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## August 5, 2003

## Cambrex Bio Science Walkersville, Inc. 

> 8800 Biggs Ford Road
>
> Walkersville, MD 21793

Dockets Management Branch,

Food and Drug Administration,

5630 Fishers Lane, Room 1061, HFA-305,

Rockville, MD 20852

Submitted electronically

RE: Docket Number: 2003P-0278

> 2003P-0280

This document constitutes the response of Cambrex Bio Science
Walkersville, Inc. to the above referenced Request for Stay of Action
and Citizen's Petition dated June 12, entered on June 18, 2003. This
submission was filed on behalf of the Associates of Cape Cod.

## Introduction

#### **Background**

Cambrex Bio Science Walkersville, Inc. (CBWI) is a manufacturer of
products including Limulus Amebocyte Lysate (LAL). LAL is a product
derived from blood that is licensed by the FDA to test for endotoxin in
products including licensed biologicals, pharmaceuticals, and
implantable devices. CBWI also manufactures unregulated products,
including PyroGene™, an endotoxin detection method using recombinant
Factor C (rFC). PyroGene and rFC are not derived from blood and are not
regulated by FDA.

The petitioner, ACC, also manufactures products including licensed LAL
for endotoxin detection. According to the Request for Stay, it is also
developing a recombinant endotoxin test.

#### **Confidentiality not waived**

FDA law and regulations require that certain information disclosed to
FDA is not available for public disclosure. 21 USC § 331(j), 21 CFR
20.61. The Request for Stay and the Petition refer to documents that ACC
believes to have been submitted to FDA, specifically a Request for
Product Designation (RFD). These submission types are generally not
publicly available. This response addresses issues related to filing and
reconsidering an RFD but does not waive any confidentiality interests
related to any pending or complete FDA submissions protected by these
confidentiality provisions.

#### **Request**

ACC filed two submissions with FDA on the matter of regulation of
endotoxin detection tests:

#### A Request for Stay of Action pending a decision on a Citizen's Petition, asking FDA to prohibit the marketing of unlicensed endotoxin tests not derived from blood; and

#### A Citizen's Petition that requests:

#### That the Commissioner reconsider the determination that PyroGene is not a biological product subject to licensure, and continue to require premarket approval for all endotoxin tests used for in process and finished product testing;

#### Alternatively, that the Commissioner:

#### clarify and reinforce the requirement that sponsors of unapproved and previously approved human and animal parenteral drugs, biological products, and medical devices submit data validating the use of unlicensed endotoxin tests; and 

#### deregulate previously licensed endotoxin tests.

Because the FDA is likely to respond first to the Petition for Stay of
Action, this response first addresses the Stay. Following that, CBWI
addresses the Citizen's Petition. Admittedly, many of the same grounds
that compel the denial for the Stay also argue for the denial of the
Petition. However, there are additional reasons for denying the Stay.

#### **Summary of Response:**

The Request for Stay does not meet the burden required for FDA to grant
the action requested. A Stay of Action should be granted only under
extraordinary circumstances, where the harm suffered pending the
petition review is irreparable, and where Petition is likely to succeed
on its merits. ACC has not suffered irreparable harm. The monetary
damages cited by ACC are easily measurable and compensable. Furthermore,
the FDA action affects all industry equally. FDA allows the marketing of
CBWI and ACC products on the same terms for blood derived products and
the same terms for non-blood derived products. Also, the Request for
Stay identifies no public health or public policy reasons for granting
the Stay independent of the reasons for granting the petition.

The Citizen's Petition must be denied because the product jurisdiction
process is the appropriate vehicle for determining the regulation of
products whose jurisdiction is in dispute. Also, blood derived endotoxin
detection methods are justifiably subject to FDA regulation. FDA does
not have jurisdiction to require licensure for non-blood derived
endotoxin detection methods. CBWI does agree that the FDA should clarify
and reinforce requirements for validating the use of endotoxin tests.

