Magic dust # 10 tablets to treat diabetics.

Today humans are using several types of “magic dust” to treat a wide variety of human illness, each with
varying safety profiles and degrees of efficacy.

Magic dust # 10 was discovered, upon discovering the magic dust through early phases of research
which are designed to identify an investigational drug and perform initial tests in the lab. Magic dust #
10 looks promising and it need for further study in preclinical and clinical research.

This first stage of the process takes approximately 3-6 years.

Diabetes is a disease that occurs when blood glucose/blood sugar is too high. Too much sugar in blood
can lead to serious health problems. There are three major types of diabetes: type 1 diabetes, type 2
diabetes and gestational diabetes.

Approximately 8.3% of the population in the United States are affected by type-2 diabetes.

Type-2 diabetes carries significant morbidity and is the leading cause of kidney failure, lower-limb
amputations, and new cases of adult blindness and it also led to death in the US., primarily as a result of
cardiovascular morbidity.

Diabetes symptoms are increased thirst, frequent urination, extreme hunger, unexplained weight loss,
irritability, blurred vision.
Our investigation reveals a diverse target set which includes; protein tyrosine phosphatase 1 B (PTP1B),
dipeptidly peptidase-4 (DPP-4), free fatty acid receptors 1 (FFAR1), G protein-coupled receptors (GPCR),
peroxisome proliferator activated receptor-γ (PPARγ), sodium glucose co-transporter-2 (SGLT2), α-
glucosidase, aldose reductase, glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase),
glucagon receptor (GCGr) and phosphoenolpyruvate carboxykinase (PEPCK).

Six stages of Drug Development

They spontaneously develop obesity and diabetes, and have distinct pre-diabetic and diabetic
phases, recapitulating the full range of diabetic complications observed in humans.

This means that the preclinical data collected in NHP studies is the most predictive available for
moving agents forward into clinical trials.
Disease Progression: Induced vs Spontaneous Diabetes
When choosing how models develop diabetes, the two main options are induced disease vs
spontaneously-developed disease. It’s known that spontaneous models more closely resemble
human disease and complications, but supplies can be limited. This means that conventional
models often have diabetes induced via diet, chemical, or surgical techniques.

Diet Induction

Diet-induced models are somewhat artificial, but can accelerate disease progression. For example,
the diet induced obesity (DIO) mouse, which relies on a high fat diet to develop T2D, is a popular
conventional model of diet induced diabetes and obesity. This is despite the model not developing
significant hyperglycemia, reducing its translatability.

The Sprague Dawley rat is especially sensitive to high fat diet, and develops insulin resistance and
diabetes more easily than other strains. This model does have a longer onset to developing diabetes
and related pathogenesis; which means longer study timelines and higher costs for researchers.

Overall, DIO models are advantageous because they are relatively easy to generate compared to
surgical induction, for example, and supply is rarely an issue. DIO models are largely used for
evaluating treatments to improve insulin resistance, or studying beta cell function and/or diet
induced obesity.

Both conventional and unique animal models are key in developing new therapeutics for type 2
diabetes. To ensure maximum success in clinical trials, specific models should be chosen at each
stage for the most appropriate applications, and that best mimic human disease progression and
inheritance.

MICE
Mice have been used in countless diabetes trials because of their easy availability, low cost and short
reproductive cycles that allow the collection of multi-generational data. One series of studies increased
the scientific community’s understanding of the impact of environmental factors on the development of
type-1 diabetes.  In other examples, mice are being used to develop stem cells that transform into insulin-
producing cells, and in trials using human growth factor in order to reverse insulin insensitivity.

RATS
Rats have also had a prominent role in research on diabetes, being a somewhat larger species with
a slightly different metabolic system. It was rat studies that indicated that long-term consumption of
fructose had an impact on the development of type-2 diabetes, an important piece of data that is changing
the way people consume food items in their daily diets. One popular diabetes-regulating drug, metformin,
owes its development to studies with rats.
PIGS
Pigs have been used as research subjects because of the similarity of their cellular structures and
processes to human. Currently, pigs are being used to test the feasibility of transplanting neonatal islet
cells to restore normal insulin production to reverse diabetes.

DOGS
Dogs have also been instrumental in diabetes research, providing critical information on insulin pump
devices and testing on the best ways to manage blood sugar levels.

PRIMATES
Preclinical research with primate studies offers valuable information on safety that is critical for diabetes
studies before they go on to human trials.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000MedR.pdf

Very good topic

CLINICAL REVIEW

Application Type NDA

Application Number(s) 207924

Priority or Standard Standard Submit Date(s) January 15, 2016

Received Date(s) January 15, 2016

PDUFA Goal Date January 15, 2017

Division/Office Division of Pulmonary, Allergy, and Rheumatology

Reviewer Name(s) Raj Nair

Review Completion Date January 9, 2017

Established Name Baricitinib

(Proposed) Trade Name Olumiant

Applicant Eli Lilly and Company Formulation(s) Tablets with two dose strengths available: 2 mg
and 4 mg

Dosing Regimen One tablet orally once daily

Applicant Proposed Indication(s)/Population(s) Rheumatoid arthritis

Recommendation on Regulatory Action Approval Recommended Indication(s)/Population(s) (if

applicable): Adult patients with moderately to severely active rheumatoid arthritis who have had
inadequate response or intolerance to methotrexate

Disease Background Patients with rheumatoid arthritis (RA) have a chronic progressive disease
that is associated with morbidity and mortality. Drugs that slow down disease progression in RA,
otherwise called disease-modifying anti-rheumatic drugs (DMARDs), are widely used in the
treatment of RA. Baricitinib is a small molecule inhibitor of janus associated kinase (JAK) for
oral administration proposed for approval for use in patients with RA. In RA, synovial tissues
become inflamed and proliferate, forming pannus that invades bone, cartilage, and ligament and
leads to joint damage and deformities. Destruction of synovial joints can lead to severe disability
and premature mortality.1, 2

Non-clinical:

Baricitinib is a JAK1/2 inhibitor that is being developed for the treatment of rheumatoid arthritis
(RA).

