12’ October 200 I

Dockets Management Branch

12420 ParkIawn Drive

Rockville, Maryland 20857

CITIZEN PETITION:

The undersigned submit this petition under Section 36Obbb-2 of the Federal Food, Drug and

Cosmetic Act, section 553(e) of the Administrative Procedures Act, and Title 21 Subsection

10.30 of the Code of Federal Regulations to request the Commissioner of Food and Drugs to take

the administrative actions listed beIow regarding anthrax vaccine adsorbed.

A. Action requested

(1) Issue a Final Rule on the drug category placement of anfhrax vaccine as Category II (unsafe,

ineffective, or misbranded) amending the as yet to be finalized Proposed Rule as published in

the Federal Register 13 December 1985.

(2) Declare as adulterated all stockpiles of anthrax vaccine adsorbed in the possession of BioPort

.- Corporation and ah doses in private, public, U.S. or foreign governme+ possession, ,‘

(3) Enforce FDA Compliance Policy Guide, Section 400.200 Consistent Application of CGMP

Determinations (CPG 7132.12) with respect to anthrax vaccine adsorbed (license #1260).

(4) Revoke the anthrax vaccine adsorbed license (license W1260) held by BioPort Corporation.

CNO-04-H CQ CL

B. Statement of grounds

(1) Issue a Final Rule on the drug category placement of anthrax vaccine as Category II (unsafe,

ineffective. or misbranded) amending. the as vet to be final&d Pranosed Rule as published in the

Federal Register 13 December 1985.

and Scientific Affairs under the Secretary of Health, Education, and Welfare to the

Commissioner of Food and Drugs and the Director, National Institutes of Health on 18 February

1972. On 14 August 1972, Food and Drug Commissioner Charles Edwards proposed procedures

for the review of all biologic products. This review would encompass the overall safety and

effectiveness of every biologic product. These procedures were fkalized on 8 February 1973 and

a total of six review categories evolved from this mandated review procedure. On 28 February

1973 a request for a safety, effectiveness and labeling review of Anthrax Vaccine, adsorbed was

published in the Federal Register.

Anthrax Vaccine, adsorbed (now referred to as anthrax vaccine adsorbed or AVA) was placed in

. ., the review .group of "Bacterial Vaccines and Toxoids with Staitdards of Potency, Single or in

Combii&on". ‘& 16 January. 1981 the Food &d Drug Adii&&tr&ion (FDA) published a

proposed rule to revise the re&tssification procedures for the biordgic products under review. In

: . . -- this propdsed rule, FDA indicated &at the%Gt.l &port for thi! prij&% -& the‘ above’review ‘group

had been received and would issue proposed orders (rules) based on this report prior to the

issuance of any final rule for reclassification Qf certain products as Category IlI. FDA published

this Proposed Rule in the Federal Register on 13 December 1985. In this Proposed Rule, the

review committee (the Panel) spent a great deal of time explainjng its evaluation criteria,

methodology, etc. and used the products under its review in examples.’

’ It is interesting to note that every product reviewed by the Panel was mentioned in this

introduction, except anthrax vaccine adsorbed.

2

license(s) be continued because there is substantial evidkne of ssfeg and effectiveness for #his

product. 9y *

This recommendation clearly conflicts with the guidelines established by the Commissioner and

with the evaluation criteria used by the Panel3 The Panel was aware that no clinical trials had

taken place writing:

"The vaccine mapr?rfactured by the Michigan Department of Public Health has not

been employed in a controlledfield trial. "

* The Panel’s report and recommendations can be found beginning at 50 FR 51002. The generic

product review and specific product review of anthrax vaccine; ads&bed begin at 5 10%.

3 The Commissioner indicated in the Federal Register Notice outlining the review procedure (38

FR 43 19) that proof of effectiveness shall consist of controlled clinic&l investigations as

defined in 21 C.F.R. $ 130.12 (a)(5O(ii) [This section can now be found at 21 C.F.R. 6

. 601.25(d)(2)1. The Commissioner @d proposed ar! amen$nent to $ 130.12 in 1970 (35 FR,

forth in the regulations, as amended by this or&r, constitute the essentiais of an &quate and

weil-controlled clinical investigation. To make the criteria guidelines or@ would be contrary to

the legal obligation. that ali claims. of eflectivene~ for drugs marketed through the’ m dnrg

and antibiotic procedure s must be supported by ‘substantial evidence ‘, derivedfionz adequate

clinical experience in an uncontrolled or partially controll& situation may be of vaiue in

precautionary neeak It can as weli be cons&red as corroborative evidence, along with &a

derived ji-om aakquate and welkontrollled clinical investigations, to support claims of

investigations, even when done by an experienced investigator or reported by a number of

Title 21 provides the opportunity for any person to seek exemption from some or ail of the

above criteria. The Michigan Department of Public Health (MDPH) did not seek exemption

from these regulations during their licensing process.

become generally understood that a successfl and acceptablti vkcine must be: (I) Safe and

of the e@cacy and safety of the new vaccine."

3

The panel briefly mentions the data gathered in support of tb license.4 The Panel’s use of data

for a similar, but different, vaccine to support its recommendation that the anthrax vaccine be

considered a Category I biologic is contrary to the 21 C.F.R. 8 130.12 et seq. The Supreme Court

has affirmed these provisions.’ Tht! Panel should have placed AVA as either a Category II or

IIIB biologic product.

