In an effort to eliminate rogue pharmacies from dispensing controlled substances over the Internet, Congress passed legislation amending the Controlled Substances Act (“CSA”).  The Ryan Haight Act (H.R. 6353), which honors a teenager who died of an overdose of controlled drugs obtained over the Internet, awaits President Bush’s signature.  The legislation follows the recent Drug Enforcement Administration (“DEA”) crackdown on Internet pharmacies and distribution of controlled substances to those pharmacies.   

The Act would permit DEA to register only certain pharmacies meeting specific criteria to dispense controlled substances over the Internet.  In summary, the Act would prohibit dispensing controlled substances by means of the Internet unless:

1.  The patient has a “valid prescription;”

2.  DEA has modified the pharmacy’s current DEA registration to dispense via the Internet. (It is unclear whether the Act would require Internet pharmacies to first register and then obtain a modification to their registration or if “online pharmacy” will be a separate category of registrant on the registration application.);

3.  The pharmacy reports to DEA the quantity dispensed over the Internet if it dispenses 100 prescriptions or 500 or more dosage units in a month;

4.  The pharmacy notifies DEA 30 days prior to offering to sell, deliver, distribute or dispense controlled substances over the Internet; and

5.  The pharmacy certifies that it complies with the Act and posts its name, address, telephone number and pharmacist in charge on its homepage.

The Act would also enhance penalties for the illegal distribution of schedule III-V controlled substances and provide state Attorneys General with the ability to bring civil action in federal district court to enjoin Internet pharmacies.

The Act prohibits controlled substances from being “delivered, distributed or dispensed by means of the Internet without a valid prescription.”  The Act defines “valid prescription” as “a prescription that is issued for a legitimate medical purpose in the usual course of professional practice by . . . a practitioner who has conducted at least 1 in-person medical evaluation of the patient . . . or a covering practitioner.”  An “in-person medical evaluation” is a “medical evaluation that is conducted with the patient in the physical presence of the practitioner, without regard to whether portions of the evaluation are conducted by other health professionals.”  A “covering practitioner” is “a practitioner who conducts a medical evaluation (other than an in-person medical evaluation) at the request of a practitioner who . . . has conducted at least 1 in-person medical evaluation of the patient or an evaluation through the practice of telemedicine, within the previous 24 months . . . and is temporarily unavailable to conduct the evaluation of the patient.”

To “deliver, distribute, or dispense by means of the Internet refers, respectively, to any delivery, distribution, or dispensing of a controlled substance that is caused or facilitated by means of the Internet.”

An “on-line” pharmacy is an entity or Internet site that “knowingly or intentionally delivers, distributes, or dispenses, or offers or attempts to deliver, distribute, or dispense, a controlled substance by means of the Internet” but does not include registered manufacturers or distributors who do not dispense to unregistered individuals or entities; registered nonpharmacy practitioners; hospitals or medical facilities operated by U.S. agencies; “mere advertisements that do not attempt to facilitate an actual transaction involving a controlled substance;” or a registered pharmacy “whose dispensing controlled substances via the Internet consists solely of” filling or refilling schedule III-V prescriptions.

The Act contains a lengthy section discussing the new requirements for telemedicine and provides the U.S. Attorney General with the authority to issue registrations to practitioners who practice telemedicine.       

There are several aspects of the Act that will need to be clarified.  For example, pharmacies do not “distribute” controlled substances pursuant to a prescription so it is unclear why the Act prohibits distributing, along with delivery and dispensing, without a valid prescription.  “Distribute” means “to deliver (other than by administering or dispensing) a controlled substance or listed chemical.”  21 U.S.C. § 802(11).  Controlled substances are “dispensed,” not “distributed,” pursuant to a prescription.  “Dispensing” is the delivery of “a controlled substance to an ultimate user or research subject by, or pursuant to the lawful order of, a practitioner.”  21 U.S.C. § 802(10).  By prohibiting distribution without a valid prescription the Act prohibits something that should not occur.

Also, the Act would define a “valid prescription,” although historically DEA has deferred to local medical standards on these issues.  Including this definition raises a number of issues.  A “valid prescription” is defined as one “issued for a legitimate medical purpose in the usual course of professional practice by . . .a practitioner who has conducted at least 1 in-person medical evaluation of the patient . . . or a covering practitioner.”  The regulations have long required that for controlled substance prescriptions “to be effective,” they must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of professional practice.  21 C.F.R. § 1306.04(a).  DEA has addressed the issue of Internet pharmacies and opined that a bona fide physician/patient relationship must exist for a doctor to issue a prescriptions in the usual course of professional practice and that the doctor must have conducted a physical examination to establish such a relationship.  The Act requires an “in-person  medical evaluation.”  Is “an in-person medical evaluation” the same as a “physical examination?”  We surmise that an “in-person medical evaluation” appears close to a “physical examination.”  But conducting an “in-person medical evaluation” may involve diagnosing a patient without physically examining them, while a physical examination seems to include, at the very least, looking at the patient, listening to their heartbeat and taking their blood pressure.  DEA needs to further clarify what qualifies as “in-person medical evaluation.” Secondly, the definition of  “covering practitioner” appears to indicate that “an evaluation of the patient through the practice of  telemedicine” is an adequate substitute for an “in person medical evaluation.”   

