By Jennifer D. Newberger –

On August 15, 2011, FDA released two Draft Guidances:  “Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review” and “Design Considerations for Pivotal Clinical Investigations for Medical Devices.”  Each is discussed in turn below.

Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review

This Draft Guidance appears to be the first time FDA has articulated, in a formal manner, the factors that, theoretically, FDA considers in balancing the risks and benefits of a medical device, and how, ideally, that balance should affect the clearance or approval of a device. 

The guidance states that it applies to devices subject to premarket approval (PMA), and, “in limited cases,” devices subject to premarket notification (510(k)) requirements.  As noted in the Draft Guidance, under section 513(a) of the Federal Food, Drug and Cosmetic Act (FDC Act), FDA determines whether PMA applications provide a “reasonable assurance of safety and effectiveness” by “weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use.”  FDA may also utilize a similar analysis in the review of 510(k) devices when there are differences between the proposed device and the predicate device that may affect the safety and/or effectiveness of the proposed device.

The Draft Guidance splits the factors FDA may consider into three categories:  effectiveness, safety, and other.  For effectiveness, the consideration is the extent of the probable benefit(s), measured by taking into account the following factors:

• Type of benefit
• Magnitude of the benefit
• Probability of the patient experiencing a benefit
• Duration of the effect(s)

The safety considerations that help FDA determine the extent of the probable risk(s) and/or harm(s) include:

• Number, severity, and types of harmful events associated with use of the device: Device-related serious adverse events, Device-related non-serious adverse events, and Procedure-related or indirect harms
• Probability of a harmful event
• Duration of harmful events
• Risk from false-positive or false-negative for diagnostics
• Number of different types of harmful events that can potentially result from using the device and the severity of their aggregated effect.

The additional factors FDA may consider when weighing probable benefits and risks include:

• Uncertainty as to the benefits and risks.  This may be due to a poorly designed clinical trial, or the generalizability of the trial results to the intended treatment and user population.
• Characterization of the disease.  How does the disease affect patients?  What is its natural history and progression?
• Patient tolerance for risk.  In determining patient tolerance for risk, FDA may consider disease severity, disease chronicity, and the availability of alternative treatment/diagnostic options.
• Availability of alternative treatments or diagnostics.  The Draft Guidance indicates that in considering alternative treatment options, FDA may even consider off-label uses of marketed products if there are no approved or cleared products for the intended condition and patient population.  The Draft Guidance states:  “[I]f a new device has a very small benefit and there is significant uncertainty about that benefit, we may still approve the product if there are no available alternative treatments or diagnostics and the risk profile is acceptable.”
• Risk mitigation, such as the inclusion of warnings in the labeling or restricting the indication to a more limited use. 
• Novelty of technology.  FDA recognizes that new technologies carry with them more uncertainty than established technologies, but also may offer previously unavailable advantages.  As a result, FDA states that it “may approve a device with less benefit or more risk than would be generally tolerated for more established technologies, particularly where providers and patients have limited alternatives available, to facilitate patient access and encourage innovation.”

The factors put forth in this Draft Guidance are likely familiar to sponsors of premarket device submissions, although presented in a more systematic fashion.  As always, of course, the question is less about what the Draft Guidance states, and more about how it will be implemented, e.g., how, exactly, the competing factors are weighed.  In light of the ongoing debate over FDA’s impact on innovation, it is interesting that FDA explicitly considers novelty as a factor in favor of approval, in part to “encourage innovation.”  While this Draft Guidance may helps sponsors better understand what information they may need to balance, for instance, uncertainty generated by a small clinical trial, it will perhaps never be possible to determine precisely what FDA will consider sufficient to outweigh the possible risks of a device.  Hopefully this Draft Guidance is a reasonable starting point in analyzing the factors that should be assessed.

Design Considerations for Pivotal Clinical Investigations for Medical Devices

The most important lesson from this Draft Guidance does not appear to be the descriptions of the different types of clinical study designs, or even FDA’s assessment of the value of those designs, but rather a conclusion that is reached from reading between the lines:  the concept of least burdensome is no more, and if a sponsor decides not to conduct a randomized, double-masked (blinded), controlled, parallel group clinical study, it better have a good reason for not doing so.  Not only must it have a good reason, it must provide that reason to FDA:  the Draft Guidance states that an IDE application “should include the details of the proposed study design and a rationale for the study design chosen, including an explanation of the alternate study designs considered and why those study designs were dismissed as inappropriate, impractical, or not possible.”  This is at odds with the Guidance FDA issued in 2002 regarding the “least burdensome provisions,” in which FDA specifically stated:  “If clinical data are needed, FDA and industry should consider alternatives to randomized, controlled clinical trials when potential bias associated with alternative controls can be addressed.”  It is also at odds with the Draft Guidance on Benefit-Risk Determinations discussed above, which states that clinical testing may include not only randomized clinical trials, but “partially controlled studies, studies without matched controls, well-documented case histories conducted by qualified experts, reports of significant human experience, and testing on clinically derived human specimens.”

For those readers not familiar with the concept of the least burdensome provisions, here is a little background.  There are two provisions in the FDC Act known as the “least burdensome provisions.”  One of these provisions, section 513(a)(3)(D)(ii), generally applies to PMAs, and states that “[a]ny clinical data, including one or more well-controlled investigations, specified in writing by [FDA] for demonstrating a reasonable assurance of device effectiveness shall be specified as a result of a determination by [FDA] that such data are necessary to establish device effectiveness.”  The second least burdensome provision, generally applicable to 510(k) submissions, states that, in requesting information to demonstrate that devices with different technological characteristics are substantially equivalent, FDA “shall only request information that is necessary to making substantial equivalent determinations.  In making such a request, [FDA] shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly.”

Each of these provisions implies that a requirement to provide clinical data to demonstrate a reasonable assurance of safety and effectiveness, or substantial equivalence, must be based on a determination that such data are necessary to make the showing.  In other words, if a showing of reasonable assurance or substantial equivalence may be made without clinical data, FDA should—or perhaps, must—permit the sponsor to provide other than clinical data to support its applications. 

While there may be room for debate as to whether a showing of substantial equivalence between two products with different technological characteristics always requires clinical data, requiring clinical data for PMAs is not new or even particularly controversial.  The type of study, however, has generally been determined based on the type of device and the endpoints desired.  This Draft Guidance, while describing many different types of clinical study designs, doesn’t explicitly reject any particular design, but makes very clear that well-controlled, randomized, masked studies are the clear favorite, and plants a seed of doubt as to whether other studies will really ever be acceptable to FDA.  The text of the document belies the assurance in the Draft Guidance stating that “the principles of study design discussed in this guidance are consistent with the principles discussed in the Least Burdensome Guidance, but expand upon them by discussing the considerations that may affect the level of evidence necessary to meet the standard for premarket approval or clearance.”

