FDA Lawyers Blog

by Kyle Deighan

Counterfeit drugs are widely recognized as a serious and growing public health hazard. Around the world, they have become a multi-billion dollar industry, with some estimating sales as high as $75 billion in 2010 alone. Whether to eliminate the risk to the public or to regain profits lost to counterfeiters, the pharmaceutical drug industry has taken notice of the problem, exploring various methods to thwart production and distribution of the phony drug products.

Last week, FDA stepped in when they released a final Guidance directing manufacturers in the pharmaceutical industry on the implementation of a specific anticounterfeiting method--the use of physical-chemical identifiers in drugs. The guide, titled "Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting," defines physical-chemical identifiers ("PCIDs") as a "substance or combination of substances possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form."

Essentially, PCIDs are intended to make drug products more difficult to duplicate. Manufacturers add a small amount of an ingredient, the PCID, to the drug product, and "a unique physical-chemical characteristic of that ingredient makes it possible to detect and authenticate legitimate dosage forms, and to identify counterfeits." The guide states that PCIDs include inks, pigments, flavors, and molecular taggants, which may be detected by a patient simply observing the drug, or by more complex means using detection instruments.

by Brian Malkin

On December I, FDA plans to hold a Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee to discuss "REMS-related topics" including the Risk Evaluation and Mitigation Strategies ("REMS") program for isotretinoin called iPLEDGE.

iPLEDGE is the latest version of one of the oldest and most restrictive risk management programs that continues to receive criticisms because of its mandatory requirements that are viewed by some as burdensome while others as not restrictive enough. Specifically, iPLEDGE fails to do what it set out to do--prevent isotretinoin-related pregnancies that have a high likelihood to result in birth defects even for small amounts given during the early weeks after conception, when a woman may not know that she is pregnant. Birth defects associated with isotretinoin exposure to fetuses have included: hydrocephaly (enlargement of the fluid-filled spaces in the brain), microcephaly (small head and brain), mental retardation and other learning disabilities, ear and eye abnormalities, cleft palate and other facial abnormalities, and heart defects. If that is not enough, the drug also increases the risk of premature birth and infant death.

by Scot Pittman

FDA has put forth significant efforts in trying to tweak its 510(k) device approval pathway, which has created discontent among medical device companies for many years. In its most recent attempt to improve the medical device approval process, FDA released draft guidelines "De Novo Classification Process (Evaluation of Automatic Class III Designation)" last Monday.

De Novo Guidance

A typical low- to moderate-risk medical device approval requires either FDA clearance of a premarket notification or approval of a 510(k) submission. 510(k) submissions require a demonstration that the new device is substantially equivalent to an already legally-marketed device. The De Novo Classification Process attempts to streamline device approval for low- to moderate-risk devices that have been classified as Class III because they cannot be shown to be substantially equivalent to any legally market devices. In addition, the guidance also describes a mechanism for obtaining timely input on the type of data necessary to support de novo classification of a suitable device. When this guidance is final, it will replace "New Section 513(f)(2) - Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff" (February 19, 1998).

by Kyle Deighan

On September 19, FDA issued a Compliance Policy Guide ("CPG") intending to crack down on countless drug products being marketed in the United States without FDA approval. The CPG."Marketed Unapproved Drugs-Compliance Policy Guide, Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs", makes clear that unapproved drugs introduced on the market after September 19, 2011 are "subject to immediate enforcement action at any time, without prior notice and without regard to the enforcement priorities." This comes as part of FDA's enforcement efforts under the Unapproved Drugs Initiative.

Unapproved Drugs-Compliance Policy Guide, Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs

FDA estimates that as many as several thousand drug products lack approval and are thus being marketed illegally. These products are on the market for various reasons, but in all cases manufacturers have failed to provide FDA with required safety and efficacy data. For these unapproved drugs, FDA stated that it will take steps to encourage the submission of required information from the manufacturers or remove the products from the market.

by Brian Malkin

On September 27, FDA published in the Federal Register a Notice about the availability of a revised guidance, User Fee Waivers, Reductions, and Refunds for Drugs and Biological Products. The Guidance updates an interim guidance issued in July 16, 1993. The Notice explains that the revised guidance was proposed on March 14, 2011 but received no comments by the end of its comment period on June 13, 2011.

