UNIT 4.

BSPh 301

CLINICAL TRIALS
UNIT 4. CLINICAL TRIALS
4.1 Investigational new drug application (IND)
4.2 Clinical trial designs
4.3 Clinical trial core documents
4.4 Clinical trial stakeholders
4.5 International and local guidelines and regulations in the conduct of clinical
trials
4.6 Clinical trials: phase I, phase II, phase III
4.7 Pre-marketing activities (FDA review and approval for marketing
authorization)
4.8 Post-marketing surveillance
4.9 Intellectual property protection
UNIT 4. CLINICAL TRIALS
Learning Outcome
• Demonstrate understanding of the standard procedures/protocols followed
in the conduct of clinical trials

Learning Objective
4.1 Investigational new drug application (IND)
• Explain the content, principles, and purpose of the IND application as well
as its review and approval process
THE DEVELOPMENT PROCESS
• A candidate drug must go through extensive studies in humans, and
it must prove to be safe and effective before the FDA will approve it
• This process involves a series of clinical trials, each with its own
specific goals and requirements
• Physicians carry out each trial working with patients in hospitals,
offices and clinics, and coordinating closely with the sponsor
company
• The clinical trials process is both expensive and time-consuming,
and ends more often in failure than success
• From start to finish it takes an average of 6-7 years
THE DEVELOPMENT PROCESS
Investigational New Drug (IND) Application and Safety
• File IND with the FDA before clinical testing can begin; ensure
safety for clinical trial volunteers through an Institutional Review
Board
• Before any clinical trial can begin, the researchers must file an
Investigational New Drug (IND) application with the FDA
• The application includes the results of the preclinical work, the
candidate drug’s chemical structure and how it is thought to work in
the body, a listing of any side effects and manufacturing information
• The IND also provides a detailed clinical trial plan that outlines how,
where and by whom the studies will be performed
• The FDA reviews the application to make sure people participating in
the clinical trials will not be exposed to unreasonable risks
What is a Drug?

 A drug is anything that meets the definition of a drug

“. . .articles intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or other animals. . .”
“…a substance (other than food) intended to affect the structure or any function of
the body”
Note: This definition includes“…compounds administered to blunt or provoke a
physiological response or to study the mechanism of action or metabolism of a
drug.”
What is an Investigational Drug?

▪ An article that is not lawfully marketed as a drug, OR

▪ An article that is lawfully marketed as a drug that is not used according to the approved label
(including a new combination of approved drugs)
Note: The practice of medicine allows a physician to use any lawfully marketed drug without
prior regulatory approval.
What is an Investigational New Drug Application (IND)?

▪ An IND is a regulatory submission to the FDA that permits the clinical investigation of a drug.
▪ An effective IND allows:
– An investigational drug (or biologic) to be used in a clinical investigation.
– A drug to be shipped lawfully for the purpose of conducting clinical investigations.
▪ Not all clinical investigations using investigational drugs require an IND.
Definitions: Categories of INDs

▪ Commercial IND
– Ultimate goal is to obtain marketing approval
▪ Research IND
– Goal is publication
– Generally sponsored by individual investigators, academic institutions, and non-profit entities
– Labeling changes
Does My Clinical Study Require an IND?
Test Article
Not legally marketed as a drug

Investigational Drug

Requires an IND

▪ Clinical investigations using a product that is not lawfully

marketed as a drug require an IND.
Does My Clinical Study Require an IND?
Test Article
Not legally marketed as a drug Legally marketed as a drug

Investigational Drug Lawfully Marketed Drug

Requires an IND Need an IND?

