Notices. Notice

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BILLING CODE 4184-01-M DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. 2006N-0528] Agency Information Collection Activities; Proposed Collection; Comment Request; Infant Formula Requirements AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration

(FDA)is announcing an opportunity for public comment on the proposed collection of certain information by the agency. Under the Paperwork Reduction Act of 1995 (the PRA), Federal agencies are required to publish notice in the **Federal Register** concerning each proposed collection of information, including each proposed extension of an existing collection of information, and to allow 60 days for public comment in response to the notice. This notice solicits comments on information collection regarding the manufacture of infant formula, including infant formula labeling, quality control procedures, notification requirements, and recordkeeping. DATES: Submit written or electronic comments on the collection of information by March 13, 2007. ADDRESSES: Submit electronic comments on the collection of information to: *http://www.fda.gov/dockets/ecomments* . Submit written comments on the collection of information to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number found in brackets in the heading of this document. FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of the Chief Information Officer (HFA-250), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4659. SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal agencies must obtain approval from the Office of Management and Budget

(OMB)for each collection of information they conduct or sponsor. “Collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a 60-day notice in the **Federal Register** concerning each proposed collection of information, including each proposed extension of an existing collection of information, before submitting the collection to OMB for approval. To comply with this requirement, FDA is publishing notice of the proposed collection of information set forth in this document. With respect to the following collection of information, FDA invites comments on these topics:

(1)Whether the proposed collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility;

(2)the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used;

(3)ways to enhance the quality, utility, and clarity of the information to be collected; and

(4)ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology. Infant Formula Requirements—21 CFR Parts 106 and 107 (OMB Control Number 0910-0256)—Extension Statutory requirements for infant formula under the Federal Food, Drug, and Cosmetic Act (the act) are intended to protect the health of infants and include a number of reporting and recordkeeping requirements. Among other things, section 412 of the act (21 U.S.C. 350a) requires manufacturers of infant formula to establish and adhere to quality control procedures, notify FDA when a batch of infant formula that has left the manufacturers' control may be adulterated or misbranded, and keep records of distribution. FDA has issued regulations to implement the act's requirements for infant formula in 21 CFR part 106 and part 107 (21 CFR parts 106 and 107). FDA also regulates the labeling of infant formula under the authority of section 403 of the act (21 U.S.C. 343). Under the labeling regulations for infant formula in part 107, the label of an infant formula must include nutrient information and directions for use. The purpose of these labeling requirements is to ensure that consumers have the information they need to prepare and use infant formula appropriately. In a notice of proposed rulemaking published in the **Federal Register** of July 9, 1996 (61 FR 36154) (the 1996 proposed rule), FDA proposed changes in the infant formula regulations, including some of those listed in tables 1 and 2 of this document. The 1996 proposed rule included revised burden estimates for the proposed changes and solicited public comment. In the interim, however, FDA is seeking an extension of OMB approval for the current regulations so that it can continue to collect information while the proposal is pending. FDA estimates the burden of this collection of information as follows: **Table 1.—Estimated Annual Reporting Burden** 1 Section of the Federal Food, Drug, and Cosmetic Act or 21 CFR Section No. of Respondents Annual Frequency per Response Total Annual Responses 2 Hours per Response Total Hours Section 412(d) of the act 5 13 65 10 650 21 CFR 106.120(b) 5 0.25 1.25 4 5 21 CFR 107.10(a) and 107.20 5 13 65 8 520 21 CFR 107.50(b)(3) and (b)(4) 3 2 6 4 24 21 CFR 107.50(e)(2) 3 0.33 1 4 4 Total 1,203 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 Manufacturers may submit infant formula notifications in electronic format. **Table 2.—Estimated Annual Recordkeeping Burden** 1 21 CFR Section No. of Recordkeepers Annual Frequency per Recordkeeping Total Annual Records Hours per Record Total Hours 106.100 5 10 50 4,000 200,000 107.50(c)(3) 3 10 30 3,000 90,000 Total 290,000 1 There are no capital costs or operating and maintenance costs associated with this collection of information. In compiling these estimates, FDA consulted its records of the number of infant formula submissions received in the past. The figures for hours per response are based on estimates from experienced persons in the agency and in industry. Dated: January 8, 2007. Jeffrey Shuren, Assistant Commissioner for Policy. [FR Doc. E7-331 Filed 1-11-07; 8:45 am] BILLING CODE 4160-01-S DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Notice Regarding 340B Drug Pricing Program-Contract Pharmacy Services AGENCY: Health Resources and Services Administration, HHS. ACTION: Notice. SUMMARY: Section 340B of the Public Health Service Act implements a drug pricing program in which manufacturers who sell covered outpatient drugs to covered entities must agree to charge a price that will not exceed an amount determined under a statutory formula. The purpose of this notice is to inform interested parties of proposed guidelines regarding contract pharmacy services that will allow covered entities to utilize contract pharmacy services arrangements previously limited to the Alternative Methods Demonstration Project program. DATES: The public is invited to comment on the proposed guidelines by March 13, 2007. After consideration of the submitted comments, the Health Resources and Services Administration

(HRSA)will issue the final guidelines. ADDRESSES: Address all comments to Mr. Bradford R. Lang, Public Health Analyst, Office of Pharmacy Affairs (OPA), Health Resources and Services Administration (HRSA), 5600 Fishers Lane, Parklawn Building, Room 10C-03, Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Mr. Jimmy Mitchell, Director, OPA, HRSA, 5600 Fishers Lane, Parklawn Building, Room 10C-03, Rockville, MD 20857, or by telephone through the Pharmacy Services Support Center at 1-800-628-6297. SUPPLEMENTARY INFORMATION: A. Background Section 602 of Public Law 102-585, the Veterans Health Care Act of 1992, enacted section 340B of the Public Health Service Act, Limitation on Prices of Drugs Purchased by Covered Entities. Previous guidelines pertaining to contract pharmacy services for the 340B drug pricing program (61 FR 43549, Aug. 23, 1996) stated that a covered entity could contract with only one pharmacy to provide all pharmacy services for any particular site of the covered entity. Furthermore, if the contract pharmacy had multiple locations, the covered entity site had to choose one, and only one, contract pharmacy location for provision of these services. In 2001, HRSA established Alternative Methods Demonstration Projects (AMDPs) which allowed covered entities that applied and were approved by HRSA to pursue alternatives to contracting with a single pharmacy. These alternative models included the following:

(1)The use of multiple contract pharmacy service sites,

(2)the utilization of a contract pharmacy to supplement in-house pharmacy services, and/or