Interestingly, a valid prescription has no time constraints during which a prescribing practitioner had to have conducted at least one in-person medical evaluation, but requires a practitioner for whom a prescriber is covering, to have conducted an evaluation within the past 24 months. 

There is also no information on the type of endorsement or registration DEA will provide to pharmacies so they can dispense via the Internet.  And while endorsement requests will assist DEA in determining the legitimate pharmacies, how will DEA keep those lacking endorsements from dispensing over the Internet, especially if they lack a permanent physical address?  The endorsement and notification requirements will help ensure a pharmacy’s legitimacy by providing DEA with a physical address, but in order for the Act to be effective, DEA must prevent patients from ordering from pharmacies that have not met the Act’s requirements.

By John A. Gilbert and Larry K. Houck

A citizen petition has been submitted to FDA asking the agency to take regulatory action under § 301(ll) against any foods to which sweetening compounds present in the botanical Stevia rebaudiana have been added, on the ground that those compounds (known as steviol glycosides) are drugs.  The petition asks FDA to seize foods to which steviol glycosides have been added, enjoin the distribution of such foods, and refuse importation of such foods.  The petition further asks FDA to “abstain from issuing a letter of no objection to any pending GRAS notification that addresses any use of a steviol glycoside in food.”  A GRAS notification is a voluntary submission that informs FDA of the notifier’s conclusion that the proposed use of a substance in food is generally recognized as safe (GRAS).  If the use of a substance is GRAS, then it is not subject to premarket approval as a food additive.

Two GRAS notifications for steviol glycosides currently are pending at FDA, and there was some expectation within the food industry that the agency might respond to those notifications as early as November.  Issuance of a letter of no objection by FDA is not required prior to marketing a substance for a GRAS use, but FDA had previously raised a number of questions about the safety of the use of steviol glycosides as sweeteners.  In light of those safety concerns, major food companies have deferred market entry until such time as FDA issues letters of no objection to the pending GRAS notifications.  The petition asserts that issuance of those letters “would effectively sanction a violation of law.”

As we have discussed in a number of previous blog posts, § 301(ll) prohibits the marketing of any food to which has been added an approved drug, a licensed biologic, or a drug or biologic for which substantial clinical investigations have been instituted and their existence made public.  The petition contends that the § 301(ll) prohibition applies to steviol glycosides because they are drugs for which substantial clinical investigations have been instituted and made public: clinical investigations focusing on the effect of steviol glycosides on hypertension have been published in peer-reviewed journals.  Although § 301(ll) provides a number of exceptions, most notably a first-to-market exception for drugs that are first marketed in food, the petition argues that none of those exceptions apply to steviol glycosides.

By Diane B. McColl & Ricardo Carvajal

FDA recently published a final rule to expand and streamline authorized health claims related to osteoporosis risk reduction. Effective January 1, 2010, companies may use the newly simplified health claims for calcium and vitamin D products, and calcium products in relation to osteoporosis risk reduction. In addition to adding a “calcium and vitamin D” health claim to FDA’s regulations, the Agency shortened and simplified the language of approved claims in an effort to promote wider use of the claims on product labeling.

The final rule:

• Adds a claim for calcium and vitamin D combination products to reduce osteoporosis risk;
• Eliminates current mandated references to age, sex and race as specific risk factors  and makes optional mention of the prevalence of osteoporosis in U.S. population (and/or subpopulations);
• Eliminates the requirement that the claim include a statement that total dietary intake greater than 200 percent of the recommended daily intake has no further benefit to bone health;
• Makes optional the currently required explanation of the mechanism through which calcium (and calcium and vitamin D) reduces osteoporosis risk; and
• Makes optional a reference to the need for physical activity in reducing risk.

FDA's examination of calcium and vitamin D health claims for osteoporosis originated in response to a 2004 citizen petition submitted by the Beverage Institute for Health and Wellness, a Coca Cola research company. Relying heavily on the 2000 National Institutes of Health “Consensus Statement on Osteoporosis, Prevention and Therapy” and the 2004 Surgeon General’s report, “Bone Health and Osteoporosis,” FDA proposed these changes to the previously allowable health claims to increase the use of osteoporosis risk health claims for calcium and vitamin D in an effort to “improve the U.S. population’s consumption of these nutrients.”

