Pharmaspective

OPDP Restructures Again: Promotional Review By Therapeutic Area Instead of Audience

By Kim C. Capone

According to a recent FDA announcement, the Office of Prescription Drug Promotion (OPDP) is restructuring its review process. OPDP currently reviews and analyzes its workload and review processes through two divisions: the Division of Consumer Drug Promotion, and the Division of Professional Drug Promotion. According to the March 8 announcement, pending final approval, OPDP will rename and restructure its divisions to oversee different therapeutic classes of drugs.

 

The divisions will be renamed and organized as follows:

The Division of Advertising and Promotion Review I:

- Neurology, Psychiatry

- Hematology/Oncology (blood cancers)

- Oncology (solid tumors)

- Analgesics, Anesthetics, Antivirals

 

The Division of Advertising and Promotion Review II:

- Osteoporosis, Reproductive, Urology

- Dental, Dermatology, Metabolic & Endocrine

- Allergy, Gastroenterology, Pulmonary, Rheumatology

- Anti-Infective, Cardiovascular, Medical Imaging,

- Ophthalmology, Renal, Transplant

 

According to Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER), "As a way to distribute the work evenly, each division will oversee different therapeutic classes of drugs. These changes will allow OPDP to review direct-to-consumer (DTC) and health professional advertising more effectively."

FDA May Change Regulations to Allow Generics to Change their Product Warnings

By Frank Fazio and Genevieve Spires

@frankfaziopls    @gmspires

A single footnote in a brief filed by the Department of Justice has garnered a lot of attention this week, and understandably so.  The footnotes states: “This office has been informed that FDA is considering a regulatory change that would allow generic manufacturers, like brand-name manufacturers, to change their labeling in appropriate circumstances. If such a regulatory change is adopted, it could eliminate preemption of failure-to-warn claims against generic-drug manufacturers.”

The background of this statement is complex, but briefly, the United States Supreme Court ruled last year that plaintiffs claiming injuries as a result of their use of generic drugs may not sue generic manufacturers for their failure to warn of an alleged drug-related danger.  In deciding this, the Court found that these claims are preempted – and therefore barred – by federal law, largely because generic manufacturers are not permitted to make changes to their product labels under the current regulatory scheme (even in cases where they think stronger warnings are needed).

Under current FDA regulations, generic manufacturers cannot unilaterally update their product labeling.  Only brand-name manufacturers have the ability to update warnings on product labeling and must get FDA approval to make those changes.  Generic manufacturers are required to adopt the warnings of their  brand-name counterpart.

Any change in regulations to allow generics to change their labels will undoubtedly reopen the litigation floodgates and result in a slew of failure to warn cases being brought against generic drug manufacturers.   Likewise, such a rule can result in inconsistencies in warning information on the same drug which can certainly result in increased liabilities for those companies who fall behind in regard to labeling updates adopted by competitors.  And while we do not know the source of the information referenced in the DOJ brief, we will definitely stay tuned to see if Congress takes steps to alter the generic drug label regulatory scheme.

A Quick Observation Regarding the FDA and the Caronia Decision…

By Kim C. Capone and Sarah M. Canberg

On December 3, 2012, the United States Court of Appeals for the Second Circuit handed down its decision in U.S. v. Caronia,  and ruled that the government cannot prosecute pharmaceutical manufacturers for speech promoting the lawful, off-label use of an FDA-approved drug.  Coincidently, the Food and Drug Administration (FDA) has not issued any Warning or Untitled Letters since the Caronia decision.  In 2012, the FDA issued twenty-eight enforcement letters.  The most recent was an Untitled Letter dated November 27, 2012, to Salix Pharmaceuticals, Inc. and Napo Pharmaceuticals, Inc. regarding its website and podcast for the investigational new drug, Crofelemer.

 

Although the Caronia decision only applies in three states, the FDA may have to change its approach regarding off-label marketing concerns.  In the past, it was enough for the FDA to allege in its letters that false or misleading speech was used to market drugs off-label.  Will the FDA now have to prove off-label marketing and make it clear that promotional statements were offered as evidence of intended use? 

 

The Wall Street Journal reported on January 23, 2013, that according to FDA officials, the government will not appeal the Caronia decision, and the FDA "does not believe that the Caronia decision will significantly affect the agency's enforcement of the drug misbranding provisions of the Food, Drug, and Cosmetic Act." In the meantime, should we expect FDA to issue guidance regarding off-label speech, issue new off-label speech regulations, or continue with business as usual? The next Warning or Untitled Letter from FDA may provide some guidance as to FDA’s position with regard to off-label speech.

