FDA Law Blog

CPSC Posts Draft Guidance Document on CPSIA Testing And Certification Requirements – Silent On Products Subject to the PPPA’s Child-Resistant Packaging Requirements

2009-11-06T15:41:13-08:00

The Consumer Product Safety Improvement Act of 2008 (“CPSIA”) made significant changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”). CPSIA Section 102 amended the Consumer Product Safety Act (“CPSA”) to require that manufacturers certify that their products are in compliance with any applicable CPSC rule, standard, or ban. In February of this year, citing industry confusion as to which testing and certification requirements apply to which products, the CPSC announced a one-year stay of enforcement of the CPSIA testing and certification requirements. Unless extended by the CPSC, the stay of enforcement will expire about three months from now in February 2010.

Yesterday, the CPSC posted on its website a draft guidance document that explains the two types of certification of compliance required by CPSIA: a general conformity certificate, based on a reasonable testing program; and, for children’s products, a certificate based on CPSC-recognized third-party testing. Previously, the CPSC has taken the position that the general conformity certification requirement applies broadly to any product subject to a CPCS rule, standard, or ban, including for example any product that requires child-resistant packaging under the Poison Prevention Packaging Act (“PPPA”). In December 2008, CPSC posted Frequently Asked Questions (“FAQs”) that specifically address how the certification requirement would apply to PPPA products.

The new guidance document, which has been sent to the Commissioners for their vote, however makes no mention of PPPA products. The CPSC will hold a public meeting on Monday November 9, 2009 to discuss the document. We will attend the meeting and report back any significant developments.

Yes, There is a Way to Market a Drug as a Supplement

2009-11-05T10:11:19-08:00

By Ricardo Carvajal –

Several Congressional representatives wrote a letter to FDA asking the agency to “fully implement” a provision of the FDCA that allows marketing as a dietary supplement of an article previously investigated for use as a drug. Section 201(ff)(3)(B)(ii) excludes from the definition of a dietary supplement any article for which an IND was authorized and for which substantial clinical investigations were instituted and made public, unless the article was marketed as a food or supplement before the IND was authorized. However, the dietary supplement exclusion can be rendered inapplicable to an article by FDA’s issuance of a regulation. This somewhat cumbersome mechanism allows for the marketing of an article as a supplement even if it was previously studied as a drug. Although the letter does not reference any specific products, a citizen petition pending with FDA asks the agency to issue a regulation allowing the marketing of homotaurine as a dietary ingredient under the rulemaking authority described above (see our prior post here).

The Congressional representatives also expresses dismay over FDA’s request for comment on the issue of whether section 301(ll) applies to dietary supplements, given the “the absence of any indication that Congress intended for [section 301(ll)] to replace any existing law.” For more on issues raised by FDA regarding its implementation of section 301(ll), see our prior post here.

GAO Issues Report on Surrogate Endpoint Accelerated Approvals; Calls for Enhanced Oversight

2009-11-05T05:14:55-08:00

By Kurt R. Karst –

A recent report from the Government Accountability Office (“GAO”), titled “FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints,” finds that weaknesses in FDA’s monitoring and enforcement process have hampered the Agency’s ability to effectively oversee postmarketing studies conducted under FDA’s accelerated approval regulations. Senate Finance Committee Ranking Member Charles Grassley (R-IA) requested that the GAO examine FDA’s oversight of drugs approved under FDA’s accelerated approval regulations based on surrogate endpoints.

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments. These regulations, which are commonly referred to as “accelerated approval,” are located in Subpart H (21 C.F.R. § 314.500) of FDA’s drug regulations, and in Subpart E (21 C.F.R. § 601.40) of the Agency’s biologics regulations. If a product meets these criteria, then FDA may grant marketing approval based: (1) on a demonstrated effect on a “surrogate endpoint” and a sponsor’s commitment to complete with “due diligence” the required postmarketing studies to demonstrate the product’s clinical benefits; or (2) on restrictions to assure safe use (that is, when FDA determines that a drug can be used safely only if distribution or use is modified or restricted). (In clinical trials, a “surrogate endpoint” is an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms.) Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.” A list of accelerated and restricted approvals is available here.