(3)the development of a network of 340B covered entities. The intent was to allow community health centers and other 340B safety-net providers to develop new ways to improve access to 340B prescription drugs for their patients. From the time of the program's inception until the end of April 2006, a total of 18 AMDPs were approved. Of those, 11 utilize a multiple contract pharmacies model, four establish a network of 340B covered entities, one is a combination of the network model and the multiple contract pharmacies model, one utilizes a contract pharmacy to supplement an in-house pharmacy, and one utilizes multiple contract pharmacies to supplement an in-house pharmacy. All but one of the projects is currently ongoing. A condition of AMDP approval is the requirement that the approved demonstration project be audited annually by an independent, outside auditor for drug diversion and duplicative discounts under Medicaid. The results of the audits are required to be reported to the Office of Pharmacy Affairs (OPA). To date, there has been no evidence of drug diversion or duplicate manufacturer's discounts on 340B drugs in the AMDP program. HRSA, acting through OPA, is proposing new guidelines that would allow covered entities to utilize multiple contract pharmacy service sites and the utilization of a contract pharmacy to supplement in-house pharmacy services that were previously limited to approved AMDPs. This proposed change is due to the success of the AMDPs, and the urging of safety net providers who wish to utilize alternatives to the single entity site/single pharmacy location contractor model to provide broader access to 340B discounted drugs to eligible patient populations. Other than permitting these specified models, HRSA is not proposing other substantive changes to the contract pharmacy guidelines. The AMDP process will continue for those covered entities wishing to develop 340B networks of covered entities. OPA will continue to review the utilization of network demonstration projects and consider adapting the rules to include them in the future. Of particular importance is the continued requirement that appropriate procedures be in place to prevent diversion of 340B drugs or a duplicative 340B drug discount and a Medicaid rebate on the same drug, which are prohibited under the statute. These proposed guidelines replace all sections of previous 340B Program guidance documents addressing non-network contract pharmacy services, including, but not limited to, the “Notice Regarding Section 602 of the Veterans Health Care Act of 1992; Contract Pharmacy Services,” 61 FR 43549 and any individual correspondence issued by HRSA on the subject. Demonstration projects previously approved under the multiple contract pharmacy model, the supplement to in-house pharmacy model, or a combination of the two models when this Federal guidance goes into effect, would be governed by this guidance and would no longer be subject to expiration of AMDPs, interim reporting or annual audits currently mandatory for all demonstration projects (this guidance only applies to audits required under the AMDP and leaves unchanged audit requirements under any other authority or program). While annual audits will no longer be required to be provided to OPA annually, covered entities are required to maintain fully auditable records and OPA expects covered entities to include appropriate sampling of multiple contract pharmacy arrangements in the course of routine annual audits. Demonstration projects previously approved to utilize the network model would continue to be subject to all program requirements and conditions set up under the AMDP. Any covered entity wishing to utilize a network model would still be required to seek approval under the AMDP and may not do so without formal approval. B. Contract Pharmacy Services Mechanism

(1)Basic Requirements for Utilization of Contract Pharmacy Arrangements Covered entities that wish to utilize contract pharmacy services to dispense section 340B outpatient drugs must have a written contract in place between themselves and a pharmacy. This mechanism is designed to facilitate program participation for those covered entities that do not have access to available or appropriate “in-house” pharmacy services, those covered entities who have access to “in-house” pharmacy services but who wish to supplement these “in-house” services, and covered entities that wish to utilize multiple contract pharmacies to increase patient access to 340B drugs. The covered entity has the responsibility to: ensure against illegal diversion and duplicate discounts, maintain readily auditable records, and meet all other 340B Drug Pricing Program requirements. OPA has provided a model agreement format below as guidance for the type of contractual provisions expected in such agreements as well as suggested contract provisions in the Appendix. All covered entities utilizing a contract pharmacy must comply with the certification requirements described in

(4)below.

(2)Potential Alternatives to Single Location, Single Pharmacy Model In addition to contracting with a single pharmacy for each clinical site, covered entities may pursue more complex arrangements that include multiple pharmacies only if:

(a)There is a written agreement and procedures meeting the basic requirements outlined in

(1)above between the covered entity and each pharmacy;

(b)the operation continues to meet all 340B Drug Pricing Program requirements and does not create unlawful diversion or duplicate discounts; and

(c)the arrangements are one of the two following models individually or in combination:

(i)The use of multiple contract pharmacy service sites, and/or

(ii)the utilization of a contract pharmacy

(ies)to supplement in-house pharmacy services. The use of multiple contract pharmacy service sites refers to any arrangement wherein a covered entity site seeks to provide drugs at 340B discounted prices for its patients at more than one pharmacy location. Supplementing in-house pharmacy services with a contract pharmacy refers to any arrangement wherein a covered entity site seeks to purchase drugs at 340B discounted prices for its patients at both an in-house pharmacy and at least one additional contract pharmacy location.

(3)Model Agreement Provisions The following are suggested provisions for a model agreement:

(a)The covered entity will purchase the drug, maintain title to the drug and assume responsibility for establishing its price, pursuant to the terms of a HHS grant (if applicable) and any applicable state and local laws and consumer protection laws. A “ship to, bill to” procedure is used in which the covered entity purchases the drug; the manufacturer/wholesaler must bill the covered entity for the drug that it purchased, but ships the drug directly to the contract pharmacy (Section 1 of Appendix.) In cases where a covered entity has more than one site, it may choose between having each site billed individually or designating a single covered entity billing address for all 340B drug purchases.

(b)The contract pharmacy will provide comprehensive pharmacy services (e.g., dispensing, recordkeeping, drug utilization review, formulary maintenance, patient profile, patient counseling, and medication therapy management services). Each covered entity which purchases its covered outpatient drugs has the option of individually contracting for pharmacy services with a pharmacy(ies) of its choice.

(c)The covered entity health care provider will inform the patient of his or her freedom to choose a pharmacy provider. If the patient does not elect to use the contracted service, the patient may obtain the prescription from the covered entity and then obtain the drug(s) from the pharmacy provider of his or her choice. When a patient obtains a drug from a retail pharmacy other than a covered entity's contract pharmacy, the manufacturer is not required to offer this drug at the 340B price.

(d)The contract pharmacy may provide other services to the covered entity at the option of the covered entity (e.g., home care, delivery, reimbursement services). Regardless of the services provided by the contract pharmacy, access to 340B pricing will always be restricted to only patients of the covered entity.

(e)The contract pharmacy and the covered entity will adhere to all Federal, State, and local laws and requirements. Additionally, all HHS grantees, disproportionate share hospitals and FQHC Look-Alikes will adhere to all rules and regulations that apply to them as grantees or otherwise eligible entities. Both the covered entity and the contract pharmacy are aware of the potential for civil or criminal penalties if the covered entity and/or the contract pharmacy violate Federal or State law. [The Department reserves the right to take such action as may be appropriate if it determines that such a violation has occurred.]

(f)The contract pharmacy will provide the covered entity with reports consistent with customary business practices (e.g., quarterly billing statements, status reports of collections and receiving and dispensing records). *See* Section 2 of Appendix.

(g)The contract pharmacy, with the assistance of the covered entity, will establish and maintain a tracking system suitable to prevent diversion of section 340B drugs to individuals who are not patients of the covered entity. Customary business records may be used for this purpose. The covered entity will establish a process for a periodic comparison of its prescribing records with the contract pharmacy's dispensing records to detect potential irregularities. *See* Section 3 of Appendix.

(h)The covered entity and the contract pharmacy will develop a system to verify patient eligibility, as defined by HRSA guidelines. Both parties agree that they will not resell or transfer a drug purchased at section 340B prices to an individual who is not a patient of the covered entity. *See* 42 U.S.C. 256a(a)(5)(B). The covered entity understands that it can be removed from the list of covered entities because of its participation in drug diversion and no longer be eligible for 340B pricing. *See* Section 4 of Appendix.

(i)Neither party will use drugs purchased under section 340B to dispense Medicaid prescriptions, unless the covered entity, the contract pharmacy and the State Medicaid agency have established an arrangement to prevent duplicate discounts. Any such arrangement shall be reported to the Office of Pharmacy Affairs by the covered entity.

(j)Both parties understand that they are subject to audits (by the Department and participating manufacturers) of records that directly pertain to the entity's compliance with the drug resale or transfer prohibition and the prohibition against duplicate discounts. *See* 42 U.S.C § 256a(a)(5). The contract pharmacy will assure that all pertinent reimbursement accounts and dispensing records, maintained by the pharmacy, will be accessible separately from the pharmacy's own operations and will be made available to the covered entity, the Department, and the manufacturer in the case of an audit.

