Download Maggots, Leeches and Now Honey— Putative Medical Devices

Maggots, Leeches
and Now Honey—
Putative Medical Devices?
By Max Sherman
I
n a previous article in this magazine, I commented on the astonishing medical device
classification and subsequent 510(k) clearances for maggots and leeches.1 Surprises continue to occur as FDA now has recognized honey
as a medical device with a legitimate medical use.
API-MED, an absorbent dressing containing active
manuka honey, was recently cleared and indicated
for treating exuding wounds such as diabetic
foot and leg ulcers and first- and second-degree
partial thickness burns. The labeling makes no
mention about antimicrobial effects, although
other countries (Canada, Australia, Great Britain
and New Zealand) permit that claim.2
Honey, maggots and leeches, by their very
nature, challenge the regulatory scheme. Assigning each to the broad category of devices was an
expedient solution to a conundrum. As drugs,
they would have required studies entailing an
interminable regulatory process. The agency’s
decision-making process is rooted in the first
inclusion of medical devices in the statute. A
historical review once again helps understand how
the agency interprets the law. However, it is not
clear how or why the agency employs the device
classification as a default category in the approval
process. All that aside, it is indeed fortunate that
FDA can be liberal in granting marketing approval
under special circumstances.
History
In reintroducing the bill that would eventually
become the Federal Food, Drug and Cosmetic Act
of 1938 (FD&C Act), Senator Royal Copeland,
its sponsor, explained that the existing law
(the Pure Food and Drug Act) defined drugs as
substances or mixtures of substances intended
to be used for the cure, mitigation or prevention
of disease. He noted that the definition permitted escape from legal control of all therapeutic
or curative devices like electric belts. During the
debate that followed, Senator Bennett Clark of
Missouri contended that it was improper, as a
matter of common language, to classify medical
devices as drugs.3 He went on to say that calling
a medical device a drug was like “calling a sheep’s
tail a leg.” Because of the continued criticism of
what constitutes a device, a separate definition
was added to the final legislation.4
Today, a medical device is defined as an
instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar
or related article including any component, part
or accessory, recognized in the official National
Formulary, or the United States Pharmacopoeia, or
any supplement to them, intended for use in the
diagnosis of disease or other conditions, or in
the cure, mitigation, treatment or prevention of
disease, in man or other animals, or intended to
affect the structure or any function of the body of
man or other animals, and which does not achieve
its primary intended purposes through chemical
action within or on the body of man of other
animals and which is not dependent upon being
metabolized for the achievement of its primary
intended purposes. The original definition of a
medical device included in the FD&C Act made no
reference to intended purposes through chemical
action or to metabolism.3 The word “article” was
not used, and there was no reference to implants,
in vitro reagents, implements or machines.
The term “drug” is defined, among other
things, as “articles intended for use in the
diagnosis, cure, mitigation, treatment or prevention of disease” and “articles” (other than
food) intended to affect the structure or any
function of the body of man or other animals.4
The term “articles” appearing in the drug definition is a broad category, in contrast to the list
of specific product types that are “devices.”
Except for implants and in vitro reagents, most
items included in the definition of a device
are mechanical products generally constructed
of solid materials like metal or plastic. Under
the definition of medical devices, FDA may
not regulate as a medical device an article that
achieves any of its principal intended medical
purposes through chemical action or by being
metabolized. Congress did not insert any counterpart clause into the definition of a “drug”
that would make chemical or metabolic action a
prerequisite to a product being regulated as such.
Neither did Congress, in its 1976 revision of the
“device” definition, substitute the broader term
“article” for listing narrower product categories
to be regulated as devices found in the FD&C
Act since 1938.5
The preceding background information
was included in my earlier article and clearly
demonstrates the marked differences between
devices and drugs. Both leeches and maggots
derive their effects through chemical action.
Maggots secrete substances that kill bacteria and
stimulate the growth of healthy tissue. Leeches
produce hirudin, a direct thrombin inhibitor and
other enzymes.1 However, according to FDA, the
primary mode of maggots is chewing; for leeches,
it is the chewing of blood.6 Both of these were
deemed mechanical processes. (Predicate devices
included scalpels and maggots that had been sold
RA focus 33
before passage of the Medical Device Amendments.)
Honey, as noted in the information that follows,
also produces an antiseptic compound. The late
Senator Clark would, no doubt, have objected to
all three agency decisions.
