailability:-
 It is defined as rate and amount of absorption of unchanged drug from its
dosage form
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4. 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.
 Types of equivalence:-
1) Chemical equivalence
2) Pharmaceutical equivalence
3) Therapeutic equivalence
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5. 1.Chemical Equivalence
 Two or more drug products contains the same labelled chemical substances
as an active ingredient in same amount.
2.Pharmaceutical Equivalence
 Two or more drug products are same in strength,quality, purity, content
uniformity, disintegration and dissolution characteristics.
3.Therapeutic or Biological Equivalence
 Two or more drug products contains same therapeutically active
ingredients elicit identical pharmacological effects and can control the
disease to same extent.
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6. CRO (Contract Research Organisation)
 CRO (also known as Clinical Research Organization) 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 works that is essential for
conducting clinical trials for the company to manufacture pharmaceuticals
required for human use and ICH related requirements for registration
purposes.
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7. Reasons of Outsourcing
 Many of the pharmaceutical companies have there own clinical and
bioanalytical units that provide full support for phase l studies. However,
even these internal resources can become saturated due to develop more
compounds in shorter time interval.
 Although generic companies have internal resources for product
development, manufacturing and release testing, they do not have clinical
and bioanalytical capabilities.
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9. Identification of appropriate CROs
 It is important that CRO has validated corporate procedures for all
segments of clinical study conduct.
 It is necessary to ensure all aspects of a study, that includes clinical
conduct, laboratory analysis, data management, biostatistics,
pharmacokinetics, and medical writing, are performed in compliance with
good clinical practices (GCP),good laboratory practices (GLP), and other
applicable regulatory practices and guidelines.
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10. ASSESSMENT OF CAPABILITIES
1. Clinical capabilities
2. Bioanalytical capabilities
3. Pharmacokinetic capabilities
4. Timeline assessment
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11. Clinical capabilities
 The first step to CRO qualification is the assessment of their capabilities
and experience. The ability of a CRO to recruit a particular patient or
volunteer population is a primary requirement.
 The CRO should be able to recruit the entire study population at a single
center, preferably as a single group. Healthy volunteer populations are the
easiest to recruit; however, some studies may require large numbers of
subjects or replicate designs.
 For example, estrogens are generally dosed to postmenopausal females.
Other drugs may be targeted to an elderly population. It is essential that the
CRO be assessed for its ability to recruit these special populations.
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12. Bioanalytical capabilities
 Validation lists (lists of analytical methods that are currently available and
validated) are available from most CROs.
 It is critical that the bioanalytical facility in analyzing the drug (and
metabolite, as appropriate) and should be able to provide a written
validation report.
 The validation should be assessed before awarding the study or at least
before dosing. The facility should follow current GLPs (cGLPs) and have
a neat U.S. Food and drug administration (FDA) inspection history.
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13. Pharmacokinetic capabilities
 Most companies focus primarily on the clinical and bioanalytical
capabilities for CRO selection.
 However, the pharmacokinetic capabilities should also be equally
assessed.
 The CRO should have validated pharmacokinetic and statistical programs
in and should be compliant with 21 CFR part 11 (especially in regard to
change control).
Timeline assessment
 The CRO should meet the company's clinical, bioanalytical, and
pharmacokinetic criteria and must be assessed for their ability to meet the
company's timeline established by the company management team.
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14. CRO Qualification
1. Due diligence
 If the pharmaceutical firm has used the CRO in the past, they should
evaluate their past experience with this CRO.
 If the experience was good, the team should identify those components
that were successful and insure that they are used for their new study.
 However, caution should be made 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.
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15. 2. 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
following area.
 Access the volunteer population pool.
 Evaluate the CRO procedures for adverse effects.
 Access of clinical data management
 Evaluation of clinical deliverables.
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16. 3. Bioanalytical site qualification
 Candidate companies should assessed for CROs bioanalytical laboratory
work (for drug, metabolite or biomakerassay).
 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.
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17. 4.Pharmacokinetic site qualification
The pharmaceutical team 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:
 Qualification of pharmacokinetic and statistical personnel.
 Validation of pharmacokinetic and statistical programs (usually SAS)
 Compliance with 21CFR(code of federal regulation) part 11.
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18. Final Report Content And Format
 The development of an effective RFP and 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
 CROs work with a large number of different clients; each client often has
their own report format preferences. Therefore, if the RFP does not
address the report format, the CRO often will make an assumption
regarding the report format.
 This assumption may or may not be stated in the resulting proposal. This
assumption can make or break a proposal because the report format
assumes a number of other important deliverables.
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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. The following 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
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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
 27/7 Outsourcing Bioavailability and Bioequivalence Studies to CROS
 Summary of subject dropout information for each study
 Summary of protocol deviations
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21. Protocol Development
 The FDA OGD published a large number of drug-specific guidances that provided
the basic information needed to conduct a generic BE trial.
