Statement of GlaxoSmithKline on the Anti-Counterfeit Drug Initiative of
the Food and Drug Administration

Docket Number 2003N-0361

November 3, 2003

GlaxoSmithKline welcomes the opportunity to comment on FDA's initiative
on Drug Product Anti-Counterfeiting as well as the FDA Open meeting held
on October 15, 2003. GSK is one of the world's leading research-based
pharmaceutical and biotechnology companies. Our company is devoted to
inventing medicines that allow patients to lead longer, happier,
healthier, and more productive lives. GSK is committed to doing its part
to protect the integrity of the American drug supply so that
pharmaceuticals patients receive meet the FDA-approved standards for
safety, purity and potency.

GSK believes that a closed distribution system is the best way to assure
the integrity of the US pharmaceutical supply. A closed system may be
defined as one where product is shipped directly from the manufacturer
to the distributor and then on to the pharmacy and ultimately, the
patient. Each business transaction in the supply chain would be recorded
and a pedigree, ultimately tracing each lot back to the manufacturer
would be maintained. Importation from within a manufacturer's supply
chain would be allowed and only reimportation under the rigorous
definition of the Prescription Drug Marketing Act (PDMA) would be
permitted. Unfortunately, the modest pedigree requirements promulgated
by the FDA under the PDMA have been stayed twice for reasons unrelated
to any public health considerations. In fact, it is safe to conclude
that the reluctance to implement this regulation may contribute to some
of the ease by which counterfeit drugs enter the marketplace.

The estimated number of dispensing sites in the United States
(approximately 80,000 by some estimates) means that the drug
distribution system is complex. There are multiplicities of both
licensed primary and secondary distributors. Secondary buying and
selling of packaged pharmaceuticals is common as a normal part of
inventory adjustment. Personal importation of small amounts of
pharmaceuticals has been documented with increasing frequency and
numerous Internet sites offer consumers pharmaceuticals at deeply
discounted prices even though these products are of dubious origin and
quality. Repackaging of pharmaceuticals takes place at a variety of
levels despite the fact the manufacturers original container/closure
system has been breached and product quality may suffer as a result.
Collectively all of the above practices make the American drug
distribution system porous and make it possible for counterfeit or
diverted drugs to enter the system thus potentially compromising the
public health of patients. Repackaging for distribution within a closed
system, such as an HMO or a Hospital Group, should be allowed using the
properly specified materials.

At this time there is no single approach to the deterrence of
counterfeiting. Companies employ a variety of approaches to assure
product integrity working within the current distribution system.
However, as noted above until the American distribution system is truly
closed via an automated secure track and trace system, the potential for
patient exposure to counterfeit or diverted drugs will exist.

Before addressing the options set forth in the interim report, GSK has
comments on several general themes set forth in the FDA report.

**[1. Real Time Authentication and the Need for a
Pedigree]{.underline}**

Key to assuring the security of the drug distribution system is the
ability of trading partners to authenticate drugs in real time.
Unfortunately for a variety of reasons this cannot be done at present.
GSK uses two forms of technology to authenticate pharmaceutical
products, covert (known only to the company) and overt (known to and
readily ascertainable by trading partners). However, the combination of
these approaches cannot assure real time authentication. Overt
technologies can and have been counterfeited within months of
employment. Forensic analytical technologies such as tagants and
formulation analysis require samples be sent off site and tests
conducted.

The statement on page nine of the interim report concerns GSK:

> *Counterfeit drugs generally associated with the practice of
> diversion. Our current regulatory system does not have legitimate,
> regulated channels for such diverted drugs (even if authentic) to
> re-enter the drug distribution system. Consequently, there is no
> reliable mechanism in place to distinguish effective authentic
> lower-cost drugs from drugs that simply appear to be so, but are not
> legitimate and may be harmful.*

GSK notes that this is exactly the problem that the PDMA was designed to
address.

GSK believes that the single most effective action FDA could take to
combat prescription drug counterfeiting is to implement the prescription
drug pedigree requirement. Congress enacted the pedigree requirements in
1987 as part of the PDMA. Although FDA finalized regulations
implementing the pedigree requirements in 1999, these regulations (which
are set forth at 21 C.F.R. §203.50) have been stayed four times at the
behest of the drug wholesalers, particularly the secondary wholesalers.
As a result, fifteen years after Congress enacted the pedigree
requirements, this potent weapon against counterfeit drugs remains
unused and in administrative limbo. GSK believes that, in light of
recent, serious threats to the U.S. drug supply, this situation is no
longer tenable, and the pedigree requirement must be implemented
immediately.

