By Ricardo Carvajal –

Last week FDA published a Q&A that explains steps the agency is taking to ensure that foods imported from Japan are safe.  Currently FDA does not believe there is any risk to the U.S. food supply, but is continuing to gather information and monitor the situation so as to detect any potential risks.  In response, Rep. DeLauro wrote a letter to Commissioner Hamburg asking the agency to explain the basis for some of the statements in the Q&A, and urging radiological testing of all food imported from Japan. 

This week, FDA followed up on its Q&A by issuing an Import Alert that targets specified products from certain prefectures in Japan based on the potential for contamination with radionuclides.  FDA has a compliance policy guide that provides guidance levels for radionuclides in domestic and imported foods. FDA also has a guidance document that provides recommendations for state and local agencies to help them respond to incidents of contamination with radionuclides. Both documents incorporate information learned in the wake of the Chernobyl accident.

FDA's Q&A also addresses the availability of FDA-approved drugs for radiation exposure.  FDA warns consumers against “internet sites and other retail outlets promoting products making false claims to prevent or treat effects of radiation or products that are not FDA-approved.”  Recent history suggests that some of those retail outlets may be the target of warning letters issued by FDA, and perhaps the Federal Trade Commission.

By Larry K. Houck –

Early March on Capitol Hill has seen a flurry of legislation designed to combat a number of perceived controlled substance problems, including opioid treatment, pain management, drugs marketed to kids and pill mills.

Prescription Drug Abuse Prevention and Treatment Act of 2011

Senator Jay Rockefeller (D-WV) introduced the ambitious “Prescription Drug Abuse Prevention and Treatment Act of 2011” that would amend the Controlled Substances Act (“CSA”) in several ways.  S. 507 would require health care practitioners to complete 16 hours of specialized pain management training before they could register to prescribe or dispense methadone and other opioids, then complete at least 16 hours of training every three years.  The bill would also award grants to states and non-profit groups for educating consumers about methadone and opioid abuse. 

The bill would require establishment of a Controlled Substances Clinical Standards Commission comprised of representatives from responsible federal agencies.  The Commission would develop guidelines for “appropriate and safe dosing” for methadone including recommendations for maximum daily doses, abuse reduction, initiation of methadone pain management for prescribing practitioners, and education for patients and practitioners for maintenance therapy and pain management.  The bill requires the Commission to establish methadone dosing guidelines for pain management and opioid treatment programs within two years after enactment of the bill with updating at least every three years thereafter. 

In addition, the bill would restrict dispensing or prescribing methadone 40 mg. diskettes consistent with the Drug Enforcement Administration’s (“DEA’s”) policy.  DEA previously sent letters to manufacturers getting them to agree to restrict distribution of 40 mg. methadone dispersible tablets to authorized opioid detoxification and maintenance treatment programs and hospitals.

Lastly, the bill provides for $25 million per year to fund interoperable prescription drug monitoring programs in each state through the National All Schedules Prescription Electronic Reporting program.

Saving Kids from Dangerous Drugs Act of 2011

Senators Diane Feinstein (D-CA) and Chuck Grassley (R-IA) introduced legislation aimed at fighting drug misuse and abuse by minors by enhancing penalties for those who add flavorings to controlled substances or otherwise market them to children.  S. 513, known as the “Saving Kids from Dangerous Drugs Act of 2011,” would increase penalties for adults who knowingly manufacture schedule I or II drugs that are combined with a beverage or candy product, that are marketed or packaged to appear similar to a beverage or candy product or that are modified by a flavoring or coloring to distribute or sell it to minors.  Individuals who alter a drug in such a manner would be subject to up to 10 years imprisonment for a first offense and up to 20 years imprisonment in addition to the penalty for the underlying offense.  Increased penalties would not apply to a drug that has been approved by FDA if its contents, marketing and packaging has not been altered from the approved form or if it has been altered by a practitioner for a legitimate medical purpose in the usual course of professional practice.

Pharmacies have at times added child-friendly flavors to prescription drugs to make them more palatable to pediatric patients.  We assume that the “practitioner” exemption would apply to pharmacists acting in this manner. 

Pill Mill Crackdown Act of 2011

A third bill introduced in the House would double prison sentences and triple fines for “pill mill” operators.  “Pill mills” are clinics, doctors’ offices or pharmacies that dispense or prescribe powerful opioids for other than legitimate medical purposes or in an inappropriate manner.  (Under 21 C.F.R. § 1306.04(a), for a controlled substance prescription to be effective, it must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice).  The “Pill Mill Crackdown Act of 2011,” was introduced by Representative Vern Buchanan (R-FL) and co-sponsored by 29 members, including 15 Florida members.  Last month DEA and other federal, state and local law enforcement officers made 22 arrests and seized over $2.2 million in cash at pain clinics in South Florida.

H.R. 1065 would also potentially have the most far-reaching impact on current controlled substance requirements by rescheduling hydrocodone combination products including Vicodin, Lorcet, Lortabs and Norco from schedule III to the more restrictive schedule II.  Prescriptions for schedule II drugs, except in limited circumstances, must be written and cannot be refilled; schedule III drug prescriptions may be written, telephoned or faxed and can be refilled up to five times within six months.  Schedule II drug transfers require DEA Official Order Forms and registrants must implement heightened security.  DEA has observed that hydrocodone is the most frequently prescribed opiate in the U.S. and that diversion and abuse of the drug has been escalating.  As of October 2009, the agency was reviewing a petition to reschedule hydrocodone combination products to schedule II.

The three bills have been referred to committee:  S. 507 to the Committee on Health, Education, Labor and Pensions, S. 513 to the Committee on the Judiciary, and H.R. 1065 to the Energy and Commerce Committee. 