(k)Upon written request to the covered entity, a copy of this contract pharmacy service agreement will be provided to a participating manufacturer which sells covered outpatient drugs to the covered entity. All confidential or proprietary information may be deleted from the document.

(4)Certification Under section 340B, if a covered entity using contract pharmacy services requests to purchase a covered outpatient drug from a participating manufacturer, the statute directs the manufacturer to sell the drug at a price not to exceed the statutory 340B discount price. If the entity directs the drug shipment to its contract pharmacy(ies), we see no basis on which to conclude that section 340B precludes this type of transaction or otherwise exempts the manufacturer from statutory compliance. However, the entity must comply, under any distribution mechanism, with the statutory prohibition on drug diversion and duplicate discounting. To provide OPA and manufacturers with assurance that the covered entity has acted in a manner which limits the potential for drug diversion, the covered entity is required to submit to OPA a certification that it has signed and has in effect an agreement with the contract pharmacy(ies) containing the aforementioned provisions (see 3 above). However, if a covered entity wishes to utilize an agreement with provisions different from those listed above that it believes meets 340B requirements; OPA will review the proposed agreement provisions for sufficiency. The names of those covered entities which submit a certification, or an alternate mechanism approved by OPA, will be listed on the OPA Web site for the convenience of participating drug manufacturers and wholesaler distributors. In addition, any covered entity that has opted to utilize any pharmacy arrangement described in

(2)must specify which arrangement or combination of arrangements it is utilizing, the names and 340B identification numbers of all covered entities participating, and the names of any pharmacies participating.

(5)Anti-Kickback Statute Contract pharmacies and covered entities should be aware of the potential for civil or criminal penalties if the contract pharmacy violates Federal or State law. In negotiating and executing a contract pharmacy service agreement pursuant to these guidelines, contract pharmacies and covered entities should be aware of and take into consideration the provisions of the Medicare and Medicaid anti-kickback statute, 42 U.S.C. 1320a-7b(b). This statute makes it a felony for a person or entity to knowingly and willfully offer, pay, solicit, or receive remuneration with the intent to induce, or in return for the referral of, Medicare or a State health care program business. State health care programs are Medicaid, the Maternal and Child Health Block Grant program, and the Social Services Block Grant program. Apart from the criminal penalties, a person or entity is also subject to exclusion from participation in the Medicare and State health care programs for a knowing and willful violation of the statute pursuant to 42 U.S.C. 1320a-7(b)(7). The anti-kickback statute is very broad. Prohibited conduct covers not only remuneration intended to induce referrals of patients, but also includes remuneration intended to induce the purchasing, leasing, ordering, or arranging for any good, facility, service, or item paid for by Medicare or a State health care program. The statute specifically identifies kickbacks, bribes, and rebates as illegal remuneration, but also covers the transferring of anything of value in any form or manner whatsoever. This illegal remuneration may be furnished directly or indirectly, overtly or covertly, in cash or in kind and covers situations where there is no direct payment at all, but merely a discount or other reduction in price or the offering of a free good(s). Arrangements between contract pharmacies and covered entities that could violate the anti-kickback statute would include any situation where the covered entity agrees to refer patients to the contract pharmacy in return for the contract pharmacy or an entity owned or controlled by the contract pharmacy agreeing to undertake or furnish certain activities or services to the covered entity at no charge or at a reduced or below cost charge. These activities or services would include the provision of contract pharmacy services, home care services, money or grants for staff or service support, or medical equipment or supplies, or the remodeling of the covered entity's premises. For example, if a contract pharmacy agreed to furnish covered outpatient drugs in return for the covered entity referring its Medicaid patients to the contract pharmacy to have their prescriptions filled, the arrangement would violate the anti-kickback statute. Similarly, if the contract pharmacy agreed to provide billing services for the covered entity at no charge in return for the covered entity referring its patients to the contract pharmacy for home or durable medical equipment, the statute would be violated. Pursuant to the authority in 42 U.S.C. 1320a-7b(b)(3), the Secretary of HHS has published regulations setting forth certain exceptions to the anti-kickback statute, commonly referred to as “safe harbors.” These regulations are codified at 42 CFR 1001.952. Each of the safe harbors sets forth various requirements which must be met in order for a person or entity to be immune from prosecution or exclusion under the safe harbors. C. Appendix—Suggested Contract Provisions

(1)“The covered entity owns covered drugs and arranges to be billed directly for such drugs. The pharmacy will compare all shipments received to the orders and inform the covered entity of any discrepancy within five

(5)business days of receipt. The covered entity will make timely payments for such drugs delivered to the (pharmacy).”

(2)“The covered entity will verify, using the contract pharmacy's (readily retrievable) customary business records, that a tracking system exists which will ensure that drugs purchased under the 340B Drug Pricing Program are not diverted to individuals who are not patients of the covered entity. Such records can include: prescription files, velocity reports, and records of ordering and receipt. These records will be maintained for the period of time required by State law and regulations.”

(3)“Prior to the contract pharmacy providing pharmacy services pursuant to this agreement, the covered entity will have the opportunity, upon reasonable notice and during business hours, to examine the tracking system. For example, such a tracking system may include quarterly sample comparisons of eligible patient prescriptions to the dispensing records and a six

(6)month comparison of 340B drug purchasing and dispensing records as is routinely done in other reconciliation procedures. The contract pharmacy will permit the covered entity or its duly authorized representatives to have reasonable access to contract pharmacy's facilities and records during the term of this agreement in order to make periodic checks regarding the efficacy of such tracking systems. The contract pharmacy agrees to make any and all adjustments to the tracking system which the covered entity advises are reasonably necessary to prevent diversion of covered drugs to individuals who are not patients of the covered entity.”

(4)“The pharmacy will dispense covered drugs only in the following circumstances:

(a)Upon presentation of a prescription bearing the covered entity's name, the eligible patient's name, a designation that the patient is an eligible patient of the covered entity, and the signature of a legally qualified health care provider affiliated with the covered entity; or

(b)receipt of a prescription ordered by telephone or other means of electronic transmission that is permitted by State or local law on behalf of an eligible patient by a legally qualified health care provider affiliated with the covered entity who states that the prescription is for an eligible patient. The covered entity will furnish a list to the pharmacy of all such qualified health care providers and will update the list of providers to reflect any changes. If a contract pharmacy is found to have violated the drug diversion prohibition, the contract pharmacy will pay the covered entity the amount of the discount in question so that the covered entity can reimburse the manufacturer.” Dated: December 22, 2006. Elizabeth M. Duke, Administrator. [FR Doc. E7-334 Filed 1-11-07; 8:45 am] BILLING CODE 4165-15-P DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Notice Regarding Section 602 of the Veterans Health Care Act of 1992 Definition of “Patient” AGENCY: Health Resources and Services Administration, HHS. ACTION: Notice. SUMMARY: Section 602 of Public Law 102-585, the “Veterans Health Care Act of 1992,” enacted Section 340B of the Public Health Service