The PDMA was an important piece of consumer legislation passed as a
result of Congressional concern that the integrity of the then-existing
distribution system for prescription drugs was insufficient to prevent
the introduction and eventual resale of substandard, ineffective, or
counterfeit drugs. While the U.S. drug supply remains the among safest
in the world -- in large measure because of the protections enacted by
the PDMA -- the risks that Congress identified in 1987 have only grown
in recent years. As FDA knows, the counterfeiters have become
increasingly sophisticated and dangerous, and the health risks from
counterfeit drugs have grown. There is even evidence that organized
crime has taken an interest in the shadow market for prescription drugs
and has begun establishing well-funded and sophisticated rings to
manufacture phony life-saving medications, such as cancer and AIDS
therapies, used by the most vulnerable patients. In order to combat this
growing public health threat, FDA should use all of the resources at its
disposal, *including the pedigree requirement*.

The primary goal of the pedigree requirement is to ensure that the U.S.
drug supply remains a closed system by preventing the introduction of
counterfeit medications into the supply chain. The pedigree requirement
accomplishes this goal by establishing a legal chain of custody for each
pharmaceutical product that permits purchasers to assure themselves that
the product originated from the manufacturer. While the existing
statutory and regulatory requirements certainly can be improved (by, for
instance, requiring authorized distributors of record (ADRs) to pass
pedigrees). GSK believes that the final rule promulgated by the FDA is
an accurate reflection of Congressional intent, will provide strong
deterrence against counterfeiters, and thus should be implemented
immediately.

GSK agrees with FDA that there is no "magic bullet" in the fight against
counterfeit drugs, and the pedigree requirement is no exception.
Implementing the pedigree requirement will not automatically safeguard
the entire U.S. drug supply. But it will throw up a powerful roadblock
against counterfeit drugs, making it significantly more difficult for
counterfeiters to breach the supply chain and increasing the likelihood
that, if they attempt to do so, they will be identified and caught.
Indeed, pedigree papers reportedly were responsible for tipping
investigators off to a major counterfeiting ring operating in Florida,
leading to the indictment in July of 18 members of that ring. *Salesman
Fell Into A Shadow Market*, Washington Post, p. A17 (Oct. 19, 2003).
Without the information provided by pedigree papers, it is likely that
this counterfeiting ring would still be operating in south Florida.

The value of the drug pedigree requirement for deterring counterfeiting
activities recently was examined by a statewide Grand Jury in Florida.
In a comprehensive report on the safety of prescription drugs in
Florida, the Florida Grand Jury reached the following conclusion with
respect to pedigree papers:

> Pedigree papers, when verified through due diligence, are the
> cheapest, easiest and most effective way to prevent diverted or
> counterfeited drugs from entering the marketplace.

First Interim Report of the Seventeenth Statewide Grand Jury, Case No.
SC02-2645, at 34 (Grand Jury Report).

GSK agrees with this position and with the Grand Jury's further
conclusion that a pedigree requirement should be implemented and
enforced.

As discussed above, GSK supports the development of track and trace
technologies, such as bar-coding and RFID chips, that could be used to
provide real-time, electronic pedigrees. These technologies hold the
promise of tracking individual medications from the manufacturer through
the distribution chain directly to the patient in real-time, creating a
virtually closed and fully automated drug supply chain. Unfortunately,
there are a host of technical, operational and legal/regulatory issues
that must be resolved before any such system could be implemented. In
light of these obstacles, GSK believes it will take three to five years,
and maybe longer, to implement a system that could provide an
"electronic pedigree."

Given the serious threats to the U.S. drug supply that exist today, GSK
does not believe that FDA and the various stakeholders have the luxury
of waiting for a track and trace system to become operational before
implementing a pedigree requirement. For this reason, GSK supports the
implementation of a paper pedigree system as an interim measure while an
electronic track and trace system is being developed. While a paper
pedigree system may not be ideal, it nonetheless provides a higher level
of protection than the current system, i.e., one without a pedigree
requirement of any kind.

GSK acknowledges that paper pedigrees are not a perfect system and can
be forged and counterfeited. However, GSK agrees with the Florida Grand
Jury that this "is not a reason to ignore them as the \[wholesaler\]
industry asserts; to the contrary, it is why they must be verified."
Grand Jury Report, at 29-30. If a pedigree paper is forged, the
prospective purchaser can detect this quickly and cheaply through
routine due diligence. GSK believes that FDA has authority under the
PDMA to require wholesalers to verify the accuracy of the information on
a drug pedigree before completing a purchase. However, even in the
absence of binding regulations, GSK believes that evolving business
standards and liability concerns will force wholesalers to use due
diligence to verify pedigree information.