Hyman, Phelps & McNamara, P.C. (“HP&M”) and VirginiaTech are pleased to announce the availability of the first two DVD’s of the VERSUS series that is being sponsored by VirginiaTech.  They provide an overview of the processes a prescription drug must follow to be FDA-approved and the pervasive regulatory requirements that apply after FDA’s approval.  These DVDs feature HP&M attorneys with decades of experience in dealing with FDA regarding these important topics.  The subjects that are discussed include: 

• An Overview of FDA’s Regulation of Rx Drugs – From Research to Your Medicine Cabinet – Are Your Prescription Drugs Safe and Effective?  The DVD features commentary from HP&M’s Roger C. Thies.
• An Overview of Generic Drug Regulation in the United States – The Continuing Struggle to Reduce the Cost of Rx Drugs and Stimulate the Development of New Therapies.  The DVD Features commentary from HP&M’s Robert A. Dormer, and contains additional discussion on the Biologics Price Competition and Innovation Act and the Family Smoking Prevention and Tobacco Control Act

The DVDs are suitable for a variety of educational and work related purposes, and can be ordered and purchased directly from VirginiaTech’s Center for Applied Health Sciences.  An order form can be obtained by contacting Angela Correa at 540-231-2075, by e-mail to versus@vt.edu, by a facsimile to (540) 231-9293, or by snail mail, using the address below.

Virginia Tech Center for Applied Health Sciences
Attention: Angela Correa
123 Duckpond Drive, mailcode 0418
Blacksburg, Virginia 24061

By Kurt R. Karst –      

Last week, Senator Robert Casey (D-PA), along with co-sponsors Sens. Scott Brown (R-MA), Sherrod Brown (D-OH), Al Franken (D-MN), and Johnny Isakson (R-GA), formally introduced S. 606, the Creating Hope Act of 2011.  The bill, which, according to Sen. Casey “has broad support among the medical community, patient advocates and biopharmaceutical companies,” such as the Pablove Foundation, Kids v Cancer, and the National Organization for Rare Disorders, “would strengthen a cost-neutral FDA program giving biopharmaceutical companies an incentive to develop treatments for rare diseases that are often less profitable than treatments for more common medical conditions.”  Specifically, the bill  would amend FDC Act § 524 to change the transferable Priority Review Voucher (“PRV”) program created by the 2007 FDA Amendments Act (the so-called “treat and trade” program), and would amend the PRV program to extend it to applications for a “rare pediatric disease.”

The Creating Hope Act of 2011 is substantially similar to the 2010 version of the bill, S. 3697, which was introduced by now-retired Sen. Sam Brownback (R-KS) and was co-sponsored by Sens. Sherrod Brown (D-OH) and Al Franken (D-MN).  We previously reported on the Creating Hope Act of 2010 here, and we refer you to that post for a summary of the bill. 

Although the 2011 version of the Creating Hope Act makes some minor revisions to the 2010 version, the most important change appears to be the conditions under which FDA may refuse to issue a PRV upon the approval of a rare pediatric disease product application – the so-called “good faith intent to market determination.”  Under both the 2010 and 2011 bills, FDA may consider several factors in determining whether to refuse to issue a PRV, including “the history of such sponsor of producing rare pediatric disease products for which such sponsor received a [PRV], orphan drugs for which the sponsor received exclusivity under [FDC Act § 527], or pediatric drugs for which the sponsor received an additional 6 months of exclusivity under [FDC act § 505A].”  (Neither version of the bill takes into account the new pediatric exclusivity provisions for biological products under new PHS Act § 351(m).)  Added to the 2011 version of the bill is the requirement that FDA issue guidance before making a good faith intent to market determination.  Specifically, the bill states that “[i]f the Secretary requires sponsors seeking a [PRV] to demonstrate a good faith intent to market the rare pediatric disease product in the United States, the Secretary shall first issue a guidance document setting forth the required evidentiary support necessary to demonstrate such a good faith intent.”

The Creating Hope Act of 2011 is one of several bills that will likely be introduced in the 112th Congress that is intended to incentivize the development of new products.  In a few weeks, Representative Phil Gingrey (R-GA), who is a member of the Rare Disease Caucus, will reportedly reintroduce the Generating Antibiotic Incentives Now Act (“the GAIN Act”).  The last iteration of the GAIN Act – H.R. 6331 – was introduced in 2010 and proposed to extend by five years the exclusivity period for a drug or biological product that is a qualified infectious disease product.

By Michelle L. Butler & Kurt R. Karst –

FDA recently published in the Federal Register notice of a long-awaited revision to its draft interim guidance on user fee waivers, reductions, and refunds.  See 76 Fed. Reg. 13629 (Mar. 14, 2011); FDA, Draft Guidance for Industry, User Fee Waivers, Reductions, and Refunds for Drug and Biological Products (Mar. 2011, rev. 1).  This is the first update to FDA’s guidance on this topic since the Agency published interim guidance in July 1993 after the enactment of the original Prescription Drug User Fee Act (“PDUFA”).  In the time since the interim guidance was published, a number of amendments to the statutory provisions relating to user fee waivers, reductions, and refunds have been enacted.  For example, the statutory exemptions from user fees for orphan drugs have been added, the small business statutory ground for a waiver has been revised, and the statutory ground for a waiver based on inequitable treatment between a 505(b)(1) applicant and a 505(b)(2) applicant has been removed.  With publication of the 2011 draft guidance, FDA is presenting formally many of the standards the Agency has used in practice over the years between the enactment of PDUFA I and PDUFA IV.

The statute provides for waivers of, reductions in, exemptions from, and refunds of user fees for a variety reasons.  See 21 U.S.C. §§ 379h(d)(1), 379h(k), 379h(a)(1)(F)-(G).  Generally, application fees, establishment fees, and product fees all may be the subject of a request for waiver, reduction, or refund, provided an applicant makes a timely request to FDA as discussed below.

The new guidance discusses categories of waivers and reductions (e.g., necessary to protect the public health, presents a barrier to innovation, and small business), types of exemptions and refunds (orphan designated products, state or federal government entity, and no substantial work), and the process for submitting requests for waivers, reduction, and refunds. 

