IP -II QUESTION BANK

UNIT-III: REGULATORY AFFAIRS

1. Explain the roles and responsibility of regulatory affair professionals

1) Regulatory affairs is a profession developed from the intention of governments to
protect public health by controlling the safety and efficacy of products
including pharmaceuticals, veterinary medicines, medical devices, cosmetics so that
that supplied products make a worthwhile contribution to public health and welfare.
2) Regulatory Affairs is a unique combination of science and management to achieve a
commercially important goal within a drug-development organization.
3) It gives strategic and technical advice at the highest level in their companies, right from
the beginning of the development of a product, making an important contribution both
commercially and scientifically to the success of a development program and the
company as a whole.
4) Some of the most common tasks and responsibilities of regulatory specialists include:
5) Maintaining a deep understanding of new and existing regulations that may impact their
organization’s products and processes.
6) Using that understanding to standardize all business operations and establish clear,
documented protocols
7) Explaining regulations, procedures, and policies to all employees and stakeholders as
necessary.
8) Maintaining data and files for future reference, particularly in the event of an audit by
a regulatory agency
9) Reviewing marketing, legal, and technical documentation (including case files and
clinical research reports) to assess compliance
10) Implementing internal audits of products and protocols to identify areas of weakness,
and putting in place corrective measures
11) Regularly reporting on compliance status and measures to both internal and external
parties
12) Preparing for and facilitating third-party audits as necessary
13) Acting as a liaison between their organization and state, local, federal, and international
agencies to submit required forms and paperwork

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 For MCQ

Q.2 Explain the responsibilities of drug development team

Responsibilities of drug development teams:
1. Review research results from experiments conducted by any of various scientific
disciplines
2. Integrate new research results with previously generated data
3. Plan research studies to further characterize a drug candidate
4. Prepare a detailed drug development plan.
5. Monitor the status of research studies to ensure that they are being conducted according
to time
6. Compare research results and development status and time with drug candidates under
development by competitors
7. Conduct appropriate market surveys to ensure that the development of drug candidate
is economically justified and continues to meet a medical need
8. Report the status of the drug development program to management
DRUG DISCOVERY PROJECT TEAM
• A small group of researchers come together to discover a new drug molecule against a
particular disease. This is the first project team and is commonly called a discovery
project team.
• Their primary responsibility is to identify lead compounds or classes of compounds
worth research and that are patentable, ie, having unique, previously undisclosed
chemical structures.

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 • Once a lead or class of lead compounds has been identified, the discovery team analyses
other scientific disciplines to determine mere fully the possibility of developing the lead
(s) of interest, and include Analytical chemistry, Pharmacokinetics, Toxicology.
Biopharmaceutics, etc.
• The discovery project team compiles all the generated information and presents results
to management and reports whether the lead compound can be entered into formal
preclinical development or not.
• Once the drug discovery project team recommends the new drug In preclinical
development, the team continues to discover other compounds that could identify a
next-generation lead.
Pre clinical drug development project team comprises of various experts as follows
• A management-assigned project team leader and coordinator who are responsible for
the development of the drug candidate
• Regulatory affairs and quality assurance experts to ensure that the developmental
studies meet regulatory agency requirements and are conducted according to regulatory
agency regulations and guidelines, including ICH guidelines.
• A clinical research scientist to provide input into study designs so that the generated
results support the proposed clinical program and to initiate development of clinical
safety and tolerance and efficacy protocols and the investigator's brochure.
• An analytical chemistry researcher to develop assays and characterize the drug
substance and proposed drug product.
• Manufacturing scientists to scale up the synthesis of the drug candidate and provide
sufficient GLP- or GMP-quality material for regulatory-driven research studies.
• A marketing person to determine that the drug candidate has potential market niche in
light of what other companies are developing or drugs that are already on the market
for the disease indication.

Q.3 Functions of pre-clinical drug development team?

1. One of the basic and primary functions of the development project team is to prepare
a drug development plan in which all the studies considered necessary for the
Successful development of a drug candidate is mentioned.
2. Based on the disease indication (life-threatening or non-life-threatening), the drug
candidate type (small organic molecule or macromolecule), the length of therapy
(acute or chronic), and the route of administration (oral, intravenous, dermal,
pulmonary, etc.), each of the scientific disciplines prepares a list of proposed research
studies,
3. All of the studies are combined into a drug development logic plan.