Moreover, pedigree papers provide an additional hurdle for
counterfeiters to overcome and an additional opportunity for legitimate
wholesalers and law enforcement officials to identify counterfeiters.
Recent events in Florida illustrate the importance of paper pedigrees in
detecting counterfeit drugs. The Washington Post recently reported that
a counterfeiting ring operating in Florida was initially identified when
a prospective purchaser became suspicious about the information
contained on a forged pedigree paper. The purchaser notified law
enforcement, which seized thousands of dollars worth of counterfeit
drugs and brought indictments against 18 members of the counterfeiting
ring. Accordingly, the possibility of forged pedigree papers is not a
valid reason for failing to implement the current regulations. On the
contrary, forged pedigree papers provide an additional opportunity to
identify counterfeiters and to block counterfeit drugs from entering the
drug supply, especially if wholesalers exercise the due diligence
contemplated by the PDMA.

Despite the clear deterrent value of paper pedigrees, FDA has failed to
implement its final pedigree regulations. This is due, in part, to
concerns that the PDMA does not require authorized distributors of
record (ADRs) to pass pedigree information to their customers. While
this clearly is a weakness in the current statute that needs to be
addressed, it does not justify FDA's wholesale refusal to implement any
pedigree requirement whatsoever. If FDA is concerned that secondary
wholesalers will not be able to obtain information tracing the drug back
to the manufacturer because of the refusal of ADRs to pass on this
information, FDA can exercise its enforcement discretion in this area.
In other words, FDA can commit not to take enforcement action if a
wholesaler provides pedigree information back to the first ADR who
received the drug from the manufacturer. GSK believes that this would be
an appropriate exercise of FDA's enforcement discretion to facilitate a
functional and effective pedigree system while FDA works with Congress
to address the weakness in the current law.

GSK also believes it would be appropriate for FDA to encourage ADRs to
pass on pedigree information voluntarily. GSK believes that ADRs should
not frustrate the pedigree system by refusing to pass on needed
information to secondary wholesalers and calls on the wholesale industry
to pass on all necessary pedigree information.

In sum, GSK believes that paper pedigrees, combined with routine due
diligence, provide the most cost-effective approach available at this
time for obtaining reliable pedigree information. Although electronic
track and trace systems ultimately may prove more cost-effective, these
systems realistically cannot be implemented throughout the distribution
system for at least several more years. In the interim, GSK agrees with
the Florida Grand Jury that "\[p\]edigree papers, when verified through
due diligence, are the cheapest, easiest and most effective way to
prevent diverted or counterfeited drugs from entering the marketplace."
Grand Jury Report, at 34. GSK urges FDA to implement its regulations
immediately as an interim step while electronic track and trace systems
are being developed.

**[2. Repackaging of Pharmaceuticals]{.underline}**

FDA should re-assess its policies regarding the repackaging of drug
products in solid oral dosage form in light of the threat of
counterfeiting. GSK believes that repackaging operations are a weak spot
in the drug distribution system that can be used as an entry point and
distribution center for diverted and counterfeit drug products. As noted
in the press, repackaging operations have been implicated in recent
high-profile counterfeiting investigations.

Repackaging is particularly problematic with respect to
anti-counterfeiting technologies and tamper resistant features
incorporated in drug packaging and labeling. Repackagers often remove
drug products from their original packaging and pack them in new
containers with new labeling. Often, these repackagers use inferior or
sub-standard materials for their container/closure system, which may
result in product quality issues. As a result, any overt or covert
anti-counterfeiting technologies and tamper resistant features applied
by the manufacturer to the original packaging and labeling will be
removed or compromised by the repackager. Repackaging operations thus
provide counterfeiters with an invaluable means of circumventing the
anti-counterfeiting and tamper resistant protections applied by the
manufacturer. GSK notes that repackaging operations also will threaten
any electronic track and trace system that relies upon bar codes or RFID
chips applied to packaging by the manufacturer or authorized
distributor. Indeed, the utility of overt and covert anti-counterfeiting
technologies and electronic track and trace systems is severely
compromised by current repackaging policies and practices.

In order to address this situation, at least partially, FDA must
increase its surveillance and enforcement activities in the area of
repackaging. GSK would suggest reviewing the need for "repackaging for
profit" operations as opposed to in-house repackagers for HMOs, buying
groups and hospitals. Given the heightened risks associated with
repackaging, FDA should significantly increase its inspections of
repackaging operations to ensure that they strictly comply with all
relevant cGMP and record keeping requirements.

**[3. Strengthening Federal And State Requirements For
Wholesalers]{.underline}**

GSK supports efforts by the states, particularly Florida and Nevada, to
strengthen requirements governing the licensure and regulation of
wholesale distributors. Recent investigations have demonstrated that
there are systemic weaknesses in the oversight of the wholesale drug
industry in many states. In Florida, for instance, a state grand jury
found that the Florida's Department of Health issued licenses to 422
instate and 977 out-of-state wholesalers -- "or approximately one
wholesaler for every three pharmacies." Grand Jury Report, at 8. Yet
with only nine field inspectors, the Grand Jury concluded it was
impossible to adequately inspect all of these facilities to ensure that
they were complying with Florida's strict requirements regarding the
proper storage and handling of drug products. Grand Jury Report, at 18.
Moreover, the Grand Jury determined that many wholesalers had been
issued licenses without proper background checks and that some
wholesalers received a permit despite one or more felony convictions.
Grand Jury Report, at 14.