A Category II designation iS for those biological products determined to be unsafe, ineffective, or

misbranded. Based on a strict interpretation of the requiretnents, placing AVA in Category II

would have been impossible, as the Panel did not have any evidence from the actual vaccine with

which to make a deterr&ation of safety or efficacy. However, the absence of data cannot be

construed to imply safety or efficacy. In fact, the Panel should have viewed this lack of data in

terms of the FDA’s mission to ‘;Protect the public health as it may be impaired by drugs" by

ensuring that these drugs are safe and effective. The gravity of l?DA’s mission is stated in the

4 Safety data for the product license application was gathered under DBS IND 180. Based on a

review of the Progress Reports for DBS IND 180, this study w&s strictly for the purpose of

establishing the safety of the vaccine. Vaccination wti a condition of employment at the

various mills; therefore one hundred percent participated. There were no "control groups". The

Pqel erroneously refers to these dat? if! .the specific’ product, review in ‘4. Critique’ as

zidequately establishing significant protection against c@aneous ax&rax. i;l Ally imm&nized

subjects. It is important to note that the license approval was ba&ti on the caveat that MDPH

would provide efficacy data to the Division of Biologic ‘Standards. In pre-lieensure

correspondence, Dr. Margaret Pittman wrote: "‘Michig~ has jriled with the Divikon all

required &form&ion and material for license exkept the results of an &qua&y controlled

clinical investigation that establishes efJacy. " "Therefore, it ii recommended that license be

granted and the NCDC @ND -180) be requested to @b&in data with & view to determine

human eflcucy of the produck " @%hibit 21 In fact, two additibnal Progress Reports were

submitted by MDPH after license recommetidation. As with’&6 &e&ensure rep’&ts, these

Progress Reports provide no data on the effectiveness of the v&cine. To date, the manufacturer

has not complied with the AD Hoc Committee request to provide human efficacy data.

5 In Weinberger, CW. v Hynson, Westcott and Dunning; Inc. (No. 72-394 and 72-414) FDA

defended and the Court a&irmed their revocation of :the licenses of unproven drugs and

vaccines. The Court determined that the FDA was with& its reg&tory authority to revoke the

licenses of those drugs that relied on clinical data fronil othei: diugs as evidence of efficacy.

Thus, the Supreme Court affirmed that efficacy data submitted for a drug license must wme

bridging studies. The Panel, in relying on the clinicd data of-a d.if%rent vaccine (a Merck,

Sharp & Dohme product used in the ‘SBrachman Study"), ignored the licensing requirements

established by Congress and Supreme Court precedent.

4

announcement of procedures for review of safety, effectiveness, and labeling published on 18

August 1972 (37 FR 16679): "The importance to the American Pubiic of sufe and effective

vaccines.. cannot be underst&ted?

Dr. M. Pittman, the Ad Hoc Committee Chair, addressed the lack of data from DBS J.ND 180 in

three separate 1969 memorandums:

"The lack of cases of anthrax in an uncontrolledpoptilation of approximate& 600

persons in the TazIadega mill can hardly be accepted as scienttfic evidence for

efficacy of the vaccine. " "‘It was also noted that clinical &a establishing eficacy

of the product hod not been submitted... " "The fact thu# the vaccine has been

used in a numbc., of textile milks and thut there has been no case of anthrax was

substantive but not conclusive evidence of efficacy. " [Exhibits 1, 2, 3]

Even the Panel criticized studies such as that used in the licensure of AVA6 Yet the Panel

determined that AVA should be placed in Category I. This platiment in Category I was not

without reservations or limitations as spelled out in the generic and’specific product reviews. For

example:

Yt is recommend&dfor individuals in industrial settings who cume in contact with

meal, as .well as &b.orqtoqv workers involved in ongoing. studies on the : I

organism. "

6 In their Generic Statement on Requirements for ai WeU~Controlled Field Triaf, the Panel, in

describing the determination of safety and efficacy, writes: "2%e’j%uI cznd most important step

is the field trial, when a large num.ber of jxe&mabiy nonimmune humans is inocukzted and ihe

inci&nce of the disease among yaccjnes and control subjects is compared" They discounted

historical controls as no longer acceptable science. The decline in disease frequency after

vaccination could not be interpreted as resulting from vaccination, because the changes may be

due to natural disease cycles or changing socioeconomic conditions, or other conditions where

the disease occurred. Likewise, the Panel considered the c&nparisons of the ;Frequency of

disease in those who do and do not volunteer for the study as urxkeptable. Based on a review

of the Progress Reports for DBS IND 180, this study was strictly for the purpose of establishing

the safety of the vaccine. Vaccination was a condition of empIoyment at the various mills;

therefore one hundred percent participated. There were no ‘"coritrol groups". A review of the

Bra&man Study reveals that a large percentage of the empioyees at the various mills were non-

volunteers, yet their numbers were considered in the effectiveness calculations. Additionally,

the Bra&man Study had no means to identify the strain of, or d&ermine, regulate, or calculate

the exposure to either the vaccinated or the control group of BacNus anthracis. Neither DBS

IND 180 nor the Bra&man Study met the definition of a well-controlled field trial.