 

Link: U.S. vs. Caronia decision

Second Circuit: Truthful Off-label Promotion of Prescription Drugs is Protected by the First Amendment

By Laura C. Conway

On December 3, 2012, the United States Court of Appeals for the Second Circuit ruled that a pharmaceutical sales representative could not be convicted for truthful off-label promotional statements made to physicians about a drug that had been approved by the FDA for other uses.  United States v. Caronia, 09-5006-cr  (2d Cir. Dec. 3, 2012). 

 

Caronia was a sales representative who promoted Xyrem, a drug that was approved for two specific uses and carried a “black box warning.”  Caronia detailed physicians who might prescribe the product and helped establish a speakers program where the drug was discussed.   During the course of a government investigation, Cardonia was recorded promoting the drug for unapproved uses, including unapproved indications and unapproved subpopulations.  The government did not allege that the statements at issue were untruthful or misleading. 

 

Caronia was convicted in the trial court for conspiracy to introduce or deliver misbranded drugs into interstate commerce, in violation of the Food, Drug and Cosmetic Act (FDCA).  The Second Circuit vacated this conviction.  The government, according to the court, incorrectly argued that off-label promotion alone constitutes “misbranding.”  The court found that the FDCA does not expressly prohibit the promotion of drugs for off-label use, but noted that promotional statements could constitute proof of an intent to use a drug in a manner that the FDA had not approved and was inconsistent with the label, which would be actionable under the FDCA. 

 

The court concluded that the government prosecuted Caronia not for his intent to sell misbranded drugs based on his statements regarding the drug’s off-label uses, which does not implicate the First Amendment, but rather for the act alone of making statements about off-label uses for the drug, which does implicate the First Amendment.  The court held that the First Amendment protects this type of commercial speech and that the government could not overcome the heightened scrutiny applicable to such commercial speech.  The court looked to the United States Supreme Court’s recent decision, Sorrell v. IMS Health, in which the Court held that “[s]peech in aid of pharmaceutical marketing . . . is a form of expression protected by the Free Speech Clause of the First Amendment."  131 S. Ct. 2653, 2659 (2011).   

 

In reaching its decision, the Second Circuit reasoned that the statements were truthful; the FDCA does not expressly prohibit the promotion of drugs for off-label use; physicians are permitted to prescribe the drug for unapproved uses, and persons other than pharmaceutical companies and their sales representatives may advise physicians of off-label uses of drugs that the FDA had approved for other uses.  The court interpreted the misbranding provisions of the FDCA as “not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs” and concluded that “the government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug.” 

 

The court noted that its decision was limited to FDA-approved drugs for which off-labels uses are permitted and that the FDA is authorized to regulate prescription drug marketing.  In addition, the court made clear that off-label promotion that is false or misleading is not protected by the First Amendment. 

 

            One of the three judges on the panel dissented from the decision and issued a lengthy opinion arguing that Caronia’s conviction should have been upheld.  In this dissent, the court disagreed with the majority’s interpretation of the government’s position and contended that Caronia was prosecuted because his speech revealed an intent to sell the drug for a use that was inconsistent with the drug’s label, not for the speech itself.  As such, the court noted, the First Amendment did not apply and did not protect Caronia’s statements.  Even if the First Amendment did apply, the dissent stated, the FDCA’s misbranding provision precludes promotion of off-label uses and passes constitutional muster.  The dissent argued that the majority opinion serves as a disincentive to pharmaceutical manufacturers to go through the premarket drug approval process and undercuts the purpose of the FDCA and the FDA to ensure the safety and efficacy of drugs before they are marketed.    

 

The Caronia decision is not binding on trial courts outside of the Second Circuit and likely is not the last word on this subject.  We anticipate a request for further review by the full panel of the Second Circuit or review by the United States Supreme Court.  Until the United States Supreme Court reviews the decision, off-label promotion is subject to prosecution outside of the Second Circuit.  In addition, both in and out of the Second Circuit, off-label promotion by sales representatives remains potentially actionable because, among other things, the government could argue that it is evidence of an intent to sell a misbranded drug.

Full Text of Decision: United States v. Caronia, 09-5006-cr  (2d Cir. Dec. 3, 2012)

FDA to Industry: Stay Tuned to 2013 For Further Guidance On Federal Sample Disclosure Reporting

By Frank Minichetti

Section 6004 of the Patient Protection and Affordable Care Act (Act) requires manufacturers and authorized distributors of record (ADRs) to disclose information related to drug sample requests and distributions on or before April 1, 2012, and each year thereafter. Earlier this year, the Food and Drug Administration (FDA) issued a draft guidance for industry on the reporting of drug sample distribution information. The FDA also issued the “ACA Industry Submission Specifications User Guide,” which provides the technical requirements for the proper submission of files through its Electronic Submissions Gateway (ESG). During this time, the FDA also indicated that it did not intend to object until at least October 1, 2012, if manufacturers and ADRs did not submit drug sample information as required by the Act. The FDA has stated that it would provide notice before it begins enforcing the drug sample reporting requirement. The FDA also asked that interested parties submit comments and suggestions regarding the draft guidance. 

