From: George A. Scheele, M.D. [gscheele@san.rr.com]
Sent: Wednesday, August 27, 2003 4:02 PM
To: fdadockets@oc.fda.gov
Cc: Scheele George (E-mail)
Subject: PUBLIC COMMENTS MEMORANDUM

MEMORANDUM
PUBLIC COMMENTS

FDA SUBMISSION:

Submitted to the FDA in relation to:
[Docket Number 75N-183H]

DATE & TIME OF SUBMISSION:
August 27, 2003, 3:59 PM, EDT

SPONSOR:
Viral Shield Pharmaceuticals, Inc.
7825 Fay Avenue, Suite 200
La Jolla, CA 92037
T: 858-456-0666

BACKGROUND:
A petition has been made by the Soap and Detergent Association and The
Cosmetic, Toiletry, and Fragrance Association, dated January 17, 2003, to
amend proposed 21 CFR 333, the June 17, 1994 Tentative final Monograph for
Health-Care Antiseptic drug Products Proposed rule [59 FR 314011] as
follows:

·	Amend relevant sections of 21 CFR 333 including 333.450, 333.455 and
333.470 to include additional organisms, specifically viruses and
appropriate test methods, performance criteria and anti-viral labeling for
health-care personnel hand products, food handler products, and consumer
hand products in the Monograph.

·	Amend 21 CFR 333.470 to establish and maintain efficacy methods indicative
of anti-viral activity in the monograph by incorporating the most current
voluntary consensus standards set by the American Society for Testing and
Materials (ASTM), specifically the finger pad method (ASTM E 1838) and the
hand method (ASTM 2011).

This petition addresses a specific issue of monograph flexibility, namely
that topical anti-microbial products should be allowed to make anti-viral
indications as well, provided they meet the monograph test methods and
performance criteria that are indicative of both anti-microbial and
anti-viral efficacy.

The petitioner urges the Agency to establish and maintain efficacy methods
that are indicative of anti-viral activity in the final Monograph by
incorporating the voluntary consensus standards set by ASTM in order to
establish anti-viral efficacy for topical anti-microbial products intended
for use on the hands.  They further recommend that non-envelope viruses,
which are important in hand-to-hand and hand-to-fomite transmission be
tested according to the ASTM anti-viral test methods.  They further
recommend that product efficacy should be demonstrated against both a
respiratory and an enteric non-envelope pathogen and propose that a Human
Rhinovirus (Type 14 or type 37) and a Human Rotavirus (type Wa) be used as
test organisms.


PUBLIC COMMENT:

The petition submitted by the Soap and Detergent Association and the
Cosmetic, Toilet and Fragrance Association would serve the critical medical
interests of the public by revealing, through appropriate and validated
testing and labeling, whether products protect the consumer against
respiratory and enteric non-envelope viruses.  These viruses are known
primarily to cause respiratory and enteric diseases related to the “common
cold”.

However, an unmet need that is potentially more important to consumers than
blocking infections due to non-envelope viruses is to block the transmission
of morbid and fatal envelope viruses into the human body by effecting early,
definitive killing of envelope viruses on topical surfaces that mediate
viral transfer from skin to mucous membranes.

Stopping the skin-to-skin spread of envelope viruses, including HIV,
Influenza, Parainfluenza, Respiratory Syncitial Virus, SARS and other
viruses listed below has become a top priority in infectious diseases around
the globe.  Although AIDS is not normally transmitted to healthy persons by
skin contact it is well known that HIV may be transmitted from
person-to-person when bodily secretions come into contact with micro and
macro skin disruptions in health-care professionals or the general public.

Furthermore, compendial agents that kill envelope viruses may be formulated
into long-acting anti-microbial hand creams that do not need to be removed
from the skin after application by an immediate hard water rinse and thus
may remain in contact with the skin for prolonged periods of time, measured
in hours.  Long acting hand creams containing such compendial materials
could provide sustained protection, up to four (4) hours or longer, against
envelope viruses for consumers.  In contrast, agents that kill non-envelope
viruses are toxic to skin if allowed to remain on skin surfaces for
prolonged periods of time in excess of 1-2 minutes and, therefore, may not
be formulated into long-acting anti-microbial hand creams.