5

its very limited distribution and the benefit-to-risk &$XWS of occupational

exposure in those individuals for whom it is-indicated " *

"T’he Panel believes that there is sq@cient evidencie to conclude that anthrax

vaccine is safe and effective under the limited circums&nces for which this

vaccine is empbyed. "

"Z5is vaccine is recommended for a limited high-risk of exposure population

along with other industrial safety measures designed to minimize contact with

potentially con&minuted material. The benefit-to-risk assessment is satisfactory

wfder the prevailing circtcmstances for use. "

The Panel clearly intended to knit the use of this vaccine to those employed in industrial and

laboratory settings. It weighed the absence of valid data with the intended population, i.e.

industrial and laboratory workers, and conctuded that the benefit outweighed the risk for this

specific group of people. Nevertheless, the fact remains that the Panel ignored the C.F.R. as well

as the Commissioners requirements in placing AVA in Category I.

Additionally, the specific product review revealed that AVA was improperly labeled.

‘The labeling seems @tiera& adequate; Khere, is a conflict, hq.er, with

addhionul S&I&W& jar anthrax vabine. Se&on ‘620.2?(a) defines a total

primary &rt~nizing dose as 3 single: doses of 0.5 mL. 77ze labeling defines

primary immunizxztion as 6 abses... "

A review of late-1960’s Annual. Progress Reports on the licensing study indicates that the

primary dosing schedule was three doses.7 FDA recognized the discrepancy and recommended

that the labeling be changed. The additional standards; published in the Code of Federal

Regulations, were the standard approved by FDA FDA; noted that the labeling indicated six

doses where the additional standards indicated three doses. ThePanel concluded: "Labe1tig

revisions in accordance with this Report are recommended? TIie labeling has never been

changed, and the FDA has not commented on or corrected this glaring discrepancy. Although

the validity of the safety and efficacy evidence is circumspect, the mislabeled status of AVA is

clear and warrants a Category XI designation.

:

’ NCDC Annual Progress Report to the Director, Division of’Biologic Standards, 1 October

1968.

6

A Category III designation is given to those biological produ& ‘determined by the Panel not to

fall within either Category I or II on the basis of the Panel’s con&&on that the available data are

insufficient to class@ such biological products, and for which further testing is therefore

required. Those biological products in Category III for which;suspension of the product licenses

pending submission of additional data are recommended are designated as Category IIIB. The

recommendation for Category IIIB is based on the assessment of the present evidence of safety

and eEectiveness of the product.

It is possible that the &and considered the extremely limited use of the vaccine between

licensure in 1970 and 1981, when the Panel submitted its final report. If this were the case, then a

small amount of evidence of safety may have been available to the Panel in addition to the safety

data from DBS IND 180. However, no ef&acy data was ever presented pre-lieensure and none

was gathered post licensure. Upon a cursory review of the data, Category IIIl3 would seem to be

the logical placement of AVA by the Panel The available data suggest that the vaccine is safe

when weighed against the risk of exposure in an industrial or laboratory setting, yet there is no

data on the effectiveness. The 1985 Specific Product Review reafGrmed this fact:

eflcucy against inhalation anthrax is not well &cun+ented ‘I

Despite the fail* of the ?nanufacturer to meet the regulatory standard for licensure of proven

efficacy in humans required by the 1962 Harris-Kefauver amendment, the FDA categorized the

anthrax vaccine as a CatFgory I biologic. This meant that they found the vaccine to be "safe,

effective, and not misbranded."

The safety and efficacy standards used by the Panel were referenced in the review’s introduction:

not cause the disease against which it is dire&$ and that the occurrence of

reactions, both Iocal and general, must be with!& ackeptable limits. Efsicacy

new vaccine. "

7

The foregoing discussion shows these standards were not’ attained. The 198.5 review

recommending that anthrax vaccine be considered as a Critegory I biologic clearly did not

anticipate the use of the vaccine for a mass immunization progism for two million U.S. military

Servicemembers by the Department of Defense or an even larger number of the general

population.

When the FDA was asked why a final rule has not been published Mr. Mark Elengold, the

Deputy Diiector of the FDA Center for Biologic Evaluation and &&arch, responded in writing:

"FDA has not issued a$nul order regarding the findings of the panel regarding

the anthrr, : vaccine. The prior@ has been to issue dbetiments, such as license

revocations, for products not placed in Cutegory I. Since the panel did not

propose further action with regard to the arathrMc vuccine, based on the pant9

However, a Fii Order is required for the placement of AVA as a Category I, II, or III biologic

product. As first published in the Federal Register:

publish in the Federal Register a @aI order 0~ the m&ers covered in the

proposed or&r. The final order shall become eflective as spe@ed in the order. ‘7

: . . . . ‘. .

The Pa& submit&d its report and review of AVA t&e&y years a& The Proposed Rule was

published 16 years ago. To date, no action has been taken by FDA to promulgate a &al order. In

- the mean time the manufacturer has not produced any humati ef5cacy data & requested. by the .

Chair of the license review committee, the vaccine remains mislabeled, the intended population

of at risk workers has virtually disappeared, and the manufacturer’ has sold millions of doses to

an agency that is using the product in an unapproved manner for an unapproved use.

Placing the AVA in Category II is warran&xl because: I) ,there is no evidence of efficacy of this

particular vaccine, 2) the safety data was gathered in a manner inconsistent with the requirements

of a well-controlled field trial, and 3) the product is mislabeled.’ Placing the AVA in Category

IIIb could be warranted as we& recommending license revoc&ion on the basis of a panel’s

8 Mark Elengold, FDA Deputy Director of the Center for Biologic Evaluation and Research,

April 6,2001, email correspondence.