Interesting, the GAO report notes a shift in the types of products approved under the accelerated approval regulations:

Since FDA began using the accelerated process in 1992, there has been a general shift in approvals based on surrogate endpoints from applications for HIV/AIDS drugs to applications for cancer drugs. In the first 9 years of the accelerated approval process, from 1992 through 2000, applications for drugs to treat HIV/AIDS made up 48 percent of the approvals, while applications for drugs to treat cancer made up 26 percent of these applications. Conversely, from 2001 through 2008, applications for drugs to treat cancer made up over half—59 percent—of the applications approved, while drugs to treat HIV/AIDS accounted for only 18 percent of approved applications. [(See the figure below from the GAO Report)]

Percentage of Approved Applications Granted Accelerated Approval for Cancer and HIV/AIDS Drugs, June 19, 1992–November 20, 2008

According to the GAO report, from June 19, 1992, through November 20, 2008, FDA approved a total of 90 applications (for 64 different drugs) based on surrogate endpoints. During that period, FDA required drug sponsors to conduct 144 postmarketing confirmatory studies associated with those surrogate endpoint accelerated approvals. Of those 144 confirmatory studies, FDA classified 92 of them (64 percent) as “closed” (that is, the studies were completed or FDA released the sponsor from conducting the studies), and 52 of them (36 percent) as “open.” Of the 92 closed studies, sponsors had fulfilled 73 of them (and FDA released sponsors from the remaining 19), according to the GAO report. In general, “sponsors were able to fulfill about two-thirds of their study requirements in less than 5 years, with time frames ranging from 7 months to more than 12 years. In contrast, nearly one-third, or 23, of these studies took over 5 years to fulfill,” with products to treat cancer comprising 61 percent of this group.

The GAO report is critical of FDA’s postmarketing study oversight and lack of enforcement of postmarket study requirements, stating that:

FDA has not been routinely monitoring the status of postmarketing studies, primarily because oversight of these studies is not considered a priority. Regarding its enforcement of postmarketing study requirements, we found FDA has not fully utilized its available enforcement tools, even when sponsors have failed to complete required studies.

FDA reportedly has three initiatives in place to address oversignt weaknesses. First, “to ensure FDA has current information on the status of open postmarketing studies and facilitate the timely review of [Annual Status Reports (‘ASRs’)], FDA retained [a] contractor in 2008 to review ASRs for all postmarketing studies classified as open.” Second “is the creation of a new tracking coordinator position within each medical review division with responsibility for a variety of tasks related to the tracking of postmarketing studies.” And third is FDA's Web-based Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”), which “should allow FDA staff greater access to information and provide enhancements over the current database, such as creating management reports on specific drugs and their respective studies.”

With respect to enforcing postmarket study requirements, the GAO report states:

FDA has not fully utilized its two enforcement tools – issuing administrative action letters and withdrawing a drug from the market in certain cases – to encourage and compel drug sponsors to complete required confirmatory postmarketing studies. FDA has the discretion to issue administrative action letters to drug sponsors if 1) sponsors are late or fail to submit ASRs, or 2) FDA determines that sponsors are not sufficiently progressing in completing their studies.

Indeed, FDA has never withdrawn approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence or because a postmarketing study failed to verify clinical benefit (under either Subpart H or Subpart E). (FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit. Instead, FDA approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.) With respect to withdrawing approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence, the report states:

Our review of the 90 applications approved based on a surrogate endpoint under the accelerated approval process revealed several circumstances that appeared to meet the regulatory conditions for withdrawal, but FDA was hesitant to use its enforcement authority. Specifically, we found that for 36 of the 90 applications, drug sponsors had not fulfilled their confirmatory study requirements by establishing the clinical effectiveness of those drugs. This includes several applications for drugs that FDA had approved more than 10 years ago and for which sponsors had not yet completed all of their required studies, and others where the studies failed to confirm the drug’s clinical effectiveness.

The example used in the GAO report of a sponsor not completing confirmatory studies is Shire’s PROAMATINE (midodrine hydrochloride) Tablets, which FDA approved in September 1996 under the Agency’s Subpart H (surrogate endpoint) regulations for the treatment of symptomatic orthostatic hypotension. (FDA subsequently approved several generic versions of the drug.) The labeling for PROAMATINE includes the following warning:

The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

To verify the drug’s clinical benefit to conclude that the drug is safe and effective, FDA required the sponsor of PROAMATINE to conduct certain postmarketing studies. According to FDA’s Postmarketing Study Commitments Database, the official status of the required postmarketing studies is “delayed.” This makes PROAMATINE the accelerated approval with the longest outstanding commitment.

We previously reported (here and here) on letters FDA has posted in a docket (Docket No. FDA-2007-N-0475) concerning the conduct and completion of confirmatory studies for PROAMATINE.