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 4. The initial drug development plan is put together with key points like submission of
an IND, completion of phase 2 clinical trial studies, and submission of an NDA.
5. The first plan is descriptive for the preclinical development, with less definition for
the clinical and nonclinical stages of development and for the manufacturing effort.
6. Once the development studies are listed and integrated into a logic plan, the next aspect
is to develop a timeline.
7. The timeline determines the start of a proposed study and when the results of the
experiment can be expected.
8. The drug development plan is a living document and should be updated or modified
regularly.
9. One of the final responsibilities of the preclinical drug development project team is to
prepare an IND, and to submit the appropriate documents to the FDA or other
regulatory agency.
10. As the drug candidate moves toward clinical development, the preclinical project team
transforms into a clinical project team.

Q.4 Explain the general consideration of Investigational New Drug (IND) application
• An IND (Investigational New Drug application) is a submission to USFDA for
requesting permission to initiate a clinical study of a new drug product.
• It allows a company to initiate and conduct clinical studies of their investigational drug
product.
• IND also allows legal import and shipping of an unapproved drug.
• An IND application is compulsory even for studies conducted with compounds not
developed for therapeutic use. All clinical studies where an unapproved drug is
administered to human subjects require an IND, regardless of whether the drug will be
commercially developed or not
• IND is required to conduct a clinical trial when the drug is
✓ A new chemical entity
✓ In a new dosage form
✓ Being administered at a new dosage level
✓ Not approved for the indication under investigation
✓ Combined with another drug and the combination is not approved.
• An IND is not required to conduct a study when\
✓ If the drug is not intended for human subjects, but is intended in-vitro testing or
laboratory research animals (nonclinical studies);
✓ if the drug is an approved drug and the study is within approved indication for use.

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 ✓ If Placebos (inert medicament) are used in studies.
✓ For study of marketed anti-cancer drug
• Content included for IND Application (EXPLAIN IN DETAIL)
1. Cover sheet: FDA form 1571
2. Table of content
3. Introductory statement and general investigational plan
4. Investigators brochure
5. Clinical Protocol
6. Chemistry, Manufacturing and Controls information
7. Pharmacology and toxicology information
8. Additional information

• PROCESS OF IND

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 Q.5 Explain the process of NDA application

• The NDA application is the vehicle through which drug sponsors formally propose to
approve a new pharmaceutical for manufacturing, sale and marketing.
• The documentation required in an NDA is supposed to tell the drug's whole story,
including what happened during the clinical tests, what the ingredients of the drug are,
the results of the animal studies, how the drug behaves in the body, and how it is
manufactured, processed and packaged.
• Animal Pharmacology and Toxicology Studies
• Manufacturing Information
• Clinical Protocols and Investigator Information
The goals of the NDA are to provide enough information to permit CDSCO/FDA
reviewer to reach the following key decisions:
• Whether the drug is safe and effective in its proposed use(s), and whether the benefits
of the drug outweigh the risks.
• Whether the drug's proposed labeling (package insert) is appropriate, and what it
should contain.
• Whether the methods used in manufacturing the drug and the controls used to
maintain the drug's quality are adequate to preserve the drug's identity, strength, quality,
and purity
NDA Classifications
✓ New Molecular Entity
✓ New Salt of Previously Approved Drug
✓ New Formulation of Previously Approved Drug
✓ New Combination of Two or More Drugs
✓ New Indication (claim) for Already Marketed Drug
✓ Already Marketed Drug Product - No Previously Approved NDA
RULES GOVERNING CLINICAL TRIALS (IMP for MCQ)
• Rule 122-A -Application for permission to import new drug
• Rule 122-B -Application for approval to manufacture new drug
• Rule 122-DA-Mandatory requirement of permission from DCG (I) for conduct of
clinical trial of new drug;
• Rule 122 DAB -Provision for examination of serious adverse event (SAE) of injury
and death and payment of compensation in clinical trial related cases.
• Rule 122 DAC -Conditions of permission for conduct of clinical trial which includes
mandatory requirement to follow Good Clinical Practice (GCP) guidelines,
• Rule 122 E-Definition of new drug