While GSK supports state efforts to increase oversight over prescription
drug wholesalers, GSK believes that these efforts must be consistent and
coordinated. If the states address this problem in a piecemeal fashion,
unscrupulous wholesalers will simply move their base of operations to
those states with less rigorous requirements and/or enforcement. This
phenomenon already has been observed in Nevada. After tightening its
wholesaler requirements in 2001, the number of licensed wholesalers
decreased the following two years from 50 to 8. Yet the Washington Post
reports that "When the Nevada regulators took action, some wholesalers
simply moved operations across the state line into California." *Nevada
Gets Tough, With Mixed Results*, Washington Post, A16 (Oct. 22, 2003).

In order to deter this type of forum shopping by unscrupulous
wholesalers, FDA should require all states to adopt the types of
regulatory enhancements that Florida and Nevada have implemented. FDA
can accomplish this by revising its Guidelines for State Licensing of
Wholesale Prescription Drug Distributors set forth at 21 C.F.R. Part
205. These regulations establish the minimum requirements that each
state must meet in order to comply with federal law regarding the
licensure and regulation of wholesale distributors. GSK recommends that
these minimum requirements be strengthened to ensure that there is
uniform coverage in every state.

GSK also believes that FDA should actively assess each state's
regulatory system governing drug wholesalers to determine whether they
meet the minimum federal requirements set forth in Part 205. Indeed, it
is unclear whether all fifty states meet the minimum requirements set
forth in the current version of Part 205. In situations where a state
does not meet those minimum requirements, FDA should work with the state
to improve its oversight of drug wholesalers. While we believe most
states will work with FDA to adopt increased federal standards, if a
situation arises where a state's oversight remains lax despite repeated
FDA warnings, FDA should consider making a formal finding that the state
does not meet minimum federal requirements under the PDMA. *See* 21
U.S.C. §353(e)(2).

**[4. Increased Civil And Criminal Penalties For
Counterfeiting]{.underline}**

GSK supports increasing the civil and criminal penalties associated with
counterfeiting activities in order to provide more effective deterrence.
GSK believes that penalties and enforcement activities should be
increased in two areas: (1) counterfeiting activities themselves; and
(2) distributing counterfeit drugs without proper due diligence (i.e.,
recklessly).

The penalties under the Federal Food, Drug, and Cosmetic Act (FFDCA) for
counterfeiting drug products are woefully inadequate. The maximum
penalty for a felony violation -- that is, one committed with the
"intent to defraud or mislead" \-- is three years imprisonment and/or a
\$10,000 fine. This is far less than the penalties associated with
counterfeiting a single dime -- which is fifteen years imprisonment --
or counterfeiting the currency from a foreign country -- which can
result in twenty years imprisonment. *See* 18 U.S.C. §§ 485, 478. It
also is far less than the penalties associated with distribution of
illicit drugs. *See, e.g.*, 21 U.S.C. §841. These disparities make
counterfeiting activities related to drug products extremely attractive
to criminals, particularly organized crime.

While prosecutors often can bring additional charges against
counterfeiters that carry stiffer penalties, such as mail fraud, wire
fraud, and conspiracy charges, GSK believes there is still a significant
deterrence value in substantially increasing the penalties under the
FFDCA for counterfeiting drug products. Counterfeit drug products
present grave public health risks, and counterfeiters often prey on the
most vulnerable patient populations, such as patients suffering from
cancer or AIDS who can least afford to use sub-potent, adulterated or
counterfeit medications. GSK believes that in order to send a strong
message that counterfeiting activities will not be tolerated, the
penalties associated with counterfeiting should be: (1) commensurate
with the significant public health threat posed by counterfeit drugs;
and (2) sufficient to deter counterfeiting activities, particularly by
organized crime.

GSK also believes that stiffer penalties are appropriate for entities
that create a market for counterfeit drug products by failing to conduct
proper due diligence into the source of the drug products they purchase.
While these entities may lack specific knowledge that the drugs they
handle are counterfeit, in many cases this lack of knowledge is
self-imposed. The Florida Grand Jury report and recent counterfeiting
examples make clear that counterfeit drugs are able to move through the
distribution system because some distributors put on blinders regarding
the source of the drugs they purchase. They ignore warning signs that
drugs may be counterfeit (such as unexplained, steep discounts) and fail
to request pedigree papers or verify the information contained in
pedigree papers because they do not want to miss a lucrative buying
opportunity, particularly one involving a discount. As the Florida Grand
Jury observed, "This is nothing less than a blatant example of willful
blindness." Grand Jury Report, at 29.