An August 7, 2007 letter FDA sent to companies marketing approved versions of midodrine HCL raised the possibility that generic sponsors might conduct the required confirmatory studies, and also raised the possibility of withdrawing approval for all midodrine applications if those studies are not conducted. FDA stated in an August 2008 letter that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved soon, we will issue a Notice of Opportunity for a Hearing on the Center’s proposal to withdraw the approval of the midodrine hydrochloride new drug application (NDA) (and all ANDAs referencing that NDA) pursuant to 21 CFR 314.530.”

FDA took an even more forceful tone in an August 2009 letter stating again that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved in a timely manner as described herein, we will issue a Notice of Opportunity for a Hearing on the Center's proposal to withdraw the approval of the midodrine hydrochloride NDA (and all abbreviated NDAs (ANDAs) referencing that NDA) pursuant to 21 CFR §§ 314.530; 314.150, and 314.151,” but adding that the required studies must have “50% enrollment by April 12, 2010,” “100% enrollment by June 12, 2010,” and that full study reports of the requested trials must be submitted “on or before October 12, 2010.” Whether FDA will take action to withdraw approval remains to be seen.

The GAO report recommends that FDA clarify its enforcement authority under the accelerated approval process to identify – perhaps in a guidance document – the conditions under which the Agency would would utilize its expedited withdrawal authority if a sponsor either fails to complete required confirmatory studies with due diligence, or if completed studies fail to demonstrate the clinical effectiveness of the drugs. FDA responded that in light of certain compexities and the need for a case-by-case assessment, the Agency “believes it would be difficult, if not impossible, to provide further clarification as to when it might utilize its authority to expedite withdrawal of drug approval on the basis of surrogate endpoints.”

Supreme Court to Decide Whether an FDA Warning Letter Starts the Statute of Limitations in a Securities Fraud Case

2009-11-04T04:45:14-08:00

By Carrie S. Martin –

On November 30, 2009, the United States Supreme Court will hear oral argument in Merck & Co. v. Reynolds, No. 08-905, a securities class action. The case concerns the standard of inquiry required to start the clock running on the statute of limitations in a private securities “fraud” case. Plaintiffs have alleged that Merck defrauded investors by not disclosing safety concerns about Merck’s product Vioxx, the nonsteroidal anti-inflammatory drug (“NSAID”) that was pulled from the market in 2004. Merck argues that plaintiffs had sufficient notice of the alleged fraud, and that the statute of limitations prohibits the lawsuit from proceeding. Merck points to a 2001 FDA Warning Letter in which FDA accused Merck of deceptive and misleading conduct by misrepresenting Vioxx’s safety profile, media coverage about study results pointing to safety concerns, and other suits filed against Merck as constituting inquiry notice. Plaintiffs argue that the statute of limitations was not triggered by the Warning Letter because the fraud cause of action requires a suspicion of scienter, i.e., Merck’s intent to deceive or defraud , and the Warning Letter etc. did not cover that subject. Under section 804(a) of the Sarbanes-Oxley Act of 2002, a private action claiming fraud under section 10(b) of the Securities Exchange Act of 1934 must be brought “not later than the earlier of – (1) 2 years after the discovery of the facts constituting the violation; or (2) 5 years after such violation.”

In Merck, the district court granted Merck’s motion to dismiss, concluding that the two-year statute of limitations provision barred the suit. In re Merck, 483 F. Supp. 2d 407, 418 (D.N.J. 2006). The district court pointed to “storm warnings” that Vioxx increased the risk of myocardial infarction, including the FDA’s 2001 Warning Letter. Id. at 419. These storm warnings stemmed from a study called the Vioxx Gastrointestinal Outcomes Research (“VIGOR”) study, which showed an increase of myocardial infarction in patients treated with Vioxx as compared to naproxen. Id. at 411-12.

The Third Circuit reversed, based on the heightened pleading requirement of the Private Securities Litigation Reform Act of 1995 (“PSLRA”) requiring that a plaintiff plead facts with particularity that the defendant acted with scienter. 543 F.2d 150, 164 n.12 (3rd Cir. 2008). Although the Third Circuit admitted that several published articles and the 2001 FDA Warning Letter discussed the negative VIGOR findings, the court concluded that the plaintiffs had no reason to suspect that Merck misrepresented the drug’s safety profile. Merck publicly hypothesized that the results were due to the cardioprotective effects of naproxen rather than any harmful effect of Vioxx. Id. at 171-72. The plaintiffs, therefore were not on inquiry notice that Merck intentionally misrepresented the study results. Only when an independent study found an increased risk of heart attack in patients taking Vioxx as compared to placebo, were Merck’s reassurances of Vioxx’s safety questioned and inquiry notice triggered. Id. at 172.