The specific clinical design study factors discussed in the Draft Guidance are not, in and of themselves, anything particularly surprising.  The Draft Guidance breaks clinical studies into two broad categories:  clinical outcome studies, for therapeutic and aesthetic devices, and diagnostic clinical performance studies, for diagnostic devices.  For both types of studies, the Draft Guidance addresses some general principles in designing a clinical study:  avoiding bias and variability in device performance; clear statement of study objectives; subject selection that adequately reflects the target population for the device; and selection of enrollment sites appropriate for the intended use of the device.

The Draft Guidance identifies the below elements in designing a clinical outcome study:

• Selection of appropriate endpoints.  These should be pre-specified at the design stage of the pivotal clinical study, and should provide sufficient evidence to fully characterize the clinical effect of the device for the desired intended use.
• Randomization.  The Draft Guidance recommends randomization of subjects so the groups are comparable at baseline prior to the intervention, and states that the inability to randomize may subject the study to “bias of unknown size and direction” which can in turn adversely impact the level of evidence provided by the study. At the same time, the Draft Guidance recognizes that there are situations in which randomization is impossible, difficult, or potentially inappropriate.  In such a situation, the Draft Guidance recommends sponsors contact FDA to discuss concerns with randomization and determine an appropriate study design.
• Masking (blinding).  The Draft Guidance notes that masking is important to reduce bias, because knowledge of treatment may affect the behavior of subjects or interpretation of clinical outcomes by investigators.  The Draft Guidance suggests certain steps a sponsor may take to minimize bias where masking is not possible, such as masking subjects until after the procedure and drafting a script for clinical staff to use to standardize the follow-up questions asked of study participants.
• Controls in comparative clinical trials.  The Draft Guidance discusses active intervention control, placebo control, no intervention control, subject as own control, and subject-level data on a parallel group (historical control), making clear that historical control is the least desirable, which has long been FDA’s policy.
• Placebo effect and other phenomenon.  Because placebo devices may appear to demonstrate effectiveness, the Draft Guidance recommends use of a placebo to compare the investigational device to a therapy that is ineffective.  If superiority to the placebo can be demonstrated, it can be inferred that that investigational device is effective.
• Non-comparative clinical outcome studies.  The Draft Guidance states that study designs that do not use concurrent (or historical) controls are not well-controlled studies.  These studies may include single-group study with objective performance criterion; single-group study with performance goals; observational studies or registries; meta-analysis; and literature summaries.

The Draft Guidance addressed the following with regard to diagnostic clinical performance studies:

• Consideration of intended use.  The pivotal diagnostic clinical performance study must support the intended use of the diagnostic device, by evaluating what the device measures or detects; what the device reports; cell, tissue, organ, part, or system examined; specimen source(s), specimen type(s), and specimen matrix(-ces); how the device is used; when the device is used; by whom the device is used; for what; and on whom device is used.
• True status of the target condition.  There generally must be an assessment of the true status of the target condition.  If no gold standard exists to make this determination, an alternative type of assessment may be used.
• Study population for evaluation of diagnostic performance.  Sites selected for investigational use should be representative of the types of sites where the device is intended to be used, and study subjects should represent the target condition spectrum.
• Study planning, subject selection, and specimen collection.  For a prospective study, specify inclusion/exclusion criteria, method of subject recruitment and selection, testing protocol, and analysis methods to be used.  Retrospective selection of previously archived specimens may introduce issues of bias, such as non-representation of the target population.  Sponsors should consult with FDA to determine if available specimens or subject data are appropriate to support a diagnostic device’s intended use.
• Diagnostic clinical performance comparison studies.  Comparative studies comparing the investigational device with an established device is only possible when a clinical reference standard is used, and sponsors designing such studies should consult with the appropriate review division at the design stage.
• Masking in diagnostic performance studies.  Diagnostic device clinical studies may involve multiple evaluations and users/readers.  The user of the investigational diagnostic device should not be aware of the result from the clinical reference standard or other diagnostic evaluation, and vice versa.
• Skill and behavior of persons interacting with the device.  Protocols should account for variability in the performance of persons interacting with the device, because use of a diagnostic device may require certain levels or types of skills or knowledge.

This Draft Guidance may in fact help sponsors design their clinical studies because they now have additional insight into what FDA likes and dislikes, and how FDA suggests adjusting for bias or other complicating factors.  Nevertheless, the unspoken conclusion of the Draft Guidance is clear—FDA will be requesting, or perhaps requiring, increasingly demanding study designs.

By Kurt R. Karst –      

The court battle over the “new drug” status of Cody Laboratories, Inc.’s and Lannett Co., Inc.’s (collectively “Cody/Lannett’s”) Morphine Sulfate Oral Solution 20mg/mL drug product has taken a new turn.  FDA’s Motion to Dismiss the case on mootness grounds has been met with opposition from Cody/Lannett in court papers filed with the U.S. Court of Appeals for the Tenth Circuit late last week.

As we previously reported, in a November 16, 2010 decision, Judge Alan Johnson of the U.S. District Court for the District of Wyoming granted FDA’s Motion to Dismiss the case, which stems from FDA’s March 2009 Warning Letters to Cody/Lannett (among other companies) to stop manufacturing certain unapproved narcotic drugs, including morphine sulfate oral solutions.  Judge Johnson ruled that the court “does not have jurisdiction over any of the agency actions [Cody/Lannett] ask this Court to review, as the FDA has yet to complete a final agency action,” and that “[a]ny attempt to review such actions would be premature and contrary to law.”  Cody/Lannett raised three issues in the litigation: (1) FDA’s alleged determination that Cody/Lannett’s product is a “new drug;” (2) FDA’s alleged failure to develop an administrative record for its determination that Cody/Lannett’s Morphine Sulfate Oral Solution 20mg/mL product is a “new drug;” and (3) FDA’s alleged disparate treatment of Cody/Lannett’s standard review NDA compared to a competitor, which obtained priority NDA review status and NDA approval in January 2010.  Following Judge Johnson’s decision, Cody/Lannett appealed the decision to the Tenth Circuit.  On June 23, 2011, however, FDA approved Lannett Holdings, Inc.’s NDA No. 201517 for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL). 