In its final rule, FDA acknowledges that the cumbersome nature of the old format for these claims and their limited scope is the likely reason that so few eligible products use the claim on their labels. These claims were long and difficult to include on labels where space already is precious. A 2001 Food Label and Package Survey report showed the health claims being used in only one of 87 shelf-stable juices and none of the ten milk products in the survey.

The current revisions make the osteoporosis health claim language shorter and more flexible and thus more appealing to put on labels. FDA hopes the simplification of calcium claims and the addition of vitamin D claims will increase their use.

Some model claims under the new regulations include:

• Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis.
• Adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis.
• Adequate calcium as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis later in life.
• Adequate calcium and vitamin D as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis later in life.

FDA presents some sobering numbers in support of its effort. According to the final rule osteoporosis “affects more than 10 million individuals and causes approximately 1.5 million fractures annually. Every year, these lead to more than 2.6 million physician office visits, over 800,000 emergency room visits, and more than 500,000 hospitalizations. . . .  The direct care expenditures for osteoporotic fractures along range from 12 to 18 billion dollars each year (measured in 2002 dollars).”

By Ricardo Carvajal & Colleen M. Brown

UPDATE:

• On October 13, 2008, the American Academy of Pediatrics issued a report recommending a doubling of vitamin D for children.

Inside Health Policy recently reported on the writings of several professors who opined on courts’ deference to the FDA.  The writings discussed in the Inside Health Policy piece were from the July 2008 Cornell Law Review, which devoted an entire issue to “Symposium: U.S. Food and Drug Regulation in its First Century and Beyond.” 

Regardless of whether you agree with the arguments the authors make, this isn’t a bad resource.  Need a good quote for a brief challenging FDA’s decision-making?  Try n. 29 to Lars Noah’s The Little Agency that Could (Act with Indifference to Constitutional and Statutory Strictures).  Want to argue in favor of deference to FDA?  Pages 943-952 of James T. O’Reilly’s Losing Deference in the FDA's Second Century: Judicial Review, Politics, and a Diminished Legacy of Expertise discusses six important Supreme Court cases involving deference to FDA. 

If you have a products liability case, several articles are worth a skim, including David C. Vladeck’s The FDA and Deference Lost: A Self-Inflicted Wound or the Product of a Wounded Agency? and Carl Tobias’ FDA Regulatory Compliance Reconsidered.

With all due respect to the learned authors, there isn’t an overwhelming amount of useful information for the FDA practitioner.  There are two exceptions, however.  Catherine Struve’s article Greater and Lesser Powers of Tort Reform: The Primary Jurisdiction Doctrine and State-Law Claims Concerning FDA-Approved Products, makes a clever – if untested – argument that the Seventh Amendment right to jury trial limits the effect of the primary jurisdiction doctrine in cases where there is such a right to trial by jury.  In addition, Gary Lawson’s Dirty Dancing – The FDA Stumbles with the Chevron Two-Step, makes the argument that FDA has incorrectly internalized the second step of a court’s analysis under Chevron U.S.A., Inc. v. NRDC, and has given itself license to make a permissible interpretation rather than the “best interpretation possible.” 

In sum, this issue of the Cornell Law Review may be worth skimming the next time you find yourself litigating with FDA or even just a litigating case involving the FDC Act.

By James P. Ellison 

On October 2, 2008, the Consumer Product Safety Commission (“CPSC”) held a public meeting on the testing and certification requirements imposed by the recently enacted Consumer Product Safety Improvement Act (“CPSIA”).  A similar meeting was held on September 4, 2008 and several others are planned for the near future.  The meeting included sessions on general conformity certification, laboratory accreditation, and mandatory third-party testing for children’s products, followed by a question and answer period.  Of particular interest was the statement by Gib Mullan, the CPSC Director of Compliance and Field Operations, that the CPSIA’s general conformity certification under section 102 applies to any drug product that is also regulated by the Commission through other laws, such as through the Poison Prevention Packaging Act.  This is true, according to Mr. Mullan, even if the drug is not indicated for use in a pediatric population.  In fact, if the drug is indicated for pediatric use, there may be additional requirements imposed by the CPSIA, such as mandatory third-party testing.  A video of the meeting is available on CPSC’s website. 

Section 102(a)(1) of CPSIA amends section 14(a)(1) of the Consumer Product Safety Act (“CPSA”) to require each manufacturer (including an importer) of any consumer product to issue a certificate that the product complies with CPSC rules under the CPSIA or similar requirements under any of the other Acts administered by the CPSC.  According to the Commission, “the certificate must be based on a test of each product or on a reasonable testing program.  This requirement is effective beginning on November 12, 2008.  There are additional third party testing requirements for children’s products.”

