Methodology of Translational Medicine

Translational Medicine: Definition, History and Strategies
Lecturer : Dr. Fangfei Li
Institute for Advancing Translational Medicine in Bone & Joint Diseases
Hong Kong Baptist University

Course outline
 Background
 Biomarkers in Drug Development
 Pharmacology: Testing the Target (POM, Proof of mechanism)
 Study Design Considerations for POM
 Confirming the Hypothesis That a Drug Target (Mechanism of

Action) Will Be Efficacious (POC, Proof of concept)
 Study Design Considerations for POC
 Human Indications Screening
 Commercial Profile and Translational Medicine
 Conclusion
Course outline
 Background
 Confirming the Hypothesis That a Drug Target(Mechanism of

 Conclusion
Translational Medicine: Definition, History, and Strategies
 Introduced at late 1980s and early 1990s
 Definition:
 Differently defined by various groups in academia, regulatory institutions,

and industry, shares the fundamental vision of translational medicine
 “The integrated application of innovative pharmacology tools, biomarkers,

clinical methods, clinical technologies, and study designs to improve
confidence in human drug targets and increase confidence in drug
candidates, understand the therapeutic index in humans, enhance cost-
effective decision making in exploratory development, and increase
success in Phase 2 leading to a sustainable pipeline of new products.”
Definition from Pfizer Company based on drug development
Drug development strategy
(Traditional v.s. Translational)
 Traditional drug development strategy:
• directly screened NCEs or naturally occurring substances for efficacy in animal
disease models and focus on:
• drug’s target
• mechanism of action
• a scientific rationale for efficacy and safety from the beginning
 Translational drug discovery strategy
• selecting drug targets (key pathways important in disease expression, enzymes that
catalyzed rate-limiting steps along the pathway, or cellular receptors that were ligated
by important relevant mediators)
• Screening chemical libraries for leads that modulated the activity of these pathways
• Optimizing the chemical leads into new chemical entities (NCEs)
• Confirming their drug like properties by in vitro and in vivo biological testing
The requirement of translational medicine in
the pharmaceutical industry
 To execute this new strategy, pharmaceutical companies formed

“experimental medicine” organizations, the primary mission of which was to
demonstrate that a drug was safe and active on its target in humans
(defined as proof of mechanism or POM) and to determine whether this
expression of pharmacology translated into meaningful efficacy in
patients (defined as proof of concept or POC).
 Within the pharmaceutical industry,it was these groups of clinician–

scientists that developed and refined their translational skills and evolved
into translational medicine groups.
The remit of translational medicine during drug
development
Translational Medicine
v.s. Experimental Medicine
 Experimental medicine
– did not have any responsibility for drug projects prior to

identification of the drug candidate or, in some cases, prior to the
first in human (FIH) studies.
 Translational medicine
– began to work further upstream in the drug discovery and

development process.
– Involved in all early phases of drug discovery from target

identification forward.
General concept of translation medicine
Translational medicine now brings human experiments into the drug

discovery process earlier so that they contribute much more to target
selection and candidate optimization.
Explanation of medical terms and short questions
Explanation of medical terms:

Translational Medicine
Short questions:
1. What are the differences between traditional drug development strategy
and translational drug development strategy?
2. What is the remit of translational medicine during drug development?
3. What are the differences between translational medicine and experimental
medicine?
Course outline
 Background

 Conclusion
Biomarkers in translational medicine
fro drug develpoment
 Biomarker: A characteristic that is measured and evaluated as an

indicator of normal biologic processes, pathogenic processes, or
pharmacological responses to a therapeutic intervention (consistent with
the National Institutes of Health [NIH]Workshop definition).
 Diagnostic: A biomarker that has clinical applicability for patient

management.
 Surrogate end point: A biomarker accepted by regulatory agencies as a

substitute for a standard clinical endpoint for drug approval.
Biomarker Types in translation medicine
 Three types of biomarkers were defined based on two parameters: its