The Guidance describes: (1) the types of waivers, refunds, and reductions available under the user fee provisions of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") and (2) procedures for requesting waivers, refunds, or reductions and reconsiderations and appeals of FDA decisions of such requests. FDA's revised guidance also clarifies related issues such as user fee exemptions for orphan drugs.

by Rachael P. McClure

On July 21, FDA issued a draft guidance setting forth proposed regulatory policies for mobile medical applications. These applications are software programs that run on smart phones, tablets, and other mobile communications devices, allowing consumers to monitor and manage their own health. They are also used by health care professionals to facilitate patient care. Examples include applications that calculate an individual's calorie needs for healthy weight loss or allow doctors to view patient test results on their mobile devices. A recent study estimated that 500 million people will be using mobile healthcare applications four years from now. While FDA supports development of mobile medical apps, it has "a public health responsibility to oversee the safety and effectiveness of a small subset of mobile medical applications that present a potential risk to patients if they do not work as intended."

In the draft guidance, FDA proposes regulation of a subset of mobile medical apps that meet two requirements. First, an application must be intended for use to: (a) diagnose a disease or other condition; (b) cure, mitigate, treat, or prevent a disease; or (c) affect the structure or any function of the human body. Second, it must either be used as an accessory to a regulated medical device or transform a mobile platform into a regulated medical device. Transformation may occur via use of attachments, display screens, or sensors, for example attachment of a blood glucose strip reader to a mobile platform to function as a glucose meter. Displaying, analyzing, storing, or transmitting patient-specific medical device data, and controlling the operation, function, or energy source of a medical device qualify as accessory uses. An example of the former is remote display of patient data from bedside monitors; an example of the latter is mobile app that controls the delivery of insulin on an insulin pump by transmitting control signals to the pumps from the mobile platform.

FDA's proposed framework will require manufacturers of applications that convert a mobile platform into a regulated medical device to satisfy the obligations associated with that device classification, i.e., Class I general controls, Class II general and special controls, or Class III premarket approval. General controls include registration and medical device listing, quality regulation, and labeling requirements. The future is less clear for manufacturers of mobile medical apps that serve as accessories to other medical devices, for which FDA is seeking comment on how it best assure safety and effectiveness.

by Rachael P. McClure

On July 14, FDA issued a draft Guidance explaining and soliciting comments on its proposed policies for regulation of in vitro companion diagnostics devices ("companion diagnostics"). The Guidance is intended to help facilitate development and review of companion diagnostics. Most notably, it recommends that a companion diagnostic which is "essential for the safe and effective use of a therapeutic product" be reviewed at the same time as that product.

Companion diagnostic are tests that assist health care professionals in determining whether a particular patient should receive a certain therapy and, if so, what dosage he should receive. For example, new technologies are able to delineate patient populations that are more or less likely to respond to a given treatment or exhibit a particular side effect. Such devices are vital to the 'personalized medicine' model, a "rapidly advancing field of healthcare that is informed by each person's unique clinical, genetic, genomic, and environmental information."

As the Guidance explains, more and more therapies require such tests to meet the safety and effectiveness claims on their labels. Because the reliability of the results of companion diagnostics is essential to these therapies, FDA believes they two should be considered for approval simultaneously, and the Guidance emphasizes collaboration between producers of drug therapies and producers of diagnostic devices. Further, it recommends that, in most cases, approval of a companion diagnostic device be a general prerequisite for approval of a therapeutic product that relies on that device for its safe and effective use.

by Brian Malkin

On July 5, FDA announced in the Federal Register that it had finalized its draft exemptions from substantial equivalence requirements. The purpose of the final rule is to "establish procedures for requesting an exemption from the substantial equivalence requirements of the Family Smoking Prevention and Tobacco Control Act ("Tobacco Control Act"). The effective date of the rule is August 4, 2011.