Therapeutic Honey
Honey has been used for treating wounds since
early antiquity. The Smith Papyrus of 1700 BC
and the Ebers Papyrus of 1500 BC describe packing severe wounds and burns with a combination
of coagulated milk and honey kept in place with
a muslin bandage.7 The early Greek and later
Roman civilizations mixed honey with grease or
fat and applied the mixture to wounds. Physicians
used honey to soothe ailments of the eye and ear,
to eliminate skin infections, and to promote the
healing of wounds or the site of surgeries such as
circumcision. Babylonians used honey to preserve
corpses by preventing putrefaction.8 Accounts
of the use of honey as a wound dressing are not
confined to ancient records. During World War I,
Russian soldiers used honey-based preparations
to prevent wound infections, and during World
War II, the Chinese mixed an ointment out of
honey and lard.8 A number of reports have been
published in the medical literature regarding the
rediscovery of honey as a therapeutic agent, no
doubt as the result of its antibacterial activity.9
Properties
Several studies have demonstrated that some
varieties of honey have a broad spectrum of
activity against a number of pathogenic bacteria
and fungi. Some of the bacterial strains tested
were antibiotic-resistant. Antibacterial activity is
greater than would be expected from honey’s
sugar content. (Honey is a complex product with
low water activity, acidity and high sugar content,
but this does not contribute significantly to the
antibacterial activity.) The action of these honeys
is linked to the production of hydrogen peroxide.
According to several authors, bees help preserve
honey in the hive by adding an enzyme, glucose
oxidase, to the nectar gathered from flowers while
it is being processed into honey. When honey
comes into contact with body moisture, the glucose
oxidase slowly releases hydrogen peroxide.10
The production of the peroxide could lead
to the formation of free radicals such as hydroxyl
and superoxide. Honey also provides a substrate
for glycolysis, which is the major mechanism for
energy production in macrophages, and thus
allowing them to function in damaged tissues
with low oxygen supply. There are additional
34 January 2008
benefits to leucocytes and monocytes that can
affect the molecular mechanisms of wound healing
and tissue repair.9,11
Therapeutic vs Culinary Honey
Therapeutic honeys are distinctly different from
the culinary honeys found in the supermarket.
Therapeutic honeys must have a high osmotic
activity and an acid pH (3.2 to 4.2); produce a slow,
low level of hydrogen peroxide; and be derived from
specific plant-derived factors, such as Leptospermum
scoparlum (Manuka).9
Final Thoughts
Therapeutic honey-impregnated dressings offer
the promise of an effective wound antiseptic with
broad-spectrum antibacterial activity.12 Unlike
antibiotics used to treat wounds, honey would
not require laboratory evaluation of susceptibility
before beginning treatment. Fortunately, honey
does not adversely affect human tissue; it may, in
fact, promote healing. Honey relies upon the release
of hydrogen peroxide for its therapeutic effect and
may prove to be an important adjunct for wound
care in light of the burgeoning incidence of bacterial
resistance to antibiotics. The availability of honeyimpregnated dressings is indicative of the agency’s
creative product approval process.
References
1.ShermanM.“Maggotsandleeches—aretheymedicaldevices?” Regulatory Affairs Focus. 2004;9(10):36-39
2. TrumpEF.“Sweetsalve”.TheWashingtonPost.7August2007.
3.HuttPB.“Ahistoryofgovernmentregulationofadulteration
andmisbrandingofmedicaldevices.”FoodDrugCosmetLawJ.
1989:44:99-117.
4.Pub L No. 75-717, 52 Stat 1040 (1938), as amended at 21
U.S.C. §§et seq.
5. Pub L No. 94-295, 90 Stat 539 (1976).
6.HarrisG.“Age-oldcures,likethemaggot,getU.S.hearing.”The
New York Times. 25 August 2005.
7.Root-BernsteinRandRoot-BernsteinM.Honey,Mud,Maggots
andOtherMedicalMarvels.HoughtonMifflin,Boston,1997.
8.MorseS.“Beebenefitsdownplayed.”TheWashingtonPost.15
August 2007
9.LusbyPEetal.“Honey—apotentagentforwoundhealing?”J
Wound Ostomy Continence Nurs. 2002; 29:295-300.
10.WhiteJWetal.“Theidentificationofinhibine,theantibacterial
factorinhoney,ashydrogenperoxideanditsorigininahoney
glucose-oxidationsystem.”BiochimBiophysActa.1963;73:57-70.
11.TonksAJetal.“Honeystimulatesinflammatorycytokineproduction from monocytes.” Cytokine. 2003;21:242-7.
12.CooperRAetal.“ThesensitivitytohoneyofGram-positivecocci
ofclinicalsignificanceisolatedfromwounds.”JAppliedMicrobiol. 2002;93:857-63.
AUTHOR
MaxShermanisPresidentofShermanConsultingServicesInc.,in
Warsaw,[email protected].