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Biotechnology Industry Organization

1225 Eye Street NW, Suite 400

Washington, DC 20006

November 3rd, 2003

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Rm. 1061

Rockville, Maryland 20852

Re: Docket No. 2003N-0361, Federal Register: August 26, 2003 (Volume 68,
Number 165, p. 51270)

Dear Sir/Madam:

The following comments are provided by the Biotechnology Industry
Organization (BIO). BIO represents more than 1,000 biotechnology
companies, academic institutions, state biotechnology centers and
related organizations in all 50 U.S. states and 33 other nations. BIO
members are involved in the research and development of health-care,
agricultural, industrial and environmental biotechnology products. BIO
appreciates the opportunity to comment on the Food and Drug
Administration's (FDA's) Counterfeit Drug Task Force Interim Report
(Docket 2003N-0361).

**General Comments**

BIO applauds the FDA's foresight in assembling the Counterfeit Drug Task
Force and in working with a variety of stakeholders intensively over a
relatively short period of time to produce a comprehensive and
thoughtful interim report. We also appreciated the agency providing a
public forum, on October 15^th^, in which various stakeholders could
present their views to the agency and share them publicly with other
interested parties.

Prescription drug counterfeiting, as well as criminal product tampering,
adulteration and mislabeling, have serious adverse effects on our
products and the patients whose lives depend on them. We agree with FDA
that all avenues should be explored to prevent these activities before
they become more prevalent in the United States, and to stop such
already occurring activities. We also strongly agree that this is a
multifaceted and complex issue that demands a multipronged approach. As
stated in the Task Force interim report, there is no magic bullet.
Offering the industry a multiplicity of approaches also recognizes the
variations among drug products and between drugs and biological products
that provide both different opportunities and different challenges to
those who want to counterfeit the products. In addition, because of the
implementation timelines for various anti-counterfeiting measures, BIO
believes that this effort must be ongoing, starting with steps that can
be taken now and implementing additional approaches over time, in a
stepwise fashion that allows for adoption as appropriate throughout the
system. We believe it is important to recognize that product
manufacturers can incorporate sophisticated and costly technology or
take other measures at the manufacturing level that will have no impact
on the problem if they cannot be used in the downstream portions of the
distribution system.

Because drug and biological product counterfeiting is still of
relatively low prevalence in the United States, BIO believes there is
time to develop and implement strategies that will take several years to
be fully operational. In that regard, the United States has an advantage
over some other countries, where counterfeiting and other illicit
incursions into the pharmaceutical supply chain place their
pharmaceutical supply and their patients in immediate and grave danger.
We have an opportunity to look closely at how a system spins out of
control and to learn, from steps taken (or not taken) in other parts of
the world, what can work and what is less likely to be successful. BIO
recommends the FDA continue along this thoughtful course, working with
the manufacturing, distribution and dispensing components of the supply
chain to define the U.S. problem clearly and to develop the best and
most viable solutions.

Finally, we reiterate the statements made by many, including the FDA
commissioner, regarding pending actions relating to prescription product
importation/reimportation. We believe it is crucial for FDA not only to
retain its authority to control the entry of pharmaceutical products
into the United States but also to receive the resources it needs to
enforce the law. BIO believes that a number of national and state
actions and statements are unfortunately signaling that the United
States is willing to become a marketplace for illicit prescription drug
traffickers. We recommend FDA continue its opposition to efforts that
weaken our border controls and invite criminal elements into our
pharmaceutical distribution system.

Our comments below are organized under the general topics of Immediate
Actions and Specific Comments. However, we intend, with our members, to
continue analyzing these issues and developing additional information.
As we do this, we want to work with the FDA and with other stakeholders
so that whatever solutions evolve will be successful. We value the
opportunity not only to comment on what is before us in this document,
but also to continue as part of the solution to a problem that already
has affected our industry and that, if unchecked, will pose serious risk
to patients.

**Immediate Actions**

[Obtaining Better Data]{.underline}

BIO believes an important first step is better definition of the
problem, through obtaining better data. Such data is unlikely to be
fully in the possession of FDA, therefore a joint effort that involves
other agencies such as the Drug Enforcement Administration and the
Bureau of Customs and Border Protection, as well as product
manufacturers, wholesalers and others in the legitimate distribution
chain, will be critical. BIO urges FDA to continue working with these
other parties and to establish a communication system that can receive
relevant information and an analytical process for assessing the level
and nature of the problem. We believe this data will help in the
development of the most appropriate longer-term strategies.