## Response to Request for Stay

## Rule:

## The Request for Stay cites 21 CFR §10.35(e), which requires 

## The petitioner will suffer irreparable injury;

## The petitioner's case is not frivolous and is being pursued in good faith;

## The petitioner has demonstrated sound public policy grounds for supporting the Stay; and

## The delay resulting from the Stay is not outweighted \[sic\] by public health or other public interests.

> Courts have required that an administrative stay application must meet
> the same standard applied by the courts. This requires a balancing of
> four factors: "whether the movant \[is\] likely to succeed on the
> merits, whether denial of the stay \[will\] cause irreparable injury,
> whether granting the stay \[will\] harm other parties, and whether the
> public interest favors granting a stay." *Kuflom v. District of
> Columbia Bureau of Motor Vehicle Services*, 543 A. 2d 340, 344 (D.C.
> 1988). See also *Barry v.Washington Post Co.*, 529 A.2d 319, 321 (D.C.
> 1987), *quoting Washington Metropolitan Area Transit Commission v.
> Holiday Tours, Inc.,* 559 F. 2d 841, 843 (D.C. Cir. 1977). It is the
> movant's obligation to justify the "extraordinary remedy" of granting
> a stay of an administrative order. *State of Missouri v. Gabbert*, 925
> S.W.2d 838, 839 (Mo. 1996). As such, "\[a\]n administrative order or
> decision will not be stayed pending appeal where the applicant has not
> sustained his or her burden of proof or otherwise has not made the
> required showings." *Id*.

## Discussion:

## [Petitioner will not suffer irreparable injury]{.underline} 

To obtain a Stay, the complainant must show that there is no plain
adequate and complete remedy at law and that irreparable injury will
occur unless relief is granted. The definition of irreparable injury is
an injury that cannot be adequately measured or compensated by financial
remuneration. Therefore a Stay is appropriate only when no adequate
remedy such as monetary damage exists. Bryan Garner, ed., *Black's Law
Dictionary*, 7^th^ ed. (1999). The loss is measured from the
implementation of the Stay to the resolution of the matter; a Stay
cannot prevent losses outside the pendency of the action.

## *Any loss is easily measurable and compensable.*

> If FDA decides to grant the petition, any amount of petitioner's
> economic loss during the pendency of the petition can be determined
> relatively easily. This figure can be based on the change to
> petitioner's market share and the profits earned by recombinant test
> products during that period. Therefore, monetary damages will be
> measurable and adequate to compensate the petitioner.

## *ACC's outlays are not relevant to the consideration.*

> ACC states it has already made an expenditure "to produce its
> products." Stay at p. 3. Only future outlays can be prevented by a
> Stay, and any amount already spent before the pendency of the petition
> is not relevant to the consideration of the Stay. Moreover, ACC does
> not explain how the expenditure is related the product that is the
> subject of the Stay, blood-derived or otherwise. ACC's submission
> suggests it will manufacturer blood derived products and other
> products in the facility. Finally, ACC attaches a value to the
> expenditure, which suggests that it is measurable and compensable.

## *Marketing requirements are imposed equally on regulated products and influenced by customer demand.*

> According to the Request for Stay, ACC has invested substantial time
> and capital to develop and meet the FDA approval requirements for its
> currently marketed LAL endotoxin tests. All LAL manufacturers have
> invested to properly manufacture its regulated products. All LAL
> products are subject to these same requirements. Inasmuch as the
> companies supply product to industry required to comply with GMP, this
> investment is associated with customer demands as well as FDA action.