On-label Off-label

* Assuming no marketing application or change

IND not Does the study meet the
in advertising is planned required* IND exemption criteria?
IND Exemption Criteria
▪ A clinical investigation of a drug product that is lawfully marketed is exempt from requiring an IND if
all five criteria are met:
1. The study is not designed to support approval of a new indication or a change in label.
2. The study is not intended to support a significant change in the advertising for the product.
3. The study does not involve a route of administration, dosage level, patient
population, or other factor that significantly increases the risks (or decreases the
acceptability of the risks) associated with the use of the drug.
4. The study is conducted in compliance with the IRB and informed consent regulations.
5. The study is conducted in compliance with regulations regarding promotion for
investigational drugs.
IND Advantages to the Investigator

▪ Mechanism to change labels

– Dissemination of information outside of publication
▪ Protocol review and feedback by FDA
▪ IRB compliance
▪ Requirement for funding agencies (government and foundations)
▪ Regulatory science training
IND Disadvantages to the Investigator

▪ Need for institutional support for submission and maintenance

▪ Protocol review and feedback by FDA
▪ Formulation questions may require additional work prior to clinical investigation
▪ Increased burden for safety reporting
▪ Data management system
 Clinical Protocol

IND
Application
Chemistry,
Pharmacology/
Manufacturing,
Toxicology
Controls
 FDA Form 21 CFR 312.23(a)(1)
 Table of Contents 21 CFR 312.23(a)(2)
 Introductory statement and general
21 CFR 312.23(a)(3)
investigational plan
 Investigator’s brochure 21 CFR 312.23(a)(5)
 Protocols 21 CFR 312.23(a)(6)
 Chemistry, manufacturing, and control data
(including environmental assessment) 21 CFR 312.23(a)(7)

 Pharmacology and toxicology data 21 CFR 312.23(a)(8)