Final Rule on Exemption for Substantial Equivalence

On January 6, 2011, FDA issued its notice of proposed rulemaking, which we blogged on here. According to the Tobacco Control Act, new products not marketed prior to February 15, 2007, require some form of premarket clearance or approval prior to marketing. For products marketed prior to March 22, 2011, the Act requires premarket approval or filing a 905(j) substantial equivalence report, unless FDA later determines the product is not substantially equivalent to a predicate (similar) tobacco product. A predicate product must have been marketed as of February 15, 2007. For products that a company intends to market after March 22, 2011, the Tobacco Control Act requires either a premarket approval, a finding of substantial equivalence, or a waiver for finding the product substantially equivalent prior to marketing. For all products not on the market as of June 22, 2009 (The date the Tobacco Control Act became law.), the Tobacco Control Act requires that FDA be provided with a list of ingredients in the product at least 90 days in advance of the intended marketing date.

Despite the promise for a waiver process, the process outlined in the final rule is only effective August 4, 2011. This means that for products not marketed until March 22, in theory they have not been able to take advantage of the waiver process yet. While most tobacco reports to FDA have been by forms, either in paper or electronic format, the substantial equivalence report has no current form. The final rule states, however, that an exemption for substantial equivalence must be filed electronically. FDA also has a webpage on substantial equivalence and associated exemptions for additional updates, which also provides information for small businesses.

by Dan Constantinescu, Ph.D.

As we previously reported, the D.C. Circuit recently vacated a preliminary injunction granted by a district court, which limited the National Institutes of Health's ("NIH's") ability to fund human embryonic stem cell ("HESC") research. The decision is one in a continuing battle between the plaintiffs and the NIH in Sherley v. Sebelius, 1:09-cv-01575, currently before the U.S. District Court for the District of Columbia. At issue is whether NIH guidelines, promulgated in response to President Obama's executive order relaxing limitations on NIH-funding of HESC research, violate the Dickey-Wicker Amendment. In part, Dickey-Wicker prohibits the NIH from using appropriated funds for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero.

The plaintiffs claim, in part, that NIH's guidelines are in violation because the guidelines (1) fund research in which a human embryo or embryos are destroyed ("destroyed" claim); (2) fund research in which a human embryo is knowingly subjected to risk of injury or death ("risk of injury or death" claim). The plaintiffs argue that the meaning of the term "research," as used in Dickey-Wicker, is wide in scope and refers to systematic or extended research. Under this interpretation, funding of a project involving research of HESC cells that have already been derived violates Dickey-Wicker because the field of HESC research generally involves the destruction of the embryos from which the cells were derived. The defendants argue that the meaning of the term "research" is narrow in scope, and refers only to discrete research projects. Under this interpretation, funding of a research project using HECSs that have already been derived does not violate Dickey-Wicker because the actual funded research project does not destroy any embryos.

In Chevron U.S.A. Inc. v. Natural Resources Defense Council, the Supreme Court adopted a two-part analysis, for determining whether to grant deference to a government agency's interpretation of a statute that it administers. Briefly, the two part test consists of:

(1) "First, always, is the question whether Congress has spoken directly to the precise question at issue. If the intent of Congress is clear, that is the end of the matter; for the court as well as the agency must give effect to the unambiguously expressed intent of Congress." "If the Court determines Congress has not directly addressed the precise question at issue, the court does not simply impose its own construction of the statute . . . Rather,

(2) [I]f the statute is silent or ambiguous with respect to the specific question, the issue for the court is whether the agency's answer is based on a permissible construction of the statute." Chevron, 467 U.S. 837, 842-843 (1984).

by Andrew S. Wasson

FDA recently released a draft guidance clarifying the requirements that the Dietary Supplement Health and Education Act of 1994 ("DSHEA") places on distributors and manufacturers of dietary supplements containing a new dietary ingredient ("NDI"). In particular, the draft guidance ("Dietary Supplements: New Dietary Ingredient Notifications and Related Issues") describes when a distributor or manufacturer must notify FDA of an NDI and the types of information required by such a notification. FDA estimates that there are approximately 55,600 dietary supplement products on the market, and that FDA has received approximately 700 NDI notifications over the last 16 years. The draft guidance presents information in a question and answer format.