## *ACC benefits from the investments that it cites as proof of loss.*

> For the law to recognize irreparable harm, the petitioner must receive
> no benefit associated with the loss. In other words, there is no loss
> when the petitioner receives value associated with the outlay. There
> is no irreparable harm associated with capital investments made to
> improve a facility. If the investments are wise and well executed, the
> new facility will produce efficiencies in costs and production. ACC is
> eligible for tax advantages related to the improvements, including a
> generous Research & Development tax credit intended to provide
> incentives, which demonstrate that public policy favors these
> improvements. The improvements also will attract and keep customers,
> another benefit from the investment. Moreover, such investments are
> necessary from time to time in depreciating assets such as a
> manufacturing facility; this is a significant expense associated with
> every manufacturing industry. LAL is a business that has been in
> existence since the 1970s, and ACC needing to upgrade a facility after
> over 30 years in business is not an unexpected or unfair expenditure.
> It is an expense that CBWI has undertaken on its own in the past and
> is again undertaking in its own facility. Because the expenditure ACC
> cites as the irreparable damage improves its customer service,
> manufacturing capability and tax status, and is a necessary expense
> that adds value to any facility regulated or not, ACC has not
> established that it has experienced any loss due to the regulatory
> status of LAL or rFC.

In sum, FDA is not authorized to Stay the marketing of a product,
particularly an unregulated product, where there is an adequate
financial remedy at resolution, merely because a technological
advancement threatens a competitor's market share, because there are
expenses related to another blood-derived regulated product, especially
where the petitioner has not availed itself of FDA procedures, in this
case the RFD process. ACC's expenditures occurred in the past and cannot
be addressed by a Stay. ACC is free to market under the same terms as
CBWI. ACC's obligations to maintain its licensed facility are the same
as CBWI's and other manufacturers equally. Furthermore, there is no
irreparable injury associated with making facility improvements where
they are necessary to improve, upgrade, and maintain manufacturing
facilities and the Requestor obtains value from these improvements.

## [The petitioner's case is frivolous or is not being pursued in good faith;]{.underline}

This element depends on the adequacy of the petition, which it
cross-references. These arguments are addressed in detail in our
petition response, below. In sum, the petition is frivolous because:

## it does not address the requirements for reconsideration of the FDA decision; 

## it does not address whether endotoxin detection tests meet the legal definition of a regulated product; and 

## it does not provide grounds to suggest how FDA has jurisdiction to grant a Stay against marketing a product that is not derived from blood and does not make drug or device claims.

## [The petitioner has not demonstrated public policy grounds for supporting the Stay.]{.underline}

> The Request has not demonstrated that public policy reasons exist for
> granting the Stay. It does not assert any independent public policy
> grounds supporting the Stay itself. Instead, it merely asserts the
> same public policy grounds described in the petition. Because a Stay
> effectively prevents FDA's decision from being implemented before the
> merits of the petition are fully addressed, petitioner must present
> additional reasons to justify the Stay to justify the request.
> Therefore, petitioner has not met this required element.

## [The delay resulting from the Stay is outweighed by public health or other public interests, and will harm other parties.]{.underline}

> While the Request states that public health may be implicated because
> of the importance of endotoxin tests, it does not address the other
> public health interests that apply to counter a requirement for
> preapproval of endotoxin detection tests not derived from blood. These
> other interests include:

#### **Other nations, *e.g.*, the European Union, require the use of products not derived from animals wherever these products are available.** As such, to sell products in the EU, manufacturers including US manufacturers may be required to use new endotoxin detection methods. Because the validation of this test will be a lengthy process, it must begin soon. Granting a Stay to require premarketing approval of the product will obstruct this effort.

#### **There is a public environmental interest in using such non-animal products.** It is difficult to protect the horseshoe crab, which is the source of traditional LAL, and its habitat on the U.S. Eastern seaboard. CBWI practices catch and release but other manufacturers do not necessarily take on this additional duty and expense. The horseshoe crab population is adversely affected by harvesting that sacrifices the animal, as well as by inadvertent take (bycatch), other predators, drought and water shortage conditions, climate changes and global warming. Between 1991 and 2000, the breeding horseshoe crab population decreased by one third.[^1] Reductions in this population affect the entire food chain, including the migratory birds that depend on horseshoe crab in their diet.[^2] This concern prompted the Atlantic States Marine Fisheries Commission to restrict the landing of horseshoe crabs; the states of Maryland, New Jersey and Delaware also have legislation to curb horseshoe crab fishing.