Preceding the October 2 sessions was a welcome by Nancy Nord, Acting Chairman of the CPSC, who emphasized that the CPSIA has ambitious time deadlines and that in an effort to meet these deadlines the CPSC will be publishing regulations via a new process not normally used by CPSC.  Ms. Nord stated that interested parties should pay attention to the Federal Register and the CPSC Website and provide comments quickly so that they receive full consideration by the Commission.  The CPSC recently posted a Request for Comment and Information regarding CPSIA’s Section 102 requirements for certificates for conformity testing and third-party testing.  The post indicates that the CPSC is particularly interested in comments on the use of electronic certificates as well as the issue of multiple certifications for the same product.  The CPSC is accepting comments regarding certification for conformity testing and third-party testing through October 29, 2008.

By John R. Fleder and Serafina E. Lobsenz

BNA, a leading provider of expert information and analysis, is holding a one-day, information-packed conference, titled “Pharmaceutical Patent Laws: A prescription for Success in Challenging Times.” Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be on a panel discussion of Non-Patent Marketing Exclusivity with Brian McCormick (Hogan & Hartson), Stephen Albainy-Jenei (Frost Brown Todd LLC; Patent Baristas Blog), and Shashank Upadhye (Apotex).

Billed as a conference to “get a prescription for success as legislative, judicial, administrative, and ‘marketplace’ developments continue to advance at breakneck speed,” the conference is intended to help participants:

• Get maximum value from your patents;
• Learn winning litigation tactics from leading practitioners;
• Avoid antitrust consequences when settling cases; and
• Look for trends – where does case law go from here?

The conference will be held at the Ritz-Carlton, Pentagon City, 1250 South Hayes Street, Arlington, VA, on November 12, 2008. A copy of the conference brochure is available here. Additional conference information is available here.

Special FDA Law Blog Discount – BNA is offering FDA Law Blog readers a 40% discount off of the registration fee. Further, if you sign up two people at the discounted rate, the third person is free. To register for the conference, go to the BNA website and enter the following code – [CONF40NE]. FDA Law Blog is a conference media sponsor.

First introduced in September 2007 as S. 2029 by Senator Charles Grassley (R-IA), the ranking member of the Committee on Finance, and Senator Herb Kohl (D-WI), the Chair of the Special Committee on Aging, the Physician Payment Sunshine Act is progressing through Congress. Representatives Peter DeFazio (D-OR) and Pete Stark (D-CA), Chairman of the Ways and Means Subcommittee, introduced a bill in the House similar to the Senate version in March of this year (H.R. 5605).  A number of trade associations, including PhRMA and AdvaMed, have voiced their support of the Senate bill and the Consumers Union, the American Medical Student Association and the Medicare Rights Center have come out in support of the House bill.  One pharmaceutical manufacturer, Eli Lilly, has announced that it will voluntarily make public certain payments to physicians even absent the legislation. 

The Act’s underlying purpose is “to shine light” on payments by pharmaceutical companies to practitioners.  Congress believes that such payments are intended to influence medical decision-making regarding patient treatment.  The Act would amend title XI of the Social Security Act to provide for transparency in the relationship between physicians and manufacturers of drugs, devices, or medical supplies for which payment is made under Medicare, Medicaid, or the State Children’s Health Insurance Program.  Specifically, both bills propose requiring electronic reporting of gifts valued at more than $25, public availability to the information reported, and stiff civil money penalties for failing to report (between $10,000 and $1000,000 for each violation, although the House bill includes a “knowing” component).   

A few states (Maine, Minnesota, Vermont, West Virginia) and the District of Columbia have enacted laws similar to the proposed bill.  The Senate bill, however, would preempt these state laws to guarantee consistency in application among the states.  So far, industry has generally come out in support of the legislation, but has advocated for a higher threshold reporting requirement.

