Industrial Pharmacy

1. Regulatory requirement for drug
Approval
Presented By
(Dr.) Kahnu Ch. Panigrahi
Asst. Professor, Pharmaceutics

2. DRUG DEVELOPMENT TEAM:
1. Drug discovery project team:
The primary responsibility of this group is to identify lead compounds
or classes of compounds worthy of continued research. They include
other scientific disciplines such as synthetic chemists, therapeutic
disease groups (cardiovascular, CNS, cancer. infectious diseases, or
metabolic pharmacologists or biologists. Once a lead or class of leads
has been identified, the discovery team further includes bioanalytical
chemists, pharmacokinetics, and toxicology experts for the
development of the drug candidate.
2. Preclinical drug development project team:
The responsibility of this group is to establish the preclinical
development of a lead candidate in coordination with other new
teams. 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 agencies. As
the development of the drug candidate moves into the clinic, the
preclinical project team becomes a clinical project team.

3. 3. Clinical drug development project team:
After the IND is submitted the project team is again expanded to
include physicians, clinical research associates, drug product
production, QA, statisticians, clinical pharmacokinetics, regulatory
team medical monitors, marketing team.
Manufacturing team: Manufacturing team, concurrently work with
various other teams, during nonclinical and clinical drug development
stage which includes pilot plant and scale-up process, validation,
regulatory documentation, packaging, and labeling requirement
according to GLP or GMP guidelines.
4. Marketing team (post-marketing and pre-marketing):
This team determines whether a drug candidate has potential in
comparison to others company’s product or drugs already in the
market for indicating the disease. Further, Phase IV studies are
undertaken after marketing has begun and evaluated new indications,
new doses or formulations, long-term safety, or cost-effectiveness.
These include the identification and monitoring of new additional
adverse drug (ADR) events from doctors or other health professionals.

4. Non- clinical Drug Development:
•The process of drug development involves non-clinical and clinical
studies.
•Non-clinical studies are conducted using different protocols
including animal studies, which mostly follow the Good Laboratory
Practice (GLP) regulations.
•During the early pre-clinical development process, also known as
Go/No-Go decision, a drug candidate needs to pass through several
steps, such as determination of drug availability (studies on
pharmacokinetics), absorption, distribution, metabolism and
elimination (ADME) and preliminary studies that aim to investigate
the candidate safety including genotoxicity, mutagenicity, safety
pharmacology and general toxicology.
•These preliminary studies generally do not need to comply with
GLP regulations.

5. •These studies aim at investigating the drug safety to obtain the first
information about its tolerability in different systems that are relevant
for further decisions.
•There are, however, other studies that should be performed
according to GLP standards and are mandatory for the safe exposure
to humans, such as repeated dose toxicity, genotoxicity and safety
pharmacology.
•These studies must be conducted before the Investigational New
Drug (IND) application.
•The package of non-clinical studies should cover all information
needed for the safe transposition of drugs from animals to humans,
generally based on the non-observed adverse effect level (NOAEL)
obtained from general toxicity studies.
•After IND approval, other GLP experiments for the evaluation of
chronic toxicity, reproductive and developmental toxicity,
carcinogenicity and genotoxicity, are carried out during the clinical
phase of development. However, the necessity of performing such
studies depends on the new drug clinical application purpose.

6. 6
FDA Mission Statement
The FDA is responsible for protecting the
public health by assuring the safety, efficacy,
and security of human and veterinary drugs,
biological products, medical devices, our
nation’s food supply, cosmetics, and products
that emit radiation.

