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U.S. Supreme Court: FDA Approval and Drug Safety

June 13, 2019

What Does FDA Approval Mean?

This presentation addresses the following question:

When a drug, Rx or OTC, injures a patient, who is responsible?

What does it mean that the drug was approved by the FDA as safe and effective?

FDA Approval Process

Drugs must be proven safe and effective to the FDA before they can be marketed.

Once a discovery is made, first step is usually obtaining a patent.

Which last for 20 years.Why does that matter?

FDA Approval Process

First step: NDA is filed. FDA sends the application and

data to its evaluation arm: Center for Drug Evaluation and Research.

Co. also sends the proposed label. CDER team consists of physicians,

chemists, statisticians, pharma-cologists and other scientists.

What Does FDA Approval Mean?

CDER evaluates company data as to whether the application provides substantial evidence to support safety and effectiveness.

CDER does some limited research on quality and safety, but no testing.

There are also processes for “accelerated approval” for needed and promising new drugs.

What Does FDA Approval Mean?

“FDA Approval” means data on effects have been reviewed by CDER and determined that the drug provides benefits to intended population that outweigh known and potential risks.

Since no regulated product is risk-free, FDA's evaluation is a judgment about (1) safety and effectiveness; (2) whether the product's benefits to users outweigh its risks.

What Does FDA Approval Mean?

As to the label, the manufacturer proposes the label – indications, side effects, warnings, etc.

CDER evaluates the proposed label. FDA ultimately controls the label, seeks

to balance importance of warnings – to alert prescribers of use/side effects…

But also to avoid “alert fatigue” caused by too many warnings.

What Does FDA Approval Mean?

Remember … FDA does not test drugs.

CDER reviews the manufacturer’sresults of laboratory, animal and human clinical testing done by manufacturers.

FDA relies on the manufacturer for original and updated data.

FDA Approval of Generics

Generic drugs are “copies” of Brand drugs – “pharmaceutically equivalent” to the Brand.

Upon expiration of the 20-year patent protection for Brand, any drug manufacturer can seek approval of a generic, whether or not they made the Brand.

Requires:

FDA Approval of Generics

“Active ingredient” must be same. Inactive ingredients must be safe. The right amount of the active

ingredient needs to “get” where it belongs.

The generic label must be identical to the brand label.

What Does FDA Approval Mean?

After a drug enters the market, manufacturers are still required to report data on safety issues that is reported to them.

If so indicated, the manufacturer may need to seek a label change to warn of reported dangers.

About 1/3 have serious effects.

When Drugs Cause Injuries

All drugs carry risks. When a risk factor materializes, the issues are:

Was the risk known and evaluated? Was the risk data adequately presented

to the FDA? Was the request for labeling adequate? If it was an after-discovered risk, did the

manufacturer make adequate efforts to warn, once known?

When Drugs Cause Injuries

Since about 1/3 of approved drugs are found to have serious safety issues after FDA approval…

…when a patient sustains serious injury as a result a bad drug, or a bad warning, who is responsible?

Hint: you can’t sue the FDA!

State Law: Failure to Warn

“Failure to warn” of side effects (drugs and other FDA products) is an issue of state law. State laws vary …

FDA regulations set minimum standards for manufacturers; state law can impose a higher standard for product warnings.

Unless: FDA actually prevents the manufacturer from issuing the type of warning allegedly required by state law.

Law calls this “impossibility preemption.”

Wyeth v. Levine (S. Ct. 2009)

Diana Levine was a musician. Her PA administered an IV push of Phenergan –drug to treat nausea from migraines.

Injected into vein, but got into an artery-which is dangerous.

She suffered horrific injuries including gangrene and the loss of her right arm.

She sued in Vermont (state) court.

Wyeth v. Levine (S. Ct. 2009)

Levine claimed failure to warn: Wyeth failed to include adequate warning label describing the possible arterial injuries that could occur from negligent IV injection of the drug.

Levine argued that in establishing an FDA approval process, Congress did not intend the FDCA to preempt state-law failure-to-warn actions.

Wyeth v. Levine (S. Ct. 2009)

In fact, it’s pretty well established that since the FDA must rely on industry self-reporting, “state tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly.”

But short of strict liability.

Wyeth v. Levine (S. Ct. 2009)

Wyeth defended on basis that FDA controls the content of the label.

Thus - Wyeth could not change it. To which the plaintiff pointed out that

drug labels can be changed without FDA approval by issuing a CBE –“changes being effected” – an immediate remedy while a request to the FDA for a change is pending.