FDA says in its Motion to Dismiss that, as a result of the approval of NDA No. 201517, “there is no likelihood that FDA will undertake enforcement action against Cody for marketing unapproved morphine sulfate, which is what Cody sought to prevent when it filed its complaint.”  Moreover, according to FDA,

For this reason, the “grandfather” issue should be moot.  In order to make it a “live” issue, Cody would have to make a convincing case that the “grandfathering” issue presents a current case or controversy.  Among other things, Cody would have to state that it would withdraw its NDA if its product were found to be grandfathered, and that it would for some reason prefer to market its product as a “grandfathered” product rather than under its approved NDA.  Unless and until Cody makes such a showing, this issue is moot.

And with respect to Cody/Lannett’s issue of alleged unfair treatment, FDA says that it “is no longer a live controversy, and it cannot be resuscitated.”  “Cody now has approval, and even if it could prove that it was treated unfairly (which it cannot do), it does not (and cannot) cannot seek damages for this alleged unfair treatment;” thus, there is “no ‘effective relief’ the Court can grant on this issue, and it is moot,” according to FDA. 

Cody/Lannett swings back at FDA in its opposition to the Agency’s Motion to Dismiss, saying that “[f]rom the very beginning, the Government has sought at every turn to deny Cody/Lannett an opportunity for judicial review of the FDA’s actions,” and that FDA’s Motion to Dismiss “is simply the latest attempt by the Government to permanently insulate the FDA’s decision-making from judicial oversight.”  According to Cody/Lannett, FDA’s June 23rd approval of NDA No. 201517 did not moot the case:

If this appeal were to be dismissed at this point in the litigation, Cody/Lannett would be forced to endure forever the additional financial and administrative burdens of manufacturing and selling the Product under a NDA rather than as a grandfathered product.  Furthermore, Cody/Lannett would never have an opportunity to obtain judicial review of their disparate treatment claim, though Cody/Lannett would suffer ongoing harm as a result of such disparate treatment.  They would likely face similar disparate treatment by the FDA in the future. 

Among other things, Cody/Lannett notes that the manufacture and sale of its morphine sulfate under an approved NDA will result in significant administrative and financial burdens.  Although not specifically mentioned, one of those burdens may be the need to pay FDA annual product and establishment user fees.  In addition, operating under an approved NDA “creates a new opportunity for generic competitors to use Lannett’s NDA as the basis for the preparation of a simple ANDA application to become generic to Lannett’s formulation.”  Moreover, “FDA could still pursue enforcement actions with respect to past sales of the Product,” says Cody/Lannett.  Thus, the grandfather status of Cody/Lannett’s Morphine Sulfate drug product is not moot and is “still a live issue between the parties.”

Cody/Lannett’s disparate treatment claims are also live and subject to judicial review, according the their opposition papers, because Cody/Lannett “continue to suffer harm as a result of the FDA’s actions” – namely, the alleged loss of their once dominant 44% share of the Morphine Sulfate Oral Solution 20mg/mL market – and because the “disparate treatment claims are capable of repetition yet evading review.”  In particular, Cody/Lannett notes that the company manufactures and distributes two other “grandfathered” products – oxycodone and topical cocaine – for which Cody/Lannett  intends to seek NDA approval because of “FDA’s current, exceedingly narrow interpretation of the FDCA’s grandfather clause and given the FDA’s demonstrated willingness to engage in de facto enforcement against manufacturers and distributors of unapproved drugs without any form of due process.”  Cody/Lannett’s competitors, however, are also likely to seek NDA approval for these drugs, and as a result, Cody/Lannett “will be denied expedited treatment while a competitor will receive such expedited consideration.”  “Thus, Cody/Lannett are faced with the very real prospect of being in exactly the same position that they are in now in the very near future.” 

By Riëtte van Laack –

FDA is reopening the comment period on the proposed rule it published on December 8, 2010, to amend the regulations on plant sterol/stanol esters and risk of coronary heart disease.  (See our previous post on the proposed rule.)

One of FDA’s proposed modifications is the discontinuation of the health claim for dietary supplements containing free (non-esterified) phytosterols.  Based on review of the literature, the Agency concluded that the evidence to support this claim did not meet the standard of significant scientific agreement.

On February 10, 2011, the Agency received a request to extend the comment period to provide additional time to collect data that support a claim for dietary supplements with free phytosterols.  Recognizing that 75 days may not have been sufficient to collect and assess data and submit comments, the Agency has decided to reopen the comment period.  The new closing date is October 25, 2011.

By Kurt R. Karst –      

With all of the hullabaloo that has been going on in court and on Capitol Hill in the continuing battle over a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 Patent”) covering The Medicines Company’s (“MDCO’s”) ANGIOMAX (bivalirudin) Injection  (see, e.g., here and here), it has been easy to overlook the other ANGIOMAX patent battle that has been brewing in the U.S. District Court for the District of Delaware over the two other Orange Book-listed patents for the drug – U.S. Patent Nos. 7,582,727 (“the ‘727 Patent”) and 7,598,343 (“the ‘343 Patent”) – both of which expire on July 27, 2028, but are subject to periods of pediatric exclusivity that expire on January 27, 2029.  Those patents, issued on September 1, 2009 (the ‘727 Patent) and October 6, 2009 (the ‘343 Patent), were timely submitted to FDA for Orange Book listing, and served as flypaper for Paragraph IV patent certifications from several ANDA sponsors, including APP Pharmaceuticals, LLC (“APP”), the company embroiled in a battle with MDCO in the Federal Circuit over a PTE for the ‘404 Patent. 

The ‘727 Patent and ‘343 Patent infringement actions have taken an interesting turn.  In court papers filed earlier this year, but only recently made available (with redactions), APP, in its Opening Brief in Support of Motion for Leave to File First Amended Answers and Counterclaims Under FRCP 15(A), seeks leave to assert unenforceability defenses and declaratory judgment counterclaims based on MDCO’s alleged inequitable conduct before the U.S. Patent and Trademark Office, and, more interesting to us, unenforceability defenses and declaratory judgment counterclaims based on MDCO’s alleged unclean hands before FDA and in filing the patent infringement lawsuits.  According to APP, MDCO “comes to these lawsuits with unclean hands that preclude MedCo’s requested relief,” because the company “knowingly submitted false certifications to FDA under penalty of perjury to have the patents-in-suit listed in the Orange Book.  MedCo then initiated this lawsuit because of those improper listings.” 

In APP’s First Amended Answers and Counterclaims to The Medicines Company’s Complaint for each patent (here and here), APP seeks declaratory and injunctive relief pursuant to FDC Act §505(j)(5)(C), among other statutory provisions.  FDC Act §505(j)(5)(C), applicable to ANDA sponsors, is the patent delisting counterclaim provision added to the statute by the 2003 Medicare Modernization Act (“MMA”), and states:

(I) In general.  If an owner of the patent or the holder of the approved application under subsection (b) for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under subsection (b) or (c) on the ground that the patent does not claim either –

(aa) the drug for which the application was approved; or

(bb) an approved method of using the drug.