(PHS)Act “Limitation on Prices of Drugs Purchased by Covered Entities.” Section 340B provides that in order to obtain Medicaid reimbursement for its covered outpatient drugs, a manufacturer must sign a pharmaceutical pricing agreement with the Secretary of Health and Human Services in which the manufacturer agrees to charge a price to covered entities for outpatient drugs that will not exceed an amount determined under a statutory formula. Section 340B is administered as the “340B Drug Pricing Program” and is commonly referred to as “the 340B Program.” Section 340B states that it is illegal for covered entities to sell medications purchased under the 340B Program to persons who are not considered “patients” of the covered entity. The purpose of this notice is to inform interested parties of proposed clarifications to the definition of “patient” for whom the covered entity can purchase discounted pharmaceuticals under the 340B Program. This clarification is necessary to protect the integrity of the 340B Program and to assist covered entities and other participants in their compliance efforts. DATES: The public is invited to submit comments on the proposed guidelines by March 13, 2007. After consideration of the comments submitted, the Secretary will issue final guidelines. ADDRESSES: Address all comments to Mr. Bradford R. Lang, Public Health Analyst, Office of Pharmacy Affairs (OPA), Healthcare Systems Bureau (HSB), Health Resources and Services Administration (HRSA), 5600 Fishers Lane, Parklawn Building, Room 10C-03, Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Mr. Jimmy Mitchell, Director, OPA, HSB, HRSA, 5600 Fishers Lane, Parklawn Building, Room 10C-03, Rockville, MD 20857, or by telephone through the Pharmacy Services Support Center at 1-800-628-6297. SUPPLEMENTARY INFORMATION: Introduction Section 340B(a)(4) of the PHS Act and section 1927(a) of the Social Security Act list the various types of organizations eligible to participate in and purchase discounted drugs under the 340B Program. Eligibility for participation in the 340B Program is strictly limited to the specific categories of entities specified in these statutes. Section 340B(a)(5)(B) of the PHS Act prohibits entities from selling (or otherwise transferring) drugs purchased under the 340B Program to anyone who is not a patient of the covered entity. Responsibility for ensuring compliance with this provision rests with the covered entity. Congress did not define the term “patient” in Section 340B, and initial HRSA guidelines implementing the 340B Program directed covered entities to “develop and institute adequate safeguards to prevent the transfer of discounted outpatient drugs to individuals who are not eligible for the discount” in order to prevent diversion. To accomplish this, entities were encouraged to utilize a separate purchasing account and separate dispensing records (See 59 FR 25110). As covered entities, manufacturers, and others began to implement the 340B Program, it became apparent that additional clarification of the patient definition was needed and on October 24, 1996, HRSA issued additional guidelines regarding the definition of a covered entity “patient” (61 FR 55156). These guidelines stated that the following definition of patient would apply for the purposes of the 340B Program: *An individual is a “patient” of a covered entity (with the exception of State-operated or funded AIDS drug purchasing assistance programs) only if:* 1. *The covered entity has established a relationship with the individual, such that the covered entity maintains records of the individual's health care; and* 2. *The individual receives health care services from a health care professional who is either employed by the covered entity or provides health care under contractual or other arrangements (e.g., referral for consultation) such that responsibility for the care provided remains with the covered entity; and* 3. * The individual receives a health care service or range of services from the covered entity which is consistent with the service or range of services for which grant funding or Federally-qualified health center look-alike status has been provided to the entity. Disproportionate share hospitals are exempt from this requirement. * *An individual will not be considered a “patient” of the entity for purposes of 340B if the only health care service received by the individual from the covered entity is the dispensing of a drug or drugs for subsequent self administration or administration in the home setting.* *An individual registered in a State operated or funded AIDS drug purchasing assistance program receiving financial assistance under Title XXVI of the PHS Act will be considered a “patient” of the covered entity for purposes of this definition if so registered as eligible by the State program. (61 FR 55157-8).* The definition of a “patient” was developed in order to identify those individuals eligible to receive 340B drugs from covered entities. Because of the large number of covered entities and the wide diversity of eligible groups (e.g., comprehensive hemophilia treatment centers, HIV/AIDS programs funded through the Ryan White CARE Act, black lung clinics, consolidated health centers, Disproportionate Share Hospitals (DSH), and Title X clinics), it was essential that HRSA work closely with each Federal program office to develop a definition flexible enough to describe accurately each covered entity's patients. As of October 1, 2005, participation in the 340B Program has grown to more than 12,000 entities. Through covered entity networking, contracting, and other arrangements, additional questions about the definition of a 340B patient have arisen. HRSA believes that the existing patient definition provides sufficient guidance to answer many of these questions. However, it is possible that some 340B covered entities may have interpreted the definition too broadly, resulting in the potential for diversion of medications purchased under the 340B Program. Therefore, HRSA finds it necessary to issue this Notice, and to include several examples that further illustrate the guidance. While similar to the existing patient definition, this clarification provides covered entities with more explicit guidance regarding the relationship between a covered entity and an individual that makes that individual a “patient” of the covered entity. Related to the definition of a “patient” is the question of which entities are eligible to provide 340B drugs. HRSA has been receiving an increasing number of questions specifically related to which entities qualify for inclusion in the 340B Program under Section 340B(a)(4)(L) of the PHS Act. HRSA invites comments with respect to which elements should be required in private non-profit hospitals' contracts with State or local governments “to provide health care services to low income individuals who are not entitled to benefits under Title XVIII of the Social Security Act or eligible for assistance under the State plan * * * ” under Section 340B(a)(4)(L)(i) of the PHS Act. HRSA is also seeking comments regarding the different situations where private, non-profit hospitals are formally granted government powers under Section 340B(a)(4)(L)(i) of the PHS Act. Final guidelines will replace all previous 340B Program guidance addressing the definition of a patient, including, but not limited to, the “Notice Regarding Section 602 of the Veterans Health Care Act of 1992 Patient and Entity Eligibility,” 61 FR 55156 and any individual correspondence issued by HRSA on the subject. Definition of a Patient Under these proposed guidelines, the criteria determining whether an individual is a “patient” of a covered entity (with the exception of State-operated or funded AIDS drug purchasing assistance programs) are: 1. The covered entity has established responsibility for the outpatient health care services it provides to the individual, such that the covered entity maintains ownership, control, maintenance, and possession of records of the individual's health care, including records that appropriately document health care services that result in the use of, or prescription for, 340B drugs; 2. The individual receives outpatient health care services that result in the use of, or a prescription for, 340B drugs as part of the diagnosis and treatment from a health care provider who is employed by the covered entity, or provides health care to patients of the covered entity under a valid, binding, and enforceable contract. If the individual received health care services from a health care provider employed by or under contract with the covered entity, then the individual may be referred for followup care for the same condition by that health care provider, to an outside health care provider and still remain a patient of the covered entity for purposes of this guidance, so long as ongoing responsibility for the outpatient health care service that results in the use of (or prescription for) 340B drugs, remains with the covered entity; and 3. The outpatient health care services the individual receives from the covered entity that result in the use of, or prescription for, 340B drugs are: a. Part of a health care service or range of services for which grant funding or Federally-Qualified Health Center look-alike status has been provided to the covered entity; or b. Provided by a Disproportionate Share Hospital