> Concern has increased regarding pollution of the water source,
> including intentional contamination of the water supply. The Homeland
> Security Plan of the US Environmental Agency includes concerns about
> protecting the safety and integrity of such bodies of water from
> intentional contamination.[^3]
>
> The supply of horseshoe crabs may plummet under any combination of
> these adverse conditions. As such, important public policy concerns
> exist for encouraging the use of endotoxin tests from alternate
> sources.

#### **FDA and the public have an interest in encouraging advancement in technology as they can be properly validated for use in inspected establishments**. These advances are consistent with implementing "Process Analytical Technology" (PAT) and FDA's Risk-based Quality Regulations.

#### FDA's new programs recognize the value of the oversight of Quality Units and the reliability of validation. If regulated industry cannot validate the rFC product to the satisfaction of their quality units and FDA, the product will not be accepted for use. However, if our experience is confirmed and not only can it be validated but it will reduce false positives by eliminating interference from glucan activity, this technological advancement will be embraced by the regulated community. This reduction in false positives will prevent unnecessary delay in the availability of products during an investigation to determine the influence of glucan on the results; this may improve availability of products, including critical products in short supply. The tests will reduce resources expended to conduct the investigation, producing savings that can be passed on to consumers.

#### **FDA and the public also have an interest in preventing the petition process from being abused**. FDA has expressed its concern regarding petitions filed merely to delay competition. 64 Fed. Reg. 66822 (11/30/99); docket 99N-2497. Although FDA withdrew a proposal to prohibit certain petitions, it did so because new efficiencies reduced its backlog of responses to these petitions. 68 *Fed.* *Reg*. 16461 (04/24/03). The backlog had meant that a petitioner could succeed by delaying a competitor's entry to market without ever prevailing on the merits. In withdrawing the proposal, FDA nevertheless reinforced its commitment to discourage abuse of the petition process to delay marketing of competitor's products. *See* 68 *Fed.* *Reg*. at 16461.

## Response to Petition

Disputes regarding product jurisdiction should be resolved through the
product jurisdiction process. Moreover, the petition fails to establish
that LAL is not a biological product. The petition also fails to
establish that rFC is a biological product; therefore FDA does not have
authority to require premarket approval.

## Product jurisdiction disputes should be resolved using the product jurisdiction process

## [Regulations]{.underline} 

> The Product Jurisdiction process was established to provide a "timely
> and effective" premarket review for products including those whose
> "jurisdiction is unclear or in dispute." 21 CFR §3.3(b); see also
> §3.1[^4]. A requestor must comply with the procedure described in the
> regulation to file a Request for Designation (RFD). Request for
> reconsideration must not contain new information. 21 CFR §3.8.
>
> A letter of designation constitutes an agency determination that is
> subject to change **only** as provided in §*3.9 Effect of letter of
> designation.*
>
> The product jurisdiction officer may change the designated agency
> component with the written consent of the sponsor, **or without its
> consent to protect the public health or for other compelling
> reasons**. A sponsor shall be given 30 days written notice of any
> proposed nonconsensual change in designated agency component. The
> sponsor may request an additional 30 days to submit written
> objections, not to exceed 15 pages, to the proposed change, and
> **shall be granted, upon request, a timely meeting** with the product
> jurisdiction officer and appropriate center officials. Within 30 days
> of receipt of the sponsor\'s written objections, the product
> jurisdiction officer shall issue to the sponsor, with copies to
> appropriate center officials, a written determination setting forth a
> statement of reasons for the proposed change in designated agency
> component. **A nonconsensual change in the designated agency component
> requires the concurrence of the Principal Associate Commissioner.**
>
> 56 *Fed. Reg.* 58756, Nov. 21, 1991, as amended at 68 *Fed. Reg*.
> 37077, (07/23-03). Emphasis supplied.
>
> A purpose of the product jurisdiction process is to enhance the
> efficiency of agency management and operations by providing procedures
> for determining which agency component will have primary jurisdiction
> for any drug, device, or biological product where such jurisdiction is
> unclear or in dispute. 21 CFR §3.1.