When Congress passed DSHEA in 1994, it created a new framework for the regulation of dietary supplements, which were previously regulated no differently than foods. Generally speaking, dietary supplements are not subject to pre-market approval, with the exception of a supplement containing an NDI. DSHEA defines an NDI as "a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994." 21 USC § 350b. DSHEA provides that a dietary supplement containing a NDI is adulterated unless the supplement (a) "contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered" or (b) the firm submits a premarket notification to FDA seventy-five days prior to introducing (or delivering for introduction) a supplement containing an NDI into interstate commerce. A firm must show in its premarket notification that there is "a history of use or other evidence of safety" establishing that the dietary ingredient "will reasonably be expected to be safe" when used as directed.

As some industry observers are quick to point out, the draft guidance does not change the requirements set forth in DSHEA or the related regulations. The draft guidance subsumes its recommendations generally under three categories: (1) when is it necessary to provide a new dietary ingredient notification, (2) a description of NDI notification procedures and timeframes, and (3) what to include in an NDI notification. In broad strokes, FDA recommends including (1) a full description of the NDI's identity, composition, and the marketed dietary supplement, (2) the basis for considering it an NDI, (3) the recommended or ordinary conditions of use, (4) and "an explanation of how the history of use or other evidence of safety in the notification justifies the notifier's conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe."

FDA suggests submitting comments within 90 days of the draft guidance's promulgation (June 29, 2010) to ensure consideration.

by Erin A. Lawrence

After 33 years of consideration, FDA finally plans to reduce consumer confusion related to the ample types of sunscreens available on the market. On Tuesday, June 14, FDA published new guidance that will specify which lotions provide the best protection against the sun.

The new rules require sunscreens that claim protection against skin cancer to prove that they filter out UVB and UVA rays. Currently, FDA only requires testing for UVB rays--the ultraviolet rays responsible for sunburn and cancer. UVA rays are responsible for wrinkles and cancer.

Next summer, sunscreens that do not protect against UVA and UVB rays or if they are below a protection factor of 15 are required to carry the warning: "This product has been shown only to help prevent sunburn, not skin cancer or early skin aging." Consumers should be on the look out for sunscreens that state protection against a "broad spectrum." By next summer, this will mean that the lotion does an acceptable job at protecting against UVA and UVB rays. Lotions that protect against "broad spectrum" and are above SPF 15 will be allowed to state that they reduce the risks of cancer and signs of early aging if used as directed.

The new rules also propose several other changes. Sunscreen marketing claims like "waterproof" or "sweat proof" are prohibited, as the agency believes that these "are exaggerations of performance." The new rules required that a lotion past a water resistance test to maintain a water claim on their label. Additionally, FDA also proposes capping the highest SPF value at 50, unless the company can provide results of testing to support better protection. FDA reasoned that there is currently no data that shows that SPF above 50 adds any value. SPF stands for sun protection factor. The SPF number relates to protection against UVB rays.

All in all, consumers will have a much easier time deciding what lotion will keep their skin safe and healthy next summer. The must only look for sunscreen that claims "broad spectrum" and then the SPF that is over 15 of their choice.

by Erin A. Lawrence

On June 9, FDA issued a draft guidance titled, "Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology." Nanotechnology is the science of particles that are less than 100nm in size. Nanomaterials can have different chemical, physical, or biological properties than conventionally-manufactured products. FDA acknowledges the need to learn more about the potential role and importance of dimensions in the characteristics exhibited by engineered nanomaterials. The guidance is FDA's current thinking on whether FDA-regulated products contain nanomaterials or otherwise involve nanotechnology.

FDA will determine whether a product contains nanomaterials by considering whether the engineered material or final product has at least one dimension in the nanoscale range and whether the product contains physical or chemical properties that are attributable to its dimensions. These considerations apply to new products and when manufacturing changes alter the dimensions, properties, or effects of an FDA regulated product or any of its components.

FDA has yet to establish regulatory definitions of "nanotechnology," "nanoscale" or related terms. Currently, FDA addresses nanomaterials on a case-by-case basis using existing review processes. The National Nanotechnology Initiative Program defines nanotechnology as the "understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications."