This "willful blindness," however, creates and sustains the shadow
market for diverted and counterfeit drug products. In order to deter
this behavior, GSK believes that civil and criminal penalties should be
imposed for the reckless distribution of counterfeit drug products. In
other words, entities that distribute drug products without conducting
proper due diligence into the source of those drugs should be subject to
civil and criminal liability if those drugs later turn out to be
counterfeit. These penalties should not apply to behavior that is merely
negligent; however, behavior, which rises to the level of recklessness,
should be punished. Given that many of these facilitators are not
hard-core criminals like the counterfeiters, GSK believes that increased
civil and criminal penalties for willful blindness will have a
particularly strong deterrent effect in rooting out this shadow market.

**[5. Phase In Period for Anti-Counterfeit Requirements]{.underline}**

At several points in the interim report FDA discusses a phase in period
for any new requirement and suggests that the focus of such efforts be
on those products at a high risk of counterfeiting. GSK believes that
any new regulations requiring use of anti-counterfeiting technologies,
all pharmaceuticals should be subject to them. There is no practical way
to identify drugs at a high risk for counterfeiting. In fact, such an
approach would have the opposite effect. Potential counterfeiters would
avoid drugs on the FDA list and counterfeit other products. Florida
tried this approach when they rewrote state regulations earlier this
year. 30 drugs were identified and placed on the list for which full
pedigree information must be supplied. This list approach was taken to
minimize regulatory burdens on secondary wholesalers. The Florida list
had to be quickly updated with the appearance on non-authentic Lipitor
in the distribution chain.

In the discussion that follows, GSK addresses the questions posed by the
FDA in the [Federal Register]{.underline} notice announcing the recently
held open meeting on this topic(68 [FR]{.underline} 52772) as well as
those questions set forth in the interim report.

**[Comments on Technology Options set forth in the FDA Interim
Report]{.underline}**

Section III of the FDA's Interim Report identifies a number of options
for improving the security of the drug distribution system in the US.
GSK's comments are covered in the following sections.

**A. Technology**

*1. Package all finished dosage drugs in unit of use packaging as
appropriate for the particular product (e.g., tablet, multi-dose vial)
at the point of manufacture, as is now done in many nations.*

GSK is constantly exploring new approaches to the packaging of
prescription pharmaceuticals as a way of improving product stability,
preventing the introduction of counterfeit medicines into the supply
chain, prevention of medication errors, and providing another avenue for
the delivery of useful information to patients. Such information
improves patient compliance, helps to avoid preventable errors, and
results in superior health outcomes.

Most non-solid, oral dosage pharmaceutical products are packaged in unit
of use (e.g., ophthalmic drops, nasal sprays, inhalers, creams and
ointments). Very few solid oral dosage forms are packaged in this format
(the major example being birth control pills and certain other
pharmaceuticals that have short, defined dosing regimens). Unit of use
packaging will permit the manufacturer to incorporate a number of
features that will contribute to counterfeiting deterrence (see
responses to options 2 & 3 below). However, decisions on packaging
format are market driven based on customer demand, financial and
regulatory considerations, and the dosage regimen of the pharmaceutical.

The dispensing system in the US is quite heterogeneous with over 80,000
sites including chain and independent pharmacies, hospital pharmacies,
managed care organizations, mail order pharmacies, clinics, and doctor's
offices. Each of these customers may have different preferences
regarding package size based on dispensing practice. Unit of use
packaging may also take up more pharmacy shelf space compared to
traditional bulk bottles of the same medication. While many pharmacies
have adjusted inventory control procedures and moved to "just in time"
inventory, this may not be universal practice. Thus, there may be a need
to produce a variety of package sizes even if there is a move to more
unit of use packaging.

It is critical to note that both regulatory and marketing considerations
raise considerable barriers against the widespread use of blister
packaging. For solid dose products, where the dosage regimen is one per
day, it is economical to design blister packs that will hold the
requisite amount. For dosing regimens of two or more per day, small
bottles are a more economical packaging unit.

The Consumer Products Safety Commission (CPSC) enforces the Poison
Prevention Act and 16 CFR 1700.20(a)(ii) outlines the type of testing
required for special packaging that meets child resistance standards.
GSK must evaluate the underlying toxicity of any unit of use packaged
pharmaceutical and make decisions based on package accessibility by
children and exposure to the active ingredient. This forces companies to
evaluate each solid oral dosage form on a case by case basis. Recent
correspondence from CPSC states that "current CPSC regulations
implementing the Poison Prevention Packaging Act (PPPA) do not restrict
a company from relying on child resistance test data generated by the
package manufacturer or from testing of similar packaging for a
different substance." GSK believes that there is a great deal of
uncertainty about the current status of type testing and how companies
approach this issue. Issues such as the child resistant feature being
tested, the design and performance compliance, and the role of standards
organizations all need to be discussed by stakeholders.

