Prepared By: Chrishmita Regulatory Affairs M.Pharmacy , 1st Sem RR College Of Pharmacy . Thanks to PAWAN DHAMALA.

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REGULATORY AFFAIRS
OUTSOURCING OF BA and BE TO CRO
RR COLLEGE OF PHARMACY
Submitted by:
Chrishmitha
1st M.Pharm
Dept. of Pharmaceutics
Submitted to
Mrs. Srilatha K.S
Associate professor
Dept. of Pharmaceutics

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Contents
 Introduction
 Identification of appropriate CROs
 CRO Qualification
 Clinical Protocol Development
 Bioanalytical
 Contractual Obligations between CRO and Sponsors

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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.
Bioavailability:-
 It is defined as rate and amount of absorption of unchanged drug from its
dosage form enters systemic circulation.
 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.
v/s time profiles will be identical without significant statistical differences.
 3 Types of equivalence:-
 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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5. 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.
 CRO is an organisation contracted by another company to manage and lead to the companies
trails, duties and functions
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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6. 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
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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7. Assessment of Capabilities
1. Clinical capabilities
2. Bioanalytical capabilities
3. Pharmacokinetic capabilities
4. Timeline assessment
 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 centre, 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
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8.  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 be experienced in analysing 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.
 PHARMACOKINETIC CAPABILITES: 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).
 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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9. CRO Qualification
 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
 Clinical site qualification
 Bioanalytical site qualification
 Pharmacokinetic site qualification
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10. COMPETITIVE BIDS/DEFINING THE DELIVERABLES
 In an effort to quickly place a clinical study, the development of the RFP(request for proposal) 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.
 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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11. Submission of Data and Reports to the FDA
The FDA OGD(office of generic drugs) 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.
The following are required for a BE review:
• Summary of BA studies, which provides study reference numbers, objectives, designs, treatments, and subjects as well as
summary statistics for pharmacokinetic parameters
• 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
• Product information with batch numbers and size, potency, and content uniformity
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12. Clinical Protocol Development
Before 1999, the FDA OGD published a large number of drug- specific guidance that provided the basic
information needed to conduct a generic BE trial. With the publication of general BA/BE guidance, the
agency withdraw the drug-specific guidance. Most of these guidance 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.
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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13. 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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14. 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.
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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15. Dose And Safety Considerations
 Generally, the dose of the RLD(reference listed drug) 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.
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
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16. 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.
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.
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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17. Contractual Obligations Between CRO And Sponsors
 Contract terms and conditions provide the best controls that both the company and CRO have
with each other
 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 CROS?
• Are there acceptable objective performance standards? What standards are used to assess
performance?
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18. • 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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19. REFERENCE
 Generic drug product development, solid dosage forms, Leon Shargel and
IsaerKaufer, Marcel Dekkar series vol.143
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