Nanotechnology has various potential applications. It can increase the bioavailability, decrease dosage, increase potency, and/or decrease toxicity of drugs. Additionally, nanotechnology can lead to better detection of pathogens, improve food packaging, and can be used cosmetics.

by Erin A. Lawrence

On June 8, 2011, FDA announced a new guidance for industry entitled "Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act". The draft guidance issued in January 2009 and clarifies verification requirements in final citizen petitions. The guidance provides FDA's current thinking on interpreting Section 914 of Title IX of the Food and Drug Administration Amendments Act ("FDAAA") which was enacted on September 27, 2007. Section 914 of Title IX of the adds new Section 505(q) which governs prevention of the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) new drug applications ("NDAs"). The guidance contains recommendations, not legally enforceable responsibilities.

Section 505(q) provides that FDA must not stay approval unless it "determines, upon reviewing the petition, that a delay is necessary to protect the public health." A delay is caused if the petition would be ready for approval "but for" the issues raised in the petition. If FDA determines that a delay is necessary, FDA is required to provide the applicant notification that a determination has been made, any additional information or clarification, and a brief summary of the specific substantive issues within 30 days. Section 505(q)(1)(E) describes the factors that will be used to determine whether a petition is submitted with the primary purpose of delaying the approval of an application.

FDA also stated that, under Section 505(q), FDA may not consider a petition for review unless the petition is in writing, signed and contains a certification that is specified in that section. The petition must be self-encompassing and cannot incorporate by reference information that is not included in the petition. All information must be submitted in full. Additionally, FDA must take action on a petition not later than 180 days after submission. This time period cannot be extended for any reason.

Section 505(q) does not apply to all petitions. Petitions relating to timing of approval (the 180-day exclusivity) and petitions that are submitted by a sponsor to have FDA take or refrain from taking action with respect to that application. Section 505(q) only applies to petitions that are submitted on or after September 27, 2007, submitted in writing, and ANDA or Section 505(b)(2) NDA is pending at the time the petition is submitted, petitioner requests an action that could delay approval, and does not fall within any exceptions. If a petition is submitted, and there is no related ANDA or Section 505(b)(2) NDA pending, then such petition will not be subject to Section 505(q). Furthermore, the status of the petition will not be subject to Section 505(q) even if a related ANDA or Section 505(b)(2) NDA is filed after the citizen petition is submitted.

by Brian Malkin

On May 9, a new prepublication copy of a 145-page Report, "A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration" was released by a Committee formed by the National Research Council. The Report was commissioned by FDA and Health and Human Services to provide a "common set of metrics that would enable each center to evaluate the public-health consequences using a common terminology and approach that would allow comparisons within and among disparate programs."

FDA provided the Committee with 16 scenarios for the type of decisions with public-health consequences that FDA regularly addresses. These scenarios were then grouped by FDA into three types of decisions: (1) mitigation-selection decisions (weighing various alternatives for addressing a public-health risk, e.g., balancing safety concerns for a new product with the consequences from removing it from the market), (2) targeting decisions (resource-allocation, e.g., how should inspection resources be allocated between seafood and fresh produce), and (3) strategic-investment (longer-term, internal decisions regarding resources allocation, e.g., allocating resources to improve data on the food-supply chain or medical device surveillance).

The Report's recommendations call for a three-step method: (1) Identify and define the decision context, e.g., options to consider or appropriate end points to evaluate and compare, (2) estimate or characterize the public-health consequence using a risk attribute methodology and summarize the values in a table to facilitate comparisons for the options, and (3) use the completed characterizations to compare decision options and to communicate their public-health consequences within the agency, to decision-makers, and to the public; these comparisons should then be used along with other relevant information to make informed decisions. The risk attribute methodology consists of two sets of attribute to consider: (1) exposed population, mortality, and morbidity, and (2) personal controllability, ability to detect adverse effects, and ability to mitigate (or reduce) adverse health effects. While it may be more "palatable" to measure the risk attributes in terms of categories such as "likely", "very unlikely", or "possible", the Committee recommended that FDA employ quantitative metrics that could be expressed as a probability distribution, e.g., 5th, 50th (median), or 95th percentiles to facilitate comparisons. The Report tests this new method with four case studies.