Preclinical study will be performed in rodent and non-rodent species (rats and dogs). Target
organs are identified in the toxicity study. In an embryofetal development study pregnant rats,
pregnant rabbits will be used. Carcinogenic toxicity was evaluated in rats and mice.

The sponsor’s proposed recommended dose is 4 mg once daily (with the notation that 2 mg once
daily may also be acceptable) either as a monotherapy or in combination with non-biologic
disease-modifying antirheumatic drugs (DMARDs).

Pivotal nonclinical toxicology studies of baricitinib were conducted in rats and dogs. In studies
up to 6 months duration in rats and 9 months duration in dogs.

Toxicology: The results of pivotal general toxicology, genetic toxicology, carcinogenicity, and
reproductive toxicology studies with baricitinib are summarized below.

Rats and dogs were chosen by the sponsor as the species to be used in their in vivo nonclinical
development program.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000PharmR.pdf

good pharmacology study

The current review includes a detailed evaluation of the relevant nonclinical Pharmacology,
Safety Pharmacology, and Pharmacokinetics/ADME studies.
Chronic toxicology studies with LY3009104 were conducted in rats (26 weeks) and dogs (39
weeks). Animals were dosed by oral gavage in both studies. Immunosuppressant effects were the
major treatment-related toxicities observed in rats and dogs. Lymphoid organs including bone
marrow, spleen, and lymph nodes were target organs of toxicity in both species.

Pharmacologic Class: Janus kinase (JAK) inhibitor

Pharmacokinetics/ADME/Toxicokinetics:

Absorption, distribution, metabolism, and elimination studies for LY3009104 have been
conducted in CD-1 mice, Tg.RasH2 mice, Sprague-Dawley rats, and beagle dogs, primarily via
the oral route of administration. LY3009104 was administered as the phosphate salt in the
majority of these studies. The free base form of LY3009104 is to be used in the commercial drug
product formulation. Eli Lilly directly compared the pharmacokinetic parameters of the
phosphate salt vs. free base form of LY3009104 in experiments conducted in mice and rats. The
pharmacokinetic parameters of the phosphate salt and free base forms of LY3009104 were found
to be highly comparable.

PK/ADME

Absorption

LY3009104 absorption parameters at steady state are summarized in Table 23. Values reported
for humans are derived from the sponsor’s Population PK analysis of Phase 2/3 clinical studies.
The sponsor’s calculations were derived from data collected in a total of 3 Phase 2 studies and 4
Phase 3 studies in male and female patients with RA. The data for nonclinical species is derived
from a 6 month carcinogenicity study (mice), and chronic (6 month or 9 month) toxicology
studies in rats and dogs respectively.

Distribution

PROTEIN BINDING

Study DMB-08.14.1: In Vitro and Ex Vivo protein binding of INCB028050 in rat, dog and
human serum and plasma Study DMB-09.41.1: In Vitro and Ex Vivo protein binding of
INCB028050 in rabbit and mouse plasma The in vitro binding of INCB028050 in plasma and
serum of rats (Sprague Dawley), dogs, rabbits, mice (CD-1), and humans was examined in two
studies. Study DMB-08.14.1 quantified INCB028050 protein binding in rat, dog, and human
serum and plasma. Study DMB-09.41.1 quantified INCB028050 protein binding in rabbit and
mouse plasma.

Metabolism: The metabolism of LY3009104 has been investigated in in vitro and in vivo studies
in humans, rats, mice, dogs, and rabbits.

IN VITRO METABOLISM Study DMB-08.20.1: Identification of in vitro metabolites of

INCB028050 The metabolism of INCB028050 phosphate was evaluated in commercially
available liver microsomes and S-9 fractions derived from rats, dogs, cynomolgus monkeys, and
humans.

Elimination Summary of elimination of LY3009104 in humans vs. nonclinical species: Orally

administered LY3009104 was eliminated primarily via the urine in humans, while fecal
excretion was the major route of elimination in mice, rats, and dogs.

General Toxicology

Single-Dose Toxicity: Single dose toxicology studies conducted early in the nonclinical
development of LY3009104 are not considered to be relevant to the support of marketing
approval.

Repeat-Dose Toxicity: The pivotal nonclinical toxicology studies conducted to support the
marketing approval of baricitinib were chronic oral toxicology studies in rats (6 months, Study
T08-04-05) and dogs (9 months, Study T10-02-01). The importance of these studies is based on
the proposed chronic administration of baricitinib in the clinical setting.

Immunosuppressant effects (e.g. decreased peripheral leukocytes, lymphoid depletion/atrophy)

were the major treatment-related toxicities observed in rats and dogs. The baricitinib systemic
exposure values (AUC0-24) at the limit doses established in the chronic rat and dog toxicology
studies support the safety of the maximum recommended human dose of 4 mg/day.

Drug Formulation Oral Capsule Drug product components for the 1 mg strengths are presented
in table 1. The drug product is supplied for clinical study use as tablets and is composed of
LY3009104 free base and the inactive ingredients microcrystalline cellulose, mannitol,
croscarmellose sodium, and magnesium stearate. Each tablet contains LY3009104 equivalent to
1 mg or 4 mg of the free base compound

There is no novel excipient in the drug product formulation; the used for the imprint of the
capsules have USP and PH. Eur. references.