7. 7
FDA STRUCTURE
• CDER (Center for Drug Evaluation and Research)
• CBER (Center for Biologic Evaluation and Research)
• CDRH (Center for Devices and Radiological Health)
• CFSAN (Center for Food Safety and Applied
Nutrition)
• CVM (Center for Veterinary Medicine)
• CTP (Center for Tobacco products)
• NCTR (National Center for Toxicology Research)

8. 8
Stages of Drug Development
• Pre-IND
• IND
• Phase 1 clinical trials
• Phase 2 clinical trials
• Phase 3 clinical trials
• NDA
• Post-marketing

9. 9
PHASE 1
PHASE 2
PHASE 3
ACCELERATED DEVELOPMENT REVIEW
SHORT-TERM
LONG-TERM
E
E
E TREATMENT IND
PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW
SYNTHESIS
AND PURIFICATION
ANIMAL TESTING
INSTITUTIONAL REVIEW BOARDS
FDA TIME
INDUSTRY TIME
SPONSORED/FDA MEETING ENCOURAGED
ADVISORY COMMITTEES
E SUBPART E
EARLY ACCESS:
IND SUBMITTED NDA SUBMITTED
REVIEW
DECISION
SPONSOR ANSWERS
ANY QUESTIONS
FROM REVIEW
Drug Development 101

10. The Review Team
• Division Director, Deputy Director
• Team Leaders from each of the review
teams
– Clinical Reviewer (Medical Officer)
– Pharmacology/Toxicology Reviewer
– Product Quality Reviewer (CMC)
– Clinical Virology Reviewer (in some divisions)
– Clinical Pharmacology Reviewer
– Statistic Reviewer
– Regulatory Project Manager

11. 11
Organizations Involved in
Drug Development
• Food and Drug Administration (FDA)
• Sponsors
– Pharmaceutical/biopharmaceutical companies
– Academic institutions
– Other
• Contract research organizations (CROs)

12. 12
Pre-IND
Before Submitting an IND,
Sponsors…
• Define chemical properties of the drug
• Conduct nonclinical
pharmacology/toxicology studies
• Develop clinical protocol(s)

13. Prior to beginning clinical trials, an Investigational New
Drug (IND) application must be submitted to the FDA. This
document must include:
1. Animal study data and toxicity
2. Manufacturing information
3. Clinical protocols for the proposed human trials
4. Data from any prior human research
5. Information about the principal investigator(s)
The FDA then conducts an extensive review of the IND,
and, after thirty days, can respond to in one of two ways:
1. Approval of the IND and commencement of clinical trials
2. Temporary hold until additional information is obtained,
or a stop of the investigation entirely

14. 14
Regulations
Code of Federal Regulations
•http://www.gpoaccess.gov/CFR/INDEX.HTML

15. 15
Examples of Regulations
• 21CFR58
Good Laboratory Practice for Non-clinical
Laboratory Studies
• 21CFR312
Investigational New Drug Application
• 21CFR314
Applications for FDAApproval to Market a
New Drug

16. 16
Chemistry, Manufacturing and
Controls
Address discipline specific scientific and regulatory
concerns to ensure that the manufacturing and
control processes result in safe drugs being produced
for clinical trials and marketing.

17. 17
Non-Clinical Perspectives
Non-clinical studies are conducted to
support clinical trials and, ultimately,
approval for new drugs

18. 18
Non-Clinical Studies M3(R2)
• Safety pharmacology GLP
• Pharmacokinetics
• ADME (absorption, distribution, metabolism, elimination)
• General toxicology
• Local Tolerance
• Genotoxicity
• Carcinogenicity
• Reproductive toxicology
• Special studies

19. 19
IND
Investigational New
Drug

20. 20
IND: A Request to Start Clinical
Trials
• Commercial IND - pharmaceutical companies
whose ultimate goal is to obtain marketing
approval for new products
• Investigator IND (Research IND) – submitted
by physicians who initiates and conducts an
investigation
• Single-Patient IND – a submission that is meant
to treat only one patient

21. 21
• Treatment IND – experimental drugs showing
promise in clinical testing for serious or life-
threatening conditions
• Emergency IND (EIND) - Emergency situation that
does not allow time for submission of IND which is
generally reserved for life-threatening situation in
which no standard acceptable treatment is available.

