medication safety FDA regualtion

FDA drug approval

The FDA will approve a new drug if substantial evidence demonstrates that its benefits outweigh its risks for the intended population and use

• 1938 - New drugs must be proven safe before marketing

  • Federal Food, Drug, and Cosmetic Act (FDCA) (1938)

• 1962 - Requires substantial evidence of efficacy, in addition to safety, before a drug is approved

  • Kefauver-Harris Amendment (1962)

designations and regulatory pathways affected FDA substantial evidence requirements

• priority review designation

• orphan designation

• accelerated approval

• fast rack designation

• breakthrough designation

• regenerative medicine advanced therapy designation

priority review designation

• A drug that treats a serious condition that is expected to provide a significant improvement in safety or effectiveness.

• FDA’s goal is to act on a priority review application within 6 months (compared to 10 months under standard review)

orphan drug designation

• A drug for a rare disease or condition that affects less than 200,000 persons in the U.S.

• No added therapeutic benefit or disease severity required

• Safety concerns

• Limited clinical trial data with small sample sizes

• Post-marketing surveillance challenges due to small patient population

• Use of accelerated Approval and surrogate endpoints

accelerated approval

• A drug that treats a serious or life-threatening disease and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict a real clinical benefit

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

• Surrogate endpoints must be confirmed after marketing

• No added therapeutic benefit required

fast track review designation

• A drug that is intended to treat a serious condition and nonclinical or clinical data demonstrate the potential to address an unmet medical need

• No added therapeutic benefit required

• Actions to expedite regulatory review, eligibility for rolling review—FDA reviewing portions of the application before the sponsor submits the complete application-, and eligibility for accelerated approval and priority review

breakthrough therapy designation

• A drug that is intended to treat a serious condition and preliminary clinical evidence indicate that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies

• Fast-track designation features, intensive guidance on efficient drug development, and organizational commitment

regenerative medicine advanced therapy designation

• Cell therapy, therapeutic tissue engineering, human cell and tissue products, and preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for serious or life-threatening diseases or conditions

• All the benefits of the fast track and breakthrough therapy designation programs

• Potential ways to support accelerated approval and satisfy post-approval requirements

FDA and drug safety

• Safety does not mean zero risk, since all medical products are associated with some level of risk

• A safe product is one that has reasonable risks, given the patient's condition, the magnitude of the benefit expected, and the alternatives available

• FDA’s product approval process identifies the benefits and the risks to patients

• The choice to use a product involves balancing the benefits to be gained with the potential risks

FDA risk/benefit assessment

• the FDA assesses:

  • preclinical and clinical information submitted by sponsors

  • nature of the disease

  • risk/benefit of available therapies

  • feasibility of risk management tools

• to determine whether the benefits of a new drug outweigh its risks

FDA regulatory safety actions

• Withdrawal of approval: Market discontinuation for safety reasons

• Risk evaluation and mitigation strategy (current or released): Known or potential serious risk

• Boxed warning: Significant safety concern

• Patient medication guide, Patient package insert/Patient information: Serious adverse events or risk, also instructions & adherence

• Safety communication: New drug warnings and other safety information after approval of a drug

FDA safety regulatory actions

• Withdrawals of approval

• Risk evaluation and mitigation strategies

• Boxed warnings

• Patient medication guides

• Patient package insert/Patient information

• Safety communications

main trends

• The number of drugs with FDA regulatory safety actions is increasing

• This is may be partially explained by the increase in approvals of orphan drugs and therapeutic classes with high risk/benefit ratio

• There is a trend towards transferring the responsibility for safe use of drugs from the FDA to clinicians and patients

• There is an important need for more involvement of pharmacists managing new drugs with complex safety/efficacy profiles

principles of conservative prescribing Dr. Gordon D. Schiff

1. Think beyond drugs (nondrug therapy, treatable underlying causes, and prevention)

2. Practice strategic prescribing (defer nonurgent drug treatment; avoid unwarranted drug switching; be circumspect about unproven uses; and start treatment with 1 new drug at a time)

3. Maintain heightened vigilance regarding adverse effects (suspect drug reactions;
   be aware of withdrawal syndromes; and educate patients to anticipate reactions)

4. Exercise caution and skepticism regarding new drugs (seek out unbiased information;
   wait until drugs have sufficient time on the market; be skeptical about surrogate rather than true clinical outcomes; avoid stretching indications; avoid seduction by elegant molecular pharmacology; beware of selective drug trial reporting)

5. Work with patients for a shared agenda (do not automatically accede to drug requests;
   consider nonadherence before adding drugs; avoid restarting previously unsuccessful treatment; discontinue treatment with unneeded medications; and respect patients' reservations about drugs)

6. Consider long-term, broader impacts (weigh long-term outcomes, and recognize that long-term safety problems may outweigh marginal benefits of new drugs)