Drug Shortages Endgame: FDA Goes On Offensive As Legislative Plot Thickens

FDA press conference on alleviating shortages shows how the agency works with industry to advance legislation that firms may not be particularly fond of themselves. But the agency still seems to face an uphill legislative battle.

The Obama administration’s approach to drug shortages seems like it will closely resemble what the President’s re-election campaign will say about the economy: Let’s not focus on where we are, but focus on the trend line instead. Not surprising, the Republican-controlled House of Representatives remains unimpressed.

And so the Feb. 21 press conference led by FDA Commissioner Margaret Hamburg revealing the resolution of the shortage of two pediatric cancer drugs, ostensibly a medical announcement, became the backdrop for some political pronouncements.

“I understand that passing legislation is complex and difficult, but it is no more complex or difficult than curing a child with cancer and no more complex or difficult than what is faced every day by children with cancer,” Peter Adamson of Children's Hospital of Philadelphia said at the press conference. “We can induce remission in children with acute lymphoblastic leukemia within four weeks, the first step in a cure that takes two-and-one-half to three-and-one-half years of treatment and more years of follow up. If we can produce a remission in children with leukemia in four weeks, I would challenge our colleagues in Washington to pass legislation in four weeks’ time.”

FDA had been pressing for legislation that would give it more enforcement powers, such as civil monetary penalties, to ensure that firms notify the agency in advance of potential shortages. Draft legislation being circulated by the House Energy and Commerce committee, however, stops well short of what the agency wanted (Also see "Drug Shortage Provisions In Draft PDUFA Bill Would Expedite Major Manufacturing Changes" - Pink Sheet, 19 Mar, 2012.).

Shortages Persist For Cancer Drugs

The American Society of Health System Pharmacists’ website lists cancer drugs for which a shortage exists. Len Lichtenfeld, chief medical officer of the American Cancer Society, said these include “many standard therapeutic agents.” The list includes:

• bleomycin injection
• cisplatin injection
• cytarabine injection
• dacarbazine injection
• daunorubicin hydrochloride injection
• denileukin diftitox injection
• etoposide injection
• fludarabine injection
• fluorouracil injection
• irinotecan injection
• leuprolide acetate (14-day kit)
• mitomycin injection
• paclitaxel injection and
• thiotepa injection

The site also lists four other cancer drugs for which shortages have been resolved: capecitabine tablets, idarubicin hydrochloride injection, tretinoin oral capsules and vincristine injection.

Stronger versions of the drug shortage legislation had already been introduced. S. 296, the Preserving Access to Life-Saving Medications Act of 2011, was introduced in the Senate in February 2011 and is often known by one of its sponsors, Sen. Amy Klobuchar (D-Minn.). H.R. 2245, often known after one of its sponsors, Diana DeGette (D-Colo.), is pending on the House side.

The American Cancer Society Cancer Action Network said in a statement that it supports the Klobuchar and DeGette bills, saying their shortage “reporting requirement would provide FDA with the information it needs to quickly respond and work with manufacturers to address problems, develop plans to work with other manufacturers that may be able to ramp up new production lines, or deploy other strategies to diminish or even stop a shortage of a particular drug from occurring.”

After the press conference, Adamson said he also supports the Klobuchar bill. “It does not solve the problem, but assures greater lead time in managing shortages. Addressing the economic and regulatory factors that drive industry away from producing these drugs will be key.”

Michael Link, president of the American Society of Clinical Oncology, took a similar view of the Klobuchar and DeGette bills, saying, “We are supportive but we don’t think they get to the bottom of the problem. We need bills that deal with price gouging and hoarding.” Comprehensive legislation should also address the need to find out why there are so many drug shortages recently and what incentives could be offered to industry to help avoid them, he added.

At the press conference, Link had pointed to a likely way forward, arguing that “generic user fees must be passed to ensure resources for reviewing applications in a timely way. This will enable also FDA to complete inspections and help companies address problems that can lead to shortages.” Inclusion of drug shortage legislation in the Prescription Drug User Fee Act reauthorization also is considered likely (Also see "PDUFA V: Can FDA Fight Off Mission Creep This Cycle?" - Pink Sheet, 6 Feb, 2012.).

Hospira Recovers The Ball On Methotrexate

The press conference was clearly important to FDA from a public relations perspective, allowing the agency to announce the availability of methotrexate, which is used to treat acute lymphoblastic leukemia among many other cancers, and a version of Janssen Biotech Inc.’s Doxil (liposomal doxorubicin) (Also see "FDA Drug Shortage Strategy: Enforcement Discretion, Patient Public Relations" - Pink Sheet, 21 Feb, 2012.).

In showcasing its efforts, FDA invited to the hearing Sara Stuckey, whose six-year-old son Nate was diagnosed with ALL and needed methotrexate, as well as representatives of APP Pharmaceuticals Inc. and Hospira Inc., which along with Mylan NV and Sandoz International GMBHwere all called on to help resolve the methotrexate shortage. Spokespeople for Mylan and Sandoz confirmed, however, that their companies were not invited to participate in the press conference.