22. 1 All the requirements for submitting an INDA are
prescribed in the Code of Federal Regulations and are
submitted under a cover sheet (Form FDA- 1571) (1).
2. Commitment that
•An “Institutional Review Board” (IRB) has approved the
study and will continue to monitor the investigation.
•Investigators brochure to submit
•not to begin clinical investigations until IND is in effect
signature of the sponsor or authorized representative and
the date of signed application.
3. After submission of IND to the FDA, it is assigned to the
various divisions of centre for Drug Research and
Evaluation wing of the FDA for its review and evaluation.
IND Process Flow

23. 8. The FDA has 30days from the receipt of IND to decide
whether the proposed clinical trial should proceed or not. If
the sponsor is not contacted within 30days, the trial may
proceed.
9. Meanwhile reviewers at FDA may put a “Clinical Hold” on
the proposed Clinical trials at any time. This prevents human
testing of drug. It may be due to the following reasons:
•If there is any unreasoned threat to the safety of the trial
subjects i.e. if the subjects face any illness or injury due to
treatment.
•Insufficient data to assess patient risks.
•If the investigators involved in the study do not meet the
necessary requirements with respect their qualification.
•Misleading or incomplete investigators brochure.
10. In case if all the requirements for FDA approval are
satisfied an IND is granted.

25. 25
IND Review
• 21 CFR 312.22
• FDA’s primary objectives in reviewing an IND are, in all
phases of the investigation, to assure the safety and rights of
subjects and in Phase 2 and Phase 3, to help assure that the
quality of the scientific evaluation of drugs is adequate to
permit an evaluation of the drug’s effectiveness and safety
• 21 CFR 312.23 (content and format)
– Cover Sheet (Form FDA 1571)
– Form 3674
– A Table of Contents
– Introductory Statement and General Investigational Plan
– Investigator’s Brochure
– Protocols – a protocol for each planned study
– Chemistry, Manufacturing and Controls Information
– Pharmacology and Toxicology Information
– Previous Human Experience with the Investigational Drug
– Additional Information

26. 26
Institutional Review Boards
(IRBs)
• IRB definition – any board, committee, or other group
formally designated by an institution to review, to approve the
initiation of, and to conduct periodic review of, biomedical
research involving human subjects. The primary purpose of
such review is to assure the protection of the rights and
welfare of the human subjects.
• IRBs ensure that:
– Informed consents is obtained and the documents meet
regulatory requirements
– Risk to subjects are minimized
– Risk to subjects are reasonable in relation to anticipated
benefits
– Adequate study monitoring for safety
– Adequate protection of subject privacy
– Rights and welfare of vulnerable subjects are protected

27. INVESTIGATOR’S BROCHURE
Introduction:
•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 IB should be reviewed at least annually and revised as necessary in
compliance with a sponsor’s written procedures.
•However, in accordance with Good Clinical Practice, relevant new information
may be so important that it should be communicated to the investigators, and
possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees
(IECs) and/or regulatory authorities before it is included in a revised IB.

28. General Considerations The IB should include:
•Title Page:
This should provide the sponsor's name, the identity of each
investigational product (i.e., research number, chemical or approved
generic name, and trade name(s) where legally permissible and
desired by the sponsor), and the release date. It is also suggested
that an edition number, and a reference to the number and date of
the edition it supersedes, be provided. An example is given in
Appendix 1.
•Confidentiality Statement:
The sponsor may wish to include a statement instructing the
investigator/recipients to treat the IB as a confidential document for
the sole information and use of the investigator's team and the
IRB/IEC.

29. Contents of the Investigator’s Brochure
The IB should contain the following sections, each with literature references where
appropriate:
Table of Contents:
An example of the Table of Contents is given in Appendix 2
Summary
A brief summary (preferably not exceeding two pages) should be given, highlighting the
significant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of
clinical development of the investigational product.
Introduction
A brief introductory statement should be provided that contains the chemical name (and
generic and trade name(s) when approved) of the investigational product(s), all active
ingredients, the investigational product (s ) pharmacological class and its expected position
within this class (e.g. advantages), the rationale for performing research with the
investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic
indication(s). Finally, the introductory statement should provide the general approach to be
followed in evaluating the investigational product.