(DSH)or by a location that qualified as a provider-based facility within a DSH under 42 CFR 413.65. If the individual received care from such DSH or qualifying provider-based facility, then the individual may be referred for followup care for the same condition by such a health care provider to an outside health care provider and still remain a patient of the covered entity for purposes of this rule, so long as the covered entity (either the DSH or a qualified provider-based facility) retains ongoing responsibility for the outpatient health care service that results in the use of (or prescription for) 340B drugs. To demonstrate the necessary retention of ongoing responsibility for the health care it is expected that, at a minimum, the covered entity will provide health care to the individual in the DSH or the qualified provider-based facility of the DSH within 12 months after the time of referral. The individual's health care relationship with the covered entity is the most important factor in determining whether an individual satisfies the criteria above. For a prescription to qualify under 340B, the covered entity must be primarily responsible for the health care which results in the use of, or prescription for 340B drugs. An individual will not be considered a “patient” of the entity for purposes of 340B if the only health care service received by the individual from the covered entity is the dispensing of a drug or drugs for subsequent self administration or administration in the home setting. An individual registered in a State operated or funded AIDS drug purchasing assistance program receiving financial assistance under Title XXVI of the PHS Act will be considered a “patient” of the covered entity for purposes of this definition if so registered as eligible by the State program. The first criterion of the patient definition above requires covered entities to establish a relationship with each individual such that the covered entity maintains records of the individual's health care. The covered entity will document in the individual's health care records the health care service provided and the drugs prescribed or used in the covered entity for this individual. A shared electronic record where several parties have access and ability to add/edit the records from their physical location would satisfy the requirements of the 340B Program guidelines, as long as the covered entity maintains control, ownership, maintenance, and possession of the individual's health care record. Mere contractual right to obtain records from a health care provider, without actual control and maintenance of the record, would not satisfy the requirements of the 340B Program. The second criterion of the patient definition requires that the responsibility for the health care services that result in the use of, or prescription for, 340B drugs remains with the covered entity. Where a referral is utilized for specialty health care, in order to result in a valid 340B prescription, the referral must be for followup care for the same condition and must originate from a health care provider who is employed by or under a valid, binding, and enforceable contract with the covered entity which retains ongoing responsibility for the health care and treatment of the individual. For the purpose of this guidance, the provision of administrative services alone, such as case management services from someone other than a health care provider, is not sufficient to demonstrate the necessary health care services set forth in the definition above. The statute requires that 340B drugs be provided for the patients of the covered entity, as opposed to offering other services to individuals who are patients of health care providers who are not part of a covered entity as defined in the statute. In cases where an individual has received health care services from a non-covered entity resulting in a prescription, the administrative act of recording such information, incorporating it into the health record, and filling the prescription does not constitute health care services for the patient's health care for purposes of the 340B Program. To demonstrate responsibility for the health care that results in the use of, or prescription for 340B drugs, health care must be provided by the covered entity through health care providers who meet the second criterion and who have the capacity and authority to issue the 340B prescription. Mere acceptance *pro forma* or rubberstamping of an outside health care provider's diagnosis or medical opinion does not demonstrate such responsibility. While the health care providers of the covered entity can take into account the diagnosis and prescription of other health care providers, they must exercise their own judgment in taking responsibility for their own patients. The third criterion of the patient definition above requires that 340B drugs be prescribed only in conjunction with outpatient services. Furthermore, subsection

(a)clarifies that the provision of 340B drugs must fall within the scope of the grant funding or Federally Qualified Health Center look-alike status which forms the basis for the eligibility of the covered entity to participate in the 340B Program. Subsection

(b)of the third criterion likewise provides clarification for DSHs that the use of, or prescription for, 340B drugs must be within the scope of the basis for including such institutions in the 340B Program. In order for an outpatient facility of a DSH to be eligible for the 340B Program, it must be demonstrated that the outpatient facility is an integral part of the DSH. HRSA has chosen to rely on the category of provider-based facilities as set forth by the Centers for Medicare and Medicaid Services

(CMS)under Title XVIII of the Social Security Act (Medicare). This decision has been made because HRSA believes that the requisite integration of facilities necessary to demonstrate that the secondary facility is functioning as part of the DSH under 42 CFR 413.65 is appropriate for facilities eligible under the 340B Program. Compliance with the rule for provider-based facilities would provide clear guidance to DSHs that wish to prescribe 340B drugs to patients at these outpatient facilities and ensure that the individuals are truly patients of the DSH. Ultimately the facility's provider-based status must be reflected in the covered entity's Medicare Cost Report. The covered entity may provide a copy of the attestation provided to its fiscal intermediary pursuant to 42 CFR 413.65 to demonstrate compliance with this guideline until such time as the facility is listed on the DSH's Medicare Cost Report. The DSH shall retain the responsibility to promptly notify the OPA in the event that the outpatient facility's provider-based status is rejected or otherwise called into question. Examples The following examples describe the issues that HRSA has identified as problematic and the relationships that do not meet the definition of “patient” for purposes of compliance with the 340B Program guidelines. Example 1: Certain Case Management Constructs HRSA has become aware that some covered entities may be using case management arrangements that inappropriately expand their “patient” populations, diverting 340B drugs to individuals who are not eligible patients of the 340B covered entity. In some cases, the covered entities claim to provide the requisite “health care services” through a third party that operates through a case management construct or call center. Although the covered entity may retain records of the encounters, supervise personnel, oversee billing, payment, and other administrative tasks in the program, the covered entity is not providing the actual outpatient health care services that can be linked to the prescriptions written for the individuals in question. An individual whose sole relationship with a covered entity is through case management services or other administrative measures, not accompanied by actual medical services from a health care provider that meets criterion 2, would not be considered a patient of the covered entity eligible to receive 340B drugs. Example 2: Loose Affiliation Networks Some DSHs have been contracting with health care providers to create a loose affiliation model for outpatient health care services. The individuals, receiving services from affiliated health care providers, have been filling prescriptions written by these health care providers with 340B drugs. The “contracts” are often simple, one-page documents that do not create contractually enforceable duties or obligations for either the health care provider or covered entity. These affiliation models claim to meet the patient definition by specifying that the individual's health care records would be available at the covered entity, that “responsibility for the patient” would also reside with the covered entity, and that in some instances, individuals would be seen by a case manager at the covered entity at specified intervals. Under this model, the services being provided directly by the covered entity are often more appropriately characterized as administrative services rather than health care services. Ultimately, the treatment plan followed is determined by the affiliated health care provider and not the covered entity. The ongoing responsibility for the individual's health care resides with the affiliated health care provider and not the covered entity. The individuals enrolled in these programs are treated by health care providers too loosely affiliated with the covered entity for the ongoing responsibility to rest with the covered entity for the patient's health care resulting in the use of, or prescription for, 340B drugs. This model improperly seeks to expand the definition of a patient beyond that envisioned by Congress in prohibiting the resale of 340B drugs outside the eligible covered entity limits. In particular, HRSA is concerned that the affiliation model extends the ability of covered entities to purchase 340B drugs for individuals who are not receiving healthcare from a health care provider employed by or having a valid, binding, and enforceable contract with the covered entity. In the DSH context, since such affiliated healthcare providers may have privileges without actually being required to provide health care services at the DSH, HRSA believes that it is reasonable to require that either the prescribing, or the referring, health care provider be employed by or have a valid, binding, and enforceable contract with the covered entity to provide outpatient medical care to patients of the DSH. Example 3: Provider-Based Designations HRSA is concerned that a number of DSHs may be attempting to expand their eligible facilities to include locations that are not integrated parts of the qualifying DSH. As noted above, HRSA has chosen to rely on a location's status as a provider-based facility as provided under 42 CFR 413.65 to demonstrate that the secondary facility is functioning as part of the DSH. While HRSA is aware of the 35 mile distance exemption that exists for certain 340B-DSHs under 42 CFR 413.65(e)(3)(i), these DSH provider-based facilities remain subject to the other requirements as set forth in 42 CFR 413.65. This requirement also applies to nursing home facilities, rehabilitation hospitals, hospice, and home health agencies. Please note that even if these facilities qualify as part of the DSH, only patients receiving outpatient health care services in these facilities would be eligible to receive 340B drugs. In addition, if HRSA suspects that these entities are being improperly designated as provider-based facilities, HRSA will decline to add the facilities to the HRSA 340B database of covered entities until it has received portions of the Medicare Cost Report demonstrating provider-based status and/or the attestation of provider-based status the covered entity provides to its fiscal intermediary pursuant to 42 CFR 413.65. Likewise, if HRSA discovers that certain covered entities may have improperly listed facilities on the 340B database with the implication that they are provider-based, HRSA will request the covered entity to provide the relevant portions of the Medicare Cost Report and/or attestation within 45 days to verify the facility's provider-based status and to verify that such health care services are being provided on an outpatient basis. If HRSA does not receive appropriate documentation to verify provider-based status within this time period, it will remove the facility from the 340B covered entity database. The covered entity shall be required to notify HRSA immediately if its provider-based status has been rejected or questioned by CMS or its fiscal intermediary. In cases where provider-based status has been rejected, the facility will be removed from the 340B covered entity database immediately. Example 4: Employees HRSA receives many questions about whether employees of a covered entity are “patients” for purposes of the 340B Program. These questions come from covered entities that provide health care coverage to employees under their own self-insured health plan, and those whose employees have third party health coverage as an employment benefit. Employees of a covered entity, regardless of their health care coverage, are not considered patients of the covered entity for the purpose of the 340B Program unless they receive health care from a provider employed by or under contract with the covered entity. The fact that the person is an employee of the covered entity, or that they receive health care benefits from their covered entity-employer is not relevant. The relevant circumstance is that the employee is a patient of the covered entity. If an employee is a patient of another provider in the community, and is referred to and receives health care from the covered entity, they can receive 340B drugs only if the other provisions of the patient definition are met. Where a covered entity operates a self-insured health plan, the covered entity retains the requisite responsibility for the individual as a patient only if the individual receives outpatient health care services under the terms of this notice. Responsibility for the patient does not extend to cover the individual if the covered entity's sole responsibility for the individual is as the administrator of its self-insured plan. Meeting administrative requirements for maintaining employee health records so as to ensure that the employees are compliant with both State and Federal health care provider regulations alone, is not sufficient for the purpose of establishing patient eligibility for the 340B Program. Rather, the covered entity must provide health care to these individuals that results in the use of, or prescription for, 340B drugs. Furthermore, employees who merely receive required health physicals as a condition of their employment by a covered entity with no other health care provided are not patients of the covered entity. Example 5: Indian Tribes and Tribal Organizations In the case of Indian tribes or tribal organizations, any attempt to serve non-Indian Health Service beneficiaries must receive prior formal approval by the Indian Health Service. Example 6: Grantee Subgrantees and Subcontractors In certain circumstances, organizations may be functioning as subgrantees to grantees who are eligible to purchase 340B drugs (section 340B(a)(4) of the PHS Act). In these situations, subgrantees are reminded that they must meet the standards set forth in 45 CFR Part 74 and 45 CFR Part 92, as applicable. As subgrantees of a covered entity's grant, these organizations are eligible to access 340B drugs for only those patients to whom they are providing health care services under the scope of their subgrant. In these instances, individuals may only receive 340B drugs for the pharmaceuticals utilized under the scope of the project for which grant funds were received by the subgrantee. Subgrantees must register with HRSA in order to participate in the 340B Program and must be listed in the HRSA 340B database of covered entities to purchase 340B drugs. Subgrantees must maintain information systems that permit them to segregate the 340B eligible patient population from the rest of their patients, and to order 340B drugs only for 340B eligible patients. If an entity is a subcontractor of a covered entity, rather than a subgrantee, all 340B drugs must be purchased by the covered entity. The covered entity, in turn, must maintain records documenting its purchase of 340B drugs for its subcontractors. Both the covered entity and the subcontractor would be responsible for ensuring the 340B drugs were ordered only for the portion of the subcontract which is within the scope of a covered entity's grant. Dated: December 22, 2006. Elizabeth M. Duke, Administrator. [FR Doc. E7-335 Filed 1-11-07; 8:45 am] BILLING CODE 4165-15-P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Government-Owned Inventions; Availability for Licensing AGENCY: National Institutes of Health, Public Health Service, HHS. ACTION: Notice. SUMMARY: The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing. ADDRESSES: Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications. Macrocyclic Grb2 SH2 Domain-Binding Inhibitors: New Anti-Cancer and Anti-Angiogenic Therapeutic Agents *Description of Technology:* Growth factor receptor bound 2