(II) No independent cause of action.  Subclause (I) does not authorize the assertion of a claim described in subclause (I) in any civil action or proceeding other than a counterclaim described in subclause (I).

The MMA also added an almost identical counterclaim provision at FDC Act §505(c)(3)(D)(ii) applicable to 505(b)(2) applications.  As we previously reported, the statutory counterclaims provisions were recently asserted in the context of a 505(b)(2) application for Intelliject, Inc.’s epinephrine auto-injector, e-cue, which FDA recently tentatively approved.  At the time we posted on the Intelliject case in March, we thought that case was the only instance in which the MMA patent delisting counterclaim provisions had been asserted (outside of a patent use code challenge that is), but APP appears to have asserted the provision in late February. 

Count Three of each of APP’s counterclaims for the ‘727 and ‘343 Patents are almost identical and state that the patents “[do] not meet the requirements of 21 U.S.C. § 355(b)(1), (b)(2), and the regulations thereunder, including, without limitation, 21 C.F.R. § 314.53(b), § 314(c)(2)(ii), § 314.3(b).  It therefore was improper for MedCo to list the [patents] in the Orange Book.”  APP requests that the court “adjudge and declare that the [patents are] not properly listed in the Orange Book and enter a mandatory injunction ordering MedCo immediately to request the FDA to delist the [patents] from the Orange Book.”

MDCO, in its Opposition Brief, shoots back, stating that APP’s proposed amendments regarding unclean hands are futile and fail to state a claim for relief.  “There is no nexus between the alleged false listing and whether or not APP's ANDA infringes the patents-in-suit.  APP’s allegations of unclean hands based on Orange Book listing certifications are an improper attempt to enforce FDA regulations.  The Court should preclude APP from asserting such allegations here in this patent litigation” (emphasis in original; citation omitted).  APP, in its Reply Brief, however, says otherwise: “The nexus here could not be stronger.  But for MedCo’s unconscionable acts of submitting false listing certifications to FDA for the patents-in-suit and then suing APP because of those improper listings, these lawsuits would not exist.”  In other words, says APP, “this Court would not have subject matter jurisdiction over these Hatch-Waxman actions against APP because activities reasonably related to securing FDA approval cannot constitute patent infringement as matter of law.”

By Kurt R. Karst –      

FDA recently denied (here and here) two citizen petitions (here and here) submitted on behalf of ECR Pharmaceuticals (“ECR”) and Laser Pharmaceuticals, LLC (“Laser”) requesting that FDA, among other things, reconsider its determinations that certain marketed unapproved drug products containing brompheniramine maleate (alone or in combination with pseudoephedrine HCl) and methscopolamine nitrate are not Generally Recognized as Safe and Effective (“GRASE”), and that FDA reconsider or stay taking enforcement action against companies marketing such drug products.  FDA’s petition decisions come on the heels of the voluntary dismissals of two separate but related Petitions for Review ECR and Laser filed earlier this year with the U.S. Court of Appeals for the District of Columbia Circuit. 

As we previously reported, ECR and Laser requested that the D.C. Circuit review and set aside FDA’s March 3, 2011 decisions that that their marketed unapproved drug products are not GRASE.  In a separate notice published in the Federal Register on the same day, FDA announced its intent to take enforcement action with respect to these and many other marketed unapproved cough, cold, and allergy drug products (see our previous post here).  The ECR and Laser lawsuits were voluntarily dismissed after FDA filed motions to dismiss the cases for lack of jurisdiction (here and here).

FDA’s petition responses, which are largely the same (but in the context of different drug products), first deny the petitions (interpreted by FDA to be petitions for stay and reconsideration) on procedural grounds.  “The Agency action you seek to stay – a Federal Register notice setting forth the Agency’s intent to take enforcement action – may not properly be the subject of a request for stay under the Agency’s regulations at 21 CFR 10.35,” FDA states in the Laser response (and echoed in the ECR response).  Moreover, FDA states that its regulation on reconsideration at 21 C.F.R. § 10.33 “does not authorize seeking reconsideration of other Agency actions, such as the ones that appear to be challenged in your Petition, namely FDA’s issuance of a Federal Register notice setting forth the Agency’s intent to take enforcement action against certain products determined to be unapproved new drugs and FDA’s determination in a Federal Register notice that certain products are not GRAS/E.”

Turning to the GRASE issues raised in both petition, FDA says that the products do not meet the applicable GRASE standards.  In doing so, FDA provides a nice refresher on what it means for a drug product to be GRASE, and therefore, not a “new drug” requiring approval of a marketing application. 

[U]nder section 201(p) of the FD&C Act, a drug is a new drug if its “composition” is such that the drug “is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof” (not GRAS/E).  Further under section 201(p), a drug that is so recognized is still a new drug if it has not “been used to a material extent or for a material time under such conditions.”

This definition includes two separate criteria, either of which is sufficient to make a product a new drug: (1) lack of general recognition of safety and effectiveness and (2) insufficient duration or extent of use.  In other words, evidence of use for a material time and to a material extent alone is insufficient to render a product not a new drug; it must also be GRAS/E.  Conversely, a GRAS/E drug that has not been used for a material time or to a material extent will be considered a new drug.

Citing decades of case law, FDA says that three criteria must be satisfied to support a GRASE claim:

First, the particular drug product must have been subjected to adequate and well-controlled clinical investigations establishing that the product is safe and effective.  Second, those investigations must have been published in the scientific literature so that they are available to qualified experts.  Third, experts must generally agree, based on those published studies, that the product is safe and effective for its intended uses.  A product’s general recognition as safe and effective must be evidenced by at least the same quality and quantity of data as are necessary to support approval of an NDA. [(Citations omitted)]

According to FDA, none of the products identified in the ECR and Laser petitions meet the criteria for GRASE status.  As such, the continued manufacture and shipment of the affected drug products past the deadlines FDA identified in its March 2011 notice “may result in legal action without further notice, including, without limitation, seizure and injunction.”