30. Physical, Chemical, and Pharmaceutical Properties and Formulation
A description should be provided of the investigational product substance(s) (including the
chemical and/or structural formula(e)), and a brief summary should be given of the relevant
physical, chemical, and pharmaceutical properties. To permit appropriate safety measures
to be taken in the course of the trial, a description of the formulation(s) to be used,
including excipients, should be provided and justified if clinically relevant. Instructions for
the storage and handling of the dosage form(s) should also be given. Any structural
similarities to other known compounds should be mentioned.
Nonclinical Studies
Introduction:
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and
investigational product metabolism studies should be provided in summary form. This
summary should address the methodology used, the results, and a discussion of the
relevance of the findings to the investigated therapeutic and the possible unfavourable and
unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
- Nature and frequency of pharmacological or toxic effects
- Severity or intensity of pharmacological or toxic effects
- Time to onset of effects
- Reversibility of effects
- Duration of effects
-Dose response

31. •Pieces tested
•Number and sex of animals in each group
•Unit dose (e.g., milligram/kilogram (mg/kg))
•Dose interval
•Route of administration
•Duration of dosing
•Information on systemic distribution
•Duration of post-exposure follow-up
•Results, including the following aspects:
The following sections should discuss the most important findings from the studies,
including the dose response of observed effects, the relevance to humans, and any
aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in
the same animal species should be compared (i.e., the therapeutic index should be
discussed). The relevance of this information to the proposed human dosing should be
addressed. Whenever possible, comparisons should be made in terms of blood/tissue
levels rather than on a mg/kg basis.

32. (a) Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product and,
where appropriate, its significant metabolites studied in animals, should be
included. Such a summary should incorporate studies that assess potential
therapeutic activity (e.g. efficacy models, receptor binding, and specificity) as well
as those that assess safety (e.g., special studies to assess pharmacological actions
other than the intended therapeutic effect(s)).
(b) Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and
disposition of the investigational product in all species studied should be given.
The discussion of the findings should address the absorption and the local and
systemic bioavailability of the investigational product and its metabolites, and
their relationship to the pharmacological and toxicological findings in animal
species.
(c) Toxicology
A summary of the toxicological effects found in relevant studies conducted in
different animal species should be described under the following headings where
appropriate:

33. Effects in Humans
Introduction:
A thorough discussion of the known effects of the investigational product(s) in humans
should be provided, including information on pharmacokinetics, metabolism,
pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities.
(a) Pharmacokinetics and Product Metabolism in Humans.
(b) Safety and Efficacy
A summary of information should be provided about the investigational
product's/products' (including metabolites, where appropriate) safety, pharmacodynamics,
efficacy, and dose response that were obtained from preceding trials in humans (healthy
volunteers and/or patients). The implications of this information should be discussed. In
cases where a number of clinical trials have been completed, the use of summaries of
safety and efficacy across multiple trials by indications in subgroups may provide a clear
presentation of the data. Tabular summaries of adverse drug reactions for all the clinical
trials (including those for all the studied indications) would be useful. Important differences
in adverse drug reaction patterns/incidences across indications or subgroups should be
discussed.The IB should provide a description of the possible risks and adverse drug
reactions to be anticipated on the basis of prior experiences with the product under
investigation and with related product.A description should also be provided of the
precautions or special monitoring to be done as part of the investigational use of the
product(s).