Just where does this leave FDA? The Committee further recommends that as next steps, key FDA personnel participate in workshops to better understand the new model, so it can be effectively employed. The Committee recognizes that the greatest challenge will be for FDA personnel to begin creating quantitative rankings of the risk attributes but believes that this is a critical step for FDA to engage in "making advances in FDA management processes and decisions." The Report's proposed methodology, however, represents only recommendations. Therefore, it will be up to FDA to accept or reject the methodology as it goes forward with new and emerging decisions with public-health consequences.

by Brian Malkin

On May 10, FDA published a Federal Register Notice requesting comments on FDA's proposed development of a user fee program for biosimilar and interchangeable biosimilar biological product applications submitted under Section 351(k) of the Public Health Service Act ("PHS Act"). The biosimilar pathway was added to the PHS Act by the Biologics Price Competition and Innovation Act of 2009 ("Biosimilars Act"). As a general theme, FDA recognizes that at least during the first phase of the biosimilar user fee program (fiscal years 2013-2017), establishing a biosimilar pathway for the first applications likely will be as resource intensive as a full biologics application submitted under Section 351(a) of the PHS Act. As a result, FDA has proposed to charge biosimilar applicants a user fees equal to the Section 351(a) user fees minus any previously-paid fees associated with early product development. The Notice also proposes FDA's performance goals for the same time period.

FDA stated that while a number of companies have come to the agency asking for initial guidance regarding the requirements for a biosimilar application, FDA has yet to receive its first biosimilar application. Recognizing that the first and possibly all biosimilar applications will require more resources during the pre-application phase, FDA has proposed ways it can collect a biosimilar application fee earlier in the process. For example, new to biosimilar applications, FDA has proposed a Biosimilar Product Development fee that would be paid once an investigational new drug application ("IND") is submitted and annually thereafter for as long as the IND is active for a contemplated biosimilar application. Similar to small molecule, new drug applications ("NDAs"), there also will be fees for submitting the biosimilar application and annual establishment and product fees.

According to the Biosimilars Act, FDA must consult with a variety of interests before making its user fee recommendations to Congress on January 15, 2012, including industry, scientific and academic experts, health care professionals, and representatives of patient and consumer groups. Unlike previous user fee programs where there was already a mature industry group, FDA recognizes that it is at this time unclear what will emerge as the biosimilar industry. Based on previous comments to dockets associated with the Biosimilars Act, FDA expects that innovator drug companies and generic drug companies will pursue biosimilar applications, but FDA announced that it will follow a different process than for other user fee programs, given the competing interests and lack of an industry group to expressly represent biosimilar applicant interests.

FDA has requested comments by June 9, 2011, on its proposals for user fees for biosimilar applications. Some of the broad questions included in the Notice include: (1) What factors should the Agency consider in determining appropriate performance goals for 351(k) applications that are filed earlier than 2 years prior to the date on which a 351(k) application would be eligible for approval (i.e., 12 years after the date of first licensure of the reference product); (2) How should the performance goals take into account readiness for inspection; and (3) What other factors relating to the unique characteristics of the 351(k) approval pathway should the Agency consider when setting performance goals for 351(k) applications?

The previous day, May 9, FDA's Center Director for Drug Evaluation and Research, Janet Woodcock, M.D., reiterated that FDA plans so issue a general guidance for companies that want to submit biosimilar applications under the Biosimilars Act. FDA guidance for what requirements FDA expects for biosimilar applications is not a quid pro quo for FDA's ability to charge user fees for biosimilar applications, which was a feature built into the Biosimilars Act. While it may be too soon for FDA to act, it has been suggested that it would be prudent for FDA to issue this guidance just prior to the Biotechnology Industry Organization ("BIO") International Convention on June 27-30, 2011, which would provide a good media opportunity at a widely-attended industry event to announce this highly-anticipated guidance (http://convention.bio.org/).