By Susan J. Matthees –

Apparently as a result of a misunderstanding of the basic principles of homeopathy, and how of necessity the efficacy testing for such drugs differs from non-homeopathic drugs, a judge in the U.S. District Court for the Central District of California recently decided that claims against a manufacturer of a homeopathic drug are not preempted by the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  The plaintiff in the case, Delarosa v. Boiron, Inc., alleged that Boiron violated the California Legal Remedies Act and the California Unfair Competition Law and committed common law fraud by claiming that its homeopathic product, Children’s Coldcalm, would provide relief from symptoms of a cold.  Boiron filed a Motion for Judgment on the Pleadings, arguing that the plaintiff’s claims were preempted by the FDC Act.  The court denied Boiron’s motion, concluding that the FDC Act did not preempt challenges to homeopathic products.   

Homeopathic drugs have a unique status under the FDC Act.  FDC Act § 201(g)(1) defines “drug” to include articles recognized in the official Homeopathic Pharmacopeia of the United States (“HPUS”) or National Formulary (“NF”).  But, unlike other drugs, FDA does not evaluate homeopathic drugs for safety or efficacy prior to marketing, has not created any monographs under which an OTC homeopathic drug might be marketed, and does not impose standards for strength, purity, or quality of homeopathic drugs.  Instead, homeopathic drugs must meet the standards of strength, quality, and purity set forth in the HPUS.  Further, product claims are subject to the FDC Act’s misbranding provisions, and therefore claims for the drugs must be truthful and not misleading.  Manufacturers of homeopathic drugs must follow labeling provisions in FDC Act sections 502 and 503 and 21 C.F.R. Part 201, register with FDA, and comply with GMP requirements.  FDA has taken action against homeopathic products that may be unsafe, but the court noted that it could find no record of any investigation of homeopathic remedies due to a reported lack of efficacy.  We note that the FTC has brought actions against manufacturers of homeopathic drugs for allegedly marketing a product without substantiation. 

Because of this unique status within FDA, the court concluded that FDC Act preemption does not apply to homeopathic drugs.  Section 751 of the FDC Act preempts any state or local laws that relate to the regulation of a drug and that are different or in addition to federal law, but the court explained that FDC Act § 751(d) contains exemptions to preemption, including an exemption for products that are not marketed pursuant to FDA approval or final FDA regulation.  The court reasoned that a homeopathic drug falls within this exemption because homeopathic drugs are not approved and are not marketed pursuant to a final FDA regulation. 

In the alternative, the court also concluded that plaintiff’s claims are not preempted because they do not constitute state-imposed requirements that are “different from or in addition to” the federal requirements.  The court explained that plaintiff’s claims are premised on the allegation that Boiron’s marketing is false and misleading, and under the FDC Act, a drug with false or misleading labeling is misbranded.  According to the court,  the claims would be preempted only if the state law requirements are not identical to the FDC Act.  Boiron argued that the state law requirements are not identical to the FDC Act because, if the plaintiff’s allegations were true, Boiron would have to change its labels and advertisements.  The court disagreed, stating that if the allegations were true, Boiron would simply have to truthfully state the product’s efficacy or not sell its products, and such relief would not impose requirements different from or in addition to the FDC Act requirements.  The court also distinguished the case National Counsel Against Health Fraud, Inc., v. King Bio Pharm, Inc. (133 Cal Rptr. 2d 207), a case where a California state court concluded that because homeopathic drugs were marketed pursuant to the HPUS, “the general efficacy and safety of the remedy ha[d] been substantiated to the extent required by federal law.”  The court in this decision stated that it was “not persuaded by the reasoning set forth in King Bio Pharmaceuticals that inclusion in the HPUS is sufficient to guarantee the efficacy and safety of a homeopathic OTC drug.”  This statement indicates that the court in Delarosa lacked understanding of the principles of homeopathy, or, despite the recognition of these principles in the FDC Act, simply rejected them.

Boiron also argued that FDA’s Compliance Policy Guide (“CPG”) 400.400, which provides FDA’s opinion on when a homeopathic drug may be marketed, is a formal FDA advisory opinion.  The court disagreed, concluding that the CPG is not a formal advisory opinion.  Although 21 C.F.R. § 10.85(d)(3) states that a CPG can be an FDA advisory opinion, the court explained that FDA’s foreword to the CPG, which states that CPGs “may derive from a request for an advisory opinion, from a petition outside the Agency, or from a perceived need for a policy clarification from FDA personnel,” shows that the opinion is not a formal advisory opinion. 

By Kurt R. Karst –      

FDA’s recent approval of ANDA No. 090358 for an AB-rated generic version of IMITREX STATdose (sumatriptan succinate) Injection, approved under NDA No. 020080, puts some meat on the bones of the Agency’s July 2009 consolidated response to two citizen petitions (here and here) submitted by King Pharmaceuticals, Inc. (“King”) requesting that FDA decline to approve (or stay the approval of) ANDAs that reference a drug product containing an auto-injector device component – and in particular ANDAs for a generic version of IMITREX – unless the auto-injector component is “identical” to that of the Reference Listed Drug (“RLD”) in terms of performance, physical characteristics, and labeled instructions.  As we previously reported, FDA granted in part and denied in part the King petitions.

FDA’s consolidated petitions response, which is specific to combination products with an auto-injector component, provides some general guidance and insight into the Agency’s thinking on what “sameness” means with respect to auto-injector performance, physical characteristics, and labeling instructions.  For example, FDA commented that “when reviewing an ANDA for a combination product that includes an auto-injector constituent part, [the Agency] must evaluate the auto-injector constituent part of the combination product for which ANDA approval is sought to ensure that its performance characteristics and critical design attributes will result in a product that will perform the same as the RLD.”  FDA clarified, however, that “[t]his does not mean . . . that all design features of the auto-injector in the ANDA and its RLD must be exactly the same.  Some design differences may be acceptable as long as they do not significantly alter product performance or operating principles and do not result in impermissible differences in labeling.”

FDA also commented that “[f]or an ANDA for a product intended for emergency use by patients without professional supervision (such as a prefilled auto-injector indicated for emergency treatment of allergic reactions), it is particularly important to ensure that patients in an emergency situation can use the product safely and effectively in accordance with instructions provided for the RLD without additional physician intervention or retraining prior to use,” and that “[a] similar standard may be applied to certain products not intended for emergency use, if appropriate.”  Indeed, in the case of sumatriptan auto-injectors, FDA noted that “individuals experiencing migraines . . . may experience varying degrees of mental impairment, and this may affect the usability of an auto-injector, leading to possible errors or misadministration of the product,” and as such, “in reviewing an ANDA referencing [IMITREX], FDA will have to consider whether, given the characteristics of the proposed auto-injector constituent, the product can be safely substituted for the RLD without additional physician intervention or retraining prior to use.”