8

assessment of the potential risks and benefits. Like other biologic products under MDPH license

#99, i.e., Diphtheria and Tetanus Toxoids Adsorbed, AVA must be reviewed and categorized

properly. Ultimately, the license for AVA should be recommended for revocation due to lack of

proper safety and efficacy data submissions, similar to the notice published on 29 May 2001 in

the Federal Register for these other MDPH products.

Therefore, we respectfully request that you take the following action. Finalize the proposed rule

with the following specific changes in the language detailed in Federal Register, Vol. 50, No.

240, Friday, December 13, 1985, page 5 1059, Specific Product Review:

Item 3. Analysis - a. Efficacy - (2) Human. Delete the entire paragraph.

Replace with:

"This product does not meet Federal req-uiremnts. The vaccine manufactured by

the Michigm Department of Public Health has not been employed in a controlled

filed trial. A similar vaccine prepared by Merck, Sharp & Dohme and employed

in a placebo-controlled field trial is corrobortitive e~idetit% of e#cacy against

cutaneous anthrax, but does not meet the Federal Fo& Drug and Cosmetic Act

requirement of substantial evidence. A review’of the Center for Disease Control

data pertinent to this pro&t for the period 1962 to 1974’32 irr risk industrial

. wor&rs in&cates that w. cases have occur@ in filly ‘hh&zized .workers. Skis .

decline in disease is substantive but not conclusive evi&nce of eficacy and not

Requirements for A W&Contr&?d FieM Th.i&). No mecinin&uI amessrpent of its

value against cutaneous or i&al&ion anthrax&possible. "

Item 4. Critique. Delete the entire paragraph. ,.

Replace with:

"This product has not met the Federal Food, Drug and Cosmetic Act requirement

of d&nonstrating substantial evidence of e&z&. litle safety requirements appear

to have been met. The product is currently mislkrlieled

Item 5. Recommendations. Delete the entire paragraph.

Replace with

9

"l;cle panel recommends that this product be placed in Categov II and that the

qpropriate license(s) be revoked "

Or in the alternative, replace with:

"The panel recommends that this prod&t be placed in Category lX3 and that the

appropriate license@) be suspended while the manufacturer completes the studies

A proper recategorization of anthrax vaccine adsorbed as Category XI, and the revocation of

BioPort’s license in aGcordance with 21 C.F.R. 6 130.12 and the Food, Drug and Cosmetics Act

is the decisive regulatory action that will ‘prutect the public health. "

INFORh4ATION KNOWN WHICH IS UNFAVOtiLE TO THE PETITION:

To our knowledge, no exceptions to the safety, efficacy and labeling requirements of the Federal

Food, Drug and Cosmetic Act are allowed.

._ .,

10

(2) Declare as adulterated all stockpiles of anthrax vaccine adk$bed in the possession of BioPort

Corporation and all doses in private. public. U.S. or foreign povetkment uossession. .

"Enforcement of current good manufacturing practices (cG&iPs), as pursued by the Food and

Drug Administration (FDA) over the past nearly ; forty years, originated with the 1962

amendment to the Federal Food, Drug and Cosmetic Act (FD&C Act). Under these amendments,

a drug was deemed to be adulterated if ‘the methods used in, or the facilities or controls used for,

its manutkctut-e, processing, packing, or holding do not conf’orm to or are not operated or

administered in conformity with current good manufacturing prktice’ to assure that the drug is

safe and has the identity and strength and meets the quality and purity characteristics which it is

represented to possess (see 21 USC. 6 351(a)(2)(B)). Judicial opinions interpreting the CGA@ *

provision of the FD&C Act have supported the FDA’s view that the 1962 amendments

significantly expanded the agency’s authority by eliminating the requirement that the agency

must demonstrate, through sampling and testing, that drugs actually are contaminated or

deficient in some way. As the court in United States v. Be&M&r Laboratories Inc. 284 F. Supp.

875 (E.D.N.Y. 1968), put it:

.

The 1962 amendments were intended to streqthen and *broa&n the [ED&cl

Act...The purpose of [21 U.S.C.] $ 351i(a)(2)@) was to attack commerce in

unsafe and unreliable’ tigs in ‘its incipien@ by gi+&g the Food .Lnzd Drug

Administralion...aaUitional authoriq to require, that so&td~etho&, facilities and

controls be used in all phases of drug mapnffbcttuing and distribution. I;hus,

the &ug actually is deficient in scime respect.

The courts also have upheld the drug cGMP regulations against tihahenges that they W&e not

specific and could not be enforced evenhandedly. For example, the. eel-Mm court said that the

regulations apply to "an industry where manufacturing practices are in a state of constant

change" and where there are "thousands of widely dif%ring and complex products tihich are

processed in a myriad of establishments under infinite& different circumstances." Nevertheless,

the courts have found that the regulations provide a sufficiently well-defined standard against

which a company’s conduct can be measured. In fact, the .court in Be&Mar viewed the

regulations as "intended to set minimum requirements."g

9 Arthur Levine. FDA Enforcement Manual. Tab 1600. Fg 7. Thompson Publishing Group

11

a) All anthrax vaccine adsorbed (AVA) produced since 1991 is adulterated by virtue of its’

having been produced using unapproved procedures in uepproved equipment.