 Three possible options exist, each with a different cost structure:
• Level 1: client provides final clinical protocol.
•Level 2: client provides protocol "outline," including design and all
specifications; CRO provides final protocol.
• Level 3: client provides objective; CRO provides design and protocol.
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22. Protocol Format
 If the company requires the CRO to follow a specific format (developed
by the company), then this information (and the format) should be
provided within the RFP.
 On the other hand, many companies do not have a preference for protocol
format. They are only concerned that all of the relevant parameters are
included in the protocol. For these companies, CROs can often provide a
standardized (and shorter) format for less money.
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23. Clinical Study Population
 In the past, to reduce variability and liability, most sponsors chose to
perform most BA/BE studies in healthy, young, male volunteers.
 In recent years, the FDA recommend that if the drug product is intended
for use in both sexes, the sponsor attempt to include similar proportions of
males and females in the study. If the drug product is to be used
predominantly in the elderly, we also recommend that the sponsor attempt
to include as many subjects of 60 years of age or older as possible.
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24. Laboratory chemistries, Special Tests/Physicals
 The number of laboratory chemistries, physical examinations (by a
physician), and special tests (such as electrocardiograms [ECGs], x-rays,
blood glucose monitoring, and special biomarkers) will have a significant
effect on the cost of the study.
 Although the protocol may be very specific regarding the timing and
numbers of tests, this information must be present in the RFP to provide an
accurate proposal.
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25. Dose And Safety Considerations
 Generally, the dose of the RLD is safe to administer to healthy volunteers.
However, for some drug products, that dose may cause adverse events and
the clinical trial will require additional safety considerations.
 For example, Prazosin has a significant first dose effect that is exhibited
by marked postural hypotension; prazosin studies usually require that
volunteers stay in a reclined position for several hours after dosing and
that blood pressure be routinely monitored.
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26. Clinical Conduct
 Clinical conduct are based on the version of the study outline or protocol
submitted with the RFP. A number of factors affect the price of clinical
studies. Some of these are shown as follows:
 Population (volunteers vs. Patients, males vs. Males and females,
postmenopausal females)
 number of volunteers or patients
 inclusion/exclusion criteria
 volunteer stipend
 number of laboratory chemistries and special tests ECGs, blood glucose
monitoring, etc.)
 Dose (with regard to safety and adverse events)
 Washout period
 number of blood draws and urine collections and times of sampling
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27. Clinical Database
 A clinical database (which contains all of the information on the) is not
necessary for BE submissions to the OGD. Also, it is rare that such a
database would be required by the FDA for a single dose BE or BA study
(in volunteers) to support an NDA submission.
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28. Bioanalytical
 Any bioanalytical method used for a human BA/BE study should conform
to current FDA guidance on analytical validation and should be conducted
according to the FDA cGLPs.
Bioanalytical Method/Technology Requirements
 On occasion, a pharmaceutical company may need to contract the method
development and validation to a CRO.
 Because the method ruggedness is dependent on the development and
validation processes, these processes should be closely evaluated before
committing a BA or be study to any CRO.
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29. Assay of Samples From Placebo
 However, some BA studies may include placebo treatments so that safety
can be more appropriately evaluated. For these studies, it is essential to
communicate with the CRO regarding the handling and analysis of these
samples.
 All CROs will charge for each sample that is assayed. Some CROs will
assay all samples,if the firm does not require placebo-treated samples to be
analyzed (because they generally will not provide any meaningful
pharmacokinetic data). It is important to provide the randomization
schedule to the laboratory before analysis.
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30. Bioanalytical Sample Handling, Shipping, And
Storage
 Samples originating in HIV-exposed or other infectious subject
populations may involve liabilities to clients, clinics, couriers, and
laboratories.
 These samples will require special documentation, shipping, and handling.
The clinic, shipping service, regulatory agencies, customs authorities, and
the bioanalytical laboratory must be formally notified of all special
handling requirements before shipment to the laboratory.
 Thorough documentation of potentially infectious samples must be
included with each shipment container.
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32. REFERENCES
 Noonan PK. Outsourcing Bioavailability and Bioequivalence Studies to Contract Research
Organizations. In Generic Drug Product Development 2014 Oct 31 (pp. 321-364). CRC
Press.
 Hayes R. Bioanalytical outsourcing: transitioning from Pharma to CRO. Bioanalysis. 2017
Aug;9(15):1149-52.
 Wilkinson M, Harper B, Peacock J, Morrison R, Getz K. Assessing outsourcing oversight
practices and performance. Therapeutic Innovation & Regulatory Science. 2020
Jan;54:158-66.
 Rehman S, Tiwari A, Turner C, Williams L. A framework for innovation outsourcing.
International Journal of Business Innovation and Research. 2018;16(1):79-111.
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33. THANK YOU
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