 Previous human experience 21 CFR 312.23(a)(9)
 Additional information 21 CFR 312.23(a)(10)
 Biosimilar User Fee Cover Sheet Form FDA 3792
 Clinical Trials Certification of Compliance Form FDA 3674
I. PRODUCT MANUFACTURING/CHARACTERIZATION
 Components and Materials
Reagents/Materials/Excipients: List of all used during
manufacturing process, indicate whether clinical grade. Describe
qualification program for acceptance
 Manufacturing Procedures
Provide an outline of the manufacturing process for the product
including timing for specific steps and overall duration
Describe facility where manufacturing takes place, list equipment
used, provide information about the qualifications of persons
responsible for performing manufacturing
Indicate final formulation, unit dosage, total number of units
produced per manufacturing run, and method of storage if
product not given fresh
II. PRODUCT RELEASE TESTING/RESULTS
 Microbiological Testing
Sterility Testing (Bacterial/Fungal): Performed in accordance
with requirements outlined
✓Sterility test appropriate to material being tested, does not
interfere or hinder the test.
✓Test must be validated to demonstrate capability to
reliably and consistently detect presence of viable,
contaminating microorganisms.
Mycoplasma: Performed when manufacturing process involves
extended periods. May use recommended assay, or PCR / other
alternative test method (demonstrate adequate
sensitivity/specificity). Test sample composition important
II. PRODUCT RELEASE TESTING/RESULTS (2)
 Identity: assay that is specific for the product, able to
uniquely identify product from others that may be
manufactured in the same facility
 Purity: testing performed to demonstrate the final
product is free from undesired extraneous materials
introduced during the manufacturing process.
Residual Contaminants: Assays to detect the presence of
residual substances used during manufacturing process and
purification.
Pyrogenicity/Endotoxin (manufacturing process impurities)
II. PRODUCT RELEASE TESTING/RESULTS (3)
 Potency: Tests for potency shall consist of either in
vitro or in vivo tests, or both, which have been
specifically designed for each product so as to
indicate its potency
Potency is interpreted to mean the specific ability or
capacity of the product, as indicated by appropriate
laboratory tests….to effect a given result.
Pharmacologic Activity is… “the specific ability or capacity of a
product to achieve a defined effect.” A measure of potency.
Potency assay(s) provides quantitative measurement of a
relevant p activity identified on the basis of preclinical testing
and product characterization that is indicative of a product’s
capacity to elicit a clinical effect.
III. FINAL PRODUCT RELEASE TESTING: ACCEPTANCE
CRITERIA (Drug Substance = Drug Product)
 Release testing is performed on the final formulated
product for each lot manufactured (could be N = 1)
 Specifications/acceptance criteria, test methods for safety
(sterility), purity, identity, and potency described in the
IND.
 Results from final product release testing should be
available prior to patient administration.
 If finalized test results will not be available prior to
product/lot release, should include in IND reporting
notification process in event acceptance criteria are not
met.
 Perform pilot manufacturing runs that demonstrate ability
to manufacture product that meets release test
specifications/acceptance criteria.
IV. FINAL PRODUCT STABILITY
 IND should include description of stability
testing program developed to demonstrate
product is sufficiently stable for use throughout
the time period covered by a clinical study.
 Stability test panel should include assays to
monitor product sterility, identity, purity, quality,
and potency. Test results should meet
specifications established prospectively.
 For each assay included in the stability test
panel, you should provide a description of the
test method, indicate sampling time points, and
specify composition of the test article.
V. OTHER ISSUES
 Product Tracking/Segregation:
 You should include in IND submission information about
adequate system to identify product from time of collection
until patient administration
 Include description of procedures developed to ensure
segregation from other products manufactured in the same
facility, preventing inadvertent cross-contamination
 Labeling:
 Describe labeling used throughout manufacturing process
and provide sample of label affixed to the final product
 Label for investigational product must contain the
statement: “CAUTION: New Drug – Limited by law to
Investigational Use”
V. OTHER ISSUES (2)
 Processing/Manufacturing at Multiple Sites:
When processing/manufacturing is performed at several
participating clinical sites, you should include in your IND a
description of the plan used for qualifying manufacturing
performed at each site.
 Shipping From Single Manufacturing Location to
Multiple Clinical Sites.
Your IND submission should include a summary of testing
performed to qualify product shipping procedures.
 Product Delivery Device:
If you will be using a novel device for product administration,
or standard syringes and needles not developed for injection of
a product, you need to supply information in your IND
demonstrating biocompatibility and uniform delivery of viable
dose.
V. OTHER ISSUES (3)
 Lot-to-Lot Comparability
 Relevant when the quantity of initial source
material or output of a single manufacturing run
may be insufficient to generate the total number
of doses necessary to complete a clinical study
 Describe in your IND in vitro and/or in vivo
preclinical testing that will be conducted to
demonstrate product comparability for:
✓ Separate manufactured lots produced from the same
starting material OR……
✓ Separate manufactured lots produced from different
starting material
 Stages of Product Development
IND Submission

Bench
Preclinical Phase I Phase II Phase III NDA
Testing

Product characterization

Qualification & Validation studies

Potency

Safety

Stage of product development serves to determine key review

issues, with safety being a primary focus during all stages of
development/clinical testing.
 Marketing Post-marketing
Pre-IND Phase IND Review Phase Application Phase Phase

Pre- IND CLINICAL TRIALS NDAA Post-

Development
Clinical Review Ph 1 Ph 2 Ph 3 Review Marketing

End of Ph 1 Pre-NDA Safety

Pre Pre-IND Pre-IND
Meeting Meeting Meetings
Interaction Meeting
(Informal) End of Ph 2
Meeting Post NDA
30-day Review Clock Meeting

Product development is an iterative process that

may involve multiple FDA and sponsor interactions
28
 Investigational New Drug (IND) Submission checklist
Please check ()
1. Cover Sheet
2. Submit completed Form as instructed by FDA
Note: If a study conduct obligations have been contracted to a CRO, indicate that a CRO is contracted rather than listing
individual obligations.
Note: If an investigation involves an exception from informed consent for emergency research, state on the Cover Sheet.