type and its degree of linkage to efficacy or safety outcomes in
humans.
 Target Biomarker: Measures physical or biological interactions with the

molecular target.
 Mechanism Biomarker: Measures a biological effect presumed to be

downstream of the target.
 Outcome Biomarker: Substitutes for a clinical outcome measure that is

independent
Linkage to outcomes of biomarker in
translational medicine
 This second dimension for describing a biomarker refers to its

linkage to human efficacy or safety outcomes.
• Low = There is no consistent information on the linkage of
biomarker change to efficacy or safety outcomes in humans.
• Medium = Biomarker differences are associated with efficacy or
safety outcome data in humans but have not been reproducibly
demonstrated in clinical studies.
• High = Biomarker differences have been reproducibly demonstrated
to be correlated with disease efficacy or safety outcomes in two or
more longitudinal studies in humans.
Biomarkers classification using this system
Validation of biomarkers in translational medicine
 Validation / quantification: Characterization of the biomarker that

confirms its fitness for a specific purpose. The degree of rigor required
varies with the purpose but always requires organizational agreement.
 Technical Validation: The process of selecting all technical attributes

required to demonstrate fitness for the purpose, setting appropriate
performance requirements for each attribute, and evaluating the
biomarker against these requirements.
 Biomarker Translation: The activities needed to ensure that the

biomarker (assay and underlying biology) is valid between preclinical
species, between preclinical species and humans, or both.

Biomarker; Diagnostic; Surrogate end point; Target Biomarker; Mechanism
Biomarker; Outcome Biomarker; Validation/quantification; Technical validation;
Biomarker translation
Short questions:
1. What are the parameters for defining the three type of biomarkers?
2. How to describe the biomarkers referring to its linkage to human efficacy or
safety outcomes in second dimension?
3. How to classify biomarkers using the biomarker types and the linkage to
outcome?
Course outline
 Background

 Conclusion
Definition of POM (Proof of Mechanism)
 POM is one of the major missions of “experimental medicine”

department in drug development. Its goal is to demonstrate that a
drug was safe and active on its target in humans. In another words,
POM could tell us whether the drug candiate appropriately modulate
the drug target in human being.
 POM is conducted during Phase 1 clinical trial.
 For POM, the translational medicine groups usually develop target

biomarkers or mechanism biomarkers that could be translated
from preclinical animal or in-vitro studies to humans.
Necessary of POM
 Success rates in phase 2 decisions have decreased to half their
level in the early 1990s.
 The most common reason for failure in Phase 2 in the 1990s was
lack of efficacy, and the failure rate for new mechanisms is
considerably higher than the industry average.
Questions when a drug fails in Phase 2 trial
 What should you do next?
POM could help to

answer these questions
 Is the molecular target still valid?
 Has the mechanism been fully tested?
 Has the target been fully engaged? Do we just need a more potent
NCE or one with better (higher or longer) exposure?
A general process of POM: from biomarker
translation to decision making
Biomarker translation from preclinical studies to phase 1

clinical trials and finally decision making.
Setting biomarker criteria and principles for POM
Example A: an UVB skin irradiation challenge model for a p38
MAP kinase inhibitor program for RA (rheumatoid arthritis)
The validation plan for POM criteria included the following steps:
 Technically validate all biochemical assays using murine and human

skin biopsies;
 Evaluate these endpoints in hairless mice after exposure to UVB

irradiation and determine the effect of the p38 inhibitor;
 Confirm UVB effects on the same endpoints in human skin;
 Evaluate reproducibility of UVB-induced changes in humans to

determine sample size for a Phase 1 clinical study; and
 Benchmark the changes seen with murine p38 inhibition in skin with the
efficacy outcomes in a collagen-induced arthritis disease model.
Example A (continued): the results
The down stream mechanism biomarkers are biochemical, and

the model could be performed in healthy volunteers during the
course of a Phase 1, single-dose trial.
Examples of POM using biomarkers
translated from preclinical models
POM Example B: Anorectic compound for obesity
Here, reduced food consumption was validated as a mechanism

biomarker and translated from a mouse model to humans.
Conclusion: the value of POM
 If POM is achieved in Phase 1: means that the drug modulates its

target sufficiently to test the efficacy of the drug mechanism in Phase 2.
 A positive POM with failure to achieve an efficacy signal in Phase 2

still provides values:
 It enables the company to discard that drug target for the disease
indication;
 It demonstrates that the drug is active at a safe dose and could be

tested in other indications or enter an “indication discovery”
paradigm.