Wyeth v. Levine (S. Ct. 2009)

The S. Ct. held for the plaintiff: Unless Wyeth could provide “clear

evidence” that FDA rejected, or would have rejected, a label change, it can be held liable under state law for an inadequate label.

Merck, Inc. v. Albrecht (2019)

Following on Levine, Albrecht (a class action) sued Merck concerning so-called “atypical” femoral fractures associated with use of Fosamax (for osteoporosis).

After FDA approval and labeling, Merck discovered an association of Fosamax with “atypical” femur fractures.

Merck, Inc. v. Albrecht (2019)

Merck defended on the basis that upon hearing of femur fractures it twice asked the FDA to allow it to include an increased warning on the product label.

But the first time Merck asked for a warning primarily of “stress fractures” which – plaintiffs claim –wasn’t accurate.

Merck, Inc. v. Albrecht (2019)

But the second request to FDA was a discussion of the “atypical” evidence, and FDA still said no.

Instead the FDA decided to commission a study about atypical fractures associated with Fosamax, and eventually agreed to change the label.

Injuries occurred in the interim.

Merck, Inc. v. Albrecht (2019)

Plaintiffs argued that under the CBE process Merck could have unilaterally changed the label itself – pending FDA review.

Merck countered that CBE is not realistic if FDA actually rejects your proposed warning.

So-called “Impossibility Preemption”

The S. Ct. remanded, allowing Merck – on the basis of “impossibility” – to prove it could not change the label because the FDA rejected its proposed change.

Further, the judge (not the jury) decides question of “impossibility.”

Brand vs. Generic

Recall in Wyeth v. Levine the Court held that a failure-to-warn claim related to a brandedpharmaceutical was viable.

What about generic manufacturers? FDCA provides that a generic drug

manufacturer cannot change a product label. Period.

PLIVA v. Mensing (2011) This was a state-law negligence

claim for failure to warn by a generic manufacturer…

Because federal law denies the generic manufacturer any right to change a product label, Ct. held a generic manufacturer cannot be held liable under state law for injuries caused by failure-to-warn.

Mutual Pharm v. Bartlett (2013)

Enter: Mutual Pharm Co. v. Bartlett. 1978: FDA approves an anti-

inflammatory pain reliever called sulindac (also made by Merck).

Patent expires; FDA approves several generic versions including one by Mutual Pharmaceutical Co.

Mutual Pharm v. Bartlett (2013) Drug has serious side-effects incl. hyper-

sensitivity skin reactions with necrosis of the skin and Stevens-Johnson Syndrome.

2004: Karen Bartlett is prescribed Mutual’s generic form of sulindac.

She develops toxic epidermal necrolysis(more severe than SJS): 60% of her skin was destroyed; dozens of surgeries; medically-induced coma …

Bartlett’s (creative) Claim

Bartlett didn’t claim failure-to-warn (precluded by Mensing)– but instead “defective design” – the drug was “unreasonably dangerous” (and thus should not be marketed).

Bartlett argued it was not “impossible” to comply with state law: company had the option not to market the product in NH.

This was simply a business decision …

Mutual Pharm v. Bartlett (2013)

US Supreme Court held there were 3 bases for finding liability under New Hampshire law: –Product not sufficiently beneficial

to patients.–Product is excessively dangerous.–the warning was inadequate.

Mutual Pharm v. Bartlett (2013)

Court rejected Bartlett’s claim: Company “is not required to

cease acting altogether in order to avoid liability.”

To hold otherwise would render FDA approval “all but meaningless” and impose strict liability.

Rafferty v. Merck (MA. 2018)

Massachusetts SJC case: Pt sued the Brand manufacturer for injuries caused by a generic.

So-called “innovator liability.” Remember generic can’t change the

label (PLIVA v. Mensing)… So – generic can not be liable for

failure-to-warn injuries.

Rafferty v. Merck (MA. 2018) And generic also cannot be responsible

for “design defects” (Mutual Pharm v. Bartlett).

But – the Brand can be liable for failure to warn (except where it was impossibleto change the label).

Can you sue a brand for an injury caused by a generic competitor – even if the brand chooses to withdraw the drug from the generic market?

More creative lawyering ….

The Mass. SJC says “yes” (though its 1 of only 4 states to so hold).

Recognizing no recourse for injured patients against the generic, only the Brand can be responsible.

Massachusetts: public policy requires the Brand to stand behind its formula, even when it morphs into another company’s generic.

FDA Proposed Rule (2013-18)

In 2013 the FDA proposed a new rule that would allow generic mfs to change a product label as new information becomes available.

Generic companies opposed change, fearing exposure to litigation.

In December, proposal withdrawn. Even FDA is not above politics …