34. (c) Marketing Experience
The IB should identify countries where the investigational product has been marketed or
approved. Any significant information arising from the marketed use should be
summarised (e.g., formulations, dosages, routes of administration, and adverse product
reactions). The IB should also identify all the countries where the investigational product
did not receive approval/registration for marketing or was withdrawn from
marketing/registration.
Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical and clinical data, and
should summarise the information from various sources on different aspects of the
investigational product(s), wherever possible. In this way, the investigator can be provided
with the most informative interpretation of the available data and with an assessment of
the implications of the information for future clinical trials. Where appropriate, the
published reports on related products should be discussed. This could help the
investigator to anticipate adverse drug reactions or other problems in clinical trials.
The overall aim of this section is to provide the investigator with a clear understanding of
the possible risks and adverse reactions, and of the specific tests, observations, and
precautions that may be needed for a clinical trial. This understanding should be based on
the available physical, chemical, pharmaceutical, pharmacological, toxicological, and
clinical information on the investigational product(s). Guidance should also be provided to
the clinical investigator on the recognition and treatment of possible overdose and
adverse drug reactions that is based on previous human experience and on the
pharmacology of the investigational product

35. 35
APPENDIX 1:
• TITLE PAGE (Example)
• SPONSOR'S NAME
• Product:
• Research Number:
• Name(s): Chemical, Generic (if
approved)
• Trade Name(s) (if legally
permissible and desired by the
sponsor)
• INVESTIGATOR'S BROCHURE
• Edition Number:
• Release Date:
• Replaces Previous Edition Number:
• Date:
APPENDIX 2:
• - Confidentiality Statement (optional)
• - Signature Page (optional)
• 1 Table of Contents
• 2 Summary
• 3 Introduction
• 4 Physical, Chemical, and Pharmaceutical
Properties and Formulation
• 5 Nonclinical Studies
• 5.1 Nonclinical Pharmacology
• 5.2 Pharmacokinetics and Product
Metabolism in Animals
• 5.3 Toxicology
• 6 Effects in Humans
• 6.1 Pharmacokinetics and Product
Metabolism in Humans
• 6.2 Safety and Efficacy
• 6.3 Marketing Experience
• 7 Summary of Data and Guidance for the
Investigator

36. 36
Overview of Clinical
Trials

37. 37
Phase 1, 2, and 3 Trials
Phase 1:
 Safety and pharmacokinetics
 Generally 20 to ~80 subjects
 Closely controlled
Phase 3:
 Efficacy and safety
 Several hundred to several
thousand subjects
Phase 2:
 Efficacy and safety
 Usually no more than
several hundred subjects
 Closely controlled

38. 38
Clinical Trials
• Phases of clinical investigation defined in
21 CFR 312.21
• IND may be submitted for one or more phases
of an investigation
• Clinical investigation of a new drug is
generally divided into 3 phases
– Phases 1, 2 and 3

39. 39
Clinical Trials
• Phase 1 Clinical Trials
– Includes initial introduction of a new drug into
humans
– Closely monitored
– Safety and pharmacokinetics, drug metabolism
and mechanism of action
– Healthy volunteers or patients
– Generally 20 to 80 subjects

40. 40
Clinical Trials
Phase 2 Clinical Trials
– Evaluate effectiveness of a new drug for a
particular indication in patients with the disease
– Define doses for Phase 3
– Determine short-term risks and side effects
– Closely monitored
– No more than several hundred subject

41. 41
Clinical Trials
Phase 3 Clinical Trials
– Performed after preliminary evidence of
efficacy has been demonstrated
– Intended to gather additional information on
safety and efficacy
– Evaluate risk vs. benefit
– Several hundred to several thousand subjects

42. 42
What are Phase 1a, 1b, 2a
and 2b?
• No regulatory definition or description
• Way to classify/subdivide clinical trials
• Example
– Phase 1a – Single dose
– Phase 1b – Repeat dose

43. What happens in phase IV?
•Phase IV clinical trials happen after the FDA has
approved medication.
•This phase involves thousands of participants and
can last for many years.
•Investigators use this phase to get more
information about the medication’s long-term
safety, effectiveness, and any other benefits.

44. 44
What is Phase 0?
• Phase 0 of a clinical trial is done with a very small
number of people, usually fewer than 15.
• Investigators use a very small dose of medication
to make sure it isn’t harmful to humans before
they start using it in higher doses for later phases.
• If the medication acts differently than expected,
the investigators will likely to do some additional
preclinical research before deciding whether to
continue the trial.