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 • Requirement of NDA (EXPLAIN IN SHORT)
1. Index
2. Summary
3. Chemistry, Manufacturing, and Control;
4. Samples, Method Validation Package, and Labeling
5. Nonclinical Pharmacology and Toxicology
6. Human Pharmacokinetics and Bioavailability
7. Microbiology (for anti-microbial drugs only);
8. Clinical Data;
9. Safety Update Report
10. Statistical;
11. Case Report Tabulations;
12. Case Report Forms;
13. Patent Information;
14. Patent Certification; and Other information

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 • GENERAL REQUIREMENTS
1. Content And Format of Application
• A copy of cover letter
• A copy of application form(FDA356h)
• A copy of overall summary
• A copy of INDEX
• An index to specific review section
• All copies are submitted in hard copy

2. Formatting, Assembling and Submitting New Drug and Antibiotic Applications

• The review copy is divide into 6 technical section and should be submitted with
each review section separately bound in specific color
• CMC-RED
• Non-clinical pharmacology and toxicology- YELLOW
• Human PK and Bioavailability : ORANGE
• Microbiology:- WHITE
• Clinical data:- LIGHT BROWN
• Statistical data- GREEN

3. NDA Summary Format and Content

• Annotated package insert
• Pharmacological class, rationale use and potential clinical benefits
• C.M.C.
• Foreign marketing history
• Non-clinical pharmacological and toxicological data
• Human Pharmacokinetics and Bioavailability
• Microbiology (for anti-microbial drugs only
• Clinical data section

4. NDA Technical Section

• C.M.C.
• Non-clinical pharmacological and toxicological data
• Human Pharmacokinetics and Bioavailability
• Microbiology (for anti-microbial drugs only
• Clinical data section
• Sample, method validation and safety.
• Case Report and Tabulations;
• Patent Information

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Q.6 Note on Clinical Research / Clinical Research Protocol
• ‘CLINICAL’: ‘Treatment of patients’
• ‘RESEARCH’ : ‘Systematic investigation & study in order to establish facts & reach
new conclusions’
• A clinical trial (also clinical research) is a research study in human volunteers to answer
specific health questions.
• Clinical trials try to answer specific scientific questions to find better ways to prevent,
detect, or treat diseases, or to improve care for people with diseases
• Clinical trials are the final step in a long research process that include preliminary
laboratory research and experiment.
• Carefully conducted clinical trials are the safest and fastest way to find treatments that
work in people and ways to improve health.
• Important of clinical research
✓ New techniques for screening and diagnosing a disease.
✓ New drugs to market.
✓ New methods for surgery.
✓ New approach for radiation therapy.
✓ New combination of standard treatments.
✓ New techniques, such as Gene therapy.
• Types Of Clinical Trials
✓ Based On Research Behave
1. Observational study
2. Interventional study
✓ Based On Purpose
1. Prevention Trials
2. Screening Trials
3. Diagnostic Trials
4. Treatment Trials

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 • Aims of the protocol.
1) To raise the question to be researched and clarify its importance.
2) To collect existing knowledge and discuss the efforts of other researchers who
have worked on the related questions (Literature review).
3) To formulate a hypothesis and objectives.
4) To clarify ethical considerations.
5) To suggest the methodology required for solving the question and achieving the
objectives.
6) To discuss the requirements and limitations in achieving the objectives.

The key points of the proposal should include justification for the need of the project and
a detailed plan for the investigation:

• What is the question? (Hypothesis) What is it to be investigated?

• Why is the study important? (Significance)
• Where and when it will take place?
• What is the methodology? (Procedures and methods to be used).
• How are you going to do it? (Research design)
• Proposed time table and budget.
• Resources required (technical, scientific, and financial).

• Drafting the protocol correctly will increase the likelihood that the
conclusions drawn from the research are scientifically sound.

• Recommendations and suggestions should be sought from colleagues and

experts so that researchers can develop their plans.