In August 2009, PhRMA submitted an amicus brief supporting Merck’s arguments. PhRMA argued that the “limitations period should commence when a reasonable investor of ordinary intelligence would suspect that he has been defrauded” without which information “suggesting scienter.” Brief of PhRMA as Amicus Curiae in Support of Petitioners at 12 (Aug. 17, 2009). The United States, in its amicus brief filed in October 2009, argued that notice “arises only if circumstances suggest a misrepresentation or omission made with scienter.” Brief of the United States as Amicus Curiae Supporting Respondents at 26 (Oct. 26, 2009).

The Supreme Court will now have the opportunity to decide whether the Third Circuit’s interpretation of “inquiry notice”, as supported by the United States’ amicus brief, is correct. If the Supreme Court affirms, it will likely restrict the statute of limitations as a bar to private securities fraud cases.

What is a Tobacco Product “Ingredient”?

2009-11-03T16:36:52-08:00

By Ricardo Carvajal, David B. Clissold & Jeffrey K. Shapiro –

FDA has published a draft guidance for industry on the listing of ingredients in tobacco products that manufacturers and importers are required to submit to the agency under FDCA section 904(a)(1). The FDCA does not define the term “ingredient” for purposes of section 904(a)(1), but that section calls for the submission of a listing of “all ingredients, including tobacco, substances, compounds, and additives that are. . . added by the manufacturer to the tobacco, paper, filter, or other part of each tobacco product.” In part, section 900(1) broadly defines “additive” to mean:

any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting he characteristic of any tobacco product (including any substances intended for use as a flavoring or coloring or in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding).

Perhaps teeing off of the broad definition of “additive” and its inclusion by reference in section 904(a)(1), the draft guidance states that “FDA considers ingredients that are introduced in packaging and that are known or may be reasonably expected to become incorporated into the consumed product to be ingredients that are added by the manufacturer to the tobacco product.” The guidance further states that, under certain circumstances, reaction products are considered to be “ingredients”:

When a material is known or reasonably expected to be formed through a chemical reaction during tobacco product manufacturing, FDA considers the resultant material to be an ingredient that is added by the tobacco product manufacturer. As such these reaction products are to be listed in the ingredient listing. Reaction products may result from, among other things, reactions that occur during a mixing operation, during an in-process holding step, or during a storage period. The reaction product(s) may result from a reaction between ingredients in the same part of a product (e.g., reconstituted tobacco) or between ingredients added to different parts of the product (e.g., tobacco, paper) or added at different manufacturing steps.

For those who would like to submit comments, time is short. Comments are due by November 13.

Senate Committee Seeks Improved Access to Controlled Meds for Long-Term Care and Hospice Patients; Drafts Legislation to Address Issue

2009-11-03T04:12:53-08:00

By John A. Gilbert and Larry K. Houck –

Senate Special Committee on Aging Chairman Herb Kohl (D-WI) and Member Sheldon Whitehouse (D-RI) have sent a letter to U. S. Attorney General Eric Holder seeking improved access to needed pain and other medications for long-term care and hospice patients. Their October 19, 2009 letter states current federal Controlled Substance Act (“CSA”) requirements lead to delays in patients receiving needed medication. The letter notes that nurses in long-term care facilities and hospices often act as the agents of prescribing physicians by transcribing medication orders and transmitting them to pharmacies serving the facilities. The letter observes, however, that the CSA does not allow pharmacies to dispense Schedule II controlled substances to patients based on such orders, instead requiring practitioners to sign hard copy prescriptions prior to dispensing, which leads to delays. The letter observes that delays in timely access to needed medication can lead to unnecessary re-hospitalizations and “needless suffering.”

The letter states that the Drug Enforcement Administration (“DEA”) has heard concerns from patient advocates for years that the CSA “is ill-suited to the unique needs of this patient population and the practice protocols of those is who provide their care.”

Noting that the CSA and regulation provisions relevant to this issue remain unchanged since 1994 when DEA permitted long-term care prescriptions to be faxed, the Committee submitted draft legislation with the letter. The draft legislation, cited as the “Long-Term Care Patients’ Access to Medically Necessary Controlled Substances Act of 2009,” would amend the CSA to allow nurses to act as the agent of the practitioner to enter medication orders on patient charts and for pharmacies to dispense controlled substances pursuant to those medication orders. The draft legislation sets the conditions and restrictions for the nurses and for the medication orders and, according to the letter, “strikes the appropriate balance between the legitimate law enforcement interest in preventing diversion and maintaining adequate controls, and the urgent needs of frail long-term care patients to prompt access to medically necessary prescription medications.”