It should also be noted that compendial agents that kill reference envelope
viruses (e.g. Influenza A Virus (Hong Kong strain) – ATCC: VR-544 or
Vaccinia Virus (Reference Strain) – ATCC: VR-117) are also known to kill
numerous other envelope viruses, including those envelope viruses listed
below.

Given the global pandemics of AIDS, Influenza, SARS and other rogue envelope
viruses, it would serve the critical medical interests of professional and
public consumers to know (i) whether anti-microbial agents are antibacterial
agents, antiviral agents or both, (ii) whether antiviral agents protect
against envelope viruses, non-envelope viruses or both and (iii) the length
of time that such agents provide protection and safety on human skin.


ACTIONS REQUESTED:

This sponsor recommends that the FDA sponsored anti-microbial monograph be
further amended to include the following recommendations - that:

·	Manufacturers may also claim anti-viral effects if performance criteria
are validated against two envelope viruses.

·	The two preferred envelope viruses be:
Ø	Influenza A Virus (Hong Kong strain) – ATCC: VR-544
Ø	Vaccinia Virus (Reference Strain) – ATCC: VR-117

·	Performance criteria require a minimum of 2 log reduction of viral titer
(load) in the presence of the active medical ingredient or device.

·	Compendial agents that show prolonged antiviral activity against envelope
viruses according to performance criteria supervised by the ASTM and
prolonged skin safety profiles according to ASTM criteria, be labeled as
“long-acting antiviral skin protectants.”

·	Under such conditions, manufacturers may be allowed to affix a clinical
claim to the commercial product that states that said product exerts
“long-acting antiviral activity” and further, that the manufacturer has the
flexibility or option to indicate, according to appropriate testing
procedures, defined by the ASTM, the length of time that both protection and
safety are maintained on the skin, said times being described in minutes or
hours.

RATIONALE:

We urge the FDA to recognize well-known scientific and medical facts and
provide increased flexibility so that the consumer can benefit from
compendial agents that exert anti-viral activity on skin directed against
either non-envelope viruses, envelope viruses or both.

Specifically, we recommend that the FDA take the following considerations in
amending the existing tentative final anti-microbial monograph:

Ø	Include additional organisms, specifically viruses, and appropriate test
methods, performance criteria and anti-viral labeling for (i) health-care
personnel hand products, (ii) food handler products, and (iii) consumer hand
products in the Monograph.

Ø	That the manufacturer has the flexibility and option to add antiviral
claims to compendial agents and products that provide anti-viral activity
against either non-envelope viruses or envelope viruses individually or,
alternatively, directed against both groups of viruses, based on
demonstrated efficacy.

Ø	This sponsor agrees with the suggested testing approach for non-envelope
viruses suggested by the Soap and Detergent Association and the Cosmetic,
Toilet, and Fragrance Association (see Background Section above).

Ø	This sponsor recommends that the testing criteria for envelope viruses
include two well-known reference envelope viruses (e.g. Influenza A Virus
(Hong Kong strain) – ATCC: VR-544 and Vaccinia Virus (Reference Strain) –
ATCC: VR-117) using the finger pad method (ASTM E 1838) or the hand method
(ASTM 2011) as performed by the American Society for Testing and Materials
(ASTM).

Ø	This sponser recommends that the performance criteria be set at a 2-log
minimum reduction in viral titer (load) to coincide with the performance
criteria designated in the tentative final anti-microbial monograph for
bacteria and the performance criteria proposed for non-envelope viruses

Ø	Once these performance criteria have been met or exceeded, according to
appropriate ASTM test methods, that clinical labeling claims may be used by
the manufacturer that indicate either “antiviral activity” or “antiviral
activity directed against envelope viruses”.

Ø	That laboratory claims may be added indicating efficacy and performance
directed against one or a multiplicity of specific envelope viruses.

Ø	In order to meet safety criteria (Generally Regarded As Safe), This
sponsor recommends that any compendial agent or material that demonstrates
anti-viral activity and falls within an approved FDA Monograph or an FDA
Tentative Final Monograph be listed in the Anti-microbial Monograph.

