Outsourcing of BA and BE to CRO.

1. Outsourcing BA and BE to CRO
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SMT.KISHORITAI BHOYAR COLLEGE
OF PHARMACY,KAMPTEE
PREPARED BY:DHANSHREE BHATTAD
M.PHARM 1ST YEAR
PHARMACEUTICS DEPARTMENT

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.
Ex. Of outsourcing is bioavailability ,
bioequivalence , R and D department
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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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Absolute Bioavailability-Systemic availability of drug
administered orally which is determined in comparison to
its intravenous administration.
Relative Bioavailability-Systemic availability of drug after
oral administration is compared with the oral std. of same
drug.

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. Time profiles will be identical
without significant statistical differences.
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Types of equivalence:-
1) Chemical equivalence
2) Pharmaceutical equivalence
3) Therapeutic equivalence

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 Equivalence
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.
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6. 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.
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7. Reasons of Outsourcing
 Many of the larger pharmaceutical companies have in-house
capabilities for most, if not all, of these services.
For example-many often have there own clinical and
bioanalytical units that provide full support for phase1 studies.
However, even these internal resources can become saturated
due to the drive to develop more compounds in shorter time
interval.
 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.
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8.  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:
• Communication at all levels between the CRO and the
pharmaceutical company
• Sensitivity to both the project specific requirements and
timelines
• flexibility to recognize and adjust to unexpected events
throughout the project timeline
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9. Identification of appropriate CROs
 It is important that your CRO has validated corporate
procedures for all segments of clinical study conduct.
 These procedures are used to ensure that all aspects of a
study, including but not limited to 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
 Just as the clinical capabilities must be assessed, the bioanalytical
capabilities are equally important.
 Validation lists (lists of analytical methods that are currently
available and validated) are available from most CROs. It is critical
that the bioanalytical facility be experienced 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. In addition to having an appropriately validated
method, the facility should follow current GLPs (cGLPs) and have a
clean 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
critically assessed.
 The CRO should have validated pharmacokinetic and
statistical programs in place and should be compliant with
21 CFR part 11 (especially in regard to change control).
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14. TIMELINE ASSESSMENT
 The list of CROs that meet the company’s clinical,
bioanalytical, and pharmacokinetic criteria must be
assessed for their ability to meet the company’s timeline.
 The CRO must be able to meet the timelines as
established by the company management team.
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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.
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16. 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 area in next slide;
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18. 3. 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.
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19. 4.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:
 Qualification of pharmacokinetic and statistical personnel.
 Validation of pharmacokinetic and statistical programs (usually SAS)
 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.
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20. COMPETITIVE BIDS/DEFINING THE
DELIVERABLES
 In an effort to quickly place a clinical study, the
development of the RFP may be rushed and result in a
document that is subject to various degrees of
interpretation.
 In light of this, it is important for companies to carefully
evaluate competitive bids to assure that each CRO has
made the same set of assumptions.
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21. 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
 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.
 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.
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22. 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
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23. • 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
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24. Clinical
Protocol Development
 Before 1999, the FDA OGD published a large number of drug-
specific guidances that provided the basic information needed to
conduct a generic BE trial.
 With the publication of general BA/BE guidance, the agency
“withdrew” the drug-specific guidances.Most of these guidances
provide some protocol design considerations, but sponsors generally
are left to their own resources to determine specific guidance on
numbers of subjects, timing of blood samples, etc.
 It is important that an RFP specify the expectations for protocol
development.
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25. 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.
Unless the sponsor provides the final clinical
protocol (as in level 1), the following items must be
addressed in the RFP to obtain an accurately priced
study.
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26. Protocol Format
 Some pharmaceutical firms are quite strict when it comes to
formatting requirements. If the firm 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.
 Another advantage to using this standardized approach is that
the CRO clinical personnel are often more familiar with the CRO
format that will result in fewer questions back to the client.
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27. Clinical Study Population
In the past, apparently to reduce variability and liability, most sponsors
chose to perform most BA/BE studies in healthy, young, male
volunteers. However, the most recent FDA guidance for BA/BE studies
states as follows:
Unless otherwise indicated by a specific guidance, subjects
recruited for in vivo be studies be 18 years of age or older and capable of
giving informed consent. This guidance recommends that in vivo BE
studies be conducted in individuals representative of the general
population, taking into account age, sex, and race. We 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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28. Inclusion/Exclusion Criteria
The protocol inclusion/exclusion criteria such as acceptable
ranges for age and weight, race restrictions, and whether
smokers will be allowed to participate can affect the clinic’s
ability to recruit and can have a significant effect on the cost of
the clinical trial.
Because a BA/BE study for any given drug product may or may
not require special inclusion criteria, it is best that any
expectations be documented in the RFP. These criteria will affect
recruitment and the study cost; when comparing proposal
between different CROs, it is best to evaluate any additional
assumptions that the CRO made with regard to these criteria.
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29. 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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30. 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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31. Clinical Conduct
Clinical bids 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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32. 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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33. 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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34. Project Timelines And Turnaround Time
 Project timelines are highly method specific. Sample analysis
timing and throughput should be discussed, understood, and
agreed upon before project agreement.
 Most CROs have standard turn around times that will apply
unless they are otherwise negotiated. It is also important to
negotiate the timeline for the final written analytical report;
otherwise, standard CRO timelines will be assumed.
Analytical Report And Data Format
 If a client-specific bioanalytical report format, template, or file is to
be used to record data, the format, template, or file, along with any
instructions, must be provided to the laboratory before or with the
shipment of samples.
 Sponsors should be aware that implementation of client-specific
formats may result in additional charges.
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35. 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, whether or not they were
generated in a placebo treated subject. 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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36. Sops
 There must be prior agreement and upfront expectations
with regard to sops. Some firms require that the CRO
follow the firm’s sops, whereas other companies permit
the CRO to operate under their own sops.
 Because the scope of work is affected by the sops, this
specification must be defined during the RFP process and
in the CROs proposal.
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37. 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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39. Contractual Obligations Between CRO And Sponsors
Contract terms and conditions provide the best controls that both
the company and CRO have with each other. These controls are
necessary because the FDA holds the company (not the CRO)
responsible for any contractor failures. A good contract provides the
company with control and remedies in the event of poor contractor
performance.
When drafting a contract, the following areas need to be
considered:
• Do the individuals responsible for drafting the contract understand
the objectives and details of the clinical trial?
• Is the contract specific as to the duties?
• Is the scope adequately defined?
• Is there a legal review by both the company and cro?
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40. • Are there acceptable objective performance standards? What
standards are used to assess performance?
• Is a schedule for critical tasks included? A detailed description of
tasks should include monitoring, audits, data handling, and timing of
the clinical, bioanalytical, and final report.
• Any contract modifications should include protocol amendments.
• The contract should provide details of mutual responsibilities.
• The contract should provide remedy for contract breech or
substandard performance. These remedies include
discussion/mediation, arbitration, and refund/rework if performance
does not meet contract specifications.
• Does the contract provide for disclosure of the FDA inspections
and/or inquiries?
• The contract should address intellectual property (e.g., Patents,
copyrights, and trade secrets) and use and disclosure of company
technology, data, and publicity.
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