(Grb2)SH2 domain is involved in signaling events leading to a variety of proliferative diseases including erb-2 dependent breast cancers and c-met dependent renal cancers. Inhibiting the Grb2 SH2 domain binding has great potential therapeutic utility in the treatment of certain cancers. This technology discloses the design and synthesis of new macrocyclic inhibitors of Grb2 SH2 domain binding. More specifically, a simple synthetic approach using upper achiral junctions has been utilized that does not require complex stereoselective synthesis. These new series of compounds have synthetic advantage over similar macrocyclic compounds and retain good binding affinity towards Grb2 SH2 domain. *Applications and Modality:*

(1)New macrocyclic inhibitors of Grb2 SH2 domain binding;

(2)New compounds have good binding affinity for Grb2 SH2 domain and can be potential anti-cancer and anti-angiogenic agents;

(3)Utilization of simple achiral upper ring junctions that do not require complex stereoselective synthesis;

(4)New compounds have synthetic advantage over more structurally complex inhibitors. *Market:*

(1)In 2006, receptor tyrosine kinase inhibitor drug sales were estimated at more than $1B dollars;

(2)In 2006, cancer drug sales were estimated to be $25 billion. *Development Status:* The technology is currently in the pre-clinical stage of development. *Inventors:* Terrence R. Burke Jr. and Fa Liu

(NCI)*Relevant Publications:* 1. F Liu *et al.* Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis. Org. Biomol. Chem. 2007;5:367-372. 2. N Atabey *et al.* Potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions. J. Biol. Chem. 2001 Apr 27;276(17):14308-14314. 3. C-Q Wei *et al.* Macrocyclization in the design of Grb2 SH2 domain-binding ligands exhibiting high potency in whole cell systems. J. Med. Chem. 2003 Jan 16;46(2):244-254. *Patent Status:* U.S. Provisional Application No. 60/867,307 filed 27 Nov 2006 (HHS Reference No. E-305-2006/0-US-01) *Licensing Status:* Available for exclusive and non-exclusive licensing. *Licensing Contact:* Adaku Madu, J.D.; 301/435-5560; *madua@mail.nih.gov* *Collaborative Research Opportunity:* The National Cancer Institute Laboratory of Medicinal Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize macrocyclic Grb2 SH2 domain-binding antagonists. Please contact John D. Hewes, Ph.D. at 301/435-3121 or *hewesj@mail.nih.gov* for more information. Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1 *Description of Technology:* Wip1 (PP2Cdelta or PPM1D) is a protein phosphatase 2C