By Serafina E. Lobsenz and Anne Marie Murphy

On October 7, 2008, the U.S. Court of Appeals for the Eleventh Circuit, in Hi-Tech Pharmaceuticals v. Lester M. Crawford, affirmed a district court decision finding that: (1) FDA complied with the Administrative Procedure Act (“APA”) in promulgating its final rule banning dietary supplements that contain ephedrine alkaloids; and (2) the government’s seizure of Hi-Tech Pharmaceuticals’ dietary supplements was proper because those supplements were adulterated.  (Hi-Tech Pharmaceuticals is not to be confused with Hi-Tech Pharmacal Co. Inc.)  Under FDC Act § 402(f)(1), a dietary supplement is adulterated if it presents a significant or unreasonable risk of illness or injury.  In any proceeding under that section, the government bears the burden of proof, and a court must decide the issues on a de novo basis.  Focusing on use of the term “de novo” in § 402(f)(1), Hi-Tech Pharmaceuticals argued that the FDC Act “requires a district court to hear original evidence on the question of adulteration, even where the FDA has conducted an administrative rulemaking process and promulgated a valid rule declaring the product adulterated.”  Noting that the issue was one of first impression, the appellate court disagreed, and held that “it is sufficient for the Government to present evidence that: (1) the regulation exists and (2) it applies to the product that is the subject of the enforcement action.”  The appellate court dismissed as meritless Hi-Tech Pharmaceuticals’ other arguments challenging the validity of FDA’s ephedra final rule.

By Ricardo Carvajal

In a surprising and likely controversial decision regarding so-called “Section 340B covered entities,” the U.S. Court of Appeals for the Ninth Circuit in County of Santa Clara v. Astra U.S.A., Inc. recently reversed the U.S. District Court for the Northern District of California’s dismissal of a complaint under Federal Rule of Civil Procedure 12(b)(6) for failure to state a claim.  Applying federal common law of contracts, the court held “that the covered entities are intended direct beneficiaries of these agreements and thus have a right to enforce the agreements’ discount provisions against the Manufacturers and sue them for reimbursement of excess payment,” a controversial stance in the absence of a contractual right to sue or statutory private right of action.

Under § 602 of the Veterans Health Care Act of 1992, Pub. L. No. 102-585, section 340B entities, also known as federally funded medical clinics, may purchase prescription drugs at a discount from drug manufacturers under a standardized agreement – called a Pharmaceutical Pricing Agreement (“PPA”) – between the federal government and drug companies.  The Ninth Circuit court pointed out that the intent underlying § 602 is to “require a manufacturer to extend the same price reduction to a covered entity for a drug or biological as is provided under the Medicaid outpatient drug rebate program.”  Joint Explanatory Statement on H.R. 5193, 138, reprinted in 2002 U.S.C.C.A.N. 4186, 4211. 

In this case, Santa Clara County alleged that it was overcharged for drugs in violation of a PPA.  The Ninth Circuit court reasoned that “[p]ermitting covered entities to sue as intended beneficiaries of the PPA is  . . . wholly compatible with the Section 340B program’s objectives.”  And later, “the section 340B program was created to give covered entities discounts so they could ‘stretch scarce Federal resources as far as possible, reaching more eligible patients and providing more comprehensive services.’”

In its decision, the Ninth Circuit court also found that covered entities who are direct beneficiaries of a PPA may enforce the manufacturers’ ceiling price obligations under the federal common law of contracts and that although the statute mandating the PPA does not create a federal private cause of action, allowing the county’s contract claim to go forward is consistent with Congress’ intent in enacting the legislative scheme.  The Ninth Circuit concluded that the case lies within the conventional competence of the courts and is not within the primary jurisdiction of the Department of Health and Human Services because it does not present a far-reaching question that requires expertise or uniformity in administration. 

By Serafina E. Lobsenz & Jeffrey N. Wasserstein

More than one might guess.  On September 26, 2008, the Government Accountability Office (“GAO”) released a report, titled "Food Safety:  Improvements Needed in FDA Oversight of Fresh Produce."  As the title suggests, the report is somewhat critical in tone, although it does acknowledge FDA’s efforts to address fresh produce safety.  Some observations and conclusions in the report are that: (1) federal spending on food safety oversight has not kept pace with the volume of goods (particularly imports) moving in commerce or the increase in FDA’s other food safety responsibilities; (2) FDA’s science base has eroded to the point where it can not conduct or fund the research needed to collect the data needed to devise appropriate solutions; (3) FDA’s efforts are hampered by its inability to get information from industry; (4) FDA has to cannibalize other programs to fund its fresh produce safety activities; and (5) FDA is in a reactive mode, with much of FDA’s attention being diverted to address counterterrorism and outbreaks of foodborne illness.  The report recommends that FDA focus on its research and information-gathering activities, update its guidance and regulations, and seek additional statutory authorities.

Now for the fun, if disturbing, part of the exercise.  One can substitute “nanotechnology” for “fresh produce/food/food safety” in the preceding paragraph and end up with a series of true statements.  That is a hint to the systemic nature of the challenges facing FDA as it seeks to stay ahead of the curve on issues that range from the seemingly humble (getting a salad to the consumer’s table) to the more exotic (evaluating the safety of an article that crosses the boundaries between drugs, biologics, and devices).  In light of those challenges, it seems a bit curious that GAO would recommend that FDA issue new regulations.  While true that a preventive approach is generally more efficient than a reactive one, it’s not clear how FDA could hope to effectively and efficiently regulate a problem that it does not yet fully understand.  In fact, it was not until October 3, 2008 that FDA announced OMB approval of the Agency’s proposal to survey domestic and foreign FDA-registered food manufacturing and processing facilities to obtain more information about their current manufacturing practices.   