POM
Short questions:
1. What is the general process of POM (from biomarker translation to decision
making)?
2. How to set biomarker criteria for POM?
3. How to set biomarker principles for POM?
4. What steps are included in the validation plan for POM criteria?
5. What is the value of POM?
Course outline
 Background

 Conclusion
Consideration 1. Population
 Whenever possible, POM should be tested in the context of a traditional
Phase 1 single- or multiple-dose study in healthy volunteers.
 The benefits:
 Will deliver the cleanest evaluation of safety;
 Will not be taking other medications;
 Will not have other disease-related issues that could confound PK or PD
endpoints.
 A disease population is necessary when:
 The drug target and its associated downstream pharmacology is not

expressed appropriately in a healthy volunteer population;
 It is not possible to use a clinical model in healthy volunteers that

stimulates the expression of the drug’s target.
Consideration 2. Risk – two areas of risk
 The first risk: the safety of the mechanism.
 If the pharmacology of the drug results in significantly increased safety risk, the
population selected must derive some benefit to justify the risk.
 Example 1: immunosuppressive drugs
 Single-dose is safe for healthy volunteers;
 Multiple-dose increases a risk of opportunistic infection and require a population that
could benefit from immunosuppression.
 Example 2: cancer drugs
 Some cancer drugs have a narrow therapeutic index and are usually tested in
cancer patients first;
 But if an oncology drug has a mechanism that is safe and measurable in healthy
subjects, it can be studied in healthy volunteers first. Because healthy volunteer
studies are small and can be done quickly.
Consideration 2. Risk – two areas of risk (continued)
 The second risk: whether the POM decision can be made using the
study design without a significant risk of a false-positive or –negative
result.
 Solutions:
 Understanding the variability around the measurements;
 Selecting a sufficient number of subjects who will receive

pharmacologically active doses.
Consideration 3. Feasibility
 A common misconception is to design a scientifically rigorous

study that has the perfect comparator controls and study population
but is not doable in a reasonable period of time in the real world.
 Inclusion and exclusion criteria will bring down the eligible

population.
 Study feasibility often requires some compromises in study design.

Consideration 4. Endpoints
 Biomarker endpoints are required to confirm the interaction and activity of

a new drug on its molecular target, downstream pathways.
 Several factors must be considered and optimized
 Optimal time after dosing for measuring change in the endpoints;
 Sample collection requirements, et al;
 Should preferably be measured over a range of dug does in order to

observe a dose-response relationship.
Consideration 5. PK-PD and PD-PD Models
 PK-PD models are important because they can be applied to other

significant questions using simulations.
 Example: a drug causes electro-cardiogram changes with Q-T prolongation

at high exposures:
 One hand, get the PK-PD model for the desired pharmacology;
 The other hand, get a model for Q-T prolongation;
 Combine them together to decide if there is a large enough therapeutic

window to continue.
Consideration 5. PK-PD and PD-PD Models (continued)
 Another example: use a PK-PD model and a lipid biomarker to examine
superiority of a novel lipid-lowering agent compared with atorvastatin
Consideration 5. PK-PD and PD-PD Models (continued)
 In some cases in which PK is not available, feasible, or applicable,

disease or PD-PD modeling can be performed.
Short questions:
1. What are five factors that taken into consideration in the study design for
POM?
2. What are the benefits when POM is tested in the context of a traditional
Phase 1 single- or multiple-dose study in healthy volunteers？
3. Please list the conditions when the disease population is necessary.
4. What are the risks in the study design for POM and how to solve?
5. Which factor must be considered and optimized when biomarker endpoints
is involved?
Course outline
 Background (the definition and history of translational medicine)