For example, if the problem is analyzed according to the risk-based
approach being employed by FDA in other areas, a strategy might focus
initially on the points in the distribution chain that appear to pose
the highest risk to the integrity of the drug supply. We believe this
offers the best opportunity to protect the public from counterfeiting.
Some of the questions that might be asked include the following: What
key features of the current U.S. system result in counterfeiting being
substantially lower here than in some other parts of the world? How can
we reinforce, capitalize on or enhance those aspects of the system? What
things seem to be working less effectively in the U.S. system today, as
compared with five to 10 years ago, with the result that the problem is
increasing?

BIO welcomes the chance to work with FDA and other stakeholders in
developing and analyzing this kind of information to determine the most
strategic approach to a solution.

[Rapid Alert and Response System]{.underline}

BIO congratulates FDA for initiating, with industry cooperation, a
system of reporting that allows the agency's criminal investigations
unit to learn of possible counterfeiting shortly after a manufacturer
detects a potential problem. To date, the system principally has
involved member companies of the Pharmaceutical Research and
Manufacturers of America, many of whom are also members of BIO. BIO
pledges to make this system known to all of its member companies and to
encourage all BIO member companies to provide FDA with information
needed to take appropriate action as quickly as possible after discovery
of a potential counterfeit biological product.

[Paper Pedigree/Regulation of "Unauthorized Distributors"]{.underline}

BIO supports the FDA's full implementation of 21 C.F.R. 203.50. This
rule, which has been on hold for several years, would require "paper
pedigrees" for pharmaceutical products, from which it would be possible
to document the source of the product, the numbers and kinds of
transactions between the initial sale by the manufacturer and the final
purchase by the end user, and other key information. Although we
recognize that any such paper documentation can itself be counterfeited,
we believe this is not a rationale for avoiding this simple step. BIO
believes that, at a minimum, requiring documentation in the form of a
paper trail tracing a pharmaceutical product from its source will serve
as a significant deterrent for some illicit dealers and at least a small
barrier for others.

[Increased Oversight of Repackaging Operations]{.underline}

BIO recognizes that repackaging in the wholesaler/distributor chain is a
component of the distribution process for many medications (although
probably less so for most biological products that are injectable,
infused or intravenous and often are not dispensed to patients by retail
pharmacies). Shipping in large-quantity containers for repackaging in
more appropriate quantities for further distribution may be
cost-effective, and total elimination of repackaging may not be feasible
in the short term. However, BIO believes that repackaging operations, as
outlined in the interim report, offer a prime opportunity for illicit
access into the distribution chain and, as such, should be subject to
far greater federal scrutiny -- scrutiny of the order of that applied to
manufacturers \-- than is now the case. At a minimum, we believe
repackagers should be required to demonstrate the same kind of "chain of
custody" as is desirable for distributors and should need to employ
deterrent anti-counterfeiting measures similar to those that would be
considered appropriate for manufacturers.

[Oversight of Various Suppliers]{.underline}

BIO also believes there is a need for greater oversight and additional
controls regarding printing and disposal of drug labeling and packaging.
This would include vendors who supply manufacturers with their materials
(through, for example, qualification and audits) as well as end-user
disposal (such as requiring verification of destruction and/or
defacement).

[Consumer Education]{.underline}

BIO believes consumers need to be educated about the problem of
counterfeit medicines and told what to do if they find their medicine
looks, tastes or feels different (both the product or the package) or
the product does not appear to have the intended effect. We believe
that, as an agency trusted by consumers, FDA is in the best position to
do such consumer education and most likely to have the most
comprehensive and objective information about the problem and risks to
consumers.

With regard to getting a better handle on the nature and extent of the
problem of counterfeiting in the United States, FDA has suggested that
suspect counterfeit medicines be reported via the MedWatch system. BIO
believes that this mechanism for reporting would be cumbersome for the
consumer and would dilute the primary purpose of the MedWatch system (to
report adverse events, medical errors or complaints). It is not designed
for reporting suspect criminal activity. BIO recommends that FDA
establish a counterfeit product reporting system separate from MedWatch
or consider setting up a counterfeit product reporting hot line.

[Increased Penalties for Counterfeiters]{.underline}

BIO agrees with comments made by many others regarding the exceedingly
low risk for those who counterfeit prescription drugs, as compared with
other illicit activities such as trading in illegal drugs. We believe
that not to increase penalties for criminal activities and transactions
with otherwise legitimate and legal prescription drugs trivializes this
activity and, furthermore, makes such criminal endeavors more attractive
to those with the lowest regard for the public health and the welfare of
our citizens. Although we recognize that increasing criminal penalties
is not within the FDA's purview, BIO strongly believes that such a
change is essential to making the overall anti-counterfeiting effort
successful.

