of Biologics Standards, National Institutes of Health, Building 29, Bethesda, Md. 20014, in writing within 30 days of the publication of this notice, that he will submit substantial evidence of the effectiveness of each such product within 180 days after the publication of this notice. A manufacturer who does not within such 30-day period state that he will submit such information shall, at the end of such period cease the interstate shipment of such products and shall surrender promptly his license by mailing it to the above address. Data and information submitted pursuant to this notice shall provide the information called for in, and shall be organized in the format for, new drug applications (21 CFR 130.4 (c) (2)) to the extent applicable, and shall also include a list of each such product currently being marketed by the manufacturer specifying, (a) the trade name, if any, of each, and (b) all bacterial components of a polyvalent product. Licensed manufacturers of products for which there is no substantial evidence of effectiveness as defined in 21 CFR 130.12 (a) (5) will be so notified. Such licenses, and the licenses of those manufacturers who have not indicated timely their intention to submit the data and information called for by this notice, or who have not submitted timely such information and data, shall be surrendered promptly or proceedings will be instituted either for the revocation of the license or against shipment in interstate commerce of such products under the applicable provisions of the Federal Food, Drug and Cosmetic Act, as may be appropriate. Dated: March 8, 1972.

ROBERT Q. MARSTON, Director, National Institutes of Health.

[FR Doc. 72-8893. Filed 3-14-72; 8:50 am]

EXHIBIT 61

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE[42 CFR PART 73]-BIOLOGICAL PRODUCTS

NEUROVIRULENCE SAFETY TESTS FOR LIVE MEASLES, MUMPS, AN REBELLA VACCINE

[Federal Register, Vol. 37, No. 37, Feb. 24, 1972]

Notice is hereby given that the Director, National Institutes of Health, proposes to amend Part 73 of the Public Health Service regulations by (1) deleting the neurovirulence safety test in monkeys for neurotropic agents presently required on each lot of Measles Virus Vaccine, Live, Attenuated; Mumps Virus Vaccine, Live and Rubella Virus Vaccine, Live and (2) revising the neurovirulence safety test on the virus seed strain of these three vaccines. It is the conclusion of the Division of Biologics Standards that the safety, purity and potency of these vaccines will not be affected by such amendments.

Inquiries may be addressed, and data, views, and arguments may be presented by interested parties, in writing in triplicate, to the Director, Division of Biologics Standards, National Institutes of Health, Public Health Service, 9000 Rockville Pike, Bethesda, Md. 20014. All comments received in response to this notice will be available for public inspection and copying in the Office of the Assistant to the Director, Division of Biologics Standards, Room 122, Building 29, National Institutes of Health, weekdays (Federal holidays excepted) between the hours of 8:30 a.m. and 5 p.m. All relevant material received not later than 30 days after publication of this notice in the Federal Register will be considered. Notice is also given that it is proposed to make any amendments that are adopted effective 30 days after publication in the Federal Register. It is therefore proposed to amend Part 73 as set forth below. Dated: February 15, 1972.

ROBERT Q. MARSTON, Director, National Institutes of Health.

1. Amend § 73.1060 by revising paragraph (c) to read as follows: $73.1060 The product

Tulence safety test of the virus seed strain in monkeys-(1) The ion shall be made in monkeys of the lack of neurotropic propstrain of attenuated measles virus used in manufacture of

measles virus vaccine. For this purpose, vaccine from each of the five consecutive lots (8 73.1065) used by the manufacturer to establish consistency of manufacture of the vaccine shall be tested separatively in the following manner :

(i) Samples of each of the five lots of vaccine shall be tested in measles susceptible monkeys. Immediately prior to initiation of a test each monkey shall have been shown to be serologically negative for neutralizing antibodies by means of a tissue culture neutralization test with undiluted serum from each monkey tested at approximately 100 TCID 50 of Edmonston strain measles virus, or negative for measles virus antibodies as demonstrated by tests of equal sensitivity. (ii) A test sample of vaccine removed after clarification but before final dilution for standardization of virus content shall be used for the test.

(iii) Vaccine shall be injected by combined intracerebral, intraspinal, and intramuscular routes into not less than 20 Macaca or Cereopithecus monkeys or a species found by the Director, Division of Biologics Standards, to be equally suitable for the purpose. The animals shall be in overt good health and injected under deep barbiturate anesthesia. The intromuscular injection shall consist of 1.0 milliliter of test sample into the right leg muscles. At the same time, 200 milligrams of cortisone acetate shall be injected into the left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 units) into the right arm muscles. The intracerebral injection shall consist of 0.5 milliliter of test sample into each thalamic region of each hemisphere. The intraspinal injection shall consist of 0.5 milliliter of test sample into the lumbar spinal cord enlargement.