Clinical

To date, LY3009104 was administered to a total of 374 subjects (162 healthy subjects, 176
subjects with RA, and 36 subjects with various degrees of renal impairment) from 18 to 80 years
of age. In Phase 1 clinical pharmacology studies, healthy volunteers was administered with either
a single dose ranging from 1 to 10 mg, or as multiple dose up to 20 mg QD for 10 days, or 10 mg
QD and 5 mg BID for up to 28 days to determine the safety, tolerability, PK/pharmacodynamic
(PD), and efficacy of LY3009104. In Phase 2 clinical study, a single 10-mg dose was
administered to subjects either with mild or moderate renal impairment, or as a single 5-mg dose
to subjects with severe renal impairment, or as single 5-mg dose to subjects with end-stage renal
disease. LY3009104 was also administered in subjects with RA at doses of up to 15 mg QD for
approximately 1 month and doses up to 10 mg QD for 24 weeks. According to the Sponsor,
LY3009104 was generally safe and well tolerated in single doses ranging from 1 to 20 mg and in
repeat oral doses ranging from 2 to 20 mg. The most commonly reported AEs were the
infections. The most common alterations in laboratory values involve decreases in hemoglobin,
hematocrit, total RBCs, and WBCs (neutrophils and other leukocytes), and increases in platelet
counts, HDL, LDL, total cholesterol, and triglycerides. Patients with RA experienced a mean
increase in ALT/AST compared to placebo, with the mean values remaining within the normal
reference range and clinically significant increases in ALT/AST occurring uncommonly. Patients
with impaired renal function have increased exposure to LY3009104.

ECG: The ECG was not conducted in this study

Proposed Clinical Protocol The proposed clinical study entitled ‘A Placebo-Controlled, Single
Dose, Dose Escalation (Part A) and a Placebo- and Positive- Controlled Study of the Effect on
the Electrocardiographic QT Interval of a Single Dose (Part B) of LY3009104 in Healthy
Subjects’ protocol # I4V-MC-JADO consists of two parts, a dose escalation to find a dose for the
TQT assessment (Part A) and a TQT assessment (Part B). The study will be conducted in healthy
subjects (18-65 years of age). Part A is a randomized, placebo-controlled, investigator and
subject-blind, incomplete block crossover, single-dose, dose-escalation study in healthy subjects
to determine a supratherapeutic dose of LY3009104 with an acceptable safety and tolerability
profile that can be included in Part B of the study. The dose of LY3009104 used in the QT
assessment (Part B) will be selected on the basis of safety information from Part A. Subjects
from Part A will not participate in Part B. In Part A of the study nine healthy subjects will be
randomly assigned to one of the three sequences in a 1:1:1 ratio, such that in each of the 3 dosing
periods, 6 subjects will receive LY3009104 and 3 will receive matching placebo (Table 1). The
first dose level proposed is 20 mg, and the subsequent anticipated dose levels are 30 mg and 40
mg. The actual dose levels to be tested may be adjusted depending on safety and tolerability data
from previous dose levels, but the maximum dose tested will not exceed 40 mg. All dose levels
will be administered as single oral doses. A washout of at least 3 days will occur between doses.

Part B is a three-period, crossover study in healthy subjects to assess the electrophysiological

effects of a single supratherapeutic dose of LY3009104 compared to a positive control
(moxifloxacin, 400 mg) and placebo. It is an in-patient study and subjects are blinded to
LY3009104 and placebo administration and unblinded to moxifloxacin administration. It is
intended that approximately 60 subjects will be randomized into 1 of 6 sequences in accordance
with two 3-sequence crossovers. Time-matched pharmacokinetic samples and quadruplicate
ECGs will be collected in each study period (Table 2). For the purposes of QT measurement,
subjects will undergo continuous ECG monitoring using an ECG 12-lead digital.
Pharmacology

4.1 Primary Pharmacology

LY3009104 is a Janus kinase (JAK) inhibitor being developed for rheumatoid arthritis.

4.3 Safety Pharmacology: LY3009140 was tested for cardiovascular safety pharmacology
assessments in an in vitro hERG channel assay and in vivo in unanaesthetized dogs.

General Toxicology: In support of the proposed doses for the TQTc study, the Sponsor has
conducted toxicology studies with LY3009104 in rats and dogs.

Preclinical Findings Related to Hepatotoxicity General toxicology studies in rodent and non-
rodent species (rats for 26 weeks, and dogs for 39 weeks), reproductive and embryofetal
development studies, and carcinogenicity studies were performed. In general toxicology studies,
immunosuppressant effects were the major treatment-related toxicities observed in rats and dogs.
Bone marrow and lymphoid organs, including the spleen, and lymph nodes were target organs of
toxicity in both species. Dose limiting toxicities in the GI tract (inflammation, infiltrates) and
liver (infiltrates/inflammation, bile duct hyperplasia) were observed in male and female dogs at ≥
3 mg/kg/day. The dog is the more sensitive nonclinical species, with an AUC0-24h of 1.21
μM*hr at the limit dose. In the 9 month dog study, the additional finding of liver toxicity was
seen in the higher dose animals (3 mg/kg and 9/6 mg/kg).

Clinical:

In the development of baricitinib in RA, several dose finding studies (JADA, JADC, and JADN) were
performed with doses ranging from 1-10 mg daily.

Product Quality The proposed commercial drug product, Olumiant tablets, contains 4 mg and 2 mg
baricitinib and standard compendial excipients. The achiral drug substance baricitinib is chemically
synthesized.

All studies were randomized, double-blind, placebo-controlled and conducted in patients 18 years of age
and older with moderately to severely active RA diagnosed according to the American College of
Rheumatology (ACR) criteria.
Target Study Population and Clinical Setting:

Adult patients with moderately to severely active RA

Clinical Trial Design, Protocol, and Analysis Plan Study:

JADV: A 52-week, Phase 3, multicenter, randomized, double-blind, double-dummy, placebo- and active-
controlled, parallel-group, outpatient study which examined the effect of baricitinib (4-mg QD) versus
placebo and versus an active comparator, adalimumab, in patients with moderately to severely active
RA who had an inadequate response to MTX and who had never been treated with a biologic DMARD.
Study JADX: A 24-week, Phase 3, multicenter, randomized, double-blind, double-dummy, placebo-
controlled, outpatient study that enrolled patients with moderately to severely active rheumatoid
arthritis who had an inadequate response to at least one cDMARD and who had never been treated with
a biologic DMARD.

Preclinical Testing:

• Nonhuman in vivo and in vitro studies performed prior to First-in-Human clinical trial.