In order for pharmaceutical manufacturers to utilize more unit of use
packaging, expeditious decisions are required during the development
process. Once a new drug is launched, commercial and manufacturing
concerns mitigate against a switch in packaging design. Thus, the type
testing process needs to be more transparent than at present in terms of
both the type of criteria needed to assure that children will not be
exposed to harm and the timeliness of decisions to enable companies to
pursue this form of packaging.

To achieve the above goal, GSK believes that performance and design
standards can be established to facilitate type testing. Working through
established standards organizations such as the American Society for
Testing and Materials (ASTM) is one avenue to accomplish this goal. GSK
believes that such a standard will have great utility. For example a
company could have the flexibility to use existing packaging designs if
the new drug has a similar safety profile to a drug already packaged in
blisters.

One final consideration for unit of use packaging is how to accommodate
medicines where there may be various dosing regimens. It is quite common
for anti-infectives to have variable dosing regimens (e.g., 7, 10, 14,
21 days; in the case of some oral antifungals, one or two pills could
constitute one of the full dosing regimens). This might lead to a
proliferation of unit of use packaging presentations, taking up
considerable pharmacy shelf space, and causing potential confusion in
filling prescriptions if the required package unit is not available.

*2. Use tamper evident packaging from the point of manufacture, with
labeling that notes the tamper evident feature, for all dosage forms,
active pharmaceutical ingredients (APIs) and bulk chemicals.*

Over the counter medicines have required tamper evident packaging for a
number of years. GSK's prescription drugs have incorporated similar
features. A good review of some of these approaches is in the recently
issued "Code of Practice for the Tamper-Evident Packaging (TEP) of
Therapeutic Goods," issued by the Therapeutic Goods Administration of
the Australian Government. Examples listed there include:

film wrappers,

blister packaging,

heat shrink bands or wrappers,

bottle mouth inner seals,

tape seals,

breakable caps, and

sealed tubes.

It is important to note that pharmaceutical repackaging defeats any
tamper evident features that the manufacturer includes on the original
packaging. In the current Tamper Evident regulation, it is unclear
whether the language "...with labeling that notes the tamper evident
feature..." refers to the label affixed to the container, the
prescription drug information that accompanies the product, or the
tamper evident feature. If FDA means the direct packaging labeling, GSK
would note that there might not be sufficient room to add more
information on some small labels.

If FDA moves towards requiring tamper evident packaging for prescription
pharmaceuticals then all products should be subject to the requirement.
GSK can find no compelling reason for only singling out a sub-category
of products that would be subject to such requirements.

GSK urges that dispensing sites adopt the practice of physically
rendering any manufacturer supplied packaging unusable when the package
is emptied. This practice will ensure that the packaging cannot be
reused. This practice will become more important as the distribution
system moves toward RFID chips which remain viable after the contents
are fully dispensed.

*3. Incorporate for all drug products at least two types of validated
anti-counterfeiting technologies into packaging and labeling at the
point of manufacture with at least one of these technologies being
covert (i.e., not made public, and requiring special equipment or
knowledge for detection) using a phased in approach starting with those
products at high risk of being counterfeited and where the introduction
of counterfeit product poses a serious health risk.*

GSK has been an industry leader in incorporating anticounterfeit
features within or on its product packaging. These features have been
either covert or overt in nature. Overt solutions to preventing
counterfeiting because they are apparent and known to trading partners
are less secure. Experts believe that such features must be changed at
regular intervals, as counterfeiters will reliably duplicate them. In
fact, it is the experience of GSK that even elaborate approaches such as
holograms are expertly counterfeited within months and that any such
feature must be carefully managed. Again, it is instructive to note that
the US Government does this by periodically redesigning currency notes.

Overt features fall into two general categories: those integral to the
container closure system and those not. In the latter category features
such as holographic images, special stickers, inks of gradated colors,
or threads in the container label all may be useful in assuring that the
container is authentic. Some of these approaches are similar to
technologies used for document authentication. One drawback to such
approaches is matter of rotating the verifying feature. How is the
pharmacist to know which is the current active overt feature versus the
previous? What the pharmacist should do if he or she questions the
authenticity of the bottle and the particular feature is past date? Best
practice would dictate not dispensing and sending off a sample for
analysis but this might result in large amounts of acceptable drug being
withheld from the market.

Features that are part of the container/closure system can incorporate
proprietary logos and other types of unique corporate identification.