## [Discussion]{.underline}

##### [The petitioner did not exhaust product designation procedures.]{.underline}

> ACC does not claim that it is an applicant, and did not use the
> procedures provided for obtaining a request for reconsideration. The
> petition does not explain why it should nevertheless be accepted. The
> petition is untimely, not in the form described in the regulation,
> contains new information and not amenable to the timeframes provided.
> As such, this request should be denied.
>
> Attempts to reconsider jurisdictional decisions outside that process
> and without following the procedures required undermines the certainty
> that the product jurisdiction process is intended to provide.[^5]
>
> ACC remains free to request a product designation for an endotoxin
> detection method, and free to obtain an answer from FDA in just 60
> days. If ACC is dissatisfied with the response, there are procedures
> for reconsideration. Apparently ACC has elected not to do this. Until
> ACC submits an initial request under 21 CFR Part 3, reconsideration is
> unripe. This failure must not be remedied another forum such as a
> Citizen's Petition. The vehicle for this determination is the RFD
> process.

##### [The standard for reconsideration of an RFD is not met.]{.underline}

> A nonconsensual change to an RFD decision must be necessary "to
> protect the public health or for other compelling reasons." 21 CFR §
> 3.9(b). This standard enhances the certainty of the product
> jurisdiction procedure. The petition does not address this standard or
> establish that it has been met.
>
> While the petition claims that public health implications would be
> raised by the use of an unregulated change to regulated products,
> these issues are addressed by FDA's current, extensive regulatory
> program. The petition does not suggest that the current regulatory
> oversight of non-blood derived endotoxin testing is inadequate. This
> oversight includes:

##### *FDA reviews and approves the chemistry, manufacturing and controls of the final products*[.]{.underline} Regulated industry files this information in an initial filing, and in updates at least annually thereafter. This filing includes validation and testing for tests such as those for endotoxin. When changes are implemented, including a change in testing such as from LAL to rFC, FDA may require more frequent filings including Pre Approval Supplements under 21 CFR §314.70 *et seq.* (for drugs), 601.12 (for biological products), and 814.39 (for devices). FDA has issued several guidance documents addressing these filings including "Guidance for Industry, Changes to an Approved NDA or ANDA" in 1999. As such, a change to rFC would be subject to FDA review, and the Agency could require preapproval of the change.

##### *The parenteral drugs and implantable devices subject to this testing are approved before marketing.* FDA determines that the products are safe. This safety determination includes a review of the release criteria including endotoxin testing. FDA review would also include that any labeling is truthful and adequate, including statements that the product is non-pyrogenic.

##### *FDA has issued a "Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test For Human and Animal Parenteral Drugs, Biological Products and Medical Devices,"* December 1987[.]{.underline} Endotoxin testing is well defined, as described in the guidance. Also, it is compendial. The performance and interpretation of endotoxin testing is well understood.

##### *FDA receives reports including reports of injuries and errors and accidents associated with distributed regulated products.* These reports include injuries and errors and accidents related to product pyrogenicity.

##### *FDA oversees requirements related to GMP, Quality Systems*, and other requirements covering validation plans including validation of rFC for final product release of regulated products.

##### *FDA inspects facilities where the products are manufactured.* An inspection includes a review of information contained in filings and updates. It includes a review of recalls and corrective actions that have occurred since the previous inspection. It also includes a review of the adequacy of the GMP/Quality System that assures product is not released unless all release criteria are met.

> FDA has extensive authority to prevent marketing of any final product,
> and FDA maintains that authority if the rFC test is unsatisfactory in
> assuring product safety. FDA does not also have to engage in an
> additional exercise to separately review and preapprove each test and
> method, especially where the test itself is not a biological product
> and is not subject to variability inherent in biologically derived
> products. This requirement would be inconsistent with the PAT and Risk
> Based Manufacturing initiatives referred to above.
>
> CBWI agrees with the petitioner that endotoxin testing is important.
> However, FDA does not require preapproval for every important test
> used on regulated products. Products not derived from blood such as
> rFC do not raise issues related to the inherent variability of the
> source material. Like other such tests it may be marketed outside the
> scope of FDA preapproval requirements. As an example, sterility
> testing is not subject to FDA premarket approval. Established test
> methods exist, the performance and interpretation of the tests are
> well understood, the tests are validated in regulated facilities, the
> facilities are properly inspected, and only sterile products are
> properly labeled as such.
>
> CBWI also agrees with the petition's requests for FDA clarification of
> the validation requirements that apply. As mentioned above, FDA has a
> guidance document on endotoxin testing. CBWI has asked FDA to confirm
> the applicability of its guidance on endotoxin testing. CBWI will
> continue to work with FDA and our customers to make sure those issues
> are addressed for rFC, so that the FDA submissions that describe
> manufacturing changes related to the validation and use of this test
> will be adequate.