MDPH" produced AVA sporadically throughout the 1970’s and 1980’s using the same

equipment and the same manufacturing process that had produced AVA for DBS IND 180. The

Division of Biologic Standards approved this equipment and the manufacturing process by

awarding the AVA license in 1970." MDPH’s need for large-scale production of AVA came as

the result of a 1988 contract with the U.S. Army.12 Until the 1988 contract with DOD, production

of AVA was infrequent, a batch being produced every three to four years, the largest being 7500

doses. The approved equipment consisted of one production line that MDPH alternately used for

other vaccine products. The 1988 contract with DOD required MDPH to drastically increase

production capacity.

MDPH originally had one fermentation train built around a 10%liter gltiss-lined fermentor. This

f&me&&ion train had a maximum capacity of 20,000 doses p&- prbduction run and required

many weeks to complete a batch and ready the equipment for the next production run. In order to

meet the production requirements of the 1988 contract, two stainless steel fermentation trains

were added in lq90. . ._

The new fermentation trains used equipment different t&m that approved for the original facility.

MDPH was &ware of the need to gain FDA approval for this new equipment and applied for &.n

amendment to their Establishme@ ‘License Application @LA) in December 1990, after the first

two fermentation trains had been installed. The FDA approved this amendment to the ELA in

lo BioPort Corporation is the current manufacturer and license holder for anthrax vaccine

adsorbed (AVA). The original license holder was the: Michigti Department of Public Health

(MDPH). MDPIX was partially privatized in 1996 with the sale of its biologics division to the

Michigan Biologic Product Institute (MBPI). For the purposes of this petition BioPort, MDPH

and MBPI are the same entity.

I1 The equipment and the manufacturing process are w&l1 described in U.S. Patent # 3,208,909.

(Puziss, M. Wright, GG. Anaerobic Process for ?rodu&$ bf a Gel-adsorbed Anthrax

Immunization Antigen. United States Patent OBice Record. September 28, 1965. page 1471).

I2 MDPH agreed to produce 300,000 doses for the De$artment 6f Defense (DOD) in 1988. The

DOD entered into three additional AVA contracts with the ma@ufacturer through 1998. These

four DOD contracts with MDPH totaled several millioq doses.

12

1993. I3 The vaccine that came off each fermentation train was considered a sublot. Sublots from

the fermentors were mixed together to form the final anthrax vaccine or FAV. Anthrax vaccine

distributed with a designation Lot FAV--- prior to the 1993 ELA amendment approval is

adulterated. Two additional stainless steel fermentation trains were subsequently added in early

1993, replacing the original glass-lined fermentation equipment. These four stainless steel

fermentation trains produced AVA until the facility ceased operation in January 1998. No ELA

amendment or these two additional fermentation trains was ever sought or made.14 The vaccine

made and distributed from these fermentation trains is likewise adulterated.

.

l3 In a 9 July 1990 telephone conversation FDA employee,RebFca Devine informed Dr. Myers,

Responsible Head for MDPW, that FD’A.considered the additional fermentation trains a ‘?najor"

change. An amendment to the establishment license was required. Bxhibit 4) Ms. Devine was

be submitted for any change in the equipment that has a substantial potential to have an adverse

a%& on the identity, strength, quality, purity or potency of the product as it may relate to the

safety and effectiveness of the prod&. 0 601.12 (b) requires approval e to distribution of

any product affected by such change. This ELA amendment application did not inform FDA

that the entire production proTss was changed, 6om. the . seed fermenters to the bulk

ferme&ors, to. the filtrati&. &d sterilization pr~c&s; to the ‘&&m&ream" processes and

equipment, i.e. centrifuge, bottling and ming. It merely stated that they would be adding two

additional stainless steel fermentation trains to the facility.

The filters were. changed. from glass sintered to tow-protein-binding nylon membranes. The

sterilization process changed because the original method ofXIa&’ heating the medium in an

autoclave to 120" C did not ensure complete inactiv@ion of the media. The new method of

sterilization used a nylon membrane to filter the mtiia. We are unaware of any attempt by

MDPH to tiorm FDA of these changes or to gain approval of them through ELA amendments.

The equipment changes and process changes are discussed in detail in a civil suit brought by

three former MDPII employees against the state of Michigan’ Please reference American

Arbitration Association Case No. ‘54‘ 390 01376 98 iCompensa&iin for Inventions De&loped

During Employment An additional report of these equipment and process changes are

challenge in guinea-pigs" by Bruce E. Ivins, et al in Vaccine, voi: 1’2, no: 10. pp 872-874,1994.

Additionally, MDPH did not seek to amend their Product License Amendment (PLA) for any

of these changes.

I4 Mr. A. Luttrell (BioPort Vice President for Quality AssuranceQuality Control) wrote Mr. J.

Eltermann from the Center for Biologics Evaluation and ’ I&%&h on 14 January 1999

following up on a conference call between Ms. F. Kaltovich, Mr. Eltermann and himself This

letter confirms that FDA had not approved the ‘two fermerittirtion trains installed in 1993.

[Exhibit S]

13

b) The manufacturer of AVA has been found to be in violation of current Good

Manufacturing Practice during every FDA inspection since 1988. ’

The Drug Industry Act of 1962 refined the concept of adulteration by amending section

501(a)(2) of the Federal Food, Drug and Cosmetic Act (the A&. A drug would be deemed

"‘adulterated" and therefore subject to multiple seizures if it was ‘made, processed, packaged, or

held under methods, facilities, or controls that did not confDrm to current good manufacturing

practice (CGMP). The Secretary would be authorized to issue interpretative regulations as to

what constitutes CGMP, and these regulations would be prima facie evidence in any proceeding

under this section of the Act.