Valerie Jensen, associate director of the CDER Drug Shortage Program, said in an interview that there was no intention to slight the latter two companies, “we just wanted to highlight a couple of examples where companies have helped out with a shortage. We do recognize that Mylan, Sandoz and other companies have helped as well.”

But the presence of Hospira CEO Michael Ball at the event must be particularly gratifying for the company, which is in the midst of cleaning up a manufacturing compliance mess at several of its facilities (Also see "Hospira on the Ball: Paying Attention to FDA Complaints Under New CEO" - Pink Sheet, 14 Nov, 2011.).

Ball was visibly happy at the event, at one point saying, “So Nate, we got you covered.” Getting to share the microphone with the commissioner, while not an official close-out letter, could be seen as an indication that Hospira has impressed FDA with its GMP turnaround – perhaps even to the point of avoiding a consent decree.

Or not.The only other industry representative at the press conference was APP VP of Quality Assurance Mitchell Ehrlich. The day after the press conference, FDA sent APP a GMP warning letter (Also see "APP Pharmaceuticals, Praised For Easing Drug Shortages, Gets Manufacturing Warning Letter" - Pink Sheet, 5 Mar, 2012.).

FDA and industry have not had the coziest relationship during the drug shortage crisis, with each feeling that the other needs to do a better job of communicating its problems, and it remains to be seen how well they will work together if the Generic Pharmaceutical Association’s private sector shortage-notification system, dubbed the Advanced Recovery Initiative, gets off the ground. But when the news is good and drugs are going out of – not into – shortage, they are eager to lock arms.

To resolve the methotrexate shortage, Jensen explained that the agency “reached out to methotrexate manufacturing firms” last fall, as soon as it realized that Ben Venue Laboratories Inc. was having problems manufacturing it at its Bedford, Ohio plant. APP Pharmaceuticals Inc. “had a supplemental application in” for a preservative-free version. “We pulled it out of the queue and are glad it was able to be approved,” she added (Also see "Foreign API Manufacturers Help Ease Methotrexate Shortage" - Pink Sheet, 19 Mar, 2012.).

Hamburg’s Crash Course On Doxil

The Doxil shortage has been a higher-profile headache for FDA. While the speakers at the FDA press conference praised the agency’s efforts in combating drug shortages, at a House Energy and Commerce Committee Health Subcomittee hearing three weeks earlier subcommittee vice chair Rep. Mike Burgess (R-Texas) was much more critical.

“We have to look at the issue of bioequivalence and whether the Food and Drug Administration chooses to exercise the flexibility they have in the approval process,” Burgess said Feb. 1. “In some instances I believe this authority has been used questionably and in others I question why it hasn’t been used at all. On Jan. 6 in response to a request for flexibility on bioequivalence studies for a substitute for Doxil … [Dale] Connor, the director of bioequivalence in the Office of Generic Drugs, wrote ‘the FDA may take steps to expedite the regulatory reviews. … However, the agency has determined that it is necessary that a bioequivalence or bioavailability study in patients be conducted.’” The letter was sent to Azaya Therapeutics Inc.

“I don’t have any other information on the quality of this submission, but I do know this,” Burgess continued. “Doxil is gone now to treat patients. Lines shut down. Any stockpile that is there is to treat the ill and that’s appropriate, but how do you conduct a bioequivalence study if you don’t have the product against which to test when you’re doing a randomized clinical trial it requires that you have the product to test?”

Hamburg replied, “I am not familiar with all the details of the particular case of Doxil that you raise, but it speaks to a set of important issues around drug shortages in terms of really needing to work closely with companies to get early warning when decisions are made to discontinue manufacture or if they believe that there’s an emerging quality or manufacturing concern, to help identify other sources of available product to treat the conditions that patients may have when there are potential shortages and help work with sponsors to help expedite the standing up of new manufacturing capability.”

Burgess asked, “Can you use your flexibility from the issue of bioequivalence to help get these patients the drug they so desperately need?”

“I don’t know enough about the specifics in terms of the options in that case,” Hamburg said.

In the end, FDA decided to allow an approved foreign drug to be imported to alleviate the Doxil shortage. The agency declined to discuss the criteria it used to evaluate the product (Also see "Doxil Shortage Solution: FDA Chooses Middle Ground, Allows Import Of Unapproved Version" - Pink Sheet, 19 Mar, 2012.).

In an interview following the FDA press conference, Burgess said he found it “interesting that FDA acted a couple of weeks after the hearing.” He also criticized the White House for inaction, arguing that little has been done since President Obama signed an executive order Oct. 31 on addressing drug shortages (Also see "Obama's Drug Shortage Efforts Focus On Personnel, Persuasion" - Pink Sheet, 31 Oct, 2011.).

At subsequent hearing, Burgess noted that the Doxil shortage had been resolved shortly after he grilled FDA on it, and asked panels for product shortages that they would like to see resolved.