Waivers and reductions based on the fees-exceed-the-costs statutory ground are subject to separate guidance.  We note that while the fees-exceed-the-costs mechanism is not often used (because many applicants are continually submitting applications to FDA and the Agency’s costs usually exceed the fees paid), it has been successfully used by companies with a small number of FDA submissions approved several years ago that are still subject to annual user fees.  For these companies, FDA’s costs remain static while the total amount of fees paid by the company continues to grow, eventually leading to an overage that could used as a basis for a fee waiver or reduction request.

As an initial matter, the guidance describes the process by which FDA sets user fee target revenues each year.  Guidance, at 2.  The guidance states that target revenues are independent of the number of waivers or reductions in fees that are granted.  However, the guidance states that the more waivers or reductions that are granted, the more fees must be increased the following year so that the annual statutory revenue targets can be met.  Id.  This could explain why FDA has seemingly set the bar high in determining that applicants meet the criteria for requests for waivers or reductions, particularly in the more subjective categories of protecting the public health and presenting a barrier to innovation. 

Public Health Waiver/Reduction.  The statute provides for a waiver or reduction in user fees “if such waiver or reduction is necessary to protect the public health.”  21 U.S.C. § 379h(d)(1)(A).  The guidance breaks this down into two components:  (1) whether the product protects the public health; and (2) whether the applicant can show that “a waiver or reduction is necessary to continue an activity that protects the public health.”  Guidance, at 5 (emphasis in original). 

With regard to whether a product protects the public health, the guidance lays out for the first time the questions FDA will ask itself in determining whether an applicant’s drug product protects the public health.  Among those questions are the following:

• Is it or does it have the potential to provide a significant improvement compared to other marketed products, including other dosage forms or routes of administration?
• Are there treatment alternatives?  The guidance indicates that the existence of alternatives would weigh against a finding that it is necessary to protect the public health.
• Is it a priority drug?  Has it been granted fast track status?  Has it been determined to be a new molecular entity?  The guidance states that affirmative answers to these questions generally indicate that a product does protect the public health.
• Is it intended for the treatment of a serious or life-threatening condition?
• Does it address or have the potential to address unmet medical needs?
• Is it designated as an orphan drug?

Id. 

With regard to whether a waiver or reduction is necessary to continue the activity that protects the public health, the guidance states that FDA believes that a financial test is appropriate.  FDA will consider the financial resources of the applicant and its affiliates.  Id. at 7.  Citing to legislative history of the original PDUFA legislation, the guidance states that FDA will consider the “limited resources” of an applicant.  Id. at 8.  In doing so, the guidance states that FDA will consider the total annual revenue of an applicant and its affiliates.  The Agency does not intend to deduct marketing costs or consider lack of profitability in as evidence of limited resources.  FDA may also consider available financial assets, including net proceeds, cash, and total assets, as well as the results of recent issuances of stock and recently raised capital.  The guidance states that FDA ordinarily expects to use a $20 million marker in determining whether an entity and its affiliates has limited resources for this purpose.  Id.  (Note that the 1993 interim guidance articulated a benchmark of $10 million for purposes of determining whether an applicant has limited financial resources – the new guidance addresses the reasoning behind the change to a benchmark of $20 million.  Id. at 9.)  The guidance also states that consideration of the financial resources of applicants that are State or Federal government entities will be handled differently and lays out those considerations.  See id. at 8-9.

FDA has applied this financial conditions analysis to both the public health waiver ground discussed above and the barrier to innovation waiver ground discussed below.

Barrier to Innovation Waiver/Reduction.  The statute provides for a waiver or reduction in user fees if “the assessment of the fee would present a significant barrier to innovation because of limited resources available to such person or other circumstances.”  21 U.S.C. § 379h(d)(1)(B).  The guidance breaks this down into two components as well:  (1) whether the product or other products under development by the applicant are innovative; and (2) whether the applicant can show that “the fee(s) would be a significant barrier to the applicant’s ability to develop, manufacture, or market innovative products or to pursue innovative technology.”  Guidance, at 6 (emphasis in original). 

As with the public health ground for waivers or reductions, the guidance lays out for the first time the questions FDA will ask itself in determining whether an applicant’s drug product or other products being developed by the company are innovative.  Id. at 7.  Among those questions are the following:

• Does the drug product or technology demonstrate advanced “breakthrough” research, new, progressive methods, and/or forward thinking, and/or forward thinking in the treatment or diagnosis of disease, or does it have the potential to be at the forefront of new medical technology?
• Does the drug product or technology introduce a unique or superior method for diagnosing, treating, or preventing a disease, or for affecting the structure or function of the body?
• Is the drug product designated as a priority drug, has it been granted fast track status, or has it been determined to be a new molecular entity?
• Has the applicant received a Federal grant for innovation?  The guidance identifies two examples that may qualify as innovative: the National Institutes of Health’s Small Business Innovative Research Program and National Institute of Standards and Technology’s Advanced Technology Program.

Id.

With regard to determining whether a fee presents a significant barrier to an applicant’s ability to develop, manufacture, or market innovative products, the guidance states that FDA will conduct the financial resources analysis of the applicant and its affiliates described above.

Small Business Waiver/Reduction.  The statute provides for a waiver or reduction in user fees if “the applicant involved is a small business submitting its first human drug application to the Secretary for review.”  21 U.S.C. § 379h(d)(1)(D).  A small business is defined as “an entity that has fewer than 500 employees, including employees of affiliates, and that does not have a drug product that has been approved under a human drug application and introduced or delivered for introduction into interstate commerce.”  Id. § 379h(d)(4)(A) (emphasis added).  The term “affiliate” is defined in the statute to mean “a business entity that has a relationship with a second business entity if, directly or indirectly – (A) one business entity controls, or has the power to control, the other business entity; or (B) a third party controls, or has power to control, both of the business entities.”  Id. § 379g(11).  The small business ground for waiver or reduction applies only to the application fee and only to the first application a small business or its affiliate submits.  Id. § 379h(d)(4)(B).  Thereafter, the small business pays application and supplemental application fees just as an entity that is not a small business does, though it is possible that a small business could subsequently be granted a waiver or reduction based on one of the other grounds, assuming it meets the criteria for those other grounds.