By Ricardo Carvajal

Earlier this week, Senator Sherrod Brown (D-OH) announced the introduction of S. 3633, the “Transparency in Drug Labeling Act.”  The bill, also know as the “COOL Pharmaceutical Bill,” would amend the FDC Act to require Country-Of-Origin (“COO”) labeling on prescription and Over-The-Counter (“OTC”) drug products.

Specifically, the bill would amend FDC Act § 502 so that a prescription drug would be misbranded unless the labeling of such drug bears the following two separate lists:

(1)       The identity of the country of manufacture of each active ingredient of the drug, listed in descending order based on the percentage of the number of active ingredients in the final dosage form manufactured in such countries; and

(2)       The identity of the country of manufacture of each inactive ingredient of the drug, listed in descending order based on the percentage of the number of inactive ingredients in the final dosage form manufactured in such countries.

Similarly, an OTC drug would be misbranded unless the label of such drug bears the following two separate lists:

(1)       The identity of the country of manufacture of each active ingredient of the drug, listed in descending order based on the percentage of the number of active ingredients in such drug manufactured in such countries; and

(2)       The identity of the country of manufacture of each inactive ingredient of the drug, listed in descending order based on the percentage of the number of inactive ingredients in such drug manufactured in such countries.

Sen. Brown has been a champion of COO labeling.  Earlier this year, Sen. Brown reportedly led a successful effort to include mandatory COO labeling for meat and produce in the 2008 Farm Bill.  Also earlier this year, Sen. Brown sent letters to Pfizer and Merck (see July 24, 2008 Pharmalot post) requesting information on the extent to which Pfizer purchases active pharmaceutical ingredients from foreign countries, and how Merck guarantees the safety of pharmaceutical ingredients and its finished drugs.  Sen. Brown has also requested that FDA evaluate drug company outsourcing and its effects on drug safety. 

S. 3633 has been referred to the Senate Health, Education, Labor, and Pensions Committee.  It seems unlikely, given ongoing debate over the economic stabilization package and the upcoming election, that S. 3633 will be passed in the 110th Congress.

By Kurt R. Karst    

Section 920 of the FDA Amendments Act (“FDAAA”) amended the FDC Act to create new § 505(t) – “Database for Authorized Generic Drugs” – that requires FDA to compile and publish a complete list of all authorized generic drugs identified in annual reports submitted to the Agency since January 1, 1999. FDC Act § 505(t) defines an “authorized generic” as a drug listed in FDA’s Orange Book that was approved under FDC Act § 505(c) (i.e., a “full” 505(b)(1) NDA or 505(b)(2) application) and that “is marketed, sold, or distributed directly or indirectly to retail class of trade under a different labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trade mark than the listed drug.” FDAAA requires that the authorized generic list be updated on a quarterly basis.  FDA first published its authorized generic list earlier this year.  Among other uses, this list is intended to assist the Federal Trade Commission as that agency moves ahead with its study of the competitive effects of authorized generics.

On September 29, 2008, FDA issued a direct final rule, as well as a companion proposed rule, to implement FDAAA § 920.  (If FDA receives any significant adverse comments on the Agency’s direct final rule, then FDA will withdraw the direct final rule and proceed to respond to comments under the proposed rule using the usual notice and comment procedures.  If no significant adverse comments are submitted to FDA, then the direct final rule will become effective on February 11, 2009.  Comments on both rules are due by December 15, 2008.)  Both rules would amend FDA’s regulations to require that NDA holders submit certain information in an annual report regarding authorized generic drugs.

Specifically, the proposals would amend FDA’s regulations at 21 C.F.R. §  314.3 to add the definition of an “authorized generic drug” (the same definition as in FDAAA § 920), and would amend FDA’s postmarketing reporting requirements to add 21 C.F.R. § 314.81(b)(2)(ii)(b) regarding the marketing of authorized generic drugs.  Under the new postmarketing reporting requirements, NDA holders must include information in their annual reports detailing: (1) the date each authorized generic entered the market; (2) the date each authorized generic ceased being distributed; and (3) the corresponding brand name drug.  FDA considers each dosage form and/or strength to be a different authorized generic drug that should be separately listed in an annual report.  Moreover, “[t]he first annual report submitted after implementation of this regulation must provide information regarding any authorized generic drug that was marketed during the time period covered by an annual report submitted after January 1, 1999.”  FDA also notes that when information is included in an annual report about an authorized generic drug, the Agency requires “that a copy of that portion of the annual report be sent to a central office in the agency that will compile the list and update it quarterly.” 