 Conclusion
The definition of POC
POC has been defined differently by many companies.
 POC means that the drug project is likely to succeed all the way to the
market (for some groups).
 POC is defined as confirmation that the drug target and mechanism of

action of the compound will provide an efficacy signal at a safe and well-
tolerated dose (for the purposes of this chapter and from the viewpoint of
translational medicine groups). In other words, it is POC for the drug target
using a compound that may still have significant issues that require larger
studies to identify and resolve.
Confirming the hypothesis that a drug
target will be efficacious
 POC must provide sufficient evidence to invest further in the drug project
and often triggers more detailed planning and resources for larger Phase
2B or 3 trials.
 When designing a clinical program to reach the POC decision point,

translational medicine groups recognize the historically high attrition rates
in Phase 2 and design these programs to be as rapid, cost-effective, and
efficient as possible.
 Programs are designed to identify the losers quickly and to conserve

resources by focusing on the efficacy question and by leaving other
important commercial and medical questions to be answered later.

Proof of concept (POC)
Course outline
 Background (the definition and history of translational medicine)

 Conclusion
The considerations in study design for POC
Population
Efficacy Endpoints
Considerations Dose Selection
Cost, Speed, and Risk
Multiple Indications
Population
Efficacy Endpoints
Population
The first step is to identify the disease phenotype and patient population
that are “molecularly correct” for the drug mechanism.
There are three principles to consider.
I. The first principle is that every chronic disease has multiple genetic
and environmental causes, but the drug candidate usually has just
one molecular target or mechanism of action.
II. The second principle is that the magnitude of the clinical response to
a drug that targets a specific pathway will be proportional to the
degree of abnormal pathway expression.
III. The third principle is that the population selected must be one that will
uniformly achieve drug exposure levels and duration of drug exposure
that ensure that the drug’s mechanism is active as defined previously
for POM.
Population
for POM.
The illustration for the first two principles
Three distributions of pathway expression for different drug targets demonstrating sizes of
disease subpopulations with good clinical responses to drugs targeting each pathway.
Population
for POM.
An example for the third principle
High exposure
A CYP2D6
Prescreening
Adverse events
substrate (drug)
Selection To exclude poor

Population
metabolizers
Reducing adverse events induced by

high doses and testing the efficacy of the
mechanism in a wide dose range
Population
 Selecting the optimal patient population for a POC clinical study should
use these three principles and validated biomarkers to identify the correct
subjects.
 The notions have been accepted by organizations:
① If an efficacy signal is not seen in this optimal population it is unlikely

to be seen at all.
② A negative POC will kill the drug and its mechanism for that indication.
Population
Efficacy Endpoints
Efficacy endpoints
 The second step in designing the POC study is to select a primary
efficacy endpoint that has low variability (to allow small sample size)
and will be responsive relatively quickly.
 Because POC studies are conducted early in development, they are

usually not supported by long-term toxicology studies, and drug
exposure may be limited to 4 weeks or less (assuming only 4-week
toxicology studies were completed).
 In some cases, if short-term efficacy endpoints are not acceptable, the

organization must accept larger up-front investments to support longer
POC trials.
 For example, a drug for obesity that requires a trial for weight loss may
require longer than 4 weeks of exposure.
Efficacy endpoints
 Often, conventional clinical endpoints will suffice, but sometimes
biomarkers with medium or high linkage to clinical outcome are selected.
Metabolic responses in fluorodeoxyglucose (FDG)-PET studies in

cancer patients have been shown in longitudinal studies in breast and
lung cancer patients to correlate with clinical outcomes later.
The FDG-PET response is therefore a mechanism biomarker that has

high linkage to clinical outcome.
Here an early metabolic response using FDG-PET quantitative

imaging may be used in a POC study because there is evidence that it
will probably predict longer term clinical outcomes.
Efficacy endpoints
 The study population can also be selected to reduce variability of the efficacy
(biomarker) endpoint.
The C allele frequency