FDA has regularly inspected the vaccine production facility. These inspections document a

pattern of non-compliance with CGMP. Every inspection resulted in discrepancies ranging from

unsa&aq conditions and unapproved procedures to contaminated products, and changing

equipment and products without approval. The following observations relating to anthrax

vaccine production were made during inspections conducted in the following years:

1988.

biological prodkcts. "

as needed was not indkated "

1990.

there was: (A)Paint peeling from the walk @).&xposkd fikhtjrixhcres (C)%racked

ceiling (D)Ekposed raceways (E)Dirt & filth & d&t on overhead pipes

(F)Cluttered work space. "

26 & 27. ‘)

1992.

"Changes in the manufacturing metho& for... were not submitted as amendments

to the product license application prior to releasing the material for

distribution... "

‘Wo SOP [stanakrd operating procedure] exists to describe procedures for

handling potentially infectious mate riai.. . "

1993.

"There are insu$kient personnel to assure comp&ance with current GMP

reguiations, e.g., failure to report changes in manufacturing, failure to maintain

c&brdion records adequately, faiture to adequaiely vaklate equipment used in

the formulation or testing of product. "

1994.

"‘There are in.su$icient personnel to assure compliance with current GW

regulations, e.g., failure to maintain calibration recor& adequately, failure to

maintain environmental controls akquately in that production area temperutures

were above gOoF, andfajiure to submit changes tb Cl3ER. ‘*

"There is no annual review of production batch recor& [anthrax]. "

.

"Raw material [anth&x vaccine materials] stored in an unapproved warehouse,

building (redacted) i.e., no ELA [establishment license qplication] supplement

has been submittedfor this area. "

19!EP

"the company did not inform FDA of the procedural and equipment change

during the production of., . "

‘ffacilities and equipment were not adequate. "

"SOP ‘s did not exist for many procedures. "

I5 These observations were made on other portions of the MDPH facility. They are illustrative of

the overall inability of MDPH to manufacture regulated biol&jiti products in compliance with

"came under military inspection." pxhibit 61

15

"SOP’s were incomplete or incorrect. "

"SOP 3 were not adhered to. "

"Frequent contamination during vaccine manufacturing was documented l&t not

investigated. *’

1996. I6

‘The firm had not completed clewzing validation s&&es for routine cleaning

procedures on multi-use equipment. "

"Vu&&ion studies to demonstrate microbial retention and com~tibility have not

been condktedfor sterilizing $iters . . . "

"?here was condensate hipping onto open (redacted) tanks... I’

"There was no procedure for clean-up of live rabies virus spiils.. . "

1997.

CBER issues a "Notice of Intent to Revoke If citation to Michig~ Biologic

Prod&s Institute on I1 March 1997. The Army respond bjt Sending iiz a team to

ass&~t the ,manufactarer develop a. "Strategic compliance plti " .

1998.

"nte’mpro~ss for Anthrax V&&te iskot va&&&ed."

"Thete are no written procedures , including specz&ations, fir the examination,

rejection, and diqwsition of Anthrax and Rabies, "

"Prior to August 1997, the (redacted) Jilters used for harvest of Anthrax vaccine

were neither validated nor integr@ tested. T&is+ filter is the only sterile filtration

step in the Anthrax manqfacturing process. "

"There is no written justification for re&ting lots of Anthrax vaccine that have

expired "

‘The firm does not trend multipie contaknations With microorganisms in

sublots. "

I6 Ibid.

16

In addition to these observations, F’DA issued a Warning Letter to MDPH on 3 1 August 1995. A

compliance follow-up inspection was conducted in 1994, This inspection resulted in a letter to

MDPH of Notice of Intent to Revoke their license (11 March 199’7). The 1998 inspection was

also a compliance follow-up inspection as a result of the ‘violative 1996 inspection. As a result of

the 1998 inspection, MBPI "voluntarily" quarantined 11 lots of AVA. The failure of FDA to

recall the quarantined vaccine resulted in some of it being shipped to the Canadian military and

being used on their Servicemembers. I7 The conditions under which AVA has been manufactured

as evidenced by continued violative inspections render that AVA adulterated and therefore a

prohibited act. l8

. .

l7 Ann Rees, "Their Dangerous Dose", The Province [Vancouver, Canada], 25 Juu 2000

‘* As stated previously, failure to cornply with CGMI! renders the drug product adulterated. 21

U.S.C. 0 331 states: "The following acts and the, causing thereof are prohibited: (3) The

17

c) AVA has been redated without an FDA approved procedure and has been labeled

improperly.

The large quantities generated by the DOD contracts required stockpiling of vaccine. The

manufacturer developed a program to extend the shelf life of AVA through redating.r9 Numerous

Lots were redated without FDA approval.20 Some of this AVA was labeled with the original Lot

number. The Lot extension approval letters from FDA to the manufacturer indicated the new Lot

number to be used with the particular Lots. The manufacturer failed to correctly indicate the

approved Lot number on the final product containers (vials) or the packagep21 The AVA labeled

under these conditions is considered misbranded, and therefore adulterated.

ig Drug products that have an expiration date are required to have an approved stabiity testing

proe (21 C.F.R 8 21 I. 137 and 21 I. 166). This requirement was introdticed in revisions to

the Current Good M&nufacturing Practices for Finished Pharmaceuticals in 1979. According to

the compliance follow-up inspection conducted in 1998, MDPH did not have stability program

until 1997. This program received several observations. (see observation #5, page 4 of Form

FDA 483 dated 4-20 1998).