Ø	This sponsor further recommends that certain antiviral agents, that are
known to be compendial in nature and show prolonged safety profiles on skin,
may be applied to the skin without subsequent removal by hard water rinsing.
This greatly increases the benefit to health-care professionals, food
handlers and general public in providing sustained antiviral protection for
distinct periods of time, estimated from performance criteria in minutes or
hours.

Ø	In the case described immediately above this sponsor recommends that the
manufacturer be allowed to affix a clinical claim to the commercial product
that states that said product exerts “long-acting antiviral activity” and
further, that the manufacturer has the flexibility or option to indicate,
according to appropriate testing procedures, defined by the ASTM, the length
of time that protection is maintained on the skin, said time being described
in minutes or hours.

ENVELOPE & NON-ENVELOPE VIRUSES - WELL KNOWN SCIENTIFIC & MEDICAL FACTS:

Many viruses, acquired as transient microflora, can survive several hours on
hands and other skin surfaces, including the face.  Abundant scientific
research conducted at the molecular level over the past twenty five years
have demonstrated that viruses fall into two broad groups, non-envelope and
envelope viruses.  Non-envelope viruses are tight protein-nucleic acid
complexes that do not contain a limiting membrane or envelope.  Envelope
viruses are more complex viral pathogens that contain a multiplicity of
proteins, nucleic acid constituents and a limiting membrane, described as an
envelope.  In all cases studied to date, the limiting membrane of envelope
viruses is derived from the host cell, whether that cell be from human
sources or vector sources.  Recent research has indicated that viral
receptors for both non-envelope or envelope viruses reside on membrane
specialized regions of the human host cell, now referred to as lipid rafts.

Although both non-envelope viruses and envelope viruses utilize cellular
receptors for entry and infection, the mechanisms for cell entry are known
to be separate and distinct.  For example the limiting membrane of envelope
viruses has the ability to fuse with the membrane of lipid rafts residing on
the host cell.  Because of fundamental differences in cell entry and
infection, the profile of antiseptic agents that interfere with viral
infection are also separate and distinct.

While both non-envelope and envelop viruses may prove to have morbid
consequences in humans, the recent emergence of envelope viruses over the
past twenty five years has led to global pandemics with serious health-care
consequences.  One of these emerging viruses is Human immunodeficiency
virus, which has led to the pandemic of AIDS around the globe.  Another
envelope virus is Severe Acute Respiratory Syndrome, which has demonstrated
a death rate approximating 7% over the past 12 months.  These two viruses,
along with a relatively large number of other envelope viruses with morbid
or fatal consequences, including all Human Herpes Viruses, Hepatitis B, C
and D, Influenza Virus, West Nile Virus, Ebola Virus and Smallpox Virus, to
name only a few, cause untold suffering and death from global spread and, in
addition, pose as bioterrorism threats as well.


ENVELOPE VIRAL TARGETS:

A partial list of envelope viruses that cause well-known diseases (acute,
recurrent and sometimes fatal) in the human population follows:

AIDS (HIV-1 and HIV-2) – HIV-1 and HIV-2 ands their mutagenic derivatives
are the cause of the world-wide pandemic of AIDS.

HTLV (human T-cell Lymphotrophic Virus) – HTLV, types 1 and 2, are endemic
to specific regions in Japan.

Human Herpes Virus, Type 1 (HHV-1) – Type 1 HHV (Herpes Labialis) infects
the oral stoma with “fever blister”or “cold sores”, reflecting the
conditions of stress that lead to the outbreak of this viral disease.

Human Herpes Virus, Type 2 (HHV-2) – Type 2 HHV (Herpes genitalis) reaches
epidemic proportions in sexually promiscuous populations.  Initial studies
have demonstrated that 2-HP-BCD reduces the titer of HSV-2 by five (5) logs,
providing 99.999% protection.

Human Herpes Virus, Type 3 (HHV-3) – Type 3 HHV (Varicella) causes Chicken
Pox, which infects the skin and internal organs in children.