(PP2C)family member that negatively regulates the p38 MAP kinase pathway. By dephosphorylating p38 kinase, p38 is unable to activate the p53 pathway; this prevents p53-mediated cell-cycle arrest and apoptosis, suggesting that Wip1 overexpression and over-activity may have implications during oncogenesis. Significantly, Wip1 is overexpressed in several human cancers, including breast cancer, ovarian clear cell adenocarcinoma and neuroblastomas. Thus, inhibitors of Wip1 may have promise as anti-cancer therapeutics. Unfortunately, no specific inhibitors have been designed to show proof of this concept. The instant technology involves the development of specific peptides for the inhibition of the Wip1 catalytic site. The inventors have modified the optimal Wip1 substrate sequence in such a manner that it successfully inhibits Wip1 activity. Importantly, the peptide effectively inhibited Wip1 without significantly affecting the activity of other PP2C family members. Thus, this compound has potential for examination as an anti-cancer agent. Claims in this technology are directed to compositions comprising the Wip1 inhibitors, as well as methods of using the inhibitors to inhibit Wip1 activity in a cell. *Application:* The inhibitors can be developed as anti-cancer therapeutics. *Market:* The cancer therapeutic market is expected to reach $27 billion by 2009. *Development Status:* The technology is at the pre-clinical stage. Optimization of the peptide sequence for delivery and efficacy, as well as the design of mimetics, are contemplated for further development. *Inventors:* Ettore Appella, Stewart R. Durell, Hiroshi Yamaguchi, Yawen Bai (NCI), *et al.* *Publications:* 1. H Yamaguchi *et al.* Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. Biochemistry 2005 Apr 12;44(14):5285-5294. 2. DV Bulavin *et al.* Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet. 2004 Apr;36(4):343-350. 3. H Yamaguchi *et al.* Development of substrate-based cyclic phosphopeptide inhibitor of protein phosphatase 2Cdelta, Wip1. Biochemistry 2006 Nov 7;45(44):13193-13202. 4. S Shreeram *et al.* Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. J. Exp. Med. 2006 Dec 25;203(13): 2793-2799. *Patent Status:* U.S. Provisional Application No. 60/850,218 filed 06 Oct 2006 (HHS Reference No. E-288-2006/0-US-01) Licensing Status: Available for non-exclusive or exclusive licensing. *Licensing Contact:* David Lambertson, PhD; 301/435-4632; *lambertsond@od.nih.gov* *Collaborative Research Opportunity:* The NCI CCR, LCB is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Cyclic Phosphopeptide Inhibitors of Protein Phosphatase 2C Delta, Wip1. Please contact John D. Hewes, Ph.D. at 301/435-3121 or *hewesj@mail.nih.gov* for more information. New Tumor Endothelial Markers: Genes That Distinguish Physiological and Pathological Angiogenesis *Description of Technology:* Angiogenesis, the formation of new blood vessels, is associated with normal physiological processes such as wound healing, ovulation or menstruation as well as with many diseases. Presently, it is thought to be required for the progressive growth of solid tumors and age-related macular degeneration. Lack of disease-specific endothelial markers has hindered the development of cancer therapies targeted against angiogenesis. This invention describes specific markers that can be used to identify tumor angiogenesis, separate from normal physiological angiogenesis. Several markers have been identified which may serve as potential targets for tumor vessels by using comparative gene expression analysis on various normal and tumor endothelial cells. Furthermore, the invention describes several organ-specific endothelial markers that can aid in the selective delivery of molecular medicine to specific sites. For example, brain endothelial markers

(BEMs)and liver endothelial markers

(LEMs)described herein could potentially be used to direct molecular medicine specifically to these tissues. The novel tumor endothelial markers

(TEMs)described in this invention also have potential diagnostic ability. These markers can be used to distinguish between normal and tumor tissues. Some of the secreted TEMs can serve as surrogate markers in the determination of the optimum biological dose

(OBD)for the current anti-angiogenic drugs in clinical trials. *Applications and Modality:*

(1)Novel therapeutic targets associated with tumor vessels;

(2)New agents can be developed against these novel targets;

(3)Novel endothelial markers that distinguish pathological angiogenesis from normal physiological angiogenesis;

(4)Surrogate tumor endothelial markers that can be used to determine optimal biological dose

(OBD)of anti-angiogenic drugs. *Market:*

(1)Sales of the first FDA approved anti-angiogenic drug Avastin TM has reached $600 million;

(2)Another promising anti-angiogenic molecule, Thalidomide TM , has been approved as an anti-cancer agent and for other use in Europe and Australia. *Development Status:* The technology is currently in the pre-clinical stage of development. *Inventors:* *Brad St.Croix* and Steven Seaman

(NCI)*Relevant Publication:* A Nanda and B St. Croix. Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol. 2004 Jan;16(1):44-49. *Patent Status:* U.S. Provisional Application No. 60/858,068 filed 09 Nov 2006 (HHS Reference No. E-285-2006/0-US-01) Licensing Status: Available for exclusive and non-exclusive licensing. *Licensing Contact:* Adaku Madu, J.D.; 301/435-5560; *madua@mail.nih.gov* *Collaborative Research Opportunity:* The NIH National Cancer Institute, Tumor Angiogenesis Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize specific biomarkers that can be used to identify tumor angiogenesis. Please contact John D. Hewes, PhD at 301/435-3121 or *hewesj@mail.nih.gov* for more information. A New Method for Improving the Therapeutic Efficacy of L-Asparaginase in Multiple Types of Cancer *Description of Technology:* For the last several decades, L-asparaginase (L-ASP) has been widely used as a clinical treatment for leukemias. Studies show that cancer cells that contain less asparagine synthetase

(ASNS)are more susceptible to L-ASP. The response to L-ASP therapy is often better when the expression of ASNS is limited. The present invention describes a new method for enhancing L-ASP activity by combining it with antagonists of ASNS—such as siRNAs, antisense nucleotides, antibodies or small-molecule inhibitors—for treatment of cancers. Reducing or suppressing the expression of ASNS potentiates the growth inhibitory activity of L-ASP. Additionally, the invention discloses a novel biomarker screening tool to identify leukemia, ovarian, and other cancer patients that would be most likely to respond to L-ASP treatment. *Applications and Modality:* A new method for improving the therapeutic efficacy of L-asparaginase. ASNS antagonists such as siRNA, antibodies, antisense nucleotides, or small-molecule inhibitors can potentially be used in combination with L-ASP in the treatment of cancers. ASNS gene or protein expression can serve as a therapeutic response biomarker for personalization of cancer therapy with the aforementioned combinations. *Market:* There were more than 500,000 deaths from cancer in 2006. The current technology has the potential of being used in conjunction with L-ASP in treating cancer patients. Oncaspar TM , the PEG-derivitized L-ASP developed by Enzon Pharmaceuticals, registered annual sales of about $25 million in 2006, largely on the basis of treatment of acute lymphoblastic leukemia. The present invention may make L-ASP applicable to treatment of types of cancers that are much more common. *Development Status:* The technology is currently in the pre-clinical stage of development. With respect to L-ASP treatment of patients with solid tumors, Phase I clinical trials have been initiated (Principal Investigator Daniel D. Von Hoff, TGen, Inc.) at three institutions using L-ASP in combination with gemcitabine. *Inventors:* Philip L. Lorenzi, *John N. Weinstein* and *Natasha J. Caplen*

(NCI)*Publication:* PL Lorenzi *et al.* Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. Mol Cancer Ther. Nov; 5(11):2613-2623. Epub 2006 Nov 6, doi 10.1158/1535-7163.MCT-06-0447. *Patent Status:* U.S. Provisional Application No. 60/779,143 filed 03 Mar 2006 (HHS Reference No. E-132-2006/0-US-01); U.S. Provisional Application No. 60/833,027 filed 25 Jul 2006 (HHS Reference No. E-132-2006/0-US-02). *Licensing Status:* Available for exclusive and non-exclusive licensing. *Licensing Contact:* Mojdeh Bahar, J.D.; 301/435-2950, *baharm@mail.nih.gov* *Collaborative Research Opportunity:* The National Cancer Institute's Genomics & Bioinformatics Group in the Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the combination therapies described in this abstract. Please contact John D. Hewes, Ph.D. at 301/435-3121 or *hewesj@mail.nih.gov* for more information. Dated: November 8, 2007. Steven M. Ferguson, Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health. [FR Doc. E7-349 Filed 1-11-07; 8:45 am] BILLING CODE 4140-01-P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Government-Owned Inventions; Availability for Licensing AGENCY: National Institutes of Health, Public Health Service, HHS. ACTION: Notice. SUMMARY: The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing. ADDRESSES: Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications. In Vivo Assessment of Tissue Microstructure and Microdynamics: Estimation of the Average Propagator From Magnetic Resonance Data *Description of Technology:* This invention relates to diffusion-weighted magnetic resonance imaging (DW-MRI) and describes a novel method for estimating the 3-D average propagator from DW-MRI data. The average propagator measures the probability that water molecules move from one place to another during a given diffusion time. This quantity provides local information about the tissue microstructure and the microenvironment in which water diffuses without making any *a priori* assumptions about the underlying diffusion process itself. Several methods, such as 3D q-space magnetic resonance imaging