IL-1/LPS stimulation is reported to be 0.4
The -174G to C SNP in Approximately

the promoter region of Approximately 84% of the
the IL-6 gene 16% of the population
Selecting for population (heterozygous
(homozygous G/C or
The amount of IL-6 C/C) homozygous
RA patients G/G)
The production of CRP
Ineligible Eligible
The clinical response in CRP/IL-6 as a

rheumatoid arthritis (RA) biomarker in the study
of anti-rheumatic drug
Population
Efficacy Endpoints
Dose selection
 Often companies and clinician-scientists are inclined to simplify POC studies
and reduce cost by studying just one dose, frequently the maximum tolerated
dose, and comparing efficacy at this dose to placebo.
 POC may also be defined as observing a significant dose response for the
efficacy signal in a smaller study where the slope of the dose response is
statistically different from zero.
 This assumption is safe if it is based on POM study PK–PD data that

demonstrate a typical E max -shaped dose-response curve for the drug’s
pharmacology.
 The doses selected for the POC study can also be based on the POM study
PK–PD data to ensure that they fall within the optimal, relatively linear range of
pharmacological activity.
Population
Efficacy Endpoints
Cost, speed and risk
The study design must reflect the organization’s tolerance for risk, cost, and speed.
 If the result of the POC trial will determine whether the organization builds a new plant
and invests heavily in a Phase 2B/3 clinical program for a compound that is expected
to generate huge revenues, the POC study result must have a low likelihood of
delivering a false-positive or -negative result.
 If the POC study will result in a more typical Phase 2B study investment, the
organization can tolerate a false-positive result but would not like to end up with a
false-negative result that kills the compound and the mechanism for the indication.
 If there are safety issues that require 4 weeks of dosing to become apparent, then a
4-week study is best even if efficacy can be observed in much shorter studies.
 If some aspects of safety and efficacy require larger numbers of subjects to evaluate,
and if there is a desire to reduce costs, one may consider using adaptive designs for
the study that require certain initial results prior to stopping the study, recruiting
additional subjects to particular dose groups, or adding new dose groups to the study.
Population
Efficacy Endpoints
Multiple indications (serial or parallel)
The following four points underpin the logic of a parallel indication approach.
I. First, mechanisms are conserved and used by different organ systems

for different purposes.
II. Second, different diseases often have the same abnormally expressed
targets and pathways, but the importance of the pathway for disease
expression may be different.
III. Third, Phase 2 attrition for efficacy may be due to a previously

unsuspected minor role of the target for disease expression.
IV. Fourth, efficacy attrition in one disease for a pharmacologically active

drug may be independent of its potential efficacy in a different, unrelated
disease phenotype.
Drug mechanisms are promiscuous.

 The probability of getting one Phase 3 start can be calculated for any specific number
of indications tested (Above figures).
 For example, the probability of getting one Phase 3 start if four indications are tested
is 0.6. The cost-effectiveness of this strategy depends on the use of biomarkers and
study designs that are looking for big efficacy signals with small numbers of subjects
selected to be the best possible responders to the drug’s mechanism.
Short questions:
1. What are the considerations in study design for POC?
2. What are the three principles to consider for patient population?
3. What are the four points underpin the logic of a parallel indication
approach?
Course outline
 Background

 Conclusion
Definition of Human Indications Screening
It is an approach that addresses the Phase 2 attrition issue and is related to

