Medication Safety and FDA Regulation (IE2)

What was the Federal Food, Drug, and Cosmetic Act (FDCA)? What was the Kefauver-Harris Amendment? How do the two relate?

FDCA (1938) — New drugs must be proven safe before marketing

Kefauver-Harris Amendment (1962) — Requires substantial evidence of efficacy, in addition to safety, before a drug is approved

Both implementations contribute to the guidelines by which the FDA approves a new drug

What are six designations and regulatory pathways that affect FDA substantial evidence requirements?

1. Priority Review Designation

2. Orphan Designation

3. Accelerated Approval

4. Fast Track Designation

5. Breakthrough Designation

6. Regenerative Medicine Advanced Therapy Designation

What does a Priority Review Designation entail?

Drug will treat serious condition and is expected to provide significant improvement in safety or efficacy

Goal is for FDA to act on application within 6 months (vs standard review of 10 months)

What does Orphan Drug Designation entail? What is a potential concern with this designation?

Designation for a drug treating a rare dz or condition affecting < 200,000 people in US

No added therapeutic benefit or disease severity is required

Concern — Safety

• Limited clinical trial data with small sample sizes

• Post-marketing surveillance challenges d/t small pt population

• Use of accelerated Approval and surrogate endpoints

What does Accelerated Approval entail?

• Drug treats a serious or life-threatening dz and demonstrates an effect on surrogate endpoint that’s reasonably likely to predict real clinical benefit

• Approval is based on a surrogate endpoint or an effect on a clinical endpoint other than survival or irreversible morbidity

• Surrogate endpoints must be confirmed after marketing

• No added therapeutic benefit is required

What is a key difference between Orphan Drug Designation and Accelerated Approval?

Orphan Drug Designation is for rare conditions affecting a very small population

Accelerated Approval is for life-threatening conditions and is specifically based on surrogate endpoints

What does Fast Track Review Designation entail?

• Drug is intended to treat a serious condition with clinical or nonclinical data that demonstrates potential to address an unmet medical need

• No added therapeutic benefit required

• May involve actions to expedite regulatory review, eligibility for rolling review (FDA review of unfinished application), or eligibility for accelerated approval and priority review

What does Breakthrough Therapy Designation entail?

• Drug intended to treat serious condition where preliminary clinical evidence indicates the drug may have significant improvement on a clinically significant endpoint compared to other available therapies

• Features intensive guidance on efficient drug development and organizational commitment

What is a key difference between Accelerated Approval, Fast Track Review Designation, and Breakthrough Therapy Designation?

Accelerated Approval is for a serious or life-threatening condition/dz in which clinical benefit is shown by a surrogate endpoint

Fast Track Review Designation is for a serious condition in which clinical/nonclinical data demonstrates potential to address an unmet medical need for that dz state

Breakthrough Therapy Designation is for serious condition where preliminary clinical evidence demonstrates a greater improvement on an endpoint compared to other available therapies

What does a Regenerative Medicine Advanced Therapy Designation entail?

• Cell therapy, therapeutic tissue engineering, human cell/tissue products, and preliminary clinical evidence indicates the drug has potential to address an unmet medical need for a serious or life-threatening dz

• Has all the benefits of the Fast Track and Breakthrough designation programs

• Can also be used to support Accelerated Approval or satisfy post-approval requirements

What is considered a “safe” product?

A product that has reasonable risks given the patient’s condition, the magnitude of the benefit expected, and the alternatives available

Does not mean there is zero risk

FDA product approval process identifies the benefits and risks to the patient

What factors make up the FDA’s risk versus benefit assessment?

FDA assesses:

1. Preclinical and clinical information submitted by sponsors

2. Nature of the disease

3. Risks vs benefit of already available therapies

4. Feasibility of risk management tools

What are the various FDA regulatory safety actions?

1. Withdrawal of Approval — market discontinuation for safety reasons

2. Risk Evaluation & Mitigation Strategy — known or potential serious risk

3. Boxed Warning — significant safety concern

4. Patient Med Guide/Package Insert — serious ADRs or risk + instructions and adherence

5. Safety Communication — new drug warnings and other safety info after approval of drug

What are the primary current trends in FDA regulatory culture?

a) Increasing number of drugs with FDA regulatory safety actions

b) May be explained by increase in approvals or Orphan Drugs and therapeutic classes with high risk-benefit ratio

c) Trend towards transferring responsibility of safe drug use from FDA to clinicians and patients

d) Important need for increased pharmacist involvement in managing new drugs with complex safety or efficacy profiles

What are key principles of conservative prescribing according to Dr. Gordon D. Schiff?

A) Think beyond drugs

• Non-drug therapy

• Treatable underlying causes

• Prevention

B) Practice strategic prescribing

• Defer non-urgent drug tx

• Avoid unwarranted drug switching

• Be circumspect about unproven uses

• Start tx with 1 new drug at a time

C) Maintain heightened vigilance regarding adverse effects

• Suspect drug reactions

• Be aware of withdrawal sx

• Educate pts to anticipate rxns

D) Exercise caution and skepticism regarding new drugs

• Seek unbiased info

• Wait until drugs have sufficient time on market to prescribe

• Be skeptical about surrogate rather than true clinical outcomes

• Avoid stretching indications

• Avoid seduction by elegant molecular pharmacology

• Beware of selective drug trial reporting

E) Work with patients for a shared agenda

• Don’t automatically comply with drug requests

• Consider nonadherence before adding drugs

• Avoid restarting previously unsuccessful tx

• D/c tx with unneeded meds

• Respect pt’s reservations about drugs

F) Consider long-term, broader impacts

• Weigh long-term outcomes and recognize that long-term safety problems may outweigh marginal benefits of new drugs