Human Herpes Virus, Type 3 (HHV-3) – Type 3 HHV (Herpes Zoster or Shingles)
is caused by a latent form of chicken pox virus that survives in the dorsal
root ganglia of the nervous system.  Immunodeficient states in adult life,
including cancer, lead to the outbreak of shingles where afferent pain
fibers come into contact with skin.  In this condition, dermal lesions are
characteristically confined to unilateral expression.

Human Herpes Virus, Type 4 (HHV-4) – Type 4 HHV (Epstein Barr Virus) causes
mononucleosis, a systemic disease of young adults often associated with
lymphadenitis, and Burkitt’s Lymphoma, an endemic disease in central Africa.

Human Herpes Virus, Type 5 (HHV-5) – Type 5 HHV (Cytomegalovirus) infections
occur along epithelial surfaces of internal organs in immunocompromised
patients.

Human Herpes Virus, Type 8 (HHV-8) – Type 8 HHV (Kaposi’s Sarcoma) occurs in
advanced AIDS patients that are severely immunocompromised.  The disease
occurs in lymph nodes, internal organs and skin.

Rubella Virus (German Measles) – This widely spread Togavirus normally
attacks neonates and children.  Other Togaviruses are Yellow Fever and
Sinbis Virus.

Molluscum Contagiosum Virus (MCV) – This sexually transmitted virus causes
firm, waxy papules found alone or in clusters on the face, trunk, lower
abdomen, pubis, inner thighs, penis and anogenital area.  This disease
represents viral skin lesions, tumorous in nature, caused by a pox virus.
Another member of the Pox Virus family is Small Pox Virus, which poses a
significant bio-terrorism threat.

Hepatitis B, C & D Virus – Transmitted across the gastro-intestinal tract
under conditions of close human contact or ingestion of contaminated
shellfish, this systemic viral infection results in acute-transient or
chronic-relapsing forms of Hepatitis.  The chronic form of Hepatitis B is
associated with a significantly increased incidence of hepatocellular
cancer.

Influenza Virus – Influenza A, B and C represent individual strains of
Influenza virus within the family of Orthomyxoviruses.  This highly
contagious acute upper and lower respiratory illness results in epidemics at
irregular intervals and causes mortality in the elderly, normally due to
secondary acquisition of bacterial pneumonia.

Parainfluenza Virus – Parainfluenza viruses, in the family of
Paramyxoviruses, cause respiratory illnesses in children.

Mumps Virus – Another member of the Paramyxovirus family, this virus causes
mumps in children and adults, characterized by marked swelling of the
parotid and submandibular glands

West Nile Virus – West Nile fever has recently been reported to spread
throughout different regions of the world, including the United States.
Transmission is believed to occur by multiple routes, including blood
transfusions and mosquitoes.

Respiratory Syncitial Virus – RSV is the most important cause of viral lower
respiratory tract disease in infants and children.

SARS Virus – The recent emergence of SARS virus in China, leading to 5,000
cases and 700 deaths, caused a public health emergency on a global scale.
SARS is a Corona virus circumscribed by human host cell membranes.

Pox Viruses – Includes Smallpox and Vaccinia Virus.

Vaccinia Virus – Vaccinia virus is a pox virus that infects cows.  Since
Edward Jenner it has been used to vaccinate humans against smallpox.

Ebola Virus – Ebola Virus, similar to Marburg Virus, has occurred in
periodic outbreaks, recorded since 1967.  These viruses cause hemorrhagic
fever, affecting the mucus membranes, lumen of the stomach and intestines,
skin and internal organs including the brain.  This disease may be rapidly
transmitted through (i) infected blood products, (ii) infected human
tissues, secretions and excretions and (iii) contaminated syringes &
needles.  Highly lethal, these viruses pose a significant bio-terrorism
threat.


CONCLUSION:

This sponsor urges the FDA to recognize these well known scientific and
medical facts and provide increased flexibility in the anti-microbial
monograph so that the consumer can benefit from compendial agents that exert
short-acting or long-acting anti-viral activity on skin directed against
envelope viruses, according to specific recommendations made under “ACTIONS
REQUESTED”.


Sincerely yours,
George A. Scheele, M.D.
Chairman & CEO
Viral Shield Pharmaceuticals, Inc.
T: 858-456-0666
E: gscheele@viralshield.com