(iv) The monkeys shall be observed for 17-21 days and symptoms of paralysis as well as other neurologic disorders shall be recorded.

(v) At least 90 percent of the test animals must survive the test period without significant weight loss, except that, if at least 70 percent of the test animals survive the first 48 hours after injection, those animals which do not survive this 48-hour test period may be replaced by an equal number of qualified test animals which are tested pursuant to subdivisions (i) through (iv) of this subparagraph. At least 80 percent of the animals used must show gross or microscopic evidence of inoculation trauma in the thalamic area and microscopic evidence of inoculation trauma in the lumbar region of the spinal cord. If less than 70 percent of the test animals survive the first 48 hours, or if less than 80 percent of the animals meet the inoculation criteria prescribed in this paragraph, the test must be repeated.

(vi) At the end of the observation period, each surviving monkey shall (a) be bled and the serum tested for evidence of serum antibody conversion to measles virus and (b) be autopsied and samples of cerebral cortex and of cervical and lumbar spinal cord enlargements shall be taken for virus recovery and identification if needed pursuant to subdivision (vii) of this subparagraph. Histological sections shall be prepared from both spinal cord enlargements and appropriate sections of the brain and examined.

(vii) Doubtful histopathological findings necessitate (a) examination of a sample of sections from several regions of the brain in question, and (b) attempts at virus recovery from the nervous tissues previously removed from the animal. (viii) The lot is satisfactory if the histological and other studies demonstrate no evidence of changes in the central nervous system attributable to unusual neurotropism of the seed virus or of the presence of extraneous neurotropic agents.

(2) Wild virus controls. As a check against the inadvertent introduction of wild measles virus, at least four uninoculated measles susceptible control monkeys shall be maintained as either cage mates to, or within the same immediate area of, the 20 inoculated test animals for each lot of vaccine for the entire period of observation (17-21 days) and an additional 10 days. Serum samples from these control contact monkeys drawn at the time of seed virus inoculation of the test animals, and again after completion of the test, shall be shown to be free of measles neutralizing antibodies.

(3) Test results. (i) For each lot of vaccine under test, at least 80 percent of the monkeys must show measles antibody serological conversion (1:4 or greater) and the control contact monkeys must demonstrate no immunological response indicative of measles virus infection.

(ii) The measles virus seed has acceptable neurovirulence properties for use in vaccine manufacture only if for each of the five lots (a) 90 percent of the monkeys survive the observation period, (b) the histological and other studies produce no evidence of changes in the central nervous system attributable to unusual neurotropism of the seed virus and (c) there is no evidence of the presence of extraneous neutropic agents.

(4) Need for additional neurovirulence safety testing. A neurovirulence safety test as prescribed in this paragraph shall be performed on vaccine from five consecutive lots whenever a new production seed lot is introduced or whenever the source of cell culture substrate must be reestablished and recertified as prescribed in § 73.1061 (a), (b), and (c).

§ 73.1062 [Amended]

2. Amend § 73.1062 by deleting paragraph (d).

3. Amend § 73.1100 by revising paragraph (c) to read as follows:

§ 73.1100 The product

(c) Neurovirulence stafety test of the virus seed strain in monkeys—(1) The test. A demonstration shall be made in monkeys of the lack of neurotropic pròperties of the seed strain of attenuated mumps virus used in the manufacture of mumps vaccine. For this purpose, vaccine from each of the five consecutive lots (§ 73.1105) used by the manufacturer to establish consistency of manufacture of the vaccine shall be tested separately in monkeys shown to be serologically negative for mumps virus antibodies in the following manner :

(i) A test sample of vaccine removed after clarification but before final dilution for standardization of virus content shall be used for the test.

(ii) Vaccine shall be injected by combined intracerebral, intraspinal, and intramuscular routes into not less than 20 Macaca or Cercopithecus monkeys or a species found by the Director, Division of Biologics Standards, to be equally suitable for the purpose. The animals shall be in overt good health and injected under deep barbiturate anesthesia. The intramuscular injection shall consist of 1.0 milliliter of test sample into the right leg muscles. At the same time, 200 milligrams of cortisone acetate shall be injected into the left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 units) into the right arm muscles. The intracerebral injection shall consist of 0.5 milliliter of test sample into each thalamic region of each hemisphere. The intraspinal injection shall consist of 0.5 milliliter of test sample into the lumbar spinal cord enlargement.