## [Conclusion on Product Jurisdiction Issues]{.underline}

> In sum, the RFD process was implemented in order to allow
> manufacturers to obtain a decision from FDA and to proceed based on
> the decision unless there are public health or other compelling
> reasons. RFD decisions should not be made or reexamined via the
> citizen petition process without the procedural safeguards that apply
> to RFD decisions. The petition does not raise any public health
> interests, compelling or otherwise, that are sacrificed under the
> current, extensive, regulatory scheme.

## Biological Products

Biological products are defined, in pertinent part, as products derived
from blood. LAL is derived from blood. PyroGene™ and rFC are not. FDA's
decision to regulate them differently is firmly grounded in this
distinction in the Public Health Service Act (PHSA). Any other decision
cannot be supported by the Act, its history of implantation, or public
health concerns.

## Rule:

Under the PHSA, 42 USC §262(i). a "biological product":

> means a virus, therapeutic serum, toxin, antitoxin, vaccine, **blood,
> blood component or derivative**, allergenic product, **or analogous
> product**, or arsphenamine or derivative of arsphenamine (or any other
> trivalent organic arsenic compound), applicable to the prevention,
> treatment, or cure of a disease or condition of human beings.

Emphasis supplied. Biologics may not be distributed in interstate
commerce without a license.\
42 USC 262(a).

## Discussion

##### [LAL and PyroGene are not derived in the same manner and must be regulated differently under the PHSA]{.underline}

> The petition states that FDA should regulate rFC just as LAL, based on
> the fact that LAL has been regulated for many years and that both
> products have the same intended use. However, the test of whether a
> product is a biological product is based on the language of the PHSA
> and not on the regulation of similar products that are biologically
> derived, and not solely on the intended use of the products.

##### *LAL is properly classified as a regulated product.* 

> Licensed LAL meets the two-tiered definition of a biological product:
> CBWI urges FDA to continue the regulation of blood derived LAL as a
> biological product under the PHSA.

-   LAL is a blood, blood component or derivative or analogous product,
    as it is derived from blood,

-   LAL is applicable to the prevention, treatment, or cure of a disease
    or condition of human beings, because test results for endotoxin in
    medical products used in humans is applicable to the prevention of
    dangerous pyrogenic reactions in patients.

> The reasons for this PHSA provision are clear: to provide consistency
> for a product from a source that is inherently variable. The manner in
> which FDA has exercised its regulation of biologically derived LAL,
> through product licensing and provisions for lot release, is
> consistent with this objective.
>
> No legislative or policy exemptions are identified in the petition
> that would support a conclusion that regulation of LAL is outweighed
> by other interests. For LAL, as with other biological products, there
> is inherent variation in products derived from animals. Consistent
> manufacturing methods may not be enough to assure safety, purity, and
> potency because of the inherent variability in the source material.
> Finally, changes in manufacturing methods may cause unpredictable
> effects on final product safety, purity, or potency because of the
> properties of the source material.