With respect to labeling and therapeutic equivalence issues, King had requested that “FDA require ANDA sponsors of drug products containing auto-injectors to use the same physical description of an auto-injector, the same operating instructions, and the same illustrations contained in the RLD labeling,” and that “the same standard should apply in assessing therapeutic equivalence. . . .”  FDA responded that although the auto-injector component in an ANDA for a combination product should be equivalent to that of the RLD product in terms of performance, operating principles, and critical design attributes. “labeling need not be identical.”  According to FDA:

Certain minor labeling changes may be acceptable to identify certain permissible differences between the ANDA and its RLD (e.g., to identify a change in materials to make the product lighter or to make it more robust or durable), as are minor differences (such as cosmetic appearance, color, shape) between the RLD and ANDA labeling when they do not interfere with operating conditions.  For products that require physician training before unsupervised patient use, differences in operation that require retraining prior to use are not expected to be acceptable in an ANDA. FDA will consider other proposed differences in labeling on a case-by-case basis.

That brings us to FDA’s decision to approve an ANDA for an AB-rated version of IMITREX STATdose.  A comparison of the FDA-approved labeling for IMITREX STATdose and its AB-rated generic version approved under ANDA No. 090358 posted on DailyMed – see here and here – while largely identical (as required by the FDC Act), includes different operating instructions under the “Patient Information – How To Use” sections of each set of labeling.  Consistent with FDA’s consolidated petitions response, however, the Agency apparently determined that these differences “do not interfere with operating conditions” and that the differences in operation do not require physician retraining. 

Whether FDA will apply the seemingly flexible approach the Agency apparently took in approving a generic version of IMITREX STATdose to other combination products that do not contain an auto-injector – such as Metered Dose Inhaler (“MDI”) and Dry Powder Inhaler (“DPI”) drug products – remains to be seen. 

Still awaiting a substantive response from FDA is a December 2009 citizen petition (Docket No. FDA-2009-P-0597) requesting “that specific legal and scientific requirements be upheld in the review of proposed generic copies of [MDI and DPI] products containing fluticasone propionate and/or salmeterol xinafoate” (i.e., SEREVENT DISKUS, FLOVENT DISKUS, FLOVENT HFA, ADVAIR DISKUS, and ADVAIR HFA).  For example, the petition requests that FDA not approve any ANDA referencing certain inhalation products unless the proposed generic version “conforms to the [RLD] in its patient instructions for use and handling. . . .”  “Different instructions for how to use an inhaler properly – including priming, dosing, cleaning, and storing – are simply too significant to possibly fit into the very limited zone of labeling differences that the law permits for generic drugs,” according to the petitioners.  Thus, the ultimate question for FDA seems to be this: To what extent must a proposed generic product be interchangeable in patient hands?  Wrapped up in this question are questions about similar external design (shape and size), number of doses, dose counter placement, and color scheme.    

By Kurt R. Karst –      

The latest battleground over the period of exclusivity that should apply to biological products is the Trans-Pacific Partnership (“TPP”) trade agreement.  As you might recall, earlier this year there was quite a hubbub over whether the 12-year reference product exclusivity period provided by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) is appropriately termed “marketing exclusivity” or “data exclusivity” (see our previous post here).  Then there was President Obama’s Fiscal Year 2012 Budget, which proposed slashing the BPCIA’s 12-year exclusivity period, such that “innovator brand biologic manufacturers would have 7 years of exclusivity and would be prohibited from receiving additional exclusivity by “evergreening” their products.” (See our previous post here.)   Cutting exclusivity, “would yield savings of $2,340,000,000 between 2012 and 2021,” according to the Obama Administration’s estimates.  Now there’s the TPP.

The TPP is an Asia-Pacific regional trade agreement being hammered out among the United States (specifically, the United States Trade Representative, Ron Kirk) and eight other partners (i.e., Australia, Brunei, Chile, Malaysia, New Zealand, Peru, Singapore, and Vietnam).  Currently, the TPP is composed of four members (Singapore, Brunei, New Zealand, and Chile) and endeavors to have full free trade between member countries by 2015.  The TPP would cover trade in goods and services and also includes a proposed chapter on intellectual property.  That proposed chapter is where the debate over biologics exclusivity is happening.

A July 27, 2011 letter signed by several members of Congress urges the Obama Administration to push for strong intellectual property rights in TPP negotiations, including consistency with U.S. biologics exclusivity under the BPCIA.  According to the letter:

Critical to increasing U.S. companies’ ability to export and contribute to U.S. GDP growth is ensuring that our government does all it can to help provide a level playing field for U.S. companies globally and advocate for intellectual property rights that provide certainty for America’s innovative companies in the biosciences and other sectors. . . . 

In the course of the TPP negotiations on intellectual property rights issues, we urge you to support current U.S. law on biologics, which provides for 12 years of protection.  The U.S.-led biopharmaceutical industry would be disadvantaged if the U.S. does not ensure consistency with U.S. law as part of the TPP, because foreign countries do not provide the same type of protection rules.  The current protections for biologic drugs were debated extensively and received strong bipartisan support in both the House and the Senate.  This provision is critical to keeping and expanding high-value U.S. jobs offered by America’s biotech sector and spurring the R&D investment needed to seize extraordinary opportunities for medical advances to combat our most costly and challenging diseases.

A rebuttal of sorts to the July 27th letter was sent to President Obama on August 4, 2011 and urges the President to refrain from negotiating exclusivity protections for biologic medicines.  According to that letter, also signed by several members of Congress:

[T]he consequences of [the BPCIA’s] mandated 12 years of biologics exclusivity are not yet known.  Additionally, the Food and Drug Administration has not yet promulgated any regulations to implement the biosimilars provisions of the new law, nor has the Agency approved any biosimilars in the United States. . . . 

Proposing 12 years of exclusivity in the context of TPP negotiations would also conflict with stated Administration policy, as reflected in the FY 2012 budget proposal, recommending that the exclusivity period for biologics be reduced to 7 years. . . .  Were the TPP ultimately to contain a 12 year biologics exclusivity provision, it would impede the ability of Congress to achieve the Administration’s proposed 7 year change without running afoul of U.S. trade obligations.  We see no reason for the United States to agree to such a provision, much less to propose it.

Another Member letter, dated August 2, 2011, and sent to Ambassador Kirk, raises several intellectual property issues regarding TPP talks.  Among other things, that letter raises concerns with proposals “that would undermine access to affordable medicines,” and specifically, one that would “propose expanding data exclusivity requirements . . . .”  The signatories to that letter “urge that any data exclusivity provisions, if included at all, be made voluntary, expire no later than a comparative period in the U.S., and include public health safeguards.” 