This has been an ongoing issue, particularly as it applies to DEA regulations involving emergency prescriptions. DEA regulations provide that a Schedule II prescription may be “called in” only if the criteria for an emergency prescription is met. DEA recently clarified these conditions which has still left many in the long term care and hospice industry unsatisfied.

The letter asks for review and comment within twenty days. We will provide updates as they occur.

HPM Posts Summary of H.R. 3962 Provisions Directly Affecting Drug and Device Manufacturers

2009-11-02T16:22:50-08:00

By Alan M. Kirschenbaum & Kurt R. Karst –

Last Thursday we reported on the release by the House of H.R. 3962, the health care reform bill that will soon be considered on the House floor. As we have done with other health care reform proposals, we have prepared a summary of the provisions of H.R. 3962 that are of direct interest to pharmaceutical and medical device manufacturers. Our summary can be found here. The full text of the bill can be found here.

FDA’s Letter to P&G over VICKS DayQuil and NyQuil Plus Vitamin C is Back (for now?)

2009-11-02T07:36:15-08:00

By Ricardo Carvajal –

FDA has again posted a warning letter to Procter and Gamble stating that the company’s VICKS DayQuil Plus Vitamin C and VICKS NyQuil Plus Vitamin C are unapproved new drugs and are misbranded. The letter states that, when “drug and dietary ingredients are combined into a single dosage form, the combination becomes a drug under section 201(g)” of the FDCA. As noted in the letter to P&G, FDA previously staked out that position in warning letters in October 2008 to Bayer for its products combining aspirin with either phytosterols or calcium, and in 2001 to Omni Nutraceuticals for its products combining acetaminophen with either glucosamine sulfate or glucosamine sulfate and chondroitin sulfate, and to B.F. Ascher its product combining acetaminophen and melatonin.

FDA first posted a warning letter to P&G over VICKS on October 14, but then removed the posting, citing an administrative error. The fact that this latest posting is accompanied by a press release emphasizes that this time it’s for real.

From Various Quarters, Pleas to Tone Down Food Marketing Claims

2009-11-01T16:28:21-08:00

By Ricardo Carvajal –

We’re used to seeing the Center for Science in the Public Interest ("CSPI") take a stick to food marketers. It seems that CSPI now has plenty of friends. First, Connecticut’s Attorney General trumpeted his success in gaining agreement from food companies to stop using the Smart Choices logo, at least until FDA decides what to do about point-of-purchase labeling (for more on that controversy, see our prior post). Then according to Sustainable Food News, Hain Celestial called for industry to stop using misleading front-of-pack labeling and to stop playing fast and loose with its use of “natural.” Hain Celestial is proposing the adoption of standards for “natural” similar to those used for “organic” (for our primer on “natural,” “organic,” and other “green” claims, see here). Now The Economist is piling on with an opinion that calls for greater scrutiny of health-related promotional claims.

For food marketers, it’s bad enough that regulators, the media, and even some in industry are on the case. But as the Food Liability Blog points out, it may yet be the plaintiffs’ bar that does the most damage.

Seventh Circuit Affirms Dismissal of FDA-related Lanham Act Case and Quotes William Blake to Boot

2009-11-01T16:28:05-08:00

JP Ellison –

In March of 2008, we reported on a Wisconsin federal district court opinion that dismissed a plaintiff’s Lanham Act claim against three manufacturers of generic prescription drug products. On October 29, 2008, the Seventh Circuit issued a decision in an appeal of that same case. As we noted in our earlier post, Hyman, Phelps & McNamara, P.C. represented one of the defendants in the case.

Between March of 2008 and October 2009, the district court had modified its dismissal from with prejudice to without prejudice and the plaintiff and two of the defendants had appealed and cross-appealed, respectively.

The central issue before the Seventh Circuit was whether a Lanham Act claim could proceed when the claim was based upon FDA-required labeling. On appeal, the panel (in an opinion written by Judge Posner) agreed with the district court’s reasoning that such a claim could not proceed unless and until FDA had made a finding with respect to that labeling, which it had not yet done. In concluding that FDA had not yet made a finding, the Seventh Circuit reached the same conclusion as the district court, namely that letters from an FDA employee to the defendants did not constitute final agency action.

The Seventh Circuit also affirmed the district court’s denial of the plaintiff’s motion for partial summary judgment based upon a claim of “literal falsity.” In doing so, Judge Posner observed: “William Blake declared that ‘to Generalize is to be an Idiot. To Particularize is the Alone Distinction of Merit.’ That is a bit extreme, but uncritical generalization is the path to error.” We’re not sure the quote is central to the court’s holding, but it seemed a shame to omit a William Blake quote from a report on an appellate court opinion.