Diagrammatic Representation of the ICH Common Technical Document

This chart provides a comprehensive view of the typical product (drug and biologic) development
timeline.
Important Steps in Drug Discovery

- Target Identification – Potential targets are investigated, screened and prioritized

- Target Validation – Role which target plays in disease is characterized and established
- Lead Identification – Potential Therapeutics are screened and prioritized
- Lead Optimization/Validation – Actions of products on disease is characterized and screened.

Preclinical studies are very important and increase overall successful product development.
Preclinical studies are helpful in discovering possible hazards to humans, and the data obtained
helps in assessing the relevance of these findings to clinical safety.

Animal toxicity study data are required to enable clinical trials to be conducted before a new drug is
marketed.

Goal of Non-clinical Testing

Preclinical testing is a crucial process within the drug development timeline. Preclinical studies are
tested in animals to collect efficacy, toxicology and pharmacokinetic information.

Diabetecs drug product class could undergo different preclinical studies such as pharmacokinetics
(PK), pharmacodynamics (PD), ADME (absorption, distribution, metabolism and excretion) and
toxicology studies.

• This phase identifies the potential risk of the lead compound(s) (leading candidate for successful
new drug) prior to the start of clinical studies in human subjects.

- Identify the Pharmacological properties

- Mode of Action through Pharmacodynamics
- Metabolism through Pharmacokinetics
- Understand the Toxicological profile
- Establish a safe initial dose level of the first human exposure
- Identify parameters for clinical monitoring of potential adverse effects
 - Special toxicity (e.g., genotoxicity, carcinogenicity, reproduction toxicity)

- Results of preclinical testing (in vivo and in vitro) are submitted to the FDA for review in an
Investigational New Drug (IND) application (21 CFR 312).

Types of Non-clinical Studies

- Pharmacology
o Safety pharmacology
o Pharmacodynamic (PD)
 Primary and secondary
 Drug Interaction
 Pharmacokinetic (PK)
 Analytical Methods and Validation
 Absorption, Distribution, Metabolism and Excretion (ADME)
 Drug interaction
 Toxicology
o Single Dose, Repeat Dose
o Genotoxicity
o Carcinogenicity
o Reproductive Toxicology
Note: How much drug is needed/ dose selection and route frequency are determined through PK-PD
relationships in relevant species.

Note: A drug’s proposed indication in humans, a drug’s target patient population, a drug’s proposed
route of administration and proposed duration of administration are determined through nonclinical
testing.

Note: No Observable Adverse Effect Levels (NOAEL) on drugs also are established based on preclinical
results, used to determine initial Phase 1 clinical trial dosage levels on a mass API per mass patient basis.

This study will be performed in a rodent and a nonrodent.

A dog will be used for Diabetes drug because it is affecting internal organs or physiochemical responses.
General Toxicology studies occur in two relevant species, 1 rodent and 1 non rodent to ensure
assessment of potential variability. General repeat dose toxicity study occurs in dogs for 9 months.

Single dose studies are carried out on a rodent (mouse or rat) and a nonrodent (rabbit). Two different
routes of administration are studied: one is the intended route for human clinical trials and the other is
intravenous injection. Various characteristics of the animals are monitored, including weight, clinical
signs, organ functions, biochemical parameters, and mortality. At the completion of the study the
animals are killed and autopsies are performed to analyze the organs, especially the targeted organ for
the drug. Single dose studies are typically 1-4 weeks in duration
Repeat dose chronic toxicity studies are performed on two species of animals: a rodent and nonrodent.
Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions
are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the
study to check toxicity recovery. Repeat dose studies can be between 2 weeks to 9 months in duration.

As noted the duration of your nonclinical studies must be greater than or equal to the duration of the
planned human clinical trials.

Both in vitro and in vivo animal tests will be performed. A drug is tested in both rodent and non-rodent
models because it may affect different species in different ways.

Preclinical studies and clinical studies are the processes by which scientist test the drugs to see if they
are safe and effective.

Preclinical study – The preclinical stage of drug development involves extensive testing in animal models
to determine if the drug is safe for human trials. Side effects of the drug need to be monitored and
addressed in this study.

Preclinical Development –

Target Identification

Cell studies, target engagement, signaling

Animal Studies (efficacy and safety)

Toxicology Studies

IND application

What pre-clinical requirements should be included and summarized and in what CTD module?

Pre-clinical requirements should be included in eCTD Module 4 Nonclinical study reports and it should
be summarized in eCTD Module 2 Summaries.

eCTD Module 4 Nonclinical study reports

4.2.1 Pharmacology

- 4.2.1.1 Primary Pharmacodynamics

- 4.2.1.2 Secondary pharmacodynamics
- 4.2.1.3. Safety pharmacology
- 4.2.1.4 Pharmacodynamic drug interactions

4.2.2 Pharmacokinetics

- 4.2.2.1 Analytical Methods and Validation Reports

- 4.2.2.2 Absorption
- 4.2.2.3 Distribution
- 4.2.2.4 Metabolism
- 4.2.2.5 Excretion
 - 4.2.2.6 Pharmacokinetic Drug Interactions
- 4.2.2.7 Other Pharmacokinetic Studies

4.2.3 Toxicology

- 4.2.3.1 Single-Dose Toxicity

- 4.2.3.2 Repeat-Dose Toxicity
- 4.2.3.3 Genotoxicity
- 4.2.3.4 Carcinogenicity
- 4.2.3.5 Reproductive and Developmental Toxicity
- 4.2.3.6 Local Tolerance
- 4.2.3.7 Other Toxicity Studies

eCTD Module 2 Summaries

2.4 Nonclinical Overview

The Nonclinical Overview presents an integrated and critical assessment of the pharmacologic,
pharmacokinetic, and toxicologic evaluation of the pharmaceutical. It is about 30 pages. The Nonclinical
Overview should be presented in the following sequence:

 Overview of the nonclinical testing strategy

 Pharmacology
 Pharmacokinetics
 Toxicology
 Integrated overview and conclusions
 List of literature references