parallel evaluation of indications is based on the idea of first reducing a portion
of the risk of failure due to lack of efficacy. This strategy should be done early in
development through the use of mechanism biomarkers and biomarkers with
medium or high linkage to outcome in the context of resource-sparing Expl-
INDs or CTAs.
The clinical goal for Human Indications Screening
The clinical plan for this approach involves two stages that may be combined
in a single protocol, particularly if the mechanism biomarker for POM also has
medium or high linkage to outcome.
 Stage 1: To achieve POM: Pharmacology expressed in humans at a safe dose.
 Stage 2: To look for an efficacy signal using informative target populations where
efficacy can be evaluated.
Expl-IND Application
Exploratory IND study is intended to describe a clinical trial that occurs very
early in Phase 1, involves very limited human exposure, and has no therapeutic
intent. Such Expl-IND studies are conducted prior to the traditional dose
escalation, safety, and tolerance studies that ordinarily initiate a clinical drug
development program. The duration of dosing in an Expl-IND study is expected
to be limited.
To understand the relationship between a specific mechanism of action

and the treatment of a disease.
The
purposes of To provide important information on pharmacokinetics.
Expl-IND To select the most promising lead product from a group of candidates
studies designed to interact with a particular therapeutic target in humans.
To explore a product’s biodistribution characteristics using various

imaging technologies.
The clinical goal for Human Indications Screening
 The statistical approach is adjusted to look for a clear (large) efficacy signal
and for “flat liners” and is not powered to look for small differences.
 Small studies within the size and cost range of a traditional Phase 1
program.
 The goal is to accelerate compound or drug target development for positive
indications knowing that much of the efficacy risk has been removed.
The duration of dosing in an Expl-IND study is limited.
 The starting dose is anticipated to be no greater than 1/50 of the no

observed adverse event level (NOAEL) from the 2-week toxicology study
in the sensitive species on an mg/m2 basis.
 The maximum clinical dose would be the lowest of the following: 1/4 of
the 2-week NOAEL; 1/2 of the AUC at the NOAEL in the 2-week rodent
study, or the AUC in the dog at the rat NOAEL, whichever is lower; or the
dose that produces a pharmacological response or at which target
modulation is observed in the clinical trial.
When using the Expl-IND route to confirm an efficacy signal for a novel
drug mechanism, it is important to define the pharmacologically active
dose and understand its relationship to the highest dose that will be
allowed based on animal safety studies.
The pharmacologically active dose

 ≤ 25% of the 2-week rat safety study NOAEL or 1/2 of its rat area under the
curve (AUC).
 It can be described by a translatable mechanism biomarker.
 Proof of Mechanism (POM) must be built into the study as part of the dose
escalation design to ensure that it is a true test of the mechanism in patients.
Low Cost Attrition and Portfolio Economics
The human indication-screening strategy could be used to eliminate bad
compounds, drug targets, mechanisms, and indications as quickly as possible
and at a low resource cost.
Risk resolved to achieving POC vs. resource costs for two strategies: Indications Screening under an
Expl-IND compared with a typical resource sparing Phase 1 and 2A approach.
Low Cost Attrition and Portfolio Economics
 It is also important to consider the size of the early drug development

portfolio and organizational structure.
 From the point of view of the acceptance of data-driven decisions based

on an indication-screening strategy, it is much better to maintain as large
an early development portfolio as possible and ensure that one body
has governance over the entire early portfolio.

Human Indications Screening
Short questions:
1. Which stages are involved in the clinical plan for Human Indications
Screening?
2. What are the purposes of Expl-IND studies?
Course outline
 Background

 Conclusion
Impact on Survival
 The negative effect of commercial requirements on translational
medicine,drug discovery, and drug development efforts.
 The requirements for commercial blockbusters may also prevent
researchers from building on new science and new unproven areas of
medical need.
No validated Great restriction on the universe of drug

biomarkers targets and indications
Blockbusters
Unprecedented Including high efficacy and safety
drug mechanisms hurdles to justify pricing goals
Focusing early on narrowly defined groups of patients will lead to more

targeted and effective therapies with fewer side effects. It will also lead to faster
and less expensive drug development programs with a high survival rate to
Impact on Decision Making
Regardless of how decision criteria are decided, translational medicine groups

flourish when organizations make development decisions based on
previously agreed criteria aligned with good scientific logic.
Commercial interests
Organizations may take greater risk
The desire to bring forward an
important new drug sooner
This also can lead to an environment in which the work of translational

medicine groups is viewed as “nice-to-have” but not essential when in reality it
is clearly the most essential part of early human drug development.
Translational Medicine and the Personalized
Medicine Option
To pursue targeted drug development and approval in a disease
subpopulation identified by a biomarker
To proceed development for the broad disease population in parallel but

be obtained later with some of the costs being paid by revenues from the
drug after approval for the subpopulation
 It is able to obtain real-life safety

information outside of the confines of a
A better strategy clinical trial.
???
 Any potential safety issues could be
approached prospectively in the broader
program.
Course outline
 Background