FDA works with the Small Business Administration (“SBA”) to determine the size of an applicant and its affiliates, and the new guidance describes this process.  Guidance, at 10.  When an applicant requests a small business waiver from FDA, the Agency asks SBA to determine what companies are affiliated with the applicant and the number of employees for the applicant and its affiliates.  SBA will send the applicant a request for information, and SBA will make a determination in accordance with SBA regulations.  Id.  If the information requested by SBA is not provided, SBA will find that the applicant is other than small, and the request for a small business waiver will be denied.  Once SBA has identified and confirmed the affiliates of the applicant and determined whether the applicant is a small business, FDA will evaluate whether the applicant meets the other criteria for the small business waiver (e.g., that the application is the first human drug application submitted by the applicant or its affiliates).  Id. 

We note that the guidance is silent on a matter that was the subject of fairly recent litigation – that is, whether FDA can take into account former affiliates in determining whether the application is the first human drug application submitted by the applicant.  We previously posted on this issue, which was presented in Winston Labs, Inc. v. Sebelius, No. 1-09-cv-04572 (N.D. Ill. 2009)  Despite the decision by the Court that the statutory definition of affiliate includes only current affiliates and not past affiliates as argued by FDA, the Agency appears to be trying to advance the position it took in Winston in negotiations for PDUFA V – see here and here.  

In addition, the guidance provides some answers to what are likely frequently asked questions about the small business waiver.  See Guidance, at 10-11.  First, an applicant that has been granted a small business waiver should submit its human drug application within one year after the date of the SBA determination, as the circumstances pertaining to a small business waiver may change over time.  Second, as discussed above, an applicant is eligible for a small business waiver only for the first human drug application it or its affiliate submits – if a human drug application is submitted and withdrawn or refused for filing, the applicant or affiliate is ineligible for another small business waiver.  If, however, an applicant does not submit the application for which it was granted a waiver, the applicant may qualify again for a small business waiver.  Third, although there is no specific provision for a waiver or reduction of product and establishment fees for small businesses, a small business may nonetheless qualify for waiver or reduction of those fees under the other statutory grounds for waivers or reductions (e.g., public health, barrier to innovation).

Orphan Drug Exemption.  A human drug application or supplement for a drug that is designated as an orphan drug is not subject to the application fee unless the application also includes an indication for a non-orphan indication.  21 U.S.C. § 379h(a)(1)(F).  The guidance explains that if the application or supplement qualifies for an orphan exemption, the applicant does not need to send FDA a written request for the exemption; rather, the applicant should notify FDA that it is claiming orphan exemption when it completes and submits the User Fee Coversheet that accompanies the application.  Guidance, at 12. 

With regard to product and establishment fees, as added to the statute by PDUFA IV, a drug that is designated as an orphan drug is exempt from such fees, provided the drug meets the public health requirements relating to requests for waivers of product and establishment fees and the applicant’s gross worldwide revenue did not exceed $50 million in the previous year.  21 U.S.C. § 379h(k)(1).

State or Federal Government Entity Exemption.  An application submitted by a State or Federal government entity for a drug that is not distributed commercially is not considered a human drug application under the statute and is therefore not subject to application, product, and establishment user fees.  21 U.S.C. § 379g(1)(B).  The guidance states that for purposes of this exemption, distributed commercially means “any distribution in exchange for reimbursement, goods, or services, whether or not the amount of the charge covers the full costs associated with the product.  Any recovery by the applicant of all or part of the costs of manufacture or distribution of a product makes the distribution commercial.”  Guidance, at 12.

Process for Submitting Requests for Waivers, Reductions, and Refunds.  The guidance discusses the timing for submitting requests for waivers, reductions, and refunds, as well as the content and format of such requests.  Guidance, at 13-16. 

With regard to timing of requests, the statute requires that any such request must be made in writing “not later than 180 days after such fee is due.”  21 U.S.C. § 379h(i).  For applications (which are not considered complete unless the application fee has been paid), if an applicant wishes to avoid paying the fee and then seeking a refund, the guidance recommends submitting the waiver or reduction request approximately three to four months before submission of the application.  Guidance, at 13.  The guidance also states that FDA discourages applicants from submitting application fee waiver or reduction requests more than four months in advance of submission of the application because the circumstances supporting the waiver request may change.  Id. at 14.  For waivers or reductions of product and establishment fees, the guidance also recommends submission of requests three to four months before the fee is due (i.e., between June 1 and July 1 as the fees are due October 1).  Id.  The guidance indicates that if applicants submit waiver or reduction requests in these time frames, “under normal circumstances and depending on available resources,” FDA will try to complete its evaluation of the requests before the application is submitted or before the product and establishment fees are due.  Id. at 13-14.

As noted, the guidance also provides recommendations for the contents of each waiver or reduction request.  Id. at 14-16.  The guidance does not provide a timeframe for responding to a waiver or reduction request other than to say that “[t]he Agency will respond to requests for waivers and reductions in a timely fashion based on available resources and collection time for additional information.”  Id. at 17.

The guidance also discusses the process and timing for requests for reconsideration and appeals.  Id.  The guidance recommends that any requests for reconsideration be made within 30 days of an FDA decision on the underlying waiver or reduction request, and that any appeals be made within 30 days of the decision on the request for reconsideration.  Id.

By Riëtte van Laack –

On March 4, 2011, FDA issued a warning letter to Goetze’s Candy Co. Inc., because the addition of calcium to Goetze’s Caramel Cream Chocolate goes against FDA’s food fortification policy, 21 C.F.R. § 104.20.   Goetze marketed its product with the (impermissible) nutrient content claim “fortified with calcium.”