By Kurt R. Karst    

We previously reported (April 25, 2007, May 22, 2007, August 14, 2007) on a trend in policing promotional and advertising claims by FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”), in which DDMAC has focused on ensuring that all claims are supported by substantial evidence and that all safety data are properly presented.  On September 25, 2008, this pattern re-emerged as FDA issued Warning Letters to five manufacturers of Attention Deficit Hyperactivity Disorder (“ADHD”) drug products.  DDMAC’s top concerns?  Promotional statements that broadened the drugs’ claims and overstated their efficacy without the requisite substantial evidence or “substantial clinical experience” to support them.  This dovetails with the caution we issued last year:  that substantial evidence was the “watchword” for companies trying to avoid running afoul of DDMAC.  Interestingly, these five letters target a particular therapeutic class – ADHD products – and for claims made in a range of material, from sales aids to a video featuring Ty Pennington posted on youtube.com.

Specifically, DDMAC sent Warning Letters to the following companies for promotional claims on the following drugs:  (1) Johnson & Johnson, Concerta® extended-related tablets; (2) Novartis Pharmaceuticals Corporation, Focalin XR® extended-related capsules; (3) Shire Development Inc., Adderall XR® capsules; (4) Eli Lilly & Corporation, Strattera®; and (5) Mallinckrodt Inc., Methylin® chewable tablets and oral solution (generic Ritalin).  The alleged FDA violations are broken down as follows:

Concerta^® extended-related tablets

(Johnson & Johnson)

Drug was misbranded under 21 U.S.C. §§ 352(a), 352(n), and 321(n) by promotional claims included on convention panels and a webpage that:

(1) Overstated its efficacy; and

(2) Omitted facts.

Focalin XR^® extended-related capsules

(Novartis)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 352(n) by promotional claims included on a professional slide deck and webpage that:

(1) Overstated its efficacy; and

(2) Broadened its indication.

Methylin^® chewable tablets and oral solution (Mallinckrodt)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 321(n) by promotional claims included on a patient brochure that:

(1) Overstated its efficacy;

(2) Omitted and/or minimized risk information; and

(3) Made unsubstantiated claims, including comparative claims.

Strattera^®

(Eli Lilly)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 321(n) by promotional claims included on a professional sales aid that:

(1) Overstated its efficacy; 

(2) Broadened its indication;

(3) Omitted material fact; and 

(4) Minimized risk information.

(3) Omitted material fact; and 

(4) Minimized risk information.

The conclusion that the companies had overstated the efficacy and broadened the indications of their drugs rested mainly on material that discussed the consequences of not treating ADHD in teenagers and adults.  For example, a Shire web page listed “[d]ifficulties caused by ADHD in adolescence” when left untreated, which included “academic problems,” “difficulty maintaining friendships,” “impulsive behavior,” and sexual promiscuity.  The Agency concluded that the references Shire cited did not support these statements, rendering the claims misleading, because they implied that the drug prevented these ADHD “side effects” without substantial evidence.  In one example, FDA stated that although a study Shire cited examined the “academic and social outcomes in young adults diagnosed with ADHD” it failed to “study the effects of drug treatment on those outcomes.” 

FDA made similar conclusions about the claims made by Eli Lilly, Novartis, and Mallinckrodt about the consequences of untreated ADHD. This begs the question of whether DDMAC is being overly cautious in its review of the claims for this drug class, one company simply pushed the proverbial promotional envelop too far and other companies followed suit, or if DDMAC is clamping down even harder on studies purported to be substantial evidence of promotional claims.  In any event, these Warning Letters serve as another important reminder that DDMAC demands a high level of “substantial evidence” in support of promotional claims. 

By Carrie S. Martin

In response to an urgent request of the European Commission, Health and Consumers Directorate, the European Food Safety Authority ("EFSA") conducted an exposure assessment for biscuits and confectionery contaminated with melamine.  Although milk and milk products originating from China currently are prohibited from importation into the EU, composite foods that contain milk powder originating from China (e.g., biscuits and chocolate) have been imported into the EU.  The exposure assessment released on September 24th concludes that, “in worst case scenarios with the highest level of contamination, children with high daily consumption of milk toffee, chocolate, or biscuits containing high levels of milk powder would exceed the TDI.  Children who consume both such biscuits and chocolate could potentially exceed the TDI by more than threefold.”  “TDI” refers to Tolerable Daily Intake, which is defined as an estimate of the amount of a substance that can be ingested daily over a lifetime without appreciable risk.  Although the exposure assessment notes that “it is presently unknown whether such high level exposure scenarios may occur in Europe,” the conclusions of the safety assessment are likely to intensify actions on the part of government agencies and industry to identify potentially contaminated foods and to further examine the integrity of their supply chains. 