 

Today, the FDA announced on its website that it is currently reviewing the comments it has received regarding the draft guidance and the ESG, and that it “expects to issue further guidance regarding its compliance policy, including the timing of agency enforcement decisions, in early 2013.”

 

Please see the FDA website for additional information on the federal sample disclosure requirements.

The Prescription Drug User Fee Act…In a Nutshell

The Prescription Drug User Fee Act (PDUFA) was originally enacted in 1992, and authorizes the federal Food and Drug Administration (FDA) to collect fees from pharmaceutical companies seeking FDA approval of new drugs and biologics.  In return for collecting fees, the PDUFA requires the FDA to meet performance benchmarks with the overall intention of making the New Drug Application review process more efficient. Since 1992, user fees collected by the FDA under the PDUFA have permitted the agency to expand its NDA review staff and considerably reduce a product’s review time while still assuring the safety of human drugs. Congress is required to reauthorize the PDUFA every 5 years by September 30^th in order to ensure the continuity of the user fee programs.

 

To this end, the United States House of Representatives has introduced House Bill 5651, which would, among other things, reauthorize the PDUFA. House Bill 5651 also provides for the reauthorization of the Medical Device User Fee Act (MDUFA), which authorizes the FDA to collect fees from medical device manufacturers seeking its approval on new medical devices. Further, House Bill 5651 would authorize two new user fee programs: the Generic Drug User Fee Act (GDUFA) to facilitate the review process for generic drugs, and the Biosimilars User Fee Act (BSUFA) to facilitate the abbreviated review of products shown to be biosimilars to an FDA-approved biologic.

 

In an effort to reauthorize the PDUFA well before the September 30, 2012, deadline, House Bill 5651 has been moving quickly through the usual legislative hurdles. To date, both the House Energy and Commerce Subcommittee on Health, and the House Energy and Commerce Committee have unanimously approved the bill. House Bill 5651 will now move to the entire House for a vote.

 

Congress’ expediency in reviewing House Bill 5651 may be attributed to its desire to reauthorize the PDUFA well before the statutory deadline.  The current version of the PDUFA was signed into law on September 27, 2007, just three days before the deadline. As the reauthorization deadline drew near without the PDUFA being reenacted, the FDA left many of its positions vacant in the event that that user fee charges were not available at beginning of the fiscal year on October 1, 2007. With thoughts of 2007 looming over their heads, supporters of the PDUFA are hoping to have House Bill 5651 enacted before the start of the upcoming fiscal year, which begins on October 1, 2012.  

 

For more information on the PDUFA, please Click Here!

 

Democrats Set Sights on Medical Device Safety Regulation

“Forewarned, forearmed; to be prepared is half the victory.” - Miguel de Cervantes

Ink-like clouds suffused over our nation’s capitol as a murder of crows converges upon fresh carrion. As the atramentous nebulae congealed over the Hill, the icy, soul-sucking breath of regulators chilled the device industry like Harry Potter’s tormenting dementors. Yes, my friends, Congress is coming and it has medical devices locked in the cross-hairs.

There is no subtlety as the portents blaze like neon along a moonless desert highway. In 2011 there were four congressional subcommittee hearings on the FDA’s regulation of medical devices. Unsatisfied with their colleagues on the other side of the aisle, Democrats, led by Henry Waxman (D-CA) as ranking member of the Committee on Energy and Commerce (“ the Committee”), have been advocating increased regulation of medical devices. In an October 12, 2011 letter to Fred Upton (R-MI), Chairman of the Committee, Joseph Pitts (R-PA), Chairman of the Subcommittee on Health, and Cliff Stearns (R-FL), Chairman of the Subcommittee on Oversight and Investigation, Waxman and colleagues Frank Pallone (D-NJ), Diana DeGette (D-CO) and John Dingell (D-MI) urged the Committee to hold hearings on device safety in conjunction with the impending reauthorization of the medical device user fee program. The letter detailed safety concerns with brain stents and metal-on-metal hip implants. Waxman et al. contended that the hearings held in 2011 focused on delays in approval and overregulation while ignoring serious health concerns. You can read the full text at http://democrats.energycommerce.house.gov/index.php?q=news/energy-and-commerce-democratic-leadership-calls-for-further-examination-of-fda-medical-device-r