Although this is not the first time FDA cited its fortification policy in a warning letter, it is the first time in recent memory that the targeted product is candy.  Previous warning letters citing the fortification policy focused on carbonated beverages.  Candy and carbonated beverages are the snack foods specifically mentioned in FDA’s fortification policy.  Thus, this warning letter does not provide insight into what other types of fortified snack foods might violate FDA’s fortification policy.

By Jennifer D. Newberger –

One of the tasks of the Office of Inspector General (“OIG”) of the Department of Health and Human Services (“HHS”) is to make recommendations that will result in cost savings and/or improvements in program efficiency and effectiveness.  Unfortunately, as we are all too aware, OIG making the recommendations is very different from HHS implementing them. 

This is all too clearly demonstrated by OIG’s March 2011 release of its “Compendium of Unimplemented Recommendations” (“Compendium”).  The following list is a small sampling of recommendations not adopted by HHS:

• Improve States’ and Localities’ Medical Surge Preparedness for Pandemics

Remember anthrax and H1N1?  Given the panic that ensued after these events, it would seem that the states and localities, working with the federal government, would prioritize preparedness.  Yet OIG found that, based on a sample of 5 states and 10 localities, while partnerships had been established to prepare for a medical surge, much improvement is needed in coordination of volunteers, tracking of medical equipment, and planning for alternative care sites.  

• Ensure That State Public Health Laboratories Meet Cooperative Agreement Requirements on Biological Threats

If a biological health threat was coming to your neighborhood, wouldn’t you want your state public health lab to be able to detect and report that threat quickly?  Unfortunately, although the Centers for Disease Control and Prevention (CDC) awarded grants for this purpose in 2006, most state labs fail to meet the requirements of those grants to demonstrate rapid detection and reporting.

• Improve and Strengthen Food Facilities’ Compliance With Records Requirements for Traceability of Food Products

Eggs.  Spinach.  Peanut butter.  We remember the stories.  Just like you want your state lab to identify biological threats quickly, you probably also want FDA to be able to trace food quickly if it has reason to believe the food poses a health threat.  And yet, when OIG tried to trace 40 food products through the supply chain, it was only able to do so with complete success, through the whole food chain, for 5 of those products. 

• Use Adverse Event Reports to Detect and Address Safety Concerns About Medical Devices

The Center for Devices and Radiological Health (CDRH) requires manufacturers and user facilities to submit reports of adverse events within certain time frames.  However, OIG found that CDRH rarely reacts when these entities submit late reports, doesn’t document any follow-up on adverse event reporting, and rarely performs its own first read of adverse events on time.  Additionally, the information contained in the reports is often incomplete and not helpful to the reader. 

• Strengthen Inspections of Domestic Food Facilities to Ensure Food Safety and Compliance

OIG found that many food facilities go 5 years or longer without an FDA inspection.  When FDA does inspect, and does find violations, they often don’t act quickly enough to prevent future health risks. 

We all know HHS has a lot to manage.  But it might want to prioritize areas identified by OIG to save costs and improve effectiveness and efficiency.  It seems hard to argue the benefits of those goals.

By Kurt R. Karst –

Last week, Judge Richard Leon of the U.S. District Court for the District of Columbia granted FDA’s Motion to Dismiss a lawsuit filed in April 2010 by a group of ear candle advocates after the Agency issued about 15 Warning Letters (see e.g., here) to companies marketing the products saying that their ear candles are unapproved medical devices and requesting that the companies cease marketing and distributing their products.

Ear candling, also known as “ear coning” or “thermal-auricular therapy,” is an alternative medicine practice that advocates claim improves general health and well-being.  Ear candles are, according to FDA, “hollow cones that are about 10 inches long and made from a fabric tube soaked in beeswax, paraffin, or a mixture of the two” that are being marketed as treatments for a variety of conditions, including “ear wax buildup, sinus infections, hearing loss, headaches, colds, flu, and sore throats.” 

And what does one do with an ear candle to promote holistic relaxation and comfort?  That’s right, you light it up, and lay on your side, potentially allowing hot wax to drip into your ear, apparently to create negative pressure that supposedly draws wax and debris out of the ear canal. 

In this case, which we previously posted on, the holistic candlers alleged violations of their First, Ninth, Tenth, and Fourteenth Amendment rights, and sought injunctive relief staying FDA’s determination that their ear candles are unapproved medical devices, as well as declaratory relief voiding FDA’s determination.  FDA moved to dismiss the case on several grounds, including lack of standing, lack of ripeness, and failure to exhaust administrative remedies. 

In addition to ruling that the holistic candlers lacked subject matter jurisdiction (standing, ripeness), Judge Leon ruled that the holistic candlers’ efforts to obtain injunctive and declaratory relief “is nothing more than a pre-enforcement challenge foreclosed by” the U.S. Supreme Court’s 61-year old decision in Ewing v. Mytinger & Casselberry, Inc., 339 U.S. 594 (1950).  Ewing and its progeny established that courts lack jurisdiction to enjoin FDA from initiating enforcement proceedings under the FDC Act.  Specifically, the Supreme Court held in Ewing that a district court lacked jurisdiction to review the FDA’s preseizure determination of probable cause because "Judicial review of this preliminary phase of the administrative procedure does not fit the statutory scheme nor serve the policy of the [FDC Act].”  (The Supreme Court’s decision in Ewing also formed the basis for a 2010 decision out of the U.S. District Court for the District of Wyoming in a case against FDA involving marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL products – see our previous post here.)

Finally, Judge Leon wrote in his opinion that even if the holistic candlers had standing to sue the FDA, if their claims were ripe, and their administrative remedies were exhausted, their remaining statutory and constitutional claims would still fail.  “Some of these claims fail because they assert conclusory allegations without pleading the elements necessary to prevail as a matter of law.  Others claims are insufficient as a matter of law.  Still others fail because no private right of action exists for the alleged violations,” wrote Judge Leon in his 14-page opinion.  Thus, “[i]n sum, plaintiffs’ remaining claims are foreclosed by plaintiffs’ failure to exhaust administrative remedies, or they fail simply as a matter of law.” 