2o MDPH did one of two things. For Lots FAV 008 through FAV016 MPDH removed the labels

from the &al conta&rs by soaking the vials in aleohol and scrapping the labels off with

razors. There was little to no attempt to recun& the vials with the original Lot. This procedure

w& un&proved. Other Lots were ‘redated by extendmg the shelf life without justification and

in the absence of an approved procedure. Some of these Lots had exceeded their shelf life prior

to being redated. (See observation 4. on page 4 of Form FDA 483 dated 4-20 February 1998.)

This redated vaccine was subsequently distributed to MDPH customers. ..

21 CAMP defines "Lot number" as "my distinctive combination of Zetter, numbers, or &boZs,

or any combination of ‘them, jkom which the complete history of the manufacture, processing,

packing, holding, and distribution of a batch or lot of atsUg pro&t or other material can be

determined" (21 C.F.R. 8 210.3 (11)). 21 C.F.R 6 201.18 requires that the lot number on the

label must be capable of yielding the complete manufacturing history of the package. An

incorrect lot number may be regarded as causing the article to be misbranded. The Federal

Food, Drug and Cosmetic Act (the Act) provides a definition of a misbranded drug: "A drug or

&W+X shall be deemed to be m~sbrandkd - (a) Fake ‘or n.Mead’ng label. Ifits labeling is fake

or miskx&ng in any ~kz&r." The Act %rther states: ‘Y&e fokwing acts and the causing

thereof are prohibited: (a) 17te introduction or delivery for intro&&on into ‘interstbte

commerce of any food dnrg, device, or cosmetic thai is adulterated or misbranded.."

Additionally, 2 1 C.F.R. 0 60 1.12 states in part that: ‘"an applicqnt shall inform Food and Drug

Administration FDA) about each change in the product, prodiztlon process, qualify controis,

equipment, facilities, reqoonsibie personnel, or labeling, established in the approved license."

Interestingly, after this mislabeling was brought to the attentio’n of DOD and FDA officials in

1999, subsequent Lots have been correctly labeled. I

18

d) The equipment used to manufacture AVA has not been used exclusively for the production

of AVA.

21 C.F.R. Q 600.1 l(3) Work with spore-forming organ&sms spells out one requirement to the

manu&turer for assuring the safety and purity of biologic products. This section states in part:

"All vessels, apparutus and equipment used for spore-beuring microorganisms

shall be permanently ident@ed cM(;E reserved exclusively for use with those

organisms.

The manufacturer has at times used the equipment approved by the FDA for the manufacture of

.2VA to manufacture other biologic productsz2 When other quality assurance provisions :n

vaccine production are lacking, as has been repeatedly documented with AVA, a true safety

hazard exists. The CGMP provisions of 21 C.F.R apply equally to section 600. As it may be

impossible to determine when and to what extent t@s permanently identified and reserved

equipment was used in the production of other biologic products, all AVA must be considered

adulterated.

It is clear that the AVA produced since the 1990 time frame is adulterated within the statutory

provisions of the Federal Food,. I+ug +nd Cosme& Act. The. Agency has promulgated .

substantive rules based on the Act, with which to enforce the spirit and the intent of the Act. The

many reasons rendering AVA adulterated likewise meet the regulatory threshold of adulteration.

Enforcement of the current good manufacturing practices is the Food and Drug Administrations

most important regulatory program for marketed products. 21 C.F.R. 5 210.1(b) states:

"The fuihre IO comply with any regulation set forth in this @art and in parts 211

through 226 of this chupfer in the mantcfacture, processing, packing, or holding of

22 A Trip Report to the commander of USAMRrm (U.S. Army Research Institute for Infectious

Disease) indicates that the ‘cdedicated" anthrax fermentor has been used for botulinum toxoid

for animal use between anthrax runs. This report krther indicates that the new equipment (see

footnote 13) will zlrternately produce botulmum toxoid and tetanus toxoid. The second

indication that the dedicated anthrax equipment was being used for other products is found in

correspondence between MDPII and the U.S. Army Contracting Officer (and others) regarding

the unapproved use of government equipment (feqnentation strains) for products not under

contract. In this instance the equipment was being used to produce botulinurn toxoid for animal

use. Included in this second set of correspondence is a reqt@t by the manufacturer to be

allowed to continue to use this equipment for alternative purposes in the future. Exhibit 7, S’j

19

act and such drug, as well as the person who is resp&siMe for the failure to

comply, shall be subject to reguiato~ action. "

We. therefore respectfully request you declare all sto+piles of anthrax vaccine adsorbed in the

possession of BioPoxt Corporation, and all doses in private, public, U.S. or foreign government

possession, "adulterated" in accordance with the above C-FIR tid 21 U.S,C. 501(a)(2)(B).

INFORMATION KNOWN WHICH IS UNFAVOIMBLE TO THE PETITION:

We are unaware of any provisions in the Federal Food, Dnjg and Cosmetic Act that allow such a

product to continue in interstate commerce or be placed in interstate commerce, nor of any acts

of discretion taken that waive the provisions of the Act regar* adulterated products.