3. Table of Contents
Provide a detailed Table of Contents Page
4. Introductory Statement and General Investigational Plan
A brief overview of the general investigational plan for the study. This information is repeated later in the IND, in a concise
detail.
First section: must include the name of drug, active ingredients, its pharmacological class, structural formula (if known),
formulation of the dosage form(s) to be used, route of administration, and broad objectives and expected duration of the
study.
Second section: must include a summary of previous human experience, reference to other INDs, if relevant, and
investigational and marketing experience in other countries, if applicable.
Third section: indicate if the drug has been withdrawn from investigation or marketing for any safety or effectiveness
reasons, including where and why.
Last section: provide a summarize plans for investigating the drug within the next 12 months, including rationale for the
study, indications(s) to be studied, general plan for evaluating the drug, kind of studies planned for the first year (specify if
these plans are not yet complete), expected number of patients to be enrolled and anticipated risks based on animal
toxicology data.
 Investigational New Drug (IND) Submission checklist
Please check ()
5. Investigator Brochure
Include a copy of the Investigator’s Brochure where applicable
6. Protocol(s)
Submit a protocol for each planned study.
Submit a Form for each Investigator participating in the study
7. Referencing Other Sources
If utilizing a drug that is currently subject to a manufacturer’s IND, or marketing application, refer to that IND or application
or Drug Master File (if appropriate) to prevent duplicating information that are already available to FDA. Include a Letter of
Authorization from the other sponsor permitting FDA to use their information for this IND. The Sponsor also must file a
copy of the letter to its own FDA file.
Available information in a published scientific literature may be referenced, if appropriate. Include a copy of each of the
copyrighted items with the IND submission. Material copyrighted by others must be included in a bibliography section, not
in the body of the IND.
May utilize references of the current edition of the United States Pharmacopoeia – National Formulary, if appropriate, to
satisfy some of the requirements in the Drug Substance and Drug Product sections.
8. Introduction
The Introduction should state whether any information in regards to the chemistry of the drug substance, drug product, or
the manufacture of either might suggest any possible human risks.
If so, document all possible human risks and indicate how these safety issues will be monitored, or why the risks can be
dismissed. Ensure to describe any differences between the drug product planned for use in clinical studies and that used
in animal toxicology studies. Does the differences in the drug product affect the safety profile, and how it is affected. If
not, please clarify.
 Investigational New Drug (IND) Submission checklist
Please check ()
9. Drug Substance
Include a summary of the following elements:
A brief description of the drug substance, including its physical, chemical, or biological characteristics, and some evidence
to support its proposed chemical structure.
The name and address of its manufacturer.
A brief description of the general method of preparation of the drug substance, including a list of the reagents, solvents,
and catalysts used. A detailed flow diagram is suggested as the most effective presentation. More information may be
needed to assess the safety of biotechnology-derived drugs or drugs extracted from human or animal sources.
The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug
substance, with a brief description of the test methods used, (e.g., IR spectrum to prove the identity, and HPLC
chromatograms to support the purity level and impurities). Submission of certificates of analysis is also suggested.
A brief description of the stability study and the test methods used to monitor the stability of the drug substance during the
toxicologic studies should be submitted. Preliminary tabular data based on representative material may be submitted.
Neither detailed stability data nor the stability protocol should be submitted.
Note: Validation data and established specifications ordinarily need not be submitted at the initial stage of drug
development. However, for some well-characterized, therapeutic biotechnology-derived products, preliminary
specifications and additional validation data may be needed in certain circumstances to ensure safety in Phase 1.
 Investigational New Drug (IND) Submission checklist
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10. Drug Product
Include a summary of the following elements:
A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the
investigational drug product, including both those components intended to appear in the drug product and those which may not
appear, but which are used in the manufacturing process. A list of one or two pages should be submitted. The quality (e.g.,
National Formulary, American Chemical Society) of the inactive ingredients should be cited. For novel excipients, additional
manufacturing information may be necessary.
Where applicable, a brief summary of the quantitative composition of the investigational new drug product, including any
reasonable variations that may be expected during the investigational stage.

