Ethics-NAPLEX Prep

Drug Development phases (1-4)

Pre-Clinical Stuides

Phase I

Phase II

Phase III

Phase IV

Drug Development phases (1-4):

Pre-Clinical

Evaluates safety and pharmacokinetics in animal models before human trials

Drug Development phases (1-4):

Phase I

20-100 healthy volunteers; assesses safety PK/PD, max tolerated dose

Drug Development phases (1-4):

Phase II

Hundreds of patients evaluate efficacy, dose-ranging

Drug Development phases (1-4):

Phase III

Large trials confirm efficacy, monitor adverse effects

Drug Development phases (1-4):

Phase IV

Post-marketing studies for long-term safety, new indication

The purpose of Lead compound identification

to identify potential therapeutic molecules through screening and optimization

Purpose of pre-clinical studies

to evaluate safety and PK in animal models before human trials

Purpose of Phase I clinical trials

assess safety, dosage, and PK in healthy volunteers

Purpose of Phase II clinical trials

to evaluate the efficacy and further assess safety in patients with the target condition

Purpose of Phase III clinical trials

confirm efficacy and further assess and monitor adverse effects in large, diverse population

Purpose of Phase IV clinical trials

post-marketing surveillance for long-term safety or new indications

Emergency Use Authorization (EUA)

allow temporary use of unapproved drugs in public health emergencies

What is a fast track designation?

Accelerate development for drugs treating serious conditions with unmet needs

Accelerated approval

early approval based on surrogate endpoints for serious diseases

Breakthrough therapy designation

expedites drugs showing substantial improvement over current therapies

ex: leukemia antibody therapy showing high remission rates gets breakthrough designation

Orphan drug designation

encourage development of drugs for rare diseases (<200,000 patients in the US)

Types of Clinical Trials:

Parallel Clinical Trial

compares treatments in separate groups

ex: group A vs. group B in HTN

Types of Clinical Trials:

Crossover Clinical Trial

Each subject gets multiple treatments

ex: migraine trial with washout

Types of Clinical Trials:

Factorial Clinical Trial

Evaluates multiple interventions simultaneously

ex: aspirine and statin for stroke

Types of Clinical Trials:

Cluster Randomized

Randomized groups, not individual people

ex: hospitals using sepsis protocols

Types of Clinical Trials:

Adaptive

Modify based on interim results

ex: oncology trial with dropped arms

Types of Clinical Trials:

Non-Inferiority

To show new drug is not worse than standard drug

Types of Clinical Trials:

Superiority

To prove new drug is better than old

Types of Clinical Trials:

Equivalence

prove two are equally effect

ex: brand vs. bioequivalence

Types of Clinical Trials Designs:

Open-Label

use when blinding isn't feasible

ex: biologic site reactions

Types of Clinical Trial Designs:

Pragmatic

test in real-world practice

ex: pharmacist led diabetes care

Blinding in clinical trials:

Open-label

All parties aware of treatment assignment

ex: trial comparing pens where delivery method visibility prevents blinding

Blinding in clinical trials:

Single-blind

participant blinded, investigator aware

Blinding in clinical trials:

Double-blind

both participant and investigator blinded

Blinding in clinical trials:

Triple-blind

participant, investigator, and outcomes assessor/statistician blinded

ex: analysis is performed by an indpendent data monitoring committee

Common biases in clinical research:

Recall Bias

Uneven accuracy in recalled data from participants

ex: cancer patients better recall smoking than healthy controls

Common biases in clinical research:

Performance bias

care/monitoring differences due to group awareness

ex: expiremental group gets more lab monitoring than control group

Common biases in clinical research:

Detection bias

outcome assessment influenced by treatment knowledge

Common biases in clinical research:

Selection bias

Differences in baseline characteristics from flawed allocation/enrollment

ex:younger patients placed in treatment group, skewing the outcome

Common biases in clinical research:

Attrition bias

unequal dropout rates between groups

ex: pain scores higher for patients on a new drug

Common biases in clinical research:

Observer bias

assessor's beliefs influence measurement

ex: researcher notes improvement they expect in treated group

Common biases in clinical research:

Publication bias

Only trials showing benefit submitted by sponsor

Randomization techniques:

Block randomization

subjects are randomized in blocks to ensure balanced allocation

Randomization techniques:

simple randomization

each subject is randomized independently like a coin flip

ex: assigning 100 patients to drug A or placebo using a random number generator

Randomization techniques:

stratified randomization

subjects are grouped by key characteristics and then randomized

ex: stratified by age then randomized

Randomization techniques:

adaptive randomization

allocation probabilities change based on interm results

ex: more patients are assigned to a COVID-19 treatment arm as early results show benefit