45. 45
NDA
New Drug Application

46. 46
NDA: A Request to Market
the Drug
• After clinical trials have succeeded, a New Drug Application (NDA)
is submitted to the FDA for review and potential approval.
• The purpose of this document is to demonstrate the clinical trials
proved the safety and efficacy of the drug, and that it is qualified
to go to market. The review process can take anywhere from six
to ten months.
NDA Consists of:
• Clinical safety and efficacy data
• Clinical pharmacokinetic data
• Nonclinical pharmacology/toxicology data
• Chemistry data
• Package labeling

49. 49
NDA Types
• Type 1: New Molecular Entity (NME)
• Type 2: New Active Ingredient (e.g. new salt)
• Type 3: New Dosage Form
• Type 4: New Combination
• Type 5: New Formulation or New Manufacturer
• Type 6: New Indication, Same Manufacturer (no
longer used)
• Type 7: Drug Already Marketed, but Without
Approved NDA
• Type 8: Rx to OTC

50. 50
Types of NDAs
• 505(b)(1) - applicant own or have a right of
reference to all of the investigations relied upon
by the application to support approval of the
NDA
• 505(j) - generic application
• 505(b)(2) – an NDA that relies for approval on
investigations not conducted by or for the
applicant and for which the application does not
have a right of reference

51. •An abbreviated new drug application (ANDA) contains data which is
submitted to FDA for the review and potential approval of a generic
drug product.
•Once approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective, lower cost
alternative to the brand-name drug it references.
•A generic drug product is one that is comparable to an innovator
drug product in dosage form, strength, route of administration,
quality, performance characteristics, and intended use.
•All approved products, both innovator and generic, are listed in
FDA's Approved Drug Products with Therapeutic Equivalence
Evaluations (Orange Book).
Abbreviated New Drug Application (ANDA)

52. •Generic drug applications are termed "abbreviated"
because they are generally not required to include
preclinical (animal) and clinical (human) data to establish
safety and effectiveness. Instead, generic applicants must
scientifically demonstrate that their product is performs in
the same manner as the innovator drug.
•One way applicants demonstrate that a generic product
performs in the same way as the innovator drug is to
measure the time it takes the generic drug to reach the
bloodstream in healthy volunteers.
•This demonstration of “bioequivalence” gives the rate of
absorption, or bioavailability, of the generic drug, which
can then be compared to that of the innovator drug.

53. •To be approved by FDA, the generic version must deliver
the same amount of active ingredients into a patient's
bloodstream in the same amount of time as the
innovator drug.
•The "Drug Price Competition and Patent Term
Restoration Act of 1984," also known as the Hatch-
Waxman Amendments, established bioequivalence as
the basis for approving generic copies of drug products.
•These Amendments permit FDA to approve applications
to market generic versions of brand-name drugs without
repeating costly and duplicative clinical trials to establish
safety and efficacy.

54. Clinical Trial Protocol
•Every clinical investigation begins with the development of a clinical
protocol. The protocol is a document that describes how a clinical
trial will be conducted (the objective(s), design, methodology,
statistical considerations and organization of a clinical trial,) and
ensures the safety of the trial subjects and integrity of the data
collected.
•A research protocol is a document that describes the background,
rationale, objectives, design, methodology, statistical considerations,
and organization of a clinical research project.
•The NIH provides many resources for protocol development to
assist investigators in writing and developing clinical research
protocols that are in compliance with regulatory/GCP requirements.