The name and address of the clinical study drug product manufacturer.

A brief, general description of the method of manufacturing and packaging procedures as appropriate for the product. A detailed
flow diagram and a brief written description of the manufacturing process should be submitted, including sterilization process for
sterile products.

A brief description of the acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the
drug product. For example, for sterile products, sterility and pyrogenicity tests should be submitted. Submitting a copy of the
certificate of analysis of the clinical batch is suggested.

A brief description of the stability study and the test methods used to monitor the stability of the drug product to be used in clinical
studies (packaged in the proposed container/closure system and under expected storage conditions), should be provided.
Preliminary tabular data based on representative material may be submitted, but not detailed stability data nor the stability
protocol.

Note: Validation data and established specifications need not be submitted at the initial stage of drug development. For well-
characterized, therapeutic, biotechnology-derived products, a detailed assessment of bioactivity and preliminary specifications
should be available.
 Investigational New Drug (IND) Submission checklist
Please check ()
11. Placebo
Provide a brief, general description of the composition, manufacture, and control of any placebo (if any) to be used in the
proposed clinical studies.
12. Labeling
Provide a copy of all labels and labeling for the investigational product. A mock-up or printed representation of the
proposed labeling that will be provided to investigator(s) is acceptable. Investigational labels must carry a "caution"
statement that reads: "Caution: New Drug - Limited by law to investigational use."
13. Environmental Impact
If applicable, must make a claim for categorical exclusion from submission of an environmental assessment.
14. Pharmacology and Toxicology Information
There are three parts in this section. FDA provides guidelines on conducting these assessments. The review division
should be contacted or the FDA website can be searched for these documents. The first IND submission should capture
all current pharmacology and toxicology information upon which the decision to proceed to study the product in humans
was based, up through what is known when the IND is ready for submission. As additional information is gathered and the
studies progress, submit informational amendments to keep the IND current.
15. Responsible Person(s)
The IND must provide identification and qualifications of individual(s) who evaluated the animal safety data and have
concluded as reasonably safe to begin the proposed human study. This person(s) should sign the summary attesting that
the written summary accurately reflects the animal toxicology data from the various completed studies. The submission
must state where the animal studies were conducted and where the records of the studies are available for inspection.
16. GLP Compliance Certification
GLP compliance is required for in vitro and in vivo, in order to assess product safety. Regulations ensure that the data are
obtained and reported to FDA appropriately. A declaration to conduct the study in full compliance with GLP must be
documented. If not in compliance, a statement of reasons for noncompliance and sponsor's view on how such non-
compliance might affect the interpretations of the findings must be provided.
 Investigational New Drug (IND) Submission checklist

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17. Pharmacology and Drug Distribution
A description of the pharmacological effects and mechanism(s) of actions of the drug in animals

Information on the absorption, distribution, metabolism, and excretions of the drug.

A summary report of up to 5 pages should be submitted.

18. Toxicology: Integrated Summary
An Integrated Summary is only used for drugs and well-characterized, therapeutic biotechnology-derived products. For novel biotechnology-derived products, the
review division should be consulted first.

Need for studies depend on the nature of the drug and the phase of human investigation, including acute, sub-acute and chronic toxicity tests, tests on
reproduction and fetal effects, any special toxicity tests unique to the product’s use (e.g., dermal, inhalation, etc.) and any necessary in vitro tests. When species
specificity, immunogenicity, or other considerations appear to make many or all of the toxicological models irrelevant, consult the review division.

If final quality-assured individual study reports are not available at the time of IND submission, an integrated summary report of toxicological findings based on
unaudited draft reports is acceptable. Unaudited draft reports might undergo minor modifications during final review and quality assurance auditing. Full toxicology
department individual study reports should be available to FDA, upon request. In addition, individual study reports should be available to FDA, upon request, as
final, fully quality-assured documents within 120 days after the start of the human study for which the animal study formed part of the safety conclusion basis. These
final reports should state in the introduction any changes from those reported in the integrated summary. If there are no changes, that should be also be stated
clearly in the introduction of the final, fully quality-assured report.