GSK questions what FDA means by "validated anti-counterfeiting
technology." Does the Agency mean that it *will* prevent the
counterfeiting of prescription drugs? GSK believes that the answer to
this must be no. There is clearly a deterrence factor by using such
approaches but that the long term solution must employ a variety of
methods within the whole drug distribution system. To this end it is
instructive to draw a comparison to the efforts made by the US treasury.
They realize that any single method towards protecting against
counterfeiting will not work.

Finally, GSK notes that all products are potentially subject to
counterfeiting and any focus should not be just on some arbitrary list
of "high risk" drugs. *Any* adverse event suffered by an American
patient as a result of being given a counterfeit drug is *one* to many.

*4. Incorporate for all drug products a tagant, chemical marker, or
other unique characteristic(s) into the manufacturing process that is
only identifiable with the use of sophisticated analytic technologies
using a phased in approach starting with the products at high risk of
being counterfeited and where the introduction of counterfeit product
poses a serious health risk.*

Covert approaches include incorporation of small amounts of a chemical
tagant into the pharmaceutical preparation. Such chemicals can be part
of the bulk formulation of active ingredient or incorporated into the
gel capsule or film coating of the tablet. The tagant can be verified by
chemical analysis by the company. Since the presence of this agent may
be part of the new drug application, FDA would have knowledge about it.
Companies can also use the known analytical composition of the
formulation for authentication purposes. For example, defined impurity
profiles and/or amounts of different inactive ingredients as well as
dissolution patterns can be tested to determine a drug's authenticity.
It must be stressed that such tests do NOT provide real time
verification of a drug's authenticity. These tests may take up to
several days to perform in order to accurately determine whether the
drug is counterfeit or not. This may be problematic if a large amount of
drug is of questionable authenticity, as it would have to be withheld
from commerce until the testing is completed.

There will be a regulatory burden to both the sponsor and the FDA to
address already marketed drugs that do not possess such features as part
of the formulation. As FDA is aware, any change to the formulation of an
already approved drug will require a change to the NDA and in some cases
perhaps the filing of a new NDA rather than just a CMC change.

*5. Create an electronic database of drugs and biologics for
authentication purposes, which consists of photographs of the product,
packaging and labeling information, and the anti-counterfeiting measures
utilized in the packaging, labeling, and the product itself.*

GSK has in the past, worked with FDA's Forensic Lab and U.S. Customs in
identifying bulk drug and drug substance containers that are used for
importing material into the US for our manufacturing and packaging
operations. GSK has some reservations about this option. Who will
maintain this database? Who will have access to it? How will it be
updated? As was noted earlier, overt anti-counterfeiting measures will
be changed periodically. They may either replace or in some cases could
augment the older measure. Thus, the database would need multiple
entries for the same package. Would this not prove confusing to
pharmacists or other authorized users of the database? If the database
were publicly available, counterfeiters would have easy access to all of
the measures currently being used.

*6. Achieve the goal of the pedigree requirements by phasing in track
and trace technology (i.e., electronic pedigree) for all drugs and
biologics starting at a case and pallet level for products at "high risk
of being counterfeited" and progressively including all products at the
case, pallet, and package level. The technology should have an
integrated infrastructure that is able to track and trace all products
at all points in the distribution chain from manufacturer to end user.*

Constructing an electronic pedigree system will markedly assist in
assuring the authenticity of the drug supply within the US. However,
this is a daunting technological task that will take considerable time
and resources.

Bar code technology has been employed for a number of years to control
inventory and for product identification. Within the UCC/EAN standards
system there is a Global Individual Asset Identifier that incorporates
serialized identification of individual package units. This lends itself
to automated track and trace, perhaps negating the need for a paper
pedigree as called for under the Prescription Drug Marketing Act (PDMA).
Unfortunately, bar codes require packaging to be actively scanned and at
certain distribution levels this could be labor intensive. Because Radio
Frequency Identification chips (RFID) emit a signal permitting passive
reading, this is perhaps more amenable to an automated system. However,
as GSK sees it, this is not a fully validated technology at this point
in time. As the technology becomes more robust, this may serve as a
viable substitute for the use of printed bar codes.

To develop a track and trace system for assuring the authenticity of
pharmaceutical products the following must be accomplished.

1)  A database that can account for each packaging unit leaving the
    pharmaceutical company must be constructed and maintained.

2)  Each packaging unit must be labeled with a unique serial
    identification. The technology to do this is open to discussion. It
    could be a bar code or RFID as long as the symbology was robust
    enough to handle the number of codes.

    a.  Each manufacturer would have to have their own assigned list of
        numbers with a leading prefix that assures that there are no
        duplicate numbers within the overall system. The NDC number is
        suitable to this task as it identifies both the product and the
        company that manufactures it. The remainder of the data field
        can be used for the serial number.

3)  At every "authorized" stop along the distribution chain (this
    includes any transaction between secondary distributors), the code
    is read and transmitted back to the database along with the full
    information on the recipient. In this manner an electronic pedigree
    would be maintained and automatically updated.