Hyman, Phelps & McNamara, P.C. is pleased to announce that Diane B. McColl has been elected to serve as the new Vice President of the International Society of Regulatory Toxicology and Pharmacology (“ISRTP”).  ISRTP’s mission is to provide an open public forum for policy makers and scientists promoting sound toxicologic and pharmacologic science as a basis for regulation affecting human safety and health, and the environment.

Ms. McColl, who is both an attorney and a pharmacist, is also an elected member to the U.S. Pharmacopeial Convention’s Expert Committee for the Food Chemicals Codex (Monographs – Food Ingredients) for the 2010-2015 cycle.

By Susan J. Matthees –

A new development in the ongoing battle involving sodium thiopental, one of the drugs used for lethal injections, surfaced today when the Drug Enforcement Administration (“DEA”) seized Georgia’s supply of the drug.  According to the Atlanta Journal-Constitution, a DEA spokesperson confirmed that the drug had been seized and stated that “[t]here were questions about the way the drugs were imported.”  DEA did not make any further statements.

As we reported two weeks ago, attorney John Bentivoglio sent a letter to Attorney General Eric Holder alleging that Georgia violated the Controlled Substances Act by importing sodium thiopental.  Inmates in 3 other states have sued FDA over the allegedly illegal importation of the drug from Europe.   

By Nisha P. Shah –

Effective March 28, 2011, sponsors and investigators of human drug and biological products subject to either an investigational new drug application ("IND") or bioavailability ("BA") or bioequivalence ("BE") studies exempt from IND requirements will have revised safety reporting requirements under the FDA regulations.  FDA issued its final rule on September 29, 2010, which amends the IND safety reporting requirements under 21 CFR Part 312 and adds safety reporting requirements for persons conducting BA or BE studies under 21 CFR Part 320.  75 Fed. Reg. 59935 (Sept. 29, 2010). 

FDA had published a proposed rule to revise its premarketing and postmarketing safety reporting regulations on March 14, 2003.  The agency decided to bifurcate the premarketing and postmarketing safety reporting requirements in separate rulemakings, and this final rule focuses only on the premarketing safety reporting regulations.  Simultaneous to finalizing the regulations, FDA issued draft guidance on the topic, “Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies,” and published a Q&A on the agency’s website.  The revised requirements are designed to clarify and improve the quality of safety information reported to FDA, harmonize international reporting standards and definitions, and improve safety monitoring by sponsors and investigators.  However, the regulations appear to impose a greater burden on sponsors to determine when an adverse event is reportable.

Definitions

Under the existing IND safety reporting regulations, sponsors were required to notify FDA and all investigators of any adverse event “associated with the use of the drug” that was both serious and unexpected and any results from animal studies which suggested a significant risk for humans.  FDA believed that sponsors were reporting frequently serious adverse experiences for which there was little evidence of a causal relationship between the drug and the event.  The final regulations, available at Revised 21 C.F.R. § 312.32, set forth five new or revised definitions which help clarify when a safety report should be submitted:

“Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”

An adverse event or suspected adverse reaction is considered a “life-threatening adverse event or life-threatening suspected adverse reaction” if, in the view of the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.

An adverse event or suspected adverse reaction is considered “serious” if the investigator or sponsor believes any of the following outcomes may occur: “death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require  medical or surgical intervention to prevent one of the outcomes listed in this definition.”

“Suspected adverse reaction” is considered “any adverse event for which there is a reasonable possibility that the drug caused” the event. “Reasonable possibility” suggests there is a causal relationship between the drug and the adverse event.  “Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”

An adverse event or suspected adverse reaction is “unexpected” if “it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.  The term ‘unexpected’ also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.”

Safety Reporting Requirements

The new definitions change when sponsors are to submit expedited safety reports and distinguish circumstances in which it is appropriate to submit individual cases compared to cases which should be aggregated and compared to a control group.  Below are some highlights of the final regulations and guidance:

Prompt Review of Safety Information: Similar to the former regulations, a sponsor must continue to “promptly” review all safety information obtained from foreign or domestic sources.  However, the sources of information listed in the regulation has expanded to include “any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.” Revised 21 C.F.R. § 312.32(b).  The guidance recommends that the sponsor also conduct literature searches at least annually to find new safety information for reporting purposes. 

Submission of Serious Risks: Sponsors will be required to notify FDA and all participating investigators in an IND safety report of potential serious risks from clinical trials or any other source within 15 calendar days after the sponsor determines that it is reportable. Revised 21 C.F.R. § 312.32(c)(1).  The sponsor must identify all other IND safety reports previously submitted to FDA concerning similar suspected adverse reactions and analyze the significance of the suspected adverse reaction in light of the other reports.  The sponsor must submit an IND safety report when any of the following criteria are met:

1. Serious and unexpected suspected adverse reaction (Revised 21 C.F.R. § 312.32(c)(1)(i): the event must be serious, unexpected, and suspected adverse reaction.  Under the revised reporting requirements, the definition of “suspected adverse reaction” imposes a greater burden on sponsors to determine whether the drug caused the event. 

2. Findings from other sources (Revised 21 C.F.R. § 312.32(c)(1)(ii)): the event must suggest a significant risk in humans exposed to the drug.  Other sources may include epidemiological studies, pooled analysis of multiple studies, and clinical studies other than those conducted under the present IND.

3. Findings from animal or in vitro testing (Revised 21 C.F.R. § 312.32(c)(1)(iii)): the event must suggest a significant risk to humans exposed to the drug.  This requirement expands a sponsor’s reporting obligations to include findings from in vitro studies.  Findings from carcinogenicity, mutagenicity, teratogenicity, and other organ toxicity studies are types of studies that could reveal a significant risk.  The guidance advises sponsors to determine whether the finding suggests a significant risk to humans or is too early to interpret without further investigation.