##### *rFC is properly classified as a product other than a regulated biological product.*

> The petition suggests that as long as LAL is regulated as a biological
> product, rFC also must be regulated under identical provisions.
> However, rFC differs from LAL in one important characteristic: rFC is
> not derived from blood. Therefore the first tier of the two-tiered
> test for a biologic is not met.
>
> No legislative or policy exemptions are identified that would support
> a conclusion that the regulation of rFC is necessary. There is no
> inherent variability of the source material as with products such as
> blood, blood components or derivatives, or analogous products.
> PyroGene™ uses rFC; all other components are synthetically produced.
> Manufacturing is simplified by eliminating inherent variability
> present in the LAL source material; manufacturing methods are likely
> to reduce or eliminate other variability in to the process.
> Additionally, rFC has a different indication statement than LAL; rFC
> and PyroGene™ are not indicated for testing blood or blood components.
>
> []{.mark}

##### *The decision has a rational basis in fact and law and does not violate the APA.*

> ACC argues that a decision to require licensure for LAL and not for
> rFC is arbitrary and capricious and not in accordance with law.
> However, the differences in the products not only provide a rational
> basis. The distinction is in the statute itself. The PHSA compels FDA
> to make the distinction for products derived from blood from products
> that are not.

##### [Bracco]{.underline}

> Petitioner argues this case is analogous to *Bracco Diagnostics, Inc.
> v. Shalala*, 963 F. Supp. 20, 24 (DDC 1997). In *Bracco*, most
> manufacturers of imaging agents were prohibited from marketing their
> products without premarket approval as a New Drug, and without
> complying with requirements for periodic application fees and filing
> updates. A competitor, a manufacturer of another medical imaging
> product admittedly regulated, was free to market as a medical device.
> FDA argued that since it had discretion to regulate the products under
> either the drug or device provisions, it could regulate each product
> under different standards. The Court disagreed, stating, that "The
> \[products\] all likely meet both the definition of a drug and the
> definition of a device . . . and the FDA therefore has discretion in
> determining how to treat them. . . . What the FDA is not free to do,
> however, is to treat them dissimilarly and to permit two sets of
> similar products to run down two separate tracks, one more treacherous
> than the other, for no apparent reason."
>
> *Bracco* is easily distinguishable in this case because FDA has not
> sent any non-blood derived endotoxin test down any "different track."
> All blood-derived endotoxin tests are subject to licensure. Tests not
> derived from blood, not intended for use in man and not for release of
> blood and blood products are not subject to premarket approval.
> Moreover, unlike the complainants in *Bracco*, *ACC is free to engage
> in the same activity, that is, with any endotoxin detection method not
> derived from blood that it wishes to market.* ACC is free to request
> and obtain an FDA opinion about its similarly situated products,
> biologically derived and otherwise, and market these products under
> the FDA determination.
>
> Another important difference is that the regulation of the imaging
> agents in *Bracco* is under the drug and device provisions of the
> Food, Drug and Cosmetic Act (FDCA). By its terms these definitions are
> mutually exclusive; once a product is defined as a device (with a
> primary mode of action that is not chemical or metabolic) it is
> incongruous to define a similar product as a drug. *See* 21 USC
> §353(g). However, the distinction between LAL and rFC does not involve
> the interpretation of the FDCA's drug or device provisions. The
> pertinent statute for LAL or rFC is the PHSA, whose applicability is
> not challenged in the Petition. The reason for treating the two
> different products differently is patently obvious: LAL is derived
> from blood and meets the statutory definition of a biological product
> under PHSA; rFC is not derived from blood and does not meet the
> definition.
>
> In other words, under *Bracco*, once FDA determined under FDCA that
> two regulated products for the same indication could be regulated
> under either statutory authority, FDA was not free to grant marketing
> clearance to the similar products under different statutory
> authorities. But FDA has not determined that LAL and rFC might be
> regulated under different statutes; FDA determined that rFC products
> are not regulated. FDA interpreted the clear words of the PHSA to
> conclude that it does not grant jurisdiction over products such as rFC
> that are not derived in this manner. FDA did not abuse its discretion
> by regulating products that do meet the statutory criteria differently
> than products that do not.