**Specific Comments**

[Technology]{.underline}

Among the suggestions made in the interim report is packaging all
finished dosage forms in unit-of-use packaging. We believe such
packaging, already employed for many biological products, has proven not
to be the ultimate prevention against counterfeiting. Some recent
examples illustrate this point. The relabeling and frank counterfeiting
of the epoetin product Procrit was not deterred or prevented by the fact
that this product is packaged in unit-of use vials and packages. The
company has undertaken to deter counterfeiters, opting to implement
sweeping anti-counterfeit measures immediately, including a new
packaging technology that uses a color-changing seal to verify the
authenticity of the product. It also has shored up security by using a
punitive strategy with its suppliers and maintains an avenue for
consumers to report suspected counterfeit Procrit batches on its Web
site. This example is illustrative both of the commitment of BIO member
companies to employing product-appropriate anti-counterfeiting
approaches and of the fact that such technology will not in itself solve
the problem. It is appropriate for companies to have individualized
response plans to address incidents of counterfeiting. BIO believes that
the unique expertise of each company with respect to its own products
must be brought to bear on all decisions about the use of
anti-counterfeiting technology and the approaches a company takes to
responding to counterfeiting of its products.

Additionally, products enclosed in blister packaging also have been
counterfeited. Whether such packaging combined with other
anti-counterfeit measures, could prove sufficiently secure is an option
that we believe, if considered, needs to be explored further. Some
considerations include the question of whether the substantial cost of
implementing such packaging for products now distributed in bulk or in
large-quantity packaging \-- costs that would accrue throughout the
system \-- would be balanced by a significant reduction in risk. BIO
recommends that data be gathered to show the extent to which this
option, where it already is in use in other countries, is viable and
successful in reducing counterfeiting. Similar comments and questions
apply to employing tamper-proof packaging.

The interim report recommends, as an option, that all drug products be
required to employ two types of validated anti-counterfeit technologies,
one overt and one covert. Because both the incorporation of such
technologies and their value with regards to reaching the goal of
deterring counterfeiting will be, in BIO's view, highly dependent on the
product, dosage form, etc., we recommend that FDA continue to lay out
the goal and allow the industry to determine, based on product types,
how best to reach the goal. BIO believes that the choice of specific
anti-counterfeit technology should be left to the manufacturers, who
have expertise in the development, manufacture and design of both
products and packaging components. Additionally, if the implementation
of the technology requires regulatory approval (such as addition of
deterrents integral to the product), BIO recommends that FDA consider
reduced regulatory filing requirements (such as, for example, reduction
of stability requirements) and regulatory reporting categories. We
believe that use of taggants or chemical markers, for example, raises
concerns about cost, the nature of regulatory controls and the
additional time that would be required to secure FDA approval to
incorporate additional chemical materials in drug products. BIO believes
that it is also important to recognize that some technologies (such as
taggants or other forensic technologies) may be inappropriate for use
with proteins. Overall, BIO is cautious about industry wide mandates
regarding technology solutions because of the sensitivity of our
biotechnology products and unknown long-term cost and benefits.
Technologies can prevent counterfeits from reaching the public only if
downstream players in the supply chain can and do recognize them and
respond appropriately.

BIO believes that the development of an electronic database for
authentication purposes may be helpful and might be of practical value.
However, BIO recommends substantial additional discussions to resolve
some key questions before initiation of any such system. For example,
who will develop and maintain the database? BIO believes FDA may well be
the most appropriate site, but also recognizes the potential resource
implications for the agency, which will raise concerns about whether
this function would become a priority that could take resources from
FDA's principal functions in the review, approval and regulation of new
products. We believe a private sector organization, under FDA contract,
also may be an option. That approach, however, will raise additional
questions about system security and the ability to maintain the
confidentiality of proprietary information as well as to prevent access
into the system by counterfeiters themselves. Further, BIO believes that
any such system will be only as effective as the extent of participation
by manufacturers. Considerable work is needed to ensure, for any such
database, that manufacturers will provide data to the system and will
not be discouraged from participation by concerns about the security of
their information.

With regards to the implementation of track and trace technology, BIO
agrees that a truly closed system would be the primary deterrent to
counterfeit medicines entering the distribution system. However, the
technology is many years away from implementation -- scanners would need
to be installed at every step of the distribution chain, and an
information technology infrastructure would need to be established from
which the validity of the serialized numbers placed on each unit package
would be determined; the technology for the information "tags" on each
unit of distribution would need to be unfailingly read by the scanners.
The current system designs have demonstrated difficulties in
transmitting and receiving data from the information tags in certain
standard configurations of packaging or if the product is in a liquid
form. BIO believes the technology will need to be refined, the
infrastructure implemented and the cost of the system absorbed.