If the integrated summary is based upon unaudited draft reports, sponsors should submit an update to their integrated summary by 120 days after the start of the
human study (s) identifying any differences found in the preparation of the final fully quality-assured study reports and the information submitted in the initial
integrated summary. If there were no differences found, that should be stated in the integrated summary update.

FDA believes 10 to 15 pages of text with additional tables (as needed) should suffice for the integrated summary. FDA also encourages the use of visual data
displays (e.g., box plots, stem and leaf displays, histograms or distributions of lab results over time). The integrated summary should contain the following:
Describe the design of the studies and any deviations from that design that occurred. Include the dates when the studies were performed. Reference to the study
protocol and protocol amendments may suffice for some of this information.

Present the animal toxicology and toxokinetic findings systematically (a "systems review" perspective, e.g., CNS, cardiovascular, pulmonary, etc.). Those findings
that an informed and experienced expert would reasonably consider as possible signals of human risk should be highlighted. If a product's effects on a particular
body system have not been assessed, that should be noted. If any well-documented toxicological "signal" is not considered evidence of human risk, the reason
should be given. In addition, the sponsor should note whether these findings are discussed in the investigator's brochure.
 Investigational New Drug (IND) Submission checklist

Please check ()

19. Toxicology - Full Data Tabulation
Submit for each animal toxicology study that support the safety of the proposed clinical investigation (a full tabulation of data suitable for detailed review). This
should consist of line listings of the individual data points, including laboratory data points for each animal in these trials, along with summary tabulations of these
data points.

To allow interpretation of the line listings, ensure the line listings should be either:

A brief (usually a few pages) description (i.e., a technical report or abstract including a methods description section) of the study
or
A copy of the study protocol and amendments.
20. Previous Human Experience
Include relevant information about previous investigations or marketing in the country and other countries, including published material relevant to the product’s
safety and/or effectiveness. List other countries where the product has been marketed and whether it was withdrawn from any of those markets (and why), or state
that there has been no previous human experience. Previous human experience may be presented in an integrated summary report.
21. Additional Information
When referencing any previously submitted information, refer to it by name, reference number, and volume and page number to assist FDA in finding the
reference(s). Examples of other information that can be included: discussion about drug dependency or abuse potential and radioactive dissymmetry information.
22. Other FDA-Requested Information
FDA may require other additional information be included in the IND
23. Material in a Foreign Language
Material in a language other than English (including scientific literature published in a foreign journal) must be included in the IND with a certified accurate and
complete English translation.
24. Format
Jackets: FDA has detailed specifications about the binders, called Jackets, which must be used for the IND. Specific Jacket colors are required:
• Red: Original (for the FDA archive)
• Green: Copy (for the FDA CMC reviewer)
• Orange: Copy (for other applicable FDA reviewers)
Tabs: tab and clearly label each part within a Jacket, including sub-sections.

Submit original and two copies of the IND to the appropriate FDA Center
LEARNING RESOURCES
• Drug discovery and development in innovation.org, page 8-
14
• Edwards, L., Fletcher, A., Fox, A., & Stonier, P. Chapter 8
Phase I Drug Development: The First Opportunity for
Extrapolation from Animal Data to Human Exposure, Phase
II and Phase III, Phase IV: Post-Marketing Studies.
Principles and Practice of Pharmaceutical Medicine, Second
Edition.
• Duke Clinical Research Institute
• U.S. Food & Drug Administration
• FDA Philippines https://ww2.fda.gov.ph/
BSPH 301 UNIT 4.1 ACTIVITY
Research COVID-19 investigational drugs and therapies.

Turn in on November 17, 2020.