Outside of the TPP agreement talks, there is significant activity in the biologics/biosimilars space.  We understand that discussions about the structure of a user fee program for applications for biosimilar and interchangeable biological products are continuing.  FDA must submit its recommendations to Congress by January 15, 2012.  (See our previous post here.)  And last week, several FDA officials co-authored an article that appeared in the New England Journal of Medicine, titled “Developing the Nation’s Biosimilars Program.”  That brief article notes that FDA’s “totality of the evidence” approach, under which the Agency  integrates various kinds of evidence in making regulatory decisions, “along with the FDA’s experience with fingerprint-like characterization of complex products, will be essential in designing a U.S. biosimilars policy that encourages development of biosimilars, emphasizing the use of innovative technologies.”

By Cassandra A Soltis –

In a decision that could have implications in the United States, the U.K.’s Advertising Standards Authority (“ASA”), which describes itself as “the UK’s independent watchdog” that regulates advertising, found both a Lancôme and a Maybelline advertisement misleading because the images of the models, which were digitally retouched, were not accurate representations of the results that the products could achieve. 

The Lancôme advertisement for “Teint Miracle,” a foundation, included claims that the product “recreates the aura of perfect skin.  Instantly complexion appears naturally bare, beautifully flawless and luminous, as if lit from within.”  The ASA stated that the advertisement was misleading because, although “the product was capable of improving skin’s appearance,” the evidence did not show “that the ad image accurately illustrated what effect the product could achieve, and that the image had not been exaggerated by digital post production techniques.” 

The ASA came to a similar conclusion regarding Maybelline’s “The Eraser” foundation advertisement, which included claims such as “covers” fine lines and “conceals” crow’s feet as well as a disclaimer that the image of the model was an “Illustrated effect.”  The ASA noted that “the area around the model’s left eye had been digitally re-touched and . . . the text had drawn particular attention to the product’s effect in this area.”  The ASA stated that the ad was misleading and “must not appear again in its current form,” even though the advertiser had consumer testing results showing the public “agreed with the claims.” 

On this side of the pond, the National Advertising Division of the Better Business Bureau (“NAD”), which is a similar self-regulatory body in the United States, reviewed an advertisement for one of Maybelline’s “Eraser” line of cosmetics and came to a slightly different conclusion.  NAD Case #5241, Maybelline New York Inc., Instant Age Rewind Eraser Treatment Makeup (Nov. 10, 2010).  The “Instant Age Rewind Eraser Treatment Makeup” advertisement included claims such as “Erase fine lines” and “crow’s feet,” along with a close-up shot of a model’s face that was digitally altered.  The ad qualified the claims with a statement that the product “[d]oesn’t just cover; after 8 weeks of use reduces imperfections without makeup on.”  In addition, the disclosure “visual is a dramatization of actual product results” appeared at the bottom of the ad.

The NAD was concerned that, despite the disclosure that the visual was a dramatization, the digitally altered image showed the complete elimination of age-related imperfections.  However, because the ad qualified the “Erase fine lines” and similar claims with the text “reduces imperfections,” and the advertiser’s consumer survey showed that 68% of the respondents thought that this was the ad’s message, the NAD concluded that the photograph could still be used in future ads but recommended that the “visual dramatization” disclosure be removed and replaced with “a disclaimer clarifying the results which consumers can expect to achieve.” 

Given the publicity that the ASA’s Lancôme and Maybelline rulings have had here in the United States (for example, see here and here), and the increased concern about the digital manipulation of ads generally, it will be interesting to see whether the NAD will take a different approach in reviewing digitally manipulated ads.

By Cassandra A. Soltis –

The Food and Drug Administration (“FDA”) has reopened the comment period for its proposed rule on “gluten-free” labeling of food to announce the availability of, and seek comments on, its report titled “Health Hazard Assessment for Gluten Exposure in Individuals with Celiac Disease:  Determination of Tolerable Daily Intake Levels and Levels of Concern for Gluten,” which discusses FDA’s gluten safety assessment.  FDA also requests comments on a number of related issues, including whether and how this safety assessment should affect the proposed “gluten-free” definition in the final rule and on FDA’s tentative conclusion to adopt the proposed rule’s analytical methods-based approach to define the term “gluten-free.”

If you recall, FDA proposed to define “gluten-free” for voluntary use in food labeling as a food that does not contain any of the following:  (1) an ingredient that is any species of wheat, rye, barley, or a crossbred hybrid of these grains; (2) an ingredient derived from one of these grains and that has not been processed to remove gluten; (3) an ingredient derived from one of these grains and has been processed to remove gluten if the use of that ingredient results in the presence of 20 ppm or more gluten in the food (i.e., 20 micrograms or more gluten per gram of food); (4) 20 ppm or more gluten.  72 Fed. Reg. 2795 (Jan. 23, 2007). 

In the Federal Register notice announcing the reopening of the comment period, FDA states that it has “tentatively concluded” that it will “use both the ELISA R5-Mendez Method and the Morinaga method” to “assess compliance with [the] gluten threshold level for foods bearing ‘gluten-free’ labeling claims,” and that these methodologies will be included in the codified language of the final rule.  76 Fed. Reg. 46671, 46672-73 (Aug. 3, 2011).  However, because there are no currently available validated methods to assess the gluten content of certain foods, such as fermented or hydrolyzed foods, “FDA is considering whether to require manufacturers of such foods to have a scientifically valid method that will reliably and consistently detect gluten at 20 ppm or less before including a ‘gluten-free’ claim in the labeling of” these foods.  Id. at 46673 (footnote omitted).  

Because the proposed rule’s definition of “gluten-free” would permit foods not completely free of gluten to bear the claim, FDA seeks comments on whether it would be necessary for a “gluten-free” claim to be qualified with a statement such as “does not contain 20 ppm or more gluten.”  Id. at 46675.  In addition, in light of FDA’s safety assessment, which suggests that a level below 20 ppm for a “gluten-free” claim might be more protective for the most sensitive individuals with celiac disease, FDA invites comments on whether a gluten threshold level lower than < 20 ppm should be adopted and, if so, what impact this might have on both manufacturers of foods with “gluten-free” claims and on consumers of these foods.  Id.  FDA also requests comments on whether a “low-gluten” claim should be defined, and if so, what threshold level should be used.  Id. at 46676.

Comments on the proposed rule and the other issues highlighted by FDA are due October 3, 2011. 