##### [Notice and Comment is not required]{.underline}

> Regarding the charge that notice and comment rulemaking is required,
> the determination to regulate products derived from blood as biologics
> is required by statute and not a departure from previous FDA policy.
> FDA does not need to engage in rulemaking to implement the plain
> meaning of a statute. Moreover, FDA also has a longstanding policy and
> practice not to regulate products that are not derived from blood, not
> intended for in vitro diagnostic use, and not for use in blood banks.
> Therefore, no notice and comment rulemaking is required.[^6]
>
> In sum, the petition does not establish that it is unreasonable under
> the PHSA to treat products derived from blood differently from other
> products. There is nothing unfair about regulating products that do
> meet the statutory definition of a biologic differently from products
> that do not meet the definition. The petition does not provide a basis
> for FDA to change its decision on LAL and rFC under PHSA. FDA has not
> changed any longstanding policy, so notice and comment rulemaking is
> not required.

##### *The Petition does not identify public health issues to justify a reversal of any decision* 

> While the petitioner argues that public health implications would be
> raised by the use of an unregulated change to regulated products, it
> does not raise new issues. All issues have been addressed by FDA in
> the current, extensive regulatory scheme, as discussed above under the
> standard for changing a product determination above. The petition does
> not suggest that current FDA oversight is inadequate.

Conclusion:

The petitioner does not meet the burden of proof for FDA to grant the
action requested:

The Request for Stay top prohibit the marketing of rFC and PyroGene™
without premarket approval does not state grounds to conclude that
irreversible harm may occur that is not adequately measurable and
compensable. By not addressing the standard or the public policy reasons
in support of the Stay, it is frivolous and not pursued in good faith.
The uncertainty and delay resulting from a change in FDA\'s decision is
outweighed by public health and other public interests. There is no
public policy reason compelling the Stay but the extensive regulatory
program for products tested for endotoxin support the denial of the
Stay.

The Citizen's Petition does not support a determination that FDA should
abandon the procedures and standard for reconsideration of a product
jurisdiction determination. The appropriate vehicle for a determination
on the regulatory status of a product where there is a dispute is the
product jurisdiction process. Also, the petition does not establish that
LAL is not a biological product. The petition fails to establish that
rFC does meet the legal definition of a regulated product and why it
must be regulated as other biological products. The petition has not
demonstrated that public health interests are sacrificed under the
current, extensive, regulatory program for rFC.

Respectfully submitted,

![](media/image2.png){width="1.8229166666666667in" height="0.78125in"}

Andrea E. Chamblee, Esq. RAC

[^1]: *See, e.g.*, Atlantic States Marine Fisheries Commission,
    Fisheries Management Report No. 32: Interstate Fishery Management
    Plan for Horseshoe Crab (Dec. 1998)

[^2]: *See* U.S. Fish & Wildlife Service, Press Release: Fishermen
    Guilty of Illegal Horseshoe Crabbing (April 5, 2000), available at
    http://northeast.fws.gov/newsrel/Horseshoe2.html.

[^3]: *See* http://www.epa.gov/ordnhsrc/htm/waterprotectplan.htm

[^4]: The Medical Device User Fee and Modernization Act of 2002 (Public
    Law 107--250) § 204 amended §503(g) of the FDC Act to require FDA to
    establish an office to ensure: (1) the prompt assignment of
    combination products to agency centers, (2) the timely and effective
    premarket review of such products, and (3) consistent and
    appropriate postmarket regulation of like products subject to the
    same statutory requirements to the extent permitted by law. See also
    68 *Fed Reg.* 37075 (07/23/03) Docket No. 2003N--0235.

[^5]: Although the product jurisdiction process targets combination
    products which are to be regulated by a Center, it is well known
    that companies have been encouraged to use the process for any
    product whose jurisdiction is unclear or in dispute, including
    potentially unregulated products. If FDA were to reconsider this
    longstanding policy, notice and comment rulemaking would be
    required.

[^6]: Petitioner quotes *Shell Offshore v. Babbitt*, which defines a
    substantive rule as involving "a significant departure from long
    established and consistent practice that substantially affects the
    regulated industry. . . . "? FDA's decision affects only an
    unregulated industry. Any effect of the determination on the market,
    and subsequently on regulated industry, is incidental, and cannot be
    deemed to be "substantial."