55. According to the ICH Good Clinical Practice guidelines, a protocol
should include the following topics:
•Title Page (General Information)
•Background Information
•Objectives/Purpose
•Study Design
•Selection and Exclusion of Subjects
•Treatment of Subjects
•Assessment of Efficacy
•Assessment of Safety
•Adverse Events
•Discontinuation of the Study
•Statistics
•Quality Control and Assurance
•Ethics
•Data handling and Recordkeeping
•Publication Policy
•Project Timetable/Flowchart
•References
•Supplements/Appendices

56. •Statistics play a crucial role in clinical trials and in the drug
development process – from trial design to protocol development.
•Following statistical concepts are generally applied by clinical trial
professional such as:
Confidence Intervals
Multiplicity
Subgroup Analysis
Parametric vs. Non-parametric statistical methods
Sample Size Calculation
Types of endpoints
Statistical Reporting
Missing Data
Adaptive Trial Design
Bayesian Model
Biostatic in Pharmaceutical Product Development

57. •Biostatistics are involved in every step of clinical
research including trial design, protocol development, data
management and monitoring, data analysis and clinical trial
reporting.
•Since statisticians can specialize in study designs (even complex
designs like Adaptive Trial Design), therapeutic areas and
statistical methods, it is crucial that the rest of the study team
understands the statistical strategy proposed by the
biostatistician.
•It is helpful in
Protocol Development & Design
Data Management
Study Implementation
Study Monitoring
Data Analysis & Reporting

58. DATA PRESENTATION FOR FDA SUBMISSION
Study Data:
Clinical study data are information about a person in a clinical trial. Study data
include demographic information, details of medical treatment, descriptions of
the participant’s progress, and other relevant information. In early studies, this
same information is captured for animals and is called nonclinical study data.
Types of Data Submission
• Commercial Investigational New Drug (IND) applications (for products that are
intended to be distributed commercially)
• New Drug Applications (NDAs)
• Abbreviated New Drug Applications (ANDAs)
• Biologics License Applications (BLAs)
• All subsequent submissions to these types of applications, including
amendments, supplements, and reports, even if the original submission was filed
before the requirements went into effect

59. •Study data must be in a format supported by FDA at the time of the study’s start date. These
formats are specified in the FDA Data Standards Catalog.
•These study data standards were developed as part of a collaboration between FDA, the non-
profit Clinical Data Interchange Standards Consortium (CDISC), and other stakeholders.
Currently supported study data standards:
•CDISC Standard for Exchange of Nonclinical Data (SEND) for nonclinical data
•CDISC Study Data Tabulation Model (SDTM) for clinical data
•CDISC Analysis Data Model (ADaM) for analysis of clinical data
•CDISC Case Report Tabulation Data Definition Specification (Define-XML) for the metadata
that accompany SEND, SDTM, and ADaM datasets
For detailed CDISC submission instructions, see the Study Data Implementation Guides.
FDA has the following procedures for updating standards:
•FDA will periodically publish its intent to begin supporting new standards and new versions of
current standards.
•FDA will give at least one year’s notice before a new version of a standard is required.
•For entirely new standards, the notice will be at least two years.
•FDA is supporting efforts to develop clinical terminology standards for particular therapeutic
areas within the SDTM.
•The SDTM will be updated periodically to include new and revised standards for specific
therapeutic areas.

60. Clinical trial management system
•A Clinical Trial Management System (CTMS) is a software system used
by biotechnology and pharmaceutical industries to manage clinical trials in clinical
research.
•The system maintains and manages planning, performing and reporting functions, along
with participant contact information, tracking deadlines and milestones.
•Available software includes budgeting, patient management, compliance
with government regulations, project management, financials, patient management and
recruitment, investigator management, regulatory compliance and compatibility with other
systems such as electronic data capture and adverse event reporting systems.
•In addition to pharmaceutical and biotechnology industries, CTMSs are widely used at
sites where clinical research is conducted such as research hospitals, physician
practices, academic medical centers and cancer centers.
•While pharmaceutical companies that sponsor clinical trials may provide a CTMS to the
sites that participate in their trials, sites may operate a CTMS to support day-to-day
operations in areas such as conducting study feasibility, streamlining the workflow of
the trial coordinators and investigators, providing a centralized place to house all trial-
related information, and improve clinical data management by equipping staff,
including biostatisticians and database administrators.
•Some CTMS are cloud based and are delivered in a software as a service (SaaS) modality,
while others require dedicated servers.

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