(iii) The monkeys shall be observed for 17-21 days and symptoms of paralysis as well as other neurologic disorders shall be recorded.

(iv) At least 90 percent of the test animals must survive the test period without significant weight loss, except that, if at least 70 percent of the test animals survive the first 48 hours after injection, those animals which do not survive this 48-hour test period may be replaced by an equal number of qualified test animals which are tested pursuant to subdivisions (i) through (iii) of this subparagraph. At least 80 percent of the animals used must show gross or microscopic evidence of inoculation trauma in the thalamic area and microscopic evidence of inoculation trauma in the lumbar region of the spinal cord. If less than 70 percent of the test animals survive the first 48 hours, or if less than 80 percent of the animals fail to meet the inoculation criteria prescribed in this paragraph, the test must be repeated.

(v) At the end of the observation period, each surviving animal shall be autopsied and samples of cerebral cortex and of cerical and lumber spinal cord enlargements shall be taken for virus recovery and identification if needed pursuant to subdivision (vi) of this subparagraph. Histological sections shall be prepared from both spinal cord enlargements and appropriate sections of the brain and examined.

(vi) Doubtful histopathological findings necessitate (a) examination of a sample of sections from several regions of the brain in question, and (b) attempts at virus recovery from the nervous tissues previously removed from the animals.

(vii) The lot is satisfactory if the histological and other studies demonstrate no evidence of changes in the central nervous system attributable to unusual neurotropism of the seed virus or of the presence of extraneous neurotropic agents.

(2) Test results. The mumps virus seed has acceptable neurovirulence properties for use in vaccine manufacture only if for each of the five lots (1) 90 percent of the monkeys survive the observation period, (ii) the histological and other studies produce no evidence of changes in the central nervous system attributable to unusual neurotropism or replication of the seed virus and (iii) there is no evidence of the presence of extraneous neurotropic agents.

(3) Need for additional neurovirulence safety testing. A neurovirulence safety test as prescribed in this paragraph shall be performed on vacine from five consecutive lots whenever a new production seed lot is introduced or whenever the source of cell culture substrate must be reestablished and recertified as prescribed in § 73.1101 (a).

§ 73.1102 [Amended]

4. Amend § 73.1102 by deleting paragraph (c).

5. Amend § 73.1120 by revising paragraph (e) to read as follows:

(e) Neurovirulence safety test of the virus seed strain in monkeys (1) The test. A demonstration shall be made in monkeys of the lack of neurotropic properties of the seed strain of attenuated rubella virus used in the manufacture of rubella vaccine. For this purpose, vaccine from each of the five consecutive lots (§ 73.1125) used by the manufacturer to establish consistency of manufacture of the vaccine shall be tested separately in monkeys shown to be serologically negative for rubella virus antibodies in the following manner:

(i) A test sample of vaccine removed after clarification but before final dilution for standardization of virus content shall be used for the test.

(ii) Vaccine shall be injected by combined intracerebral, intraspinal, and intramuscular routes into not less than 20 Macaca or Cerocopithecus monkeys or a species found by the Director, Division of Biologics Standards, to be equally suitable for the purpose. The animals shall be in overt good health and injected under deep barbiturate anesthesia. The intramuscular injection shall consist of 1.0 milliliter of test sample into the right leg muscles. At the same time, 200 milligrams of cortisone acetate shall be injected into the left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 units) into the right arm muscles. The intracerebral injection shall consist of 0.5 milliliter of test sample into each thalamic region of each hemisphere. The intraspinal injection shall consist of 0.5 milliliter of test sample into the lumbar spinal cord enlargement.

(iii) The monkeys shall be observed for 17-21 days and symptoms of paralysis as well as other neurologic disorders shall be recorded.

(iv) At least 90 percent of the test animals must survive the test period without significant weight loss, except that, if at least 70 percent of the test animals survive the first 48 hours after injection, those animals which do not survive this 48-hour test period may be replaced by an equal number of qualified test animals which are tested pursuant to subdivisions (i) through (iii) of this subparagraph. At least 80 percent of the animals used must show gross or microscopic evidence of inoculation trauma in the thalamic area and microscopic evidence of inoculation truma in the lumbar region of the spinal cord. If less than 70 percent of the test animals survive the first 48 hours, or if less than 80 percent of the animals fail to meet the inoculation criteria prescribed in this paragraph, the test must be repeated.