4. Increased occurrence of serious suspected adverse reactions (Revised 21 C.F.R. § 312.32(c)(1)(iv)): any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.  The decision about whether to report depends on several factors, including study population and the nature and seriousness of the event.

Submission of Unexpected Fatal or Life-Threatening Risks:  Similar to the former regulations, a sponsor must continue to notify FDA of any unexpected fatal or life-threatening suspected adverse reaction within 7 calendar days after the sponsor’s receives the information.  Revised 21 C.F.R. § 312.32(c)(2). 

Reporting of Certain Study Endpoints: FDA clarified that study endpoints must not be reported as IND safety reports for trials that are designed to evaluate the effect of the drug on disease-related mortality or morbidity.  Revised 21 C.F.R. § 312.32(c)(5).  The sponsor must report study endpoints to FDA as described in the protocol.  However, if a serious and unexpected adverse event occurs for which a causal relationship between the drug and the event is suggested, the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint.

Unblinding: FDA acknowledged that breaking the blind may be necessary to determine the reportability of serious, unexpected, suspected adverse reactions.  Knowledge of the treatment may provide important safety information and could impact the ongoing conduct of a clinical trial.  If the sponsor believes that breaking the blind may compromise study integrity, the sponsor can propose an alternative reporting format to maintain the blind.

Investigator Reporting Requirements: FDA’s revised regulations imposes additional investigator reporting requirements.  Under the final regulations, investigators must report immediately to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and the report must include a causality assessment.  Revised 21 C.F.R. § 312.64(b).  Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event.  In that case, investigators are required to report the event immediately to the sponsor. 

Bioavailability and Bioequivalence Studies: Under the former regulations, certain in vivo BA/BE studies in humans were exempt from the IND safety reporting requirements.  The final rule contains safety reporting requirements for such BA/BE studies that are conducted in the United States.  The person conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event that is observed in a BA/BE study.  This requirement does not apply to human BA and BE studies exempt from the IND requirements that are conducted outside of the United States. 

Timing of Safety Reports Submission: The timing of the safety reports remains unchanged.  Safety reports must be submitted to FDA and all participating investigators no later than 15 calendar days after the sponsor or person conducting the study becomes aware of the event, except for fatal and life-threatening adverse events which must be submitted no later than 7 calendar days.

Format of Safety Reports: The format for IND safety reports is based on the type of expedited report; for individual case reports, a sponsor would use FDA Form 3500A, though FDA will accept foreign suspected adverse reaction reports on a CIOMS I Form. Revised 21 C.F.R. § 312.32(c)(1)(v).  For reports of overall findings or pooled analyses, a narrative format must be used.  FDA may require a sponsor or a sponsor may request to submit IND safety reports in a different format or frequency than that prescribed in the regulations.  Revised 21 C.F.R. § 312.32(c)(3).  For BA/BE studies, each report must be submitted on FDA Form 3500A or in an electronic format that FDA can process.  Revised 21 C.F.R.§ 320.31(d)(3).

By Kurt R. Karst –      

Each year, thousands – indeed, tens of thousands – of pages are written concerning the Hatch-Waxman Amendments.  As we were clearing out our in-box this past weekend, we came across two scholarly articles from some Hatch-Waxman “regulars” that we think merit a read-through by our FDA Law Blog readers (not that we agree or disagree with the views expressed in the articles). 

The first article – published in the University of Florida Law Review – comes to us from Michael A. Carrier, a professor at the Rutgers University School of Law-Camden, and is titled “A Real-World Analysis of Pharmaceutical Settlements: The Missing Dimension of Product Hopping.”  Professor Carrier, an opponent of patent settlement agreements (or what opponents call “pay-for-delay” or “reverse payment” agreements), explores the intersection of patent settlement agreements and so-called “product hopping.”  Federal Trade Commission (“FTC”) Commissioner Rosch recently defined “product hopping” in a speech (pages 14-17) as the practice of “introducing new patented products with minor or no substantive improvements in the hopes of preventing substitution to lower-priced generics.”  One example of product hopping, also known as “evergreening,” “line extension,” or “product switching,”  is when a company switches the market, usually around the time generic competition is expected, from one dosage form to another.

According to Professor Carrier, patent settlement agreements and product hopping create a “lethal combination” that “erects a significant roadblock to pharmaceutical competition.”  Specifically:

For a settlement that prevents patent challenges for a period of time – even if less than the duration of the patent – gives the brand firm the space in which it can comfortably switch the market to the new product.  By the time, years later, when the generic enters, the market will have already been switched to the new product.  As a result, the generic firm, which can no longer take advantage of state drug product selection laws, fails to provide meaningful competition.

Although we are certainly not antitrust or patent settlement experts, it seems to us that one way generic drug companies can and do attempt to shield themselves from the potential effects of product hopping (or at least dampen its potential effects) is to include in agreements provisions that create a trigger to early marketing based on some market erosion target. 

The second article that caught our eye is a working paper co-authored by Columbia Law School Professor C. Scott Hemphill and Stanford Law School Professor Mark A. Lemley.  Titled “Earning Exclusivity: Generic Drug Incentives and the Hatch-Waxman Act,” the article, like the Carrier article, discusses patent settlement agreements and product hopping, but suggests an  overhaul to the 180-day generic drug marketing exclusivity incentive created by the Hatch-Waxman Amendments (and significantly modified by the Medicare Modernization Act) that reminded us of those 1980’s Smith Barney commercials with the legendary John Houseman – “We make money the old-fashioned way.  We earn it.”

According to Professors Hemphill and Lemley, the original intent of creating the 180-day exclusivity incentive – i.e., to encourage generic drug companies “to challenge weak patents and enter the market earlier, lowering prices and benefiting consumers” – has been “hijacked.”  Today, they argue, 180-day exclusivity “is a tool that encourages weak challenges to patents in the hopes of prompting settlement, and leads generic firms to settle even strong challenges for delayed entry in exchange for keeping their exclusivity.” 