2.6 Nonclinical written and tabulated summaries

 2.6.1 Introduction
 2.6.2 Pharmacology written summary
 2.6.3 Pharmacology tabulated summary
 2.6.4 Pharmacokinetic written summary
 2.6.5 Pharmacokinetic tabulated summary
 2.6.6 Toxicology written summary
 2.6.7 Toxicology tabulated summary

Generally, Pharmacology study conducted first to see what the drug does to the body.
Pharmacodynamic study is the study of interactions between drugs and body to figure out the effect of a
drug on some particular response, such as heart rate, enzyme levels and it allows us to understand the
potency, effectiveness, therapeutic index and safety margins of drugs. Pharmacokinetics is the study of
the kinetics of adsorption, distribution, metabolism and excretion of drug that analyze the same way the
human body deals with a drug after it has been administered. Toxicity study is to determine the
maximum tolerable dose and the No Observable Adverse Event Level (NOAEL) in rodents and
nonrodents.
How can the indications for use for each “magic dust” be isolated and refined? Why is it important to do
this?

The IND application is the mechanism for providing the FDA with this data so they can decide if your
proposed clinical trial poses a “reasonable risk” to the people who would be participating in the trial. All
medication poses some degree of risk. The mission of the FDA is to assure that drugs delivered to
humans are reasonably safe and effective.

 Effective PK/PD study design, analysis, and interpretation can help scientists elucidate the relationship
between PK and PD, understand the mechanism of drug action, and identify PK properties for further
improvement and optimal compound design. Additionally, PK/PD modeling can help increase the
translation of in vitro compound potency to the in vivo setting, reduce the number of in vivo animal
studies, and improve translation of findings from preclinical species into the clinical setting.

The major objective of early drug development is to select promising compounds and to identify
potentially safe and effective doses and dosing regimens. Integration of PK/PD in early development
helps with compound selection and guides creation of an efficient clinical development strategy. PK/PD
modeling is a valuable approach to integrate quantitative information about the pharmacologic
properties of a compound with its pharmacokinetics. As data becomes available, initial models can be
refined through an iterative process. The ultimate output is a powerful predictive tool based on an in-
depth understanding of the requirements for efficacy. A well-designed PK/PD study offers a rational
approach to efficient and informative drug development and can help the project team to understand
the mechanism of action of a drug and select the optimal compound. Applying PK/PD modeling in early
discovery and development programs can minimize animal usage, shorten the development time,
estimate the therapeutic index, and predict the dose ranges in early clinical testing. PK/PD models allow
integration of data from different studies in a logical manner based on the understanding of drug and
disease.

Although project teams may see this as a significant investment at a very early stage of the program,
extensive early understanding of the relationship between PK and PD will likely decrease the resource
investment in the long term. One risk of moving directly into assessment of novel compounds with
limited insight on optimal study design is that considerable effort and resources might be spent on a
model that is not fully understood, characterized, or optimized based upon the intrinsic pharmacokinetic
and pharmacologic properties of the compounds of interest.

Once a PK/PD model has been validated with a suitable tool compound, the team needs to establish if
data from the reference compound can be extrapolated to future molecules. Validation of PK/PD
models using known model compounds may be required to ensure desired outcome and sensitivity. If
the PK/PD strategy is found suitable to triage new compounds, integration of the PK/PD analysis into the
project workflow is highly encouraged. The set-up and screening with a PK/PD model in drug discovery is
typically an iterative process that requires ongoing refinement as new information become available and
the project moves forward.

Once suitable drug candidates are identified, sub-chronic main PK/PD studies are performed to establish
dose-exposure-response relationships and the effective plasma target concentration ranges. Sub-chronic
disease models involving repeated dosing for days at multiple dose levels may be utilized to determine
the effective concentration range of the compounds. Finally, full chronic disease models are conducted
on promising drug candidates to determine the minimum efficacious dose and the relationship between
steady-state exposure levels and sustained efficacy.

Once a robust PK/PD relationship has been developed in a preclinical species or relevant model system,
these data can be used to help predict anticipated effects in the clinic with some assumptions.

Effective translation of preclinical data is critical to the design of appropriate and successful clinical
trials. By incorporating a translational PK/PD framework that can be validated with clinical outcomes, we
will improve our ability to treat and cure disease.

The Investigational New Drug Process

Drug developers, or sponsors, must submit an Investigational New Drug (IND)

application to FDA before beginning clinical research.

In the IND application, developers must include:

 Animal study data and toxicity (side effects that cause great harm) data
 Manufacturing information
 Clinical protocols (study plans) for studies to be conducted
 Data from any prior human research
 Information about the investigator

Step 4: Phase 1 clinical studies

The first phase of human clinical testing involves a relatively small group of
healthy people, usually a dozen to a few dozen, and it'll focus entirely on safety.
This stage of study involves looking at how a drug is absorbed and eliminated
from the body, as well as what side effects it may cause and whether or not it's
producing the desired effect. Phase 1 clinical studies are also where maximum
tolerated doses are established. It really is all about safety, although it's not
uncommon for drug developers to tout early signs of efficacy in phase 1. If
everything looks promising the study moves to phase 2, or midstage trials.

 Step 5: Phase 2 clinical studies

The two big changes between early stage and mid-stage trials are that the
patient pool widens from a few dozen to perhaps 100 or more patients, and the
patients being treated are no longer healthy volunteers but people being
afflicted by the disease in question. Safety remains a big focus of phase 2 studies,
with short-term side effects being closely monitored, although an increasing
emphasis will begin to be placed on whether or not a drug is working as
expected and if it's improving the condition or not. Phase 2 studies also establish
which dose (if multiple doses were tested, as is often the case) performed most
 optimally. If the experimental drug continues to look promising it'll move onto
late-stage studies.
Step 6: Phase 3 clinical studies
In phase 3 studies, safety remains a priority, but this is where efficacy also plays a big role. Phase
3 studies are designed by drug developers but approved by the FDA with guidelines for a clearly
defined primary endpoint to determine the success or failure of a tested drug. Phase 3 trials
involve even more patients, perhaps a few hundred to maybe thousands, and they are by far the
longest and costliest of all components of the drug development process. This is also the stage
where drug developers will begin to think about how they're going to ramp up production if the
phase 3 results are promising. Assuming an experimental drug meets its primary endpoint and is
demonstrated to be safe, the next step is to file for its approval.