• However, once the study is launched, the protocol should not be altered
during the progression of the study or trials. If the changes during progress of
study are minor, then that part of the study should be excluded from the
analysis.

• The components of the protocol.

1) Title of the study
2) Administrative detail
3) Project summary
4) Introduction to the research topic, background (Literature review)
5) Preliminary studies
6) Study objectives and/or questions. Statement of the problem.
7) Methodology: Study design, study population and methods of recruitment,
variables list, sample size, methods of data collection, data collection tools, plan
of analysis
8) Project management: Work plan (Timeline - proposed schedule)
9) Strengths and limitations of the study
10) Issues for ethical review and approvals

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 Q.7 Importance of bioequivalence studies
• Bioequivalence is the biochemical similarity of two (or more) drugs that share the
same active ingredient(s) and desired outcome(s) for patients.
• Pharmacokinetic studies must be done to determine whether a commercially
available brand and a potential generic version share core attributes.
• Bioequivalence or pharmaceutical equivalence must be present showing that the
two drugs release the active ingredient into the bloodstream at the same amount,
the same rate, and have the same quality.
• United States Food and Drug Administration (FDA) guidance, bioequivalence is
defined as: “the absence of a significant difference in the rate and extent to which
the active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action when
administered at the same molar dose under similar conditions in an appropriately
designed study” (FDA, 2003). Bioequivalence is actually the comparison of the
bioavailability of two drug products.

• NEED FOR BIOEQUIVALENCE STUDIES

1. New product is intended to be a substitute for an approved medicinal product as a
pharmaceutical equivalent or alternative
2. To ensure clinical performance of such drug products
3. Bioequivalence studies are conducted if there is A risk of bio-in equivalence
and/or A risk of pharmacotherapeutics failure or diminished clinical safety
4. In vivo bioavailability / bioequivalence studies and in vitro dissolution testing
recommended to applicants intending to submit Investigational new drug
application (INDs)New drug applications (NDAs)Abbreviated new drug
applications (ANDAs) for conventional and extended-release dosage forms
administered orally.
5. In conditions where a suitable method for determining active drug is not available,
an indirect indication of bioavailability and bioequivalence by comparing the
pharmacodynamic responses of the formulations may be possible

IMPORTANCE OF BIOEQUIVALANCE STUDIES

• To evaluate the absolute bioavailability of dosage form compared with reference
dosage forms.
• Dose proportionality study to determine if bioavailability parameters are linear over
proposed dosage range.
• Intra/inter subject variability
• Intervention study to examine effect of e.g. Food and concomitant medication.
• Dosage form proportionality study to determine if equipotent drug treatments
administered at different dose strength of the market form produce equivalent drug
bioavailability.
• Bioequivalence study needed as a result of changes in the formulation or
manufacturing processes.

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 DESIGN OF BIOEQUIVALENCE STUDIES DESIGN:
• The design and evaluation of well-controlled bioequivalence studies require
cooperative input from pharmacokinetics, statisticians, clinicians, bioanalytical
chemists, and others.
• The basic design for a bioequivalence study is determined by:
• The scientific questions to be answered,
• The nature of the reference material and the dosage form to be tested,
• The availability of analytical methods, and
• Benefit–risk and ethical considerations with regard to testing in humans.
• Bioequivalence study protocol
1. Title
• Project number & date
• Principal investigator
2. Study objective
3. Study design
• Design
• Drug product
• Dosage regimen
• Sample collection schedule
• Housing
• Fasting/meals schedule.
• Analytical methods a
4. Subject selection –
• Medical history
• Physical examination
• Laboratory tests
• Inclusion/exclusion criteria
5. Clinical procedures
• Dosage & drug administration
• Biological sampling schedule
• Activity of subjects.
6. Ethical considerations
• Basic principles
• Institutional review board
• Informed consent data
• Indications for subject withdrawal
• Adverse reactions & administration emergency procedures
• 10. Appendix
7. Facilities
8. Data analysis
9. Analytical validation