As an alternative that harkens back to and is inspired by FDA’s old “successful defense” prerequisite to 180-day exclusivity that the D.C. Circuit struck down in the late 1990s finding it inconsistent with the statute (see e.g., Mova Pharm. Corp. v. Shalala, 140 F.3d 1060 (D.C. Cir. 1998)), Professors Hemphill and Lemley argue that “first-filing generic drug companies should be entitled to 180 days of exclusivity only if they successfully defeat the patent owner, for example, by invalidating the patent or by proving that they did not infringe that patent.”   Under their approach, “if the generic firm files a Paragraph IV certification, is sued, and wins the suit, it receives the [180-day exclusivity] bounty.  If the generic firm instead loses the suit, it loses the exclusivity.  Nor can it receive the bounty if it settles for delayed entry.”  The professors “suggest that this change could be implemented without any legislative action, for example, by the FDA in interpreting the Hatch-Waxman Act, and by the [FTC] in its enforcement of the FTC Act.” 

The Hemphill/Lemley earned exclusivity proposal is interesting, and if seriously considered, will certainly garner some criticism from those who think the current system created by the MMA is adequate with some tweaks, such as addressing the circumstances under which 180-day exclusivity is forfeited if an ANDA sponsor fails to obtain timely tentative approval.

By Jennifer B. Davis –

Three and a half years ago, Congress directed FDA to identify lower risk devices for reporting malfunction MDRs on a quarterly basis in summary form.  FDA still has not done so. 

Specifically, the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), Title II, section 227, amended section 519(a) of the FDC Act.  The amendment directed FDA to identify in a Federal Register notice, or through letters to manufacturers, those Class I and Class II devices (if not permanently implantable, life supporting, or life sustaining) that the agency determined should remain subject to the Part 803 Medical Device Reporting requirements, and to establish new, less burdensome criteria for reporting malfunctions for such devices in summary form on a quarterly basis.  (The reporting requirements for Class III devices, and for Class II devices that are permanently implantable, life supporting, or life sustaining were not affected by FDAAA.  We also note that some devices could, if FDA so determines, be altogether exempt from malfunction reporting.)

Since the enactment of FDAAA, FDA has taken no action to implement this amendment,  prompting understandable industry confusion as to what the current malfunction reporting requirements really are – until now, that is.  Last week, FDA published a Federal Register notice clarifying that manufacturers and importers of class I and class II not permanently implantable, life supporting, or life sustaining devices “must continue to report in full compliance with part 803, pending further FDA notice . . . as to specific device types subject to part 803, and the establishment of [alternative reporting] criteria.”  Notwithstanding congressional intent that the reporting burden be reduced, the agency maintains “it is necessary to subject all such devices to part 803 in the interim, in order to protect the public health by ensuring that there is no gap in malfunction reporting for any device.”  Given the uncertainties about whether and how FDA actually reviews and uses malfunction medical device reports once they are submitted, this rationale seems questionable.  The notice does not say when FDA plans to propose regulations implementing the amendment.  The wait continues . . . .

By Peter M. Jaensch & John R. Fleder –

On January 18, 2011, the President issued a significant Order entitled a “Memorandum for the Heads of Executive Departments and Agencies.”  The Memorandum directs “agencies with broad regulatory compliance and administrative enforcement responsibilities” to, within 120 days, “develop plans to make public information concerning their regulatory compliance and enforcement activities accessible, downloadable, and searchable online.”

On March 11, 2011, this firm sent a letter to the FDA Chief Counsel, Ralph S. Tyler, calling on FDA to commit to posting on its website information regarding its enforcement activities, including:

• the names and judicial districts of all lawsuits filed by the government with regard to activity regulated by FDA;
• the names and judicial district of all lawsuits filed against the FDA (and/or its officials) in connection with FDA’s regulatory or enforcement activities; and
• all briefs and other pleadings publicly filed in such cases.

Although some agencies already post online much of this type of information, FDA’s website has not provided a comprehensive picture of the agency’s activities in court. We believe that making all public information available online will promote consistency in FDA actions, and permit industry and the general public to make informed decisions about FDA-regulated products.  Whether FDA will agree – or respond – remains to be seen.

By Ricardo Carvajal - 

In an upcoming issue of the Federal Register, FDA is announcing a public meeting scheduled for March 29 to solicit comment on the import safety provisions of the Food Safety Modernization Act ("FSMA").  At the meeting, appropriately titled “Food Safety Modernization Act; Title III – A New Paradigm for Importers,” attendees will have “multiple opportunities . . . to actively express their views by making presentations at the meeting, participating in break-out sessions . . . , and submitting comments to the docket” on the four major import safety provisions of the FSMA:

• The foreign supplier verification program under section 301, which “requires importers to conduct risk-based foreign supplier verification activities to verify that imported food is not adulterated under [FDC Act section 402] or misbranded under [FDC Act section 403(w)] (relating to allergens) and is produced in compliance with FDA’s preventive controls requirements and produce safety standards, where applicable;"

• The voluntary qualified importer program under section 302, which “requires FDA to establish a voluntary, user-fee funded program to expedite entry into the United States of imported food from eligible, qualified importers;”

• The mandatory import certification authority under section 303, which authorizes FDA, “based on risk considerations, to require an article of food offered for import into the United States to be accompanied by certifications or other assurances that the food complies with relevant provisions” of the FDC Act; and

• The third-party auditor accreditation system provided for by section 307, which “directs FDA to establish a system for the recognition of accreditation bodies that accredit third-party auditors to issue certifications for purposes of” the import certification provision and the voluntary qualified importer program.

FDA is also announcing a public hearing scheduled for March 30-31 to solicit views on international comparability assessments and equivalence determinations, and to obtain information on “policies, practices, and programs used by foreign regulators to ensure the safety of imported foods and animal feed.”  FDA expects that “initiatives discussed at the 2-day hearing will align with and help support FSMA implementation.”

The scheduling of these hearings within three months of the FSMA’s enactment suggests that FDA intends to adhere to an aggressive timetable for the new law’s implementation – resources permitting.