On this side of the Atlantic,FDA’s latest melamine advisory, dated September 26th, alerts consumers to a recall of several instant coffee and milk tea products manufactured in China because of possible contamination with melamine.  The advisory further states that “FDA has broadened its domestic and import sampling and testing of milk-derived ingredients and finished food products containing milk, such as candies, desserts, and beverages that could contain these ingredients from Chinese sources.”  The advisory is silent as to the relevance of EFSA's exposure assessment to the U.S. population.

By Ricardo Carvajal

Yesterday, the U.S. Senate passed S. 3560, the “QI Program Supplemental Funding Act of 2008.”  Section 4 of the bill would amend the FDC Act to add new subsection 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for so-called “old” antibiotics.  “Old” antibiotics are antibiotic active ingredients (and derivatives of such ingredients) included in an application submitted to FDA for review prior to November 21, 1997, the date of enactment of the FDA Modernization Act (“FDAMA”).  The 1984 Hatch-Waxman Amendments excluded antibiotic drugs, which were then approved under FDC Act § 507, from the Act’s patent and non-patent market exclusivity provisions (except for the availability of a patent term extension).

FDAMA repealed FDC Act § 507 and required all NDAs for antibiotic drugs to be submitted under FDC Act § 505.  FDAMA included a transition provision declaring that an antibiotic application approved under § 507 before the enactment of FDAMA would be considered to be an application submitted, filed, and approved under FDC Act § 505. 

Congress created an exception to this transition provision.  FDAMA § 125(d)(2) exempts certain applications for antibiotic drugs from those provisions of § 505 that provide patent listing, patent certification, and market exclusivity.  Specifically, FDAMA § 125(d)(2) exempts an antibiotic application from Hatch-Waxman benefits when “the drug that is the subject of the application contains an antibiotic drug and the antibiotic drug was the subject of an application” received by FDA under § 507 of the FDC Act before the enactment of FDAMA (i.e., November 21, 1997). 

Thus, applications for antibiotic drugs received by FDA prior to November 21, 1997, and applications submitted to FDA subsequent to November 21, 1997 for drugs that contain an antibiotic drug that was the subject of an application received by FDA prior to November 21, 1997 are within the FDAMA § 125(d)(2) exemption and are not currently eligible for Hatch-Waxman benefits.  Applications for antibiotic drugs not subject to the FDAMA § 125(d)(2) exemption – so-called “new” antibiotics – are eligible for Hatch-Waxman benefits.  A 1998 FDA guidance document explains the effects of FDAMA § 125 in greater detail.  On January 24, 2000, FDA published proposed regulations in the Federal Register that include a list of “old,” pre-FDAMA antibiotic drugs not subject to Hatch-Waxman benefits.  FDA has not yet promulgated final regulations.  In addition to the specific chemical substances listed, the list also includes “‘any derivative’ of any such [listed] substance, such as a salt or ester of the [listed] substance.”

S. 3560, if passed by the U.S. House of Representatives (as widely anticipated) and signed into law, would effectively undo FDAMA § 125.  Under the bill, for those antibiotic drugs approved before November 21, 1997, a sponsor can obtain 3-year exclusivity for a new condition of use.  For those antibiotic drugs submitted before November 21, 1997, but not approved, a sponsor may elect to be eligible for 3-year exclusivity, 5-year exclusivity, or a patent term extension (provided the applicable legal and regulatory requirements are met).  The bill would also make the Hatch-Waxman Amendments fully applicable to those antibiotic drugs subject to new FDC Act § 505(v).  Finally, the bill includes three “transition provisions.”   Those provisions: (1) require antibiotic drug NDA sponsors to submit to FDA for Orange Book listing information on applicable patents within 60 days of enactment of S. 3560; (2) require FDA to list those patents in the Orange Book not later than 90 days after the enactment of S. 3560; and (3) create “fist applicant” status (for 180-day exclusivity purposes) for each ANDA applicant that not later than 120 dates after enactment of S. 3560 amends a pending application to contain a Paragraph IV certification to a newly listed antibiotic drug patent.  A summary of the bill is available here. 

Section 4 of S. 3560 is not new.  It was included in the Staff Agreement version of the FDA Amendments Act (§ 1111), but due to cost concerns was removed immediately before passage of the bill in the House of Representatives.  Also, earlier this year, there was a failed attempt to add the provision to the Animal Drug User Fee Amendments of 2008 as part of a technical corrections package.

By Kurt R. Karst 

UPDATE:

• President Bush signed S. 3560 into law on October 8, 2008 – Pub L. No. 110-379.