Clinical trials for drugs are conducted in phases such as phase I, phase II, phase III and phase IV.

Phase I:

The objective in a phase I trial is to evaluate the product’s metabolism and pharmacologic action,
determine a safe dosage range, identify side effects and, if possible, gain early evidence on
effectiveness. Subjects in Phase I studies usually receive 24-hour medical attention and monitoring.
Doses in Phase I often are sub-therapeutic, but with ascending or escalating doses, so the best and
safest dose can be established.

Phase II:

Once a dose or range of doses has been established, the drug is given to a larger group of subjects (i.e.,
100-300) to study its effectiveness and further evaluate its safety.

Phase III:

During Phase III studies, drug is given to larger groups of subjects (hundred to thousands, depending on
the condition being studied) to confirm its effectiveness, monitor side effects, compare it to commonly
used treatments and collect information to allow the drug to be used safely. Phase III studies are
randomized, multicenter trials and usually have a longer duration, sometimes lasting several years.
Phase III studies of chronic conditions or disease often have a short follow-up period, three to six
months, for ongoing evaluation.

Phase IV:

Post-marketing studies are conducted in Phase 4, used to gather information on the drug’s effect in
various populations and any side effects associated with its long-term use.

Phase I Clinical Development (Human Pharmacology)

Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale
Phase I clinical trial unless the FDA places a hold on the study. Phase I studies are used to
evaluate pharmacokinetic parameters and tolerance, generally in healthy volunteers.  These
studies include initial single-dose studies, dose escalation and short-term repeated-dose studies.
Phase II Clinical Development (Therapeutic Exploratory)
Phase II clinical studies are small-scale trials to evaluate a drug’s preliminary efficacy and side-
effect profile in 100 to 250 patients.  Additional safety and clinical pharmacology studies are also
included in this category.

Phase III Clinical Development (Therapeutic Confirmatory)

Phase III studies are large-scale clinical trials for safety and efficacy in large patient populations.
While phase III studies are in progress, preparations are made for submitting the Biologics
License Application (BLA) or the New Drug Application (NDA).  BLAs are currently reviewed
by the FDA’s Center for Biologics Evaluation and Research (CBER).  NDAs are reviewed by the
Center for Drug Evaluation and Research (CDER).
Clinical phase
Clinical trials involve three or four steps:[4]

 Phase I trials, usually in healthy volunteers, determine safety and dosing.

 Phase II trials are used to get an initial reading of efficacy and further explore safety in small
numbers of patients having the disease targeted by the NCE.
 Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large
numbers of patients with the targeted disease. If safety and efficacy are adequately proved,
clinical testing may stop at this step and the NCE advances to the new drug application (NDA)
stage.
 Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA,
also called post-market surveillance studies.

The Stages of Treatment Trials

The most common type of clinical trial in HIV is a treatment or drug study. There are four
stages, or phases, of clinical trials for new treatments. With each phase, a little more is
known about the treatment being studied. Each phase has a different purpose and helps
researchers answer specific questions about the drug in the trial.

 Phase I: Is the drug safe?

A Phase I trial tests a drug in a small number of participants (usually fewer than 100) to
find a safe dose and to document the side effects of the drug. Phase I trials are usually
short, lasting a few days to a few weeks.
 Phase II: Is the drug effective?
A Phase II trial tests a drug in a larger number of participants (on average 100 to 300) to
see if the drug works. Phase II trials may also test different doses of the drug to find the
dose that works best. The safety of the drug also continues to be evaluated. A Phase II
trial usually lasts six months to one year.
 Phase III: Is the drug safe and effective in larger groups of people for longer
periods of time?
 A Phase III trial tests a drug in a very large group of participants (typically 1,000 to
3,000). Phase III trials compare the drug to an existing medication or treatment. This lets
researchers gather more information about the safety and effectiveness of the drug.
Phase III trials generally last two to three years.
 Phase IV or Post-Marketing Studies:
What are the long-term results of using the drug? These trials are done after the US
Food and Drug Administration (FDA) has approved the drug. They let researchers get
more information about the drug's best use and learn more about long-term side effects.

Overall the content would be the same, yes. Basically all the nonclinical research you do over the life of
the IND phase would be submitted to your IND application. Then once you reach the point of NDA/BLA
submission you would include all the study reports collected over that time in Module 4 of your NDA/BLA
and summarize in Module 2.4 and 2.6. The CTD structure of Module 4 for the IND and NDA/BLA is
exactly the same.

The objectives of the preclinical safety program for biologics and small-molecule drugs are
similar. Preclinical studies are pharmacodynamics (how a drug acts on the body, mode of
action), pharmacokinetics (how the body acts on the drug) and toxicity (safety). Toxicity study
includes single dose, repeat dose, genotoxicity, reproductive and embryofetal development,
carcinogenicity, immunotoxicity and tissue cross-reactivity to maximize the safety associated
with usage of new pharmaceutical and biological products in human.  There are some similar
studies for biologics and small molecules such as acute and multiple-dose toxicity studies,
single-dose PK studies in the toxicologically relevant species and toxicokinetic.
The goal of preclinical testing is to assess the human adverse event potential and identify a safe
and efficacious starting dose for first-in human trials accurately. Given this context, Module 4 of
the CTD format assist manufacturers with demonstrating through pre-clinical studies that new
pharmaceutical or biological products can be considered safe for testing in human populations.
What clinical requirements should govern their approval for general use in study populations and where
should this information be incorporated into the CTD?

Module 5 has the organization of all clinical studies, clinical study reports, other clinical data and
references within a CTD for registration of pharmaceutical product for human use.