(MRI)and diffusion spectrum imaging have been developed to measure the average propagator, but these techniques currently require acquisition of large numbers of DW images, making them infeasible for routine animal and clinical imaging. The proposed methodology introduces a new data reconstruction concept, which involved using computer tomography

(CT)algorithms to estimate the average propagator from the MR data. The proposed CT reconstruction requires many fewer DW-MRI data than conventional methods consistent with a clinically feasible period of MR image acquisition. The novel technique can be used to diagnose medical disorders that are associated with alterations in water diffusion, such as stroke and several neurodegenerative diseases and other disorders for which diffusion tensor MRI is currently used. Additional applications include drug development (screening drug candidates), material science (testing the quality of materials that have restricted and hindered compartments, e.g. porous media, gels and films) and food processing (testing structural changes in food). *Applications:* In vivo Functional MRI of humans and animals; Drug development; Material science; Food processing. *Development Status:* Early stage; only testing using fixed tissues and numerical phantoms have been performed at this time. *Inventors:* Peter J. Basser and Valery Pickalov ( *NICHD* ). *Patent Status:* U.S. Patent Application No. 11/407,096 filed 20 Apr 2006 (HHS Reference No. E-164-2006/0-US-01). *Licensing Status:* Available for non-exclusive or exclusive licensing, as well as for collaborative research, provided that non-disclosure agreements and MTAs have been executed. *Licensing Contact:* Chekesha S. Clingman, Ph.D.; 301/435-5018; *clingmac@mail.nih.gov.* *Collaborative Research Opportunity:* The NICHD Laboratory of Integrative and Medical Biophysics, Section on Tissue Biophysics and Biomimetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Peter J. Basser, Ph.D. at *pjbasser@helix.nih.gov* for more information. Fast Electron Paramagnetic Resonance Imaging

(EPRI)Using CW-EPR Spectrometer With Sinusoidal Rapid-Scan and Digital Signal Processing *Description of Technology:* Electron Paramagnetic Resonance

(EPR)Imaging is an indispensable tool that may be applied to a variety of disciplines for evaluation of chemical species having unpaired electrons such as free radicals and transition metal ions. In Continuous Wave (CW)-EPR the sample is continuously irradiated with weak RF radiation while sweeping the magnetic field relatively slowly. Existing CW-EPR techniques utilize a signal detection method known as phase-sensitive detection which results in data acquisition times that are too long for *in vivo* applications. The present technology represents significant improvements on conventional CW-EPR. The subject technology includes three approaches to collecting image data with increased spatial, temporal and spectral resolution and improved sensitivity. Spectral data acquisition is performed by a direct detection strategy involving mixing a signal to base-band and acquiring data with a fast-digitizer. Projection data is acquired using a sinusoidal magnetic field sweep under gradient magnetic fields. Data collection times are decreased with the utility of rotating gradients. Further, the current technology improves sensitivity by employing Digital Signal Processing, which decreases background analog noise. Increased speed and sensitivity makes CW-EPR a potentially useful and complementary tool to Magnetic Resonance Imaging for *in vivo* imaging. The presently described improvements to CW-EPR will allow changes of blood perfusion and oxygenation in tumors to be observed in nearly real-time, while improved resolution will permit angiogenesis in and around tumors to be carried out in a non-invasive manner. Additionally, rapid scan imaging provides excellent temporal resolution and will help quantify pharmaco-kinetics and metabolic degradation kinetics of bioactive free radicals. *Applications:*

(1)Enhanced spatial, temporal, and spectral resolution of Continuous Wave-Electron Paramagnetic Resonance Imaging;

(2)Real-time assessment of changes in blood perfusion and oxygenation. *Development Status:* Preliminary experiments have been conducted and the technology has been tested for feasibility. *Inventors:* Sankaran Subramanian, Nallathamby Devasahayam, Janusz Koscielniak, *James Mitchell,* and *Murali Krishna* (NCI). *Publication:* S Subramanian, JW Koscielniak, N Devasahayam, RH Pursley, TJ Pohida, TJ Pohida, MC Krishna. A new strategy for fast radiofrequency CW-EPR imaging: Direct detection with rapid scan and rotating gradients. Submitted to Journal of Magnetic Resonance for publication. *Patent Status:* U.S. Provisional Application No. 60/818,052, filed 30 Jun 2006 (HHS Reference No. E-221-2005/0-US-01). *Licensing Status:* Available for non-exclusive or exclusive licensing and commercial development. *Licensing Contact:* Chekesha S. Clingman, PhD; 301/435-5018; *clingmac@mail.nih.gov.* *Collaborative Research Opportunity:* The Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, MD is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the above Rapid scan-Rotating gradients strategy for performing routine *in vivo* Radiofrequency CW-EPR imaging in small animals. Please contact John D. Hewes, PhD at 301-435-3121 or *hewesj@mail.nih.gov* for more information. Dated: January 5, 2007. Steven M. Ferguson, Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health. [FR Doc. E7-350 Filed 1-11-07; 8:45 am] BILLING CODE 4140-01-P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2), notice is hereby given of the following meetings. The meetings will be closed to the public in accordance with provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., as amended. The grant applications and the discussions could disclose confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the grant applications, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. *Name of Committee:* National Heart, Lung, and Blood Institute Special Emphasis Panel; Conference Grants (R13). *Date:* January 24, 2007. *Time:* 8 a.m. to 9 a.m. *Agenda:* To review and evaluate grant applications. *Place:* National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD 20892 (Telephone Conference). *Contact Person:* Valerie L. Prenger, PhD, Scientific Review Administrator, Review Branch, Room 7214, Division of Extramural Research Activities, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, MSC 7294, Bethesda, MD 20892-7294,

(301)435-0270, *prengerv@nhibi.nih.gov.* *Name of Committee:* National Heart, Lung, and Blood Institute Special Emphasis Panel; Shared Resource Grant (R24). *Date:* January 25, 2007. *Time:* 3 p.m. to 4:30 p.m. *Agenda:* To review and evaluate grant applications. *Place:* National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD 20892 (Telephone Conference Call). *Contact Person:* Shelley S. Sehnert, PhD, Scientific Review Administrator, Review Branchy, NIH/NHLBI, 6701 Rockledge Drive, Room 7206, Bethesda, MD 20892-7294,

(301)435-0303, *ssehnert@nhlbi.nih.gov.* (Catalogue of Federal Domestic Assistance Program Nos. 93.233, National Center for Sleep Disorders Research; 93.837, Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood Diseases and Resources Research, National Institutes of Health, HHS) Dated: January 8, 2007. Anna Snouffer, Acting Director, Office of Federal Advisory Committee Policy. [FR Doc. 07-101 Filed 1-11-07; 8:45 am]

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