Med Safety and FDA Regulation

When will the FDA approve a new drug?

• If substantial evidence demonstrates that its benefits outweigh its risks for the intended population and use

What happened in 1938?

• 1938 - New drugs must be proven safe before marketing

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

What happened in 1962?

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

  • Kefauver-Harris Amendment (1962)

What are the designations and regulatory pathways affecting FDA substantial evidence requirements?

• Priority review designation

• Regenerative Medicine Advanced Therapy Designation

• Orphan designation

• Fast track designation

• Accelerated approval

• Breakthrough designation

  
  

What is priority review designation?

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

What is the FDA’s goal in terms of acting on a priority review application?

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

What is 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

What are safety concerns in an orphan drug designation?

• Limited clinical trial data with small sample sizes

• Post-marketing surveillance challenges due to small patient population

• Use of accelerated Approval and surrogate endpoints

What is 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

In accelerated approval, what is approval based on? What is known about after marketing? Are therapeutic benefits required?

• 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

  
  

What is a fast track review designation? Is therapeutic benefit required?

• 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

In fast track review designation, what are the actions for?

• 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

  
  

What is 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

In breakthrough therapy designation, what features does it have?

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

  
  

What is regenerative medicine advanced therapy designation? What benefits does it have? What does it support?

• 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 requirement

Safety doesn’t mean what?

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

A safe product is one that has what?

• 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 what?

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

The choice to use a product involves what?

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

What does the FDA assess? What does this determine?

• 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

  
  

In the FDA regulatory safety actions, what is withdrawal of approval?

• Market discontinuation for safety reasons

In the FDA regulatory safety actions, what is risk evaluation and mitigation strategy?

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

In the FDA regulatory safety actions, what is a boxed warning?

• Significant safety concern

In the FDA regulatory safety actions, what is patient med guide, patient package insert/patient info?

• Serious AE/risk, also instructions and adherence

In FDA regulatory safety actions, what is safety communication?

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

What is the summary of all the FDA safety regulatory actions?

• Withdrawals of approval

• Risk evaluation and mitigation strategies

• Boxed warnings

• Patient medication guides

• Patient package insert/Patient information

• Safety communications

What are main trends occurring in the FDA?

• The number of drugs with FDA regulatory safety actions isincreasing

• 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

  
  

What are the principles of conservative prescribing?

• (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