5.1 TABLE OF CONTENTS FOR CLINICAL STUDY REPORTS AND RELATED INFORMATION

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

5.3 CLINICAL STUDY REPORTS AND RELATED INFORMATION

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports

5.3.1.3 In Vitro-In Vivo Correlation Study Reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.2.1 Plasma Protein Binding Study Reports

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

5.2.2.3 Reports of Studies Using Other Human Biomaterials

Not required for non biopharmaceuitcals

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

Module 5.3.3 includes the reports of characterization of the drug’s PK and information about the
absorption, distribution, metabolism, and excretion of a drug and any active metabolites in healthy
subjects and patients. It also includes the dose proportionalities and time of the subjects.

Reports of PK and initial tolerability studies in healthy subjects should be placed in section 5.3.3.1.

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

Reports of PK and initial tolerability studies in patients should be placed in section 5.3.3.2.

5.3.3.2 Patient PK and Initial Tolerability Study Reports

Reports of PK studies to assess effects of intrinsic factors (e.g., age, gender, racial, weight, height, and
disease) should be placed in section 5.3.3.3.

5.3.3.3 Intrinsic Factor PK Study Reports

Reports of PK studies to assess effects of extrinsic factors (e.g., drug-drug interactions, diet, smoking and
alcohol use) should be placed in section 5.3.3.4.

5.3.3.4 Extrinsic Factor PK Study Reports

The standard multiple-sample PK studies are substantially different from those used in standard PK
studies, population PK studies should be placed in section 5.3.3.5.

5.3.3.5 Population PK Study Reports

5.3.4 Reports of Human Pharmacodynamic (PD) Studies

Reports of studies with a primary objective of determining the PD effects of a drug product in human
should be placed in this section.

Reports of dose finding, PD, and PK/PD studies conducted in healthy subjects should be placed in section
5.3.4.1.

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

Reports of dose finding, PD, and PK/PD studies conducted in patients should be placed in section 5.3.4.2.

5.3.4.2 Patient PD and PK/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies

Reports of all clinical studies of efficacy and safety carried out with the drug including all completed and
ongoing studies of the drug.

Placebo control trials and controlled safety studies are placed in section 5.3.5.1.

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

Uncontrolled clinical study reports are placed in placed in section 5.3.5.2.

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

Integrated safety and efficacy data and reports are placed in section 5.3.5.3.

5.3.5.3 Reports of Analyses of Data from More Than One Study (Including Any Formal Integrated
Analyses, Meta-analyses, and Bridging Analyses)

Published report of clinical experience that not included in section 5.3.5.1 or 5.3.5.2 and Bioresearch
Monitoring (BIMO) information can be placed in section 5.3.5.4.

5.3.5.4 Other Study Reports

5.3.6 Reports of Post marketing Experience

Not required for first submission.

5.3.7 Case Report Forms and Individual Patient Listings

Not used in USA.

Copies of all references cited in the Clinical Overview and copies of important references cited in the
Clinical Summary or in the individual technical reports that were provided in Module 5.3.

5.4 LITERATURE REFERENCES

Clinical Overview should be placed in Module 2.5. It provides a critical analysis of the clinical data in the
CTD. It presents the strengths and limitations of the development program and study results, analyze
the benefits and risks of the medicinal product in its intended use, and describe how the study results
supports critical parts of the prescribing information. The Clinical Overview is relatively short document
about 30 pages.

Identification of pharmacological class, description of the targeted indications, scientific backgrounds

and clinical development program should be listed in Module 2.5.1 Product Development Rationale.

A critical analysis of the pharmacokinetic (PK), pharmacodynamic (PD), and related in vitro data are
presented in the CTD Module 2.5.3 Overview of Clinical Pharmacology. It also explains why and how the
data support the conclusions and addresses the potential problems.

A critical analysis of the positive or negative clinical data pertinent to the efficacy of the medicinal
product in the intended population are presented in Module 2.5.4 Overview of Efficacy.

A concise critical analysis of the safety data, noting how results support and justify proposed prescribing
information are presented in Module 2.5.5 Overview of Safety.

A succinct, integrated, and clearly explained benefit-risk assessment of the medicinal product for its
intended use is presented in Module 2.5.6 Benefits and Risks Conclusions. The benefit-risk assessment is
based on a weighing of the key benefits and key risks of the medicinal product.

A detailed summarization of all of the clinical information are listed in the Module 2.7 Clinical Summary.
Its about 50 to 400 pages. Module 2.7 Clinical Summary includes

2.7.2 Summary of Clinical Pharmacology Studies

It provides overall view of the clinical pharmacology studies

2.7.3 Summary of Clinical Efficacy

2.7.4 Summary of Clinical Safety

It provides a summary of data relevant to safety in the intended patient population, integrating the
results of individual clinical study reports as well as other relevant reports. It also provides an analysis of
adverse events.

2.7.5 Literature references

2.7.6 Synopses of Individual Studies

One synopsis will be prepared per study for use in all regions and that the same synopsis will be included
in this section. It should be about 3 pages.

Clinical Development –
Phase I – FIM, PK, PoC (proof of concept)

Phase II – Dose finding (focusing)

Phase III – Efficacy and Safety

CV Safety

 Diabetes is a complex and chronically progressive disease with increasing world-wide prevalence

 There is a need for additional diabetes drugs

 Many potential targets exist to improve glycemic control and prevent diabetic complications

 Development of new drugs is challenging and expensive

Advancing to Clinical Trials

Investigational New Drug (IND) Application
 Prior to beginning clinical trials, an Investigational New Drug (IND) application must be
submitted to the FDA. This document must include:

 Animal study data and toxicity

 Manufacturing information
 Clinical protocols for the proposed human trials
 Data from any prior human research
 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
Due to the nature of the drug development process and the cost of research up until this point, it
is rare that an IND is submitted and then canceled by the FDA. Most times, the FDA suggests
improvements to the clinical trial process being proposed and allows the release of the IND.
How can the risk vs. benefit profile associated with utilization of the “magic dust” for clinical purposes
be established and where should this be described in the CTD submission?