Primary outcome

main, pre-specified outcome that the trial is designed to assess

ex: time to CV death in HF

Seondary outcome

additional outcomes that support or provide supplementary data to the primary

ex: 6-min walk distance in addition to mortality in a COPD trial

Compositive outcomes

combines multiple endpoints to increase statistical power

ex: stroke, MI, CV death in an anticoag trial

Exploratory outcome

not powered for signficance; hypothesis generating or post-hoc

Patient-centered outcomes

reflects outcomes that matter most to the patient (QOL, function, preferences)

Surrogate outcome

biomarkers or intermediate endpoints that predict clinical trials

Safety outcomes

outcomes focused on identifying adverse effects and risks

Ethics

discipline focused on what is good or bad and moral duty

Bioethics

study of moral dimensions in healthcare decisions

Autonomy

respecting a patient's right to self-determination and informed decision making

Beneficience

acting to do good for patients

Nonmalfesasance

doing no harm; avoiding harm to patients

Core Ethical principles:

Justice

fair and equitable treatment for all individuals

Core Ethical principles:

Veracity

telling the truth and ensuring confirmed consent

Core Ethical principles:

Fidelity

keeping promises and commitments to patients

Core Ethical principles:

Professionalism

adhere to laws, avoid conflicts, maintain integrity

Core Ethical principles:

Alturism

putting the patient's interest above one's own

Core Ethical principles:

Accountability

taking responsibility for one's actions

Core Ethical principles:

Excellence

commitment to lifelong learning

Core Ethical principles:

Duty

Serve and meet patients needs

Core Ethical principles:

Honor and integrity

upholidng honesty and fairness

Core Ethical principles:

Respect for others

acknowledge other's dignitiy and beliefs

Informed consent

patient agrees to treatment after receiving all facts

requires: disclosure, comprehension, voluntaries, competency

Patient confidentiality

protect health under HIPAA and state law

disclose only with consent or to authorized personnel

Use discretion and secure record handling

Ethical dilemmas

conflicts between ethical principles

resulution: use frameworks and consult ethics committes

Paternalism

overriding patient decisions for their benefit

ethical tip: educate and seek voluntary agreement

Cultural competence

understand and interact effectively across cultures

avoid assumptions and respect beliefs

adapt care to align with cultural values

End of life care

respect directives and DNR orders

promote and predescripbe unneeded meds

support autonomy in treatment refusal

moral distress

discomfort when unable to act ethically

Causes of moral distress

policy, hieracrchy, fear of retaliation

Coping with moral distress

document, escalate concerns, seek support

**Managing drug recalls

Class I Recall

product may cause serious health problems or death

ex: contaiminated injectable drug causing septic shock

**Managing drug recalls

Class II Recall

Product may cause temporary or medically reversible health issues

ex: wrong dosage strength on label

Managing drug recalls

Class III recalls

Product not likely to cause harm, but violates labeling/manufacturing

ex: minor packaging error or incorrect expiration date

How to manage drug recalls - Steps to take

Pharmacies must:

1. Remove affected products from shelves immediately

2. Notify patients and prescribers if applicable

3. Document actions taken

How to manage a drug shortage - steps to take

1. Monitor FDA and ASHP shortage bulletins regularly

2. Communicate with providers regarding alternative therapies

3. Update formulary substitituons and alert staff

Precepting Responsibilites

Preceptors should guide, evaluate, and support student development

Mistakes made by students should be addressed as opportunities for learning

Precepting responsibilities:

Delegating Principles

Only delegate tasks wihtin legal scope and job descriptions - as a pharmacist/preceptor

Precepting responsibilities:

Feeback techniques

feedback should be structured, timely, and actionable

Effective feedback is behavior focused and private

Third-party payers & reimbursement:

PBMS

intermediates that manage prescription drug benefits on behalf of insurers and employers

they negotiate drug prices, create formularies, and determine reimbursement to pharmacies

contracts with PBMS dictate how much a pharmacy is paid per claim

DIR fees (Direct and Indirect Remuneration fees)

post-claim fees charged by PBMS to pharmacies based on performance metrics - not disclosed upfront these fees reduce the final reimbursement

AWP (Average wholesale price)

a list price for what drug wholesalers charge pharmacies (sticker price)

used by payers to calculate reimbursement

typicall overestimates true market price

MAC (Maximum Allowable Cost)

a pricing benchmark that limits the amount paid for generic drugs. Pharmacies are reimbursed based on MAC values which can vary between PBMs

WAC (Wholesale Acquisition Cost)

the manufacturers list price to wholesalers, not including discounts. Often used as a benchmark for brand name reimbursement

Payer Contracts

Legal agreements between pharmacies and PBMs or insurance companies. They set terms for reimbursement, drug coverage, claim submission, and audit compliance