BIO 302 - Exam 3 - Rx Development PowerPoint

Question 1

Overall, only ______ of patients respond to Rx we have to offer.
We typically don’t know which ______ those are.
______ of drugs work in only ______ individuals.

Answer 1

25-30% / 30% / 90% / 30-50%

Question 2

The limited effectiveness of current treatment

Answer 2

Different oncogenes mutated in different cancers of the same “type.”
Different mutation types in same oncogene.
Different resistance mechanisms in same oncogene in same patient.

Question 3

Formidable performance requirements

Answer 3

Hit all clones

Hit all clones in all metastases in all body locations

Hit all newly emerging Rx-resistant clones

Question 4

Multi-drug combination chemotherapies with different mechanisms of action help to increase therapeutic efficacy BUT it:
*
*
*
Multi-drug combos may delay emergence of Rx-resistant clones BUT the probability is high that Rx-resistant variants WILL eventually emerge

Answer 4

(1) Increase toxicity that limits patient tolerance
(2) Increase costs
(3) Involve complicated dosing schedules

Question 5

PHASES OF THERAPY DEVELOPMENT

Answer 5

Discovery
Preclinical development
Clinical trials
Regulatory (FDA) review
Post-market surveillance

Question 6

Discovery:
Two approaches to IDENTIFY POTENTIAL NEW MEDICINES

Answer 6

Rational drug design based on knowledge of detailed structure of the desired target
Screening of libraries of structurally diverse molecules against desired target(s) to identify ‘hits’ for subsequent refinement as potential candidate Rx

Question 7

Design of candidate drug requires detailed tertiary ( 3-dimensinal) structural knowledge of the “active site” in the target molecule.

Question 8

RATIONALE DESIGN OF CANDIDATE DRUG

Prediction of likely desired activity is based on what 2 things?

Prediction of activity utilizes databases of accumulated knowledge of What 3 things?

Answer 8

Chemical structure and calculated reactivity.

(1) Drug-like properties of the molecule
(2) Structure activity relationships (SAR) of particular classes of chemical structures.
(3) SAR = relationship between the 3-D structure of a molecule and its biological activity.

Question 10

THE ETHICS OF HUMAN EXPERIMENTATION

What is the Nuremburg Code?

Answer 10

• Developed in reaction to Nazi atrocities of WWII.
• Human experimentation is justified when the results are for the good of society and cannot be procured by other means.
• Must satisfy moral, ethical and legal concepts.
• Voluntary consent of human subject is absolutely essential.

Question 11

THE ETHICS OF HUMAN EXPERIMENTATION

What is the Declaration of Helsinki?

Answer 11

• World Medical Association declaration of recommendations for physicians involved in research involving human subjects.
• Consent should be in writing
• Interests of science should never take precedence over well- being of the patient.

Question 12

What are the Belmont Reports?

What are the 3 important points to protect humans?

Answer 12

Summarized basic ethical principals identified by the commission.

• Respect for persons: individuals treated as autonomous agents who enter research voluntarily.
• Beneficence: do no harm
• Justice: who should receive benefits of research?

Question 13

PHASE I CLINICAL TRIALS: SAFETY

Answer 13

First human testing
Healthy volunteers (but paid) for most Rx classes
Cancer drug trials initiated directly in patients
Evaluation of safe dosage range and potential side effects
Initial trial in small cohort (20-80 people)
Evidence of efficacy valuable but not the primary objective or endpoint assessment (safety is primary focus)

Question 14

PHASE II CLINICAL TRIALS: DOSE AND RESPONSE

Answer 14

Evaluation in larger patient population with disease
Establish optimum dosage and evidence of treatment response Additional assurance on safety profile
Typically 100-300 patients
Typically ‘single arm’ trial without comparison to placebo/standard Rx

Question 15

PHASE III CLINICAL TRIALS: PROOF OF EFFICACY

Answer 15

“Pivotal” trial to demonstrate efficacy and safety for regulatory approval to market
Randomized clinical trial (RTC) protocols dominated trial design until recently.
The approved design cannot be change once the trial is launched.
Efficacy endpoint possibilities:
No response (NR), partial response (PR) or complete response (CR)
Durable stable disease: time to progression (TTP): progression-free survival (PFS)
Overall survival (OS)

Question 16

CANCER TRIAL INNOVATION: BIOMARKER-DRIVEN DESIGN

Umbrella vs. Shopping Cart Design

Answer 16

Umbrella Design: multiple drugs tested against multiple genetic mutations within a single cancer type.

Shopping Cart Design: A handful (typically 1 or 2) of drugs tested against a handful of genetic mutations across multiple cancer types.