The benefit-risk assessment is based on a weighing of the key benefits and key risks of the medicinal
product. Key benefits are generally assessed by primary and other clinically important endpoints across
the studies in a development program. Key risks are unfavorable effects that are important from a
clinical and public health perspective in terms of their frequency and severity. The benefit-risk
assessment should be presented for the intended population. The identification of the key benefits and
key risks of a magic dust requires a critical evaluation of the entirety of the efficacy and safety
information regarding the magic dust. Data on benefits and risks may arise from multiple sources across
different populations and benefit-risk assessment should be presented for the intended population.
Summary tables or graphs can be displays to communicate the clinical importance of the key benefits
and key risks, as well as the resulting benefit-risk assessment.

Discussion of Benefit/Risk Relationship associated with utilization of the “magic dust” is presented in
Module 2.5.6 Benefits and Risks Conclusions.

What types of quality associated documentation should be incorporated into the submission and where
should this information be included in the CTD?

If you want look for week 5 discussion article.

Both drug substance and drug product, with each required presentations of drug technical information,
processes and key parameters, and various validation studies are presented in Module 3.
Pharmaceutical development reports include drug substance, drug product, and analytical reports.
These reports need to tell the historical story of the evolution of these three development aspects
during the lifetime of the product’s development.
Module 3 (CMC) contains all the information of the quality of the drug product (in this case new
biomedical products). It tells the reviewers the story of how from simple excipients (32P4) and drug
substance(s) (32S), a product was developed (32P2) and went through a validated (32P35)
manufacturing process (32P33) that led to a product with certain specifications and limits (32P51) when it
was analysed through validated (32P53) methods (32P52). This product was then packaged in a suitable
container closure system (32P7) that kept it stable for the rest of its shelf life (32P8). This story, when
structured in a specific format rather in any other forms, offers the detail of the data that a regulator needs
to review in order to give the "green light" for the approval.

This article very well explains the Drug Product Sections (3.2.P) of ICH’s Module 3 of
CTD format from quality and regulatory perspective. Module 3 is all about drug’s quality.
Module 3 includes from selection of product development designs (3.2.P.2
pharmaceutical development) to manufacturing of drug product (3.2.P.3), control of
excipients and its effect on the drug products by analyzing excipients and drug products
(3.2.P.4 and 3.2.P.5), materials used to test the drug product including drug substance,
excipients, and drug product related impurities (3.2.P.6 Reference standard or
materials), then drug product packed into appropriate packages and check its stability at
controlled room temperate (25°C/60% RH) and accelerated temperature
(40°C/75%RH ) to see if any impurity grow using package and temperature/humidity or
maintain the quality of the drug product for longer period of time (3.2.P.7 and 3.2.P.8).
Therefore, each section of module 3 is very critical and supportive in terms of
establishing a more effective means of communicating pre-approval data to regulators
that evaluate marketing approval applications.

In the article, author provide two aspect of pharmaceutical development (1) design of
the nanoparticles that have “novel” excipients and (2) additional “standard” excipients.
Depending on the excipients with their concentration and characteristics, the drug
products performance can be change in terms of stability and bioavailability. Therefore,
product development design is very important in the beginning of the stage to maintain
quality even it goes into large scale up and it gives idea to regulators that how they start
to develop the product and come up with tentative final formulation.

Another example, Manufacturing of nanoparticles has a complex process. Therefore,

appropriate process parameters should be identified such as time, speed, temperature,
pH of the solution and humidity of the room in the M3 section 3.2.P.3.4 control of critical
steps and intermediates.

Therefore, the use of these formatted submission standards makes the review easier
and thus potentially more efficient and effective for regulators.

What are the components of the study including inclusion and exclusion criteria in each phase of clinical
evaluation?
https://www.slideshare.net/TuracozHealthcareSolutions/components-of-a-clinical-study-protocol

Each clinical trial has a written plan, or study protocol, that describes the goals of the study,
how long the study will last, who can participate (also called inclusion and exclusion
criteria), and what tests and procedures will be conducted for each participant.

Inclusion and exclusion criteria are the guidelines for determining who can and cannot
participate in a specific clinical trial. Inclusion criteria are requirements that a person must
meet to participate (such as HIV drug-naïve — never having taken HIV drugs — CD4
cell count, viral load, age, or many others). Exclusion criteria are factors that prevent a
person from participating, either for his or her safety or to make it easier to understand the
study results. For example, people might be excluded for having liver problems, or if they
have already taken a drug that is being studied.

Each participant in a clinical trial must sign a document called "informed consent". When
you sign this document, it means that you understand the details of the study and you agree
to participate. You may want to take the document with you and talk about the study with
your health care provider, family, or friends before you decide to participate. If your native
language is not the language spoken by the people describing the study, you should ask if a
translation is available. It is important that you truly understand the study and what you will
be asked to do. If you have any questions, be sure to ask the study staff. It is their job to
make sure that you understand what you are agreeing to do when you sign this document.

You may be paid for travel expenses to and from the study site and for your time; this
payment is sometimes called compensation. Childcare may also be provided. You can
choose to leave (drop out of) a study at any time and for any reason.

What Are Inclusion/Exclusion Criteria?

All clinical trials have guidelines about who can participate—these are specified in the
inclusion/exclusion criteria: • Factors that allow someone to participate in a clinical trial are "inclusion
criteria" • Factors that exclude or do not allow participation in a clinical trial are "exclusion criteria"
These factors may include: • Age • Gender • The type and stage of a disease • Previous treatment
history • Specific lab values • Other medical conditions Inclusion and exclusion criteria are not used to
reject people personally. The criteria are used to: • Identify appropriate participants • Keep them safe •
Help ensure that researchers can answer the questions they want answered

https://www.hanc.info/cp/Documents/ParticipantGuide102209.pdf

What is the general overall structure/outline of the appropriate CTD submission and what would the
outline look like? Note that you can make as many assumptions as you need to here, but these
assumptions should be clearly explained and/or defined.