4)  When the dispensing site, which is the final stop opens the bottle,
    the code is again transmitted and the record of this product is
    closed out. Thus, anyone seeking to reuse the bottle could not
    because the database would have a record of the bottle being "used."

For a robust track and trace system to evolve, all packages must conform
to a simple open data standard for serialized identification. This is
different from the proprietary systems that UPS and FedEx used to track
packages. One major unresolved question is the construction and
management of the database(s). Will this be centralized or will each
manufacturer maintain their own? There will also have to be a uniform
communication process from trading partners to the database(s). In the
case of multiple databases there will have to be a centralized routing
system so that information on a given product will get to each
manufacturer's database. This could be similar to the current systems
that support global credit card transactions.

Implementation of such a system will not be a minor undertaking. Since
each transaction will have to be registered, readers of the serialized
information will need to be at all distributors, pharmacies, and other
dispensing sites. Manufacturer packaging lines will have to be modified
to print serialized bar codes or incorporate RFID chips. Alternatively,
the requirement for packaging system serialization and maintenance
tracking system could be made the responsibility of the primary
distributor who receives the initial shipment from the manufacturer. The
full costs of such a system and the timing for its implementation are
unknown. GSK has joined with the Healthcare Distribution Management
Association (HDMA) and other stakeholders to study all of the aspects of
a track and trace system and report the findings to the FDA.

Because the time to full implementation of an "electronic" pedigree is
unknown, a complete paper pedigree must be required as part of a
comprehensive systems approach to anti-counterfeiting.

GSK cautions FDA that simply coding packaging at the pallet or case
level will not fully assure authenticity down to the individual
packaging unit. In fact, it may lead to a false sense of security as
countless individual packaging units coming from different cases in the
same lot or different lots are bundled and shipped. At this level, the
ability to track and trace is lost.

*7. On an interim basis, because the technologies described above may
take several years to implement, all drugs and biologics "at high risk
of being counterfeited," should be tracked and traced either (1) by
limiting the number of transactions of the product (e.g., shipping the
product from the manufacture either (a) directly to the retailer or
health care entity, (b) to the retailer or health care entity through a
single licensed wholesaler who would sell the product directly to
retailers or health care entities, (c) identifying steps that multiple
wholesalers can implement to reduce the risk of counterfeit
introductions, or (2) by using available track and trace technology,
identifying the drug at least to the case and pallet level, and
preferably the product level, throughout the distribution system.*

Please refer to GSK's comments above regarding the definition of "at a
high risk of being counterfeited." Options 1 (a) & (b) are marketing
decisions that can only be made by individual companies. GSK's response
to 1(c) is to require a paper pedigree that traces the product back to
the original manufacturer. With respect to option 2, GSK would prefer an
orderly introduction of track and trace technology so that the cost of
introducing the technology can be minimized. As noted in our response to
#6, bar coding can be utilized today. However, this would necessitate an
large investment in a technological approach that may soon be outdated
(e.g., equipment to print and test serialized bar codes along with an
investment in readers by all of the trading partners).

*8. Issuance of an FDA guidance document concerning the appropriate use
of anti-counterfeiting technologies as well as the FDA application and
review process for incorporating or changing tagants, chemical markers,
or other unique characteristic(s) of the product.*

A Guidance in this area would be useful but FDA should take a very
general role. In particular, it would be most helpful for FDA to
articulate what application requirements would be required for
incorporation of tagants and other chemical markers for products already
marketed. FDA should not specify which technologies companies should
use. The technological landscape is constantly changing and GSK would
not want the use of new approaches limited because they were not covered
in a regulation or guidance. A good example of such an approach is the
one adopted by the Australians in their code of practice as referenced
earlier. That code only specifies that tamper evident packaging be
employed but leaves the specifics up to the manufacturer.

*9. Issuance of an FDA guidance document concerning physical site
security and supply chain integrity.*

GSK is unsure of the value of such a guidance. Pharmaceutical
manufacturing and facilities are already quite secure. As GSK has
already noted, the rapid implementation of a pedigree requirement for
all transactions is the best approach towards assuring the integrity of
the supply chain.

**C. Rapid Alert and Response Systems**

*15. Create a counterfeit alert network through use of existing, or
newly developed communication tools that allow reception, dissemination,
and sharing of information about counterfeit drugs in a timely manner
(e.g., to pharmacists, manufacturers, wholesalers, and law enforcement
and public health officials).*

GSK is working with PhRMA, in conjunction with pharmacy trade
associations, on developing an electronic drug label distribution
system. When employed, every dispensing site will have access to the
most current prescribing information. The vendors that PhRMA is working
with have the capacity to update this information daily. PhRMA believes
such a system could also be used to disseminate timely reports about
counterfeit medicines that are found in the drug supply.