A second letter was sent on January 20, 2012 by Waxman, DeGette, and Dingell renewing their prior request for hearings. This communication detailed concerns over the “Lap Band” gastric band and urogynecologic surgical mesh. The authors concluded by requesting the Committee hold hearings to determine “whether FDA device regulation has been ineffective in protecting the public from dangerous medical devices” and urging the Committee to obtain documents in regard to the Lap Band and surgical mesh. Waxman again tied this review into the reauthorization of the Medical Device User Fee Act noting that “we [Congress] need to understand the safety of devices on the market, the tactics device manufacturers and others use to market these devices, and the extent to which these tactics may increase risks.” Full text of letter at http://democrats.energycommerce.house.gov/index.php?q=news/democratic-committee-leaders-call-on-committee-republicans-to-hold-hearings-on-dangerous-medica

If you remain doubtful that Democrats are setting up device safety as an election year issue, then you likely missed President Obama’s State of the Union Address. Buried deep in the President’s remarks, it inconspicuously passed in a heartbeat. But it was there and worthy of repeating:

“We’ve all paid the price for lenders who sold mortgages to people who couldn’t afford them, and buyers who knew they couldn’t afford them. That’s why we need smart regulations to prevent irresponsible behavior. Rules to prevent financial fraud, or toxic dumping, or faulty medical devices, don’t destroy the free market. They make the free market work better.” President Barack Obama’s third state of the union address to Congress, January 24, 2012.

It was there. Just four days after Representative Waxman’s second letter to the Committee, the President slipped device safety regulation into the State of the Union. There can be no doubt that democrats are setting this up for an election year showdown. Although the President’s remarks are couched in terms of safety, Waxman specifically tied safety into marketing tactics. There is certainly evidence that impending regulation will not simply address safety in the approval process but will further impose stricter regulatory oversight of device marketing.

You have been forewarned. In the immortal words of Rubeus Hagrid, “It's changing out there. ... There's a storm coming, Harry. And we all best be ready when she does.”

Happy New Year! The FDA provides guidance on responding to “public” unsolicited requests for off-label information.

By: Frank Fazio

While the pharmaceutical and device industries are enjoying the Holiday break, the Food and Drug Administration (“FDA”) released a draft guidance for comment that will soon be published in the Federal Register.  The document, entitled “Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices” (“Guidance”) provides much needed insight into FDA’s current thinking about those pesky “public” requests posted on web sites or in social media.

 The Guidance applies to unsolicited requests for information about unapproved uses of prescription drugs and biological products.  It also applies to medical devices marketed for a specific use without  product approval or clearance.  In regard to such devices, the FDA notes that a request for off-label information would include any use for which approval or clearance would be required.

 Through the use of various examples, the Guidance attempts to establish the boundary between solicited and unsolicited requests for off-label information.   Making that determination has always been the first step in deciding whether a response is appropriate.  The FDA concedes that internet and social media have provided new outlets whereby companies might be confronted with an unsolicited request for off-label information.  The Guidance classifies such requests as either non-public or public.  Non-public requests are those that are privately directed to the firm and are not visible to the public at large.  We all know what to do with those requests, although the Guidance reiterates and reaffirms the standard principles.  More interesting are the public requests.  The FDA defines these as “an unsolicited request in a public forum, whether directed to a firm specifically, or to a forum at large.”  The FDA notes that such requests can occur on company sponsored sites as well as on sites run by third-parties.  The FDA recognizes that it is in the interest of the public to permit the company to respond to such requests rather than relying on speculation and the misinformation that might be provided by other lay people on a thread.

 So how can the company respond in a compliant manner?  The FDA has determined that a response to a public request, whether on a company or third-party site, should be answered in a private manner.  The FDA cited concerns about the dissemination  of information to other individuals who did not make the unsolicited request as well as the enduring nature of a posted response.  The Guidance notes that a firm’s public response to a public request should clearly convey that the question pertains to an off-label use along with specific contact information for the medical or scientific personnel (e-mail, phone, etc.), so that the individual can follow up for additional information.  The individual providing such information must clearly disclose their involvement with the firm, and the response may not be promotional in any regard.  The public response should also include a direct link to the FDA approved labeling, but may not include links to any other information (e.g. firm or product websites, third-party websites, or other promotional materials).  Likewise, the URL for the labeling should not itself be promotional in any way.  By way of example, the Guidance notes that www.bestcancercure.com would not be an appropriate URL for the product label.  If the individual that made the public request then contacts the medical or scientific personnel, the request is then treated as any other non-public request.    