(v) At the end of the observation period, each surviving animal shall be autopsied and samples of cerebral cortex and of cervical and lumbar spinal cord enlargement shall be taken for virus recovery and identification if needed pursuant to subsection (vi) of this subparagraph. Histological sections shall be prepared from both spinal cord enlargements and appropriate sections of the brain and examined.

(vi) Doubtful histopathological findings necessitate (a) examination of a sample of sections from several regions of the brain in question, and (b) attempts at virus recovery from the nervous tissues previously removed from the animal. (vii) The lot is satisfactory if the histological and other studies demonstrate no evidence of changes in the central nervous system attributable to the pres ence of unsual neurotropism of the seed virus or of the presence of extraneous neurotropic agents.

(2) Test results. The rubella virus seed has acceptable neurovirulence properties for use in vaccine manufacture only if for each of the five lots: (i) 90 percent of the monkeys survive the observation period, (ii) the histological and other studies produce no evidence of changes in the central nervous system attributable to the presence of unusual neurotropism or replication of the seed virus and (iii) there is no evidence of the presence of extraneous neurotropic agents.

(3) Need for additional neurovirulence safety testing. A neurovirulence safety test as prescribed in this paragraph shall be performed on vaccine from five consecutive lots whenever a new production seed lot is introduced or whenever the source of cell culture substrate must be reestablished and recertified as prescribed in § 73.1121 (a), (b), (c), and (c−1).

$73.1122 [Amended]

6. Amend § 73.1122 by deleting paragraph (d).

(Sec. 215, 58 Stat. 690, as amended; 42 U.S.C. 216. Sec. 351, 58 Stat. 702, as amended; 42 U.S.C. 262)

[FR Doc. 72-2712 Filed 2-23-72; 8:48 a.m.]

EHXIBIT 62

OFFICE OF THE SECRETARY-HUMAN DRUGS WHICH ARE BIOLOGICAL

PRODUCTS

REDELEGATION OF AUTHORITY TO ADMINISTER CERTAIN PROVISIONS OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT

[Federal Register, February 25, 1972]

The following authority delegated to the Assistant Secretary for Health and Scientific Affairs by the Secretary of Health, Education, and Welfare under section 6 of Reorganization Plan No. 1 of 1953 and section 2 of Reorganization Plan No. 3 of 1966 is hereby redelegated to the Commissioner of Food and Drugs and the Director, National Institutes of Health, as follows:

1. Effective this date, each of you is hereby concurrently redelegated the authority vested in me to administer, enforce, and apply all applicable provisions of the Federal Food, Drug and Cosmetic Act, as amended, with respect to those human drugs that are biological products as defined in, and subject to licensing under, section 351 of the Public Health Service Act, as amended (42 U.S.C. 262) and the regulations thereunder, 42 CFR Part 73.

2. This authority shall be exercised in accordance with the attached Memorandum of Understanding between the Commissioner of Food and Drugs, and the Director, National Institutes of Health, which memorandum sets forth with particularity the function to be undertaken by each agency.

3. Any prior delegation, statement of organization, functions and delegations of authority, or chapter of the Department of Health, Education, and Welfare Organization Manual inconsistent with this delegation or the attached Memorandum of Understanding is hereby superseded to the extent of such inconsistency. 4. The authority delegated in paragraph 1, other than the authority to promulgate regulations, may be redelegated as, in the judgment of the Commissioner of Food and Drugs or the Director, National Institutes of Health, may be necessary or advisable for the effective administration of such authority by them. Effective date. This redelegation of authority shall be effective immediately. Dated: February 18, 1972.

MERLIN K. DUVAL,

Assistant Secretary for Health and Scientific Affairs.

Memorandum of understanding between the Food and Drug Administration and the National Institutes of Health concerning authority to enforce applicable provisions of the Federal Food, Drug, and Cosmetic Act with respect to human drugs which are biological products.

Background. Every virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man (henceforth referred to as biological products) is subject to the licensing provisions of section 351 of the Public Health Service Act enforced by the Division of Biologics Standards (henceforth referred to as DBS) of the National Institutes of Health. These biological products are also human "drugs" as that word is defined under the Federal Food, Drug, and Cosmetic Act enforced by the Food and Drug Administration (henceforth referred to as FDA). Section 351 of the Public Health Service Act contains a statement indicating that "nothing contained in this Act