In his recent article appearing in FDLI Update, Hyman, Phelps & McNamara, P.C.’s Douglas B. Farquhar discusses the recent and highly publicized directed verdict for Lauren Stevens, the former in-house lawyer at GlaxoSmithKline, who was on trial for charges that she, basically, lied to the federal government in response to a subpoena demanding documents.  (See our previous post here.)  United States District Court Judge Roger W. Titus’ ruling, writes Mr. Farquhar, “should be a clarion call that prosecutors need to be mindful stewards of the enormous power that they have to decimate people’s lives.”

The American Conference Institute will be holding its 12th annual “Maximizing Pharmaceutical Patent Life Cycles” conference in New York City from October 3-5, 2011.  A copy of the conference program is available here.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be presenting at the conference in a session titled “REMS Studies and Generic Entry: Exploring the Latest Regulatory Conundrum Affecting Pharmaceutical Patent Life Cycle Strategies.”  (We’ve previously posted on this topic here.)

The conference will include presentations from key representatives from the PTO (invited), FTC and FDA (invited), an update on biosimilars, in-depth discussions on life-cycle management developments including, analyses of recent critical cases affecting patent life cycle planning, and much more.

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier (which expires this Friday).  The discount code is: FLB 200.  We look forward to seeing you at the conference.

By Ricardo Carvajal –

The Federal Trade Commission ("FTC") issued the latest in a series of reports on sales, advertising, and promotion of cigarettes and smokeless tobacco.  The reports are based on data submitted to FTC by industry.  The cigarette report states that the “total number of cigarettes reported sold or given away decreased by 7.7 billion cigarettes (2.2 percent) from 2006 to 2007, and then by another 20.2 billion units (4.5 percent) from 2007 to 2008,” such that the total number of cigarettes sold or given away in 2008 was 322.6 billion.  For purposes of reference, that figure was reported as 402.2 billion in 2001.  There was also a decline in advertising and promotional expenditures, from $12.49 billion in 2006 to $9.94 billion in 2008 – the lowest figure reported since 2000.

The smokeless tobacco report states that “the total amount of smokeless tobacco sold by manufacturers to wholesalers and retailers increased from 115.82 million pounds in 2006 to 118.23 million pounds in 2007. Sales rose again in 2008 to 119.92 million pounds.”  That figure was reported as 112.2 million pounds in 2001.  The report also presents data on the number of units of smokeless tobacco given away, by package size.  Advertising and promotional expenditures increased from $354.1 million in 2006 to $547.9 million in 2008 – more than twice what was reported in 2000. 

FDA regulations issued under the authority of the Family Smoking Prevention and Tobacco Control Act curtail the distribution of free samples of cigarettes and smokeless tobacco, and FDA recently published a final rule that will require more prominent and graphic health warnings on cigarette labeling and advertising – assuming it survives a court challenge.  It will be interesting to see whether advertising expenditures are influenced by FDA’s implementation of the new law.

The Institute of Food Technologists (“IFT”) is requesting proposals for its March 28-29, 2012 annual Wellness Conference, which will explore new trends and examine recent scientific, technological, and business information in the health and wellness sector of the food industry.  The conference will cover a variety of topics related to consumer lifestyles and demographics, health issues, and weight management.  Submission Guidelines and topical priorities can be viewed here.  The deadline for submissions is August 18, 2011.  Hyman, Phelps & McNamara, P.C.’s Cassandra Soltis, a Wellness 2012 Advisory Panel Member, will moderate some of the sessions. 

By Cassandra A. Soltis & Anne Marie Murphy –

The Department of Health and Human Services, Office of the Secretary, along with the Office of Science and Technology Policy, has issued an advance notice of proposed rulemaking (“ANPRM”) requesting comments on how to update current regulations on the protection of human subjects who participate in research. 

Existing regulations on human research have been in place for decades with little significant change.  Thus some have dubbed the current initiative “historic.”  The impetus to modernize the regulations is in part a result of the way human research has evolved over the years.  Changes in the way human research is conducted include an increase in multi-site clinical trials and observational studies; research in the social and behavioral sciences; research using databases, the Internet, and biological specimen repositories; and perhaps most significantly the use of advanced technologies, such as genomics.  Other factors motivating change include criticism of the existing regulatory scheme by government bodies (e.g., Government Accountability Office) and academics.  A recent Executive Order also charges Federal agencies to review and update existing significant regulations to ensure that objectives are being met in the most efficient manner.  Improving Regulation and Regulatory Review, January 18, 2001. 

The ANPRM addresses a host of concerns over the “Common Rule,” which is codified at 45 C.F.R. part 46, subpart A, and has been adopted by about 15 Federal departments and agencies.  The Common Rule generally requires that Federally funded investigators obtain and document the informed consent of research subjects and describes, among other things, the requirements for membership, function, operations, research review, and recordkeeping of institutional review boards (“IRBs”).  Regulations to protect human subjects involved in FDA-regulated research include the provisions set forth at 21 C.F.R. parts 50 (informed consent), 56 (IRBs), 312 (investigational drugs), and 812 (investigational medical devices).  FDA’s regulations on informed consent and IRBs are separate from, but largely track, the provisions of the Common Rule.  The proposed rulemaking notes that other regulatory schemes, such as FDA regulations and the HIPAA Privacy Rule, will be affected and “will need to be harmonized.”

Seven primary categories of concern are highlighted in the ANPRM:
 
(1) Ensuring that the rules relate to the magnitude of risk to study subjects.  For example, IRBs have been criticized for spending too much time reviewing studies that involve minimal risk or overestimating foreseeable risks to subjects, particularly in the context of social and behavioral research.

(2) Streamlining IRB review of multi-site studies. 

(3) Improving informed consent.  Particularly in biomedical research where risks can be significant, there is value in ensuring that the consent process conveys the information needed for a potential subject to make an informed decision in a manner that the subject can understand.  At the same time, a rigid requirement to obtain written informed consent for certain types of research, e.g., surveys or interviews, has been questioned. 

(4) Strengthening data protections to minimize information risks.  For example, where genetic information is collected and stored, study subjects incur the risk of accidental or unauthorized disclosure of personal information.  HIPAA requirements address such risks in part, but apply only to covered entities. 

(5) Collecting information that would better allow evaluation of the system and how well human subjects are protected.

(6) Extending the scope of the Common Rule to include research studies conducted at institutions that receive any Federal funding, even if not specific to the study at issue.  This responds in part to those who have called for legislation to expand the Common Rule to cover all human subjects research conducted in the United States, regardless of the source of funding.

(7) Clarifying and harmonizing regulatory requirements and guidance across Federal agencies.

The ANPRM requests public comment on these issues and asks for responses to more than 70 specific related questions.  Barring an extension, comments must be submitted by 5 p.m. on September 26, 2011.