 Conclusion
Conclusion
 This chapter has summarized the methods, strategies, hurdles,

and consequences of supporting the translational medicine
discipline within a pharmaceutical company.
 Because this has become more commonplace across the

industry, over the next 5 to 10 years we will see if these
investments pay off in terms of drug development productivity.
~~ Thank You ~~

Methodology of Translational Medicine

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Translational Medicine: Deﬁnition, History and Strategies

Lecturer : Dr. Fangfei Li

Institute for Advancing Translational Medicine in Bone & Joint Diseases

Hong Kong Baptist University

 Biomarkers in Drug Development

 Pharmacology: Testing the Target (POM, Proof of mechanism)

 Study Design Considerations for POM

 Confirming the Hypothesis That a Drug Target (Mechanism of

 Study Design Considerations for POC

 Human Indications Screening

 Commercial Profile and Translational Medicine

 Biomarkers in Drug Development

 Pharmacology: Testing the Target (POM, Proof of mechanism)

 Study Design Considerations for POM

 Confirming the Hypothesis That a Drug Target(Mechanism of

 Study Design Considerations for POC

 Human Indications Screening

 Commercial Profile and Translational Medicine

 Introduced at late 1980s and early 1990s

 Differently defined by various groups in academia, regulatory institutions,

 “The integrated application of innovative pharmacology tools, biomarkers,

 To execute this new strategy, pharmaceutical companies formed

 Within the pharmaceutical industry,it was these groups of clinician–

– did not have any responsibility for drug projects prior to

– began to work further upstream in the drug discovery and

– Involved in all early phases of drug discovery from target

Translational medicine now brings human experiments into the drug

Explanation of medical terms:

 Biomarkers in Drug Development

 Pharmacology: Testing the Target (POM, Proof of mechanism)

 Study Design Considerations for POM

 Confirming the Hypothesis That a Drug Target(Mechanism of

 Study Design Considerations for POC

 Human Indications Screening

 Commercial Profile and Translational Medicine

 Biomarker: A characteristic that is measured and evaluated as an

 Diagnostic: A biomarker that has clinical applicability for patient

 Surrogate end point: A biomarker accepted by regulatory agencies as a

 Three types of biomarkers were defined based on two parameters: its

 Target Biomarker: Measures physical or biological interactions with the

 Mechanism Biomarker: Measures a biological effect presumed to be

 Outcome Biomarker: Substitutes for a clinical outcome measure that is

 This second dimension for describing a biomarker refers to its

 Validation / quantification: Characterization of the biomarker that

 Technical Validation: The process of selecting all technical attributes

 Biomarker Translation: The activities needed to ensure that the

Explanation of medical terms:

 Biomarkers in Drug Development

 Pharmacology: Testing the Target (POM, Proof of mechanism)

 Study Design Considerations for POM

 Confirming the Hypothesis That a Drug Target(Mechanism of

 Study Design Considerations for POC

 Human Indications Screening

 Commercial Profile and Translational Medicine

 POM is one of the major missions of “experimental medicine”

 POM is conducted during Phase 1 clinical trial.

 For POM, the translational medicine groups usually develop target

 What should you do next?

POM could help to

 Has the mechanism been fully tested?

Biomarker translation from preclinical studies to phase 1

 Technically validate all biochemical assays using murine and human

 Evaluate these endpoints in hairless mice after exposure to UVB

 Confirm UVB effects on the same endpoints in human skin;