 The Guidance is well thought out and makes sense.  It permits firms to provide appropriate information in response to public requests without fear that such responses will lead to claims of off-label promotion.  The full text can be found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM285145

Happy New Year!

FDA Blueprint: Gateway, Not a Barrier to Innovation

In our prior post, “Biotechnology Industry Pushing for Progressive Changes within FDA,” we discussed one industry group’s proposals for changes within FDA aimed at improving and expediting the drug and biologics approval process. This month, FDA Commissioner Margaret Hamburg outlined FDA’s blueprints for changes within FDA to encourage biomedical innovation as set forth in the document titled “Driving Biomedical Innovation: Initiatives to Improve Products for Patients."  This announcement follows an increase in criticism from lobbyists and political opposition regarding FDA’s approval process and burdensome regulatory process. According to FDA’s press release, Commissioner Hamburg stated, “America is at an important crossroads, where the science before us presents unprecedented opportunities to create new and better medical products and to promote better health for the public. Our innovation blueprint highlights some of the initiatives FDA will be implementing to ensure that these opportunities are translated into safe and effective treatments that can help keep both American patients and American industry healthy and strong.” Following public hearings and external meetings with stakeholders, FDA’s blueprint identifies the following seven areas for major action within FDA:

1. Rebuilding FDA’s small business outreach services;
2. Building the infrastructure to drive and support personalized medicine;
3. Creating a rapid drug development pathway for targeted therapies;
4. Harnessing the potential of data mining and information sharing, while maintaining strong privacy protections;
5. Increasing consistency and transparency in the medical device review process;
6. Training the next generation of innovators; and
7. Streamlining and reforming FDA regulations.

A number of FDA’s proposed major actions set forth mechanisms of change within FDA intended to lead to an improved and expedited approval process, specifically for personalized medicine, targeted therapies, and devices. To achieve this end, such proposed changes include clarification of agency policies, streamlining the necessary coordination between Centers, and improving transparency and predictability within FDA. To create a rapid drug development pathway for targeted therapies, FDA proposes to host a series of scientific meetings with stakeholders and develop draft guidance on an expedited development pathway. From the outside looking in, FDA’s blueprint is a great starting point, but does not include many, if any, ground shifting methodologies that will initiate significant change within FDA on an expedited basis. However, maybe the changes that need to be made within FDA are fundamental regulatory shifts rather than reinventing the process.

While FDA’s announcement is timely and likely well received amidst industry concerns of regulatory burdens to obtaining approvals of new drugs and the growing chorus of Americans disgruntled about the loss of jobs to outsourcing and the stalled economy, the success of FDA’s blueprint will be determined by whether FDA effectively implements these initiatives and industry and the public sees tangible results. In a post on the White House Blog, Vicki Seyfert-Margolis, Senior Advisor for Science Innovation and Policy for the FDA’s Commissioner’s Office, referred to FDA’s blueprint as “a productive and important first step toward smart innovation-focused reform at FDA.” If this innovative-driven reform is successful as a first-step in putting true change into motion, industry can hope to see a less burdensome approval process resulting in an increase in America’s life science development pipeline and innovative advances from start-up life science companies.

Goodbye DDMAC, Hello OPDP

Following an 18 month approval process, Director Janet Woodcock announced in an email to Center for Drug Evaluation and Research (“CDER”) staff on Monday, September 19^th that the Division of Drug Marketing, Advertising and Communication (“DDMAC”) is now reorganized and elevated into the newly formed Office of Prescription Drug Promotion (“OPDP”).  FDA first announced that it was considering the elevation of DDMAC to office status in February 2010.  Given the size of DDMAC, FDA no longer considered the designation of division appropriate.  This recent elevation and reorganization comes as CDER’s Office of Medical Policy undergoes a transition into a super office, which continues to be led by Rachel E. Behrman, Director of the Office of Medical Policy.

The new OPDP will house two divisions, the Division of Professional Promotion and the Division of Direct-to-Consumer Promotion.  The reorganization did not involve a change in leadership.  Thomas Abrams will be the Director of OPDP with Mark Askine as the Associate Director, Marci Kiester as Associate Director of Operations, Catherine Gray as Acting Director of Division of Professional Promotion, and Robert Dean as Acting Director of Division of Direct-to-Consumer Promotion.

The regulated community waits with baited breathe to see if these monumental changes result in equally monumental shifts in regulations and enforcement.  Perhaps OPDP’s first regulatory act will be to issue the long promised internet and social media rules.