Further, current FDA regulatory requirements, including Part 11
compliance, Stability Requirements (for example, some tags' bandwidth is
UHF; are stability studies required prior to their implementation?), and
Validation, may provide hurdles to employing RFID/EPC technology. Also,
would the information provided in the chip be considered labeling?

BIO supports the notion that, as an initial step, low-tech solutions may
be considered. We believe such low-tech approaches may prove to be
appropriate for many products in the long run. FDA's recommendations
regarding limiting transactions, more fully documenting transactions,
etc., may be appropriate interim steps, especially in light of the fact
that the high-tech approaches may be very far from feasible at this
point. We also note, as mentioned earlier, that improved regulation of
the so-called secondary wholesale market is a key component of such an
approach.

BIO recommends that FDA pursue the development, with industry and other
stakeholder input, of draft guidance documents on appropriate
anti-counterfeiting steps and on physical plant and supply chain
security. With regard to the former, BIO suggests that
anti-counterfeiting guidances be issued as a series, in a stepwise
fashion as more information becomes available and various technologies
become more feasible.

[Secure Business Practices]{.underline}

We strongly support FDA's continuing work with the National Association
of Boards of Pharmacy on development of appropriate rules for licensing
wholesalers. BIO also recommends that FDA, as mentioned earlier,
implement its own rules applicable to unauthorized wholesalers. Strong
federal oversight of the wholesale market is critical to any
anti-counterfeiting effort.

With regards to business practices of individual manufacturers, BIO
believes that companies should be encouraged to develop such practices
voluntarily. However, we believe that it might be helpful, especially
for smaller companies new to the pharmaceutical marketplace, for FDA to
develop a list of voluntary activities and actions that the agency
believes contribute to effective security. Such a list would constitute
FDA's best assessment of optimal conditions, but such activities and
actions would not be a requirement for companies seeking FDA approval of
new products.

[Rapid Alert and Response Systems]{.underline}

As noted earlier, BIO believes that any system to receive reports of
possible counterfeiting should be separate from the MedWatch system,
which is not -- and should not be -- designed for criminal activity
reporting or oversight. BIO strongly supports enhancement of FDA's
investigative activities, as well as response actions when the agency
becomes aware of possible counterfeiting. Finally, we suggest the agency
further develop its recommendation to create a "counterfeit alert
network" with manufacturers, distributors, pharmacists and others
participating. We believe appropriate communication among all the
components of the system, will greatly facilitate early detection of
problems and also serve as a real deterrent to criminal activity. BIO
offers its assistance in this effort.

[Education and Public Awareness]{.underline}

We support increased public education and believe that education of
health-care providers and pharmacies is especially crucial. Counterfeits
should be stopped before they reach the consumer.

[]{.mark}

[International Issues]{.underline}

Importation/reimportation is yet another uncontrolled point in the
supply chain that provides an entry point for counterfeiters. BIO is
opposed to loosening controls on importation and supports increased
authority for FDA to access foreign manufacturer records for
investigating counterfeiting cases.

[]{.mark}

**Conclusion**

In summary, BIO is eager to work with FDA on finding solutions, both
interim and long term, to the still small but growing problem of drug
product counterfeiting. We applaud the FDA's recognition that the
problem is complex because it involves sophisticated criminals but also
because it must deal with drug and biological products that are so
different that single solutions cannot possibly apply equally to all of
them. We believe that closed distribution systems -- such as that for
controlled substances, including electronic ordering systems -- may be
approaches worth considering. However, those systems, too, have been
violated by criminals, and therefore do not offer the perfect solution.

BIO recommends FDA continue its thoughtful approach based on the
assumption that there is no magic bullet. We believe FDA will provide
invaluable guidance based on its comprehensive knowledge of the kinds of
products in the marketplace, its global perspective on distribution and
its breadth and depth of experience in both product regulation and
criminal investigation. However, in the end, it will be the
manufacturers, distributors and dispensers of products whose actions
will determine how and whether the goal of preventing counterfeiting
will be achieved. BIO pledges its help and that of its member companies
to this effort.

Thank you for your consideration of these comments. Please do not
hesitate to contact me should you have any questions.

> Sincerely,
>
> ![](media/image2.png)
>
> Gillian R. Woollett, MA, DPhil
>
> Vice President
>
> Science and Regulatory Affairs