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Q.8 Explain the role of biostatistics in pharma industry
• Statistics is the discipline that concerns the collection, organization, analysis,
interpretation and presentation of data.
• Biostatistics
• Biostatistics is the application of statistics in the development and use of therapeutic
drugs and devices in humans and animals.
• Biostatistics involve the use of scientific and quantitative procedures to evaluate the
quality of evidence in biological sciences.
• It also involves the statistical processes and methods used for analyzing the biological
phenomena.
• Biostatistics is a science that includes designing of biological and experimental study
designs as well as synthesis, analysis, and interpretation of data obtained from such
studies.
• Standard pharmaceutical development practices in experimental design, trial
conduct, and statistical analysis are in need of review and revision if the goals of
assuring the development and approval of safe, effective pharmaceuticals are to be
maintained.
• The last four decades have confirmed the value of prospective, controlled, blinded,
randomized clinical trials in pharmaceutical development.
• Medicine is essentially an empirical science. It depends on observations and not on
theories or theorems.
• As a part of clinical practice or research we deal with many observations, which when
systematically arranged, are called Data.
• The process of converting data into information requires a special approach called
statistics.

ROLE OF BIOSTATISTICIANS
• Identify and develop treatments for disease and estimate their effects.
• Identify risk factors for diseases.
• Design, monitor, analyze, interpret, and report results of clinical studies.
• Develop statistical methodologies to address questions arising from medical/public
health data.
• Locate, define & measure extent of disease
• Improve the health of individual & community
• To find the action of drug - a drug is given to animals or humans to see whether the
changes produced are due to the drug or by chance.
• To compare the action of two different drugs or two successive dosages of the same
drug.
• To find the relative potency of a new drug with respect to a standard drug
• To find action of drug.
• In Medicine,
• a. To compare efficacy of particular drug, operation or line of treatment.
• b. To find association between two attributes eg. Oral cancer and smoking
• c. To identify signs and symptoms of disease/ syndrome.

Specific Applications of Biostatistics in Pharmacy Research

• Provides methods of data collection and presentation and analysis of results for better
understanding and for drawing valid conclusions.
• During the stage of planning the experiments, design of experiments (DOE) provides
inputs for planning experiments to get the relevant information.

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 • Provide methods to reduce experimental error in the investigation
• Provide methods to estimate sample size (n) or replication needed for the given
accuracy in the results
• Provides standard designs and methods of analysis suitable for various experimental
and observational studies.
• Provides a variety of “tests of significance” to test the significance of the observed
results and to make comparisons.
• Provides methods of analysis of bivariate population and to evaluate the correlation
between two variables.
• Provides methods of regression and multiple regression for establishing mathematical
relationship between two or more variables.
• Provides statistical optimization techniques for drug development,
• formulation development and analytical method development.

Q.9 Short Note On I.B (Investigator’s Brochures)

• The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data
on the investigational product(s) that are relevant to the study of the product(s) in
human subjects.
• Its purpose is to provide the investigators and others involved in the trial with the
information to facilitate their understanding of the rationale for, and their compliance
with, many key features of the protocol, such as the dose, dose frequency/interval,
methods of administration: and safety monitoring procedures.
• The IB also provides insight to support the clinical management of the study subjects
during the course of the clinical trial.
• The information should be presented in a concise, simple, objective, balanced, and non-
promotional form that enables a clinician, or potential investigator, to understand it and
make his/her own unbiased risk-benefit assessment of the appropriateness of the
proposed trial.
• For this reason, a medically qualified person should generally participate in the editing
of an IB.
• It is expected that the type and extent of information available will vary with the stage
of development of the investigational product.
• If a marketed product is being studied for a new use (i.e., a new indication), an IB
specific to that new use should be prepared.
• The IB should be reviewed at least annually and revised as necessary in compliance
with a sponsor’s written procedures.
General Considerations The IB should include:
• Title Page
• Table of contents of investigator's brochure (example)
• Confidentiality Statement (optional)
• Table of Contents
1. Summary
2. Introduction
3. Physical, Chemical, and Pharmaceutical Properties and Formulation
4. Nonclinical Studies
• Nonclinical Pharmacology
• Pharmacokinetics and Product Metabolism in Animals
• Toxicology

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 • Effects in Humans
• Pharmacokinetics and Product Metabolism in Humans
• Safety and Efficacy
• Marketing Experience
• Summary of Data and Guidance for the Investigator

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