20

(3) Enforce FDA Comoliance Policv Guide Section 400.200 C~psi~ent Application of CGMP

Determinations KPG 7132.1% with resnect to anthrax vaccine a&orbed (license #1260] , . ,

Compliance Policy Guides explain the Food and Drug Administration (FDA) policy on

regulatory issues reiated to FDA laws or regulations. They advise compliance staffs as to the

Agency’s standards and procedures to be applied when d~~~~ning industry compliance.

Recently, FDA has assumed the additional role of assuring drug quality involving good

manufacturing practice (CGMP) for the Government-Wide ^Qualitjr Assurance Programs for drug

purchase contract by the Department of Defense. Decisions regarding compliance are based upon

inspection of the facilities, and the compliance history Of the firm. FDA Compliance Policy

Guides Manual, Sec. 400.200 Consistent Application of CGMP Det&minations (CPG 7132.12)

states:

‘%G-Mp deJicienc&s mpporting a rt@atory q@un u/s? support d&s&as

regarding non-approval of drug marketing i+plicatioiw;’ gOverntient purchasing

contracts, cam&&es for MAC, etc. Therefore, ihe issuance of a warning letter or

initiation of other regulatory action based upon, CGA@ &$ciencies must be

accompanied ‘by disapproval of any pending drug marketing application, or

government contract for a product pr&ced under the me dq7ciencie.x "

‘JYhe l?DA.issued a Wm Letter to the anthrax va@.ne manufactwer on .pusUst 3.1, 1995 for .’

an inspection conducted from 24 April to5 May 1995. Another violative inspection took place

18 thrqugh 27 November 1996 resulting b a Notice of Intent to Revoke 1etteF issued on March .

11, 1997.23 An FDA follow-up inspection conducted between 4 through 20 February 1998 found

the previous deficiencies had not been corrected. All three inspections document CGMP

violations.

On September 3, 1998, the FDA informed the new owner of the ~@IKIX vaccine manufacturing

f&.&y, BioPort Corporation, that "the Notice of Intent to. Revoke issued to MBPI on M’ch II,

1997 will efsectively trans$er with the issuance of the license to BioPort and will remain in effect

until all compliance issues have been sati@actoriiy resolved " These regulatory actions, until

corrected, made the manuf&urer subject to the Compliance Policy Guide restrictions found in

CPG 7132.12.

23 http://www.fda.gov/cber/iiosheet~mieh-infhtm

The deficiencies in the Warning Letter, inspections, and the Notice of Intent to Revoke have

nevex been corrected, as evidenced by the failure of the manufz#urer to pass FDA’s repeated

inspections after it ceased production in January 1998.24 Therefore, FDA was required by this

long-standing (198 1) policy to:

other appropriate government agency that all government contracts "musf’ be disapproved

for the manufacture, storage, bottling, or shipment across State lines of the anthrax vaccine

adsorbed until the manufacturing deficiencies are corrected.

2. Reject the investigational new drug @ID) application submitted by the anthrax vaccine

manufacturer, and prepared by the U.S. Army, on September 20, 1996 (IND 6847).25f6

24 Violative inspections occurred in October 1998, November 1999 and October 2000.

25 FDA accepted an investigational new drug (IND) application to use the anthrax vaccine for the

specific indication of "inhalation anthrax" (IND 6847) dated September 2@‘, 1996. Following

the departure of FDA Commissioner David Kessler, the Assistant Secretary of Defense for

Health A&.& Dr. Stephen Joseph, wrote to Acting Le$d Deputy Commissioner Dr. Michael

Friedman. Dr. Joqeph asserted that DOD had "long .intezpret@" that the vaccine was, e?ective

fo~‘in.bal&ion anthrax. His ‘a&&i& ignored. the IND ap&ication prep&d by the Army for the

anthrax vaccine manufacturer just six months earl&. Lead Deputy Commissioner Dr.

Friedman’s response, on March 13, 1997, abandoned the FDA’s -date to enforce the Food,

Drug, and Cosmetic Act% statutory requirements of proven safety and efficacy in humans for

specific applied uses, On 13 Mar 1997 FDA Lead Commissioner Michael Friedman wrote to

ASDIHealth AE&rs .Stephen Joseph - the language spqifically said the DOD’s use for the

vaccine, ‘"was not inconsistent" with the product’s license. As the GAO noted in House

Congressional Hearing on 11 October 2000, this also did not maintain that the use was

"consistent" with the AVA label or license. Dr. Friedman acknowledged the lack of legally

required human efficacy data to support such a decisiorx "...while there is a paucity of &a

subsequently been submitted to support Dr. Friedman’s decision. 21 C.F.R $ 10.85 (k) states:

"A statement made or advice provided by an FDA employee constitutes an advisory opinion

only if it is issued in writing under this section. A statement or advice given by an FDA

communication that represents the best judgment of that emyloyee at that time but does not

constitute an advisory opinion, does not necessarily represent the formaI position of FDA, and

does not bind or oth,erkse obligate or commit the agency to the viavs eqxessed "

Dr. Friedman’s memo of 13 March 1997 does not comply with the requirements of 21 C.F.R. 0

10.85, and therefore is an informal communication versus an advisory opinion by the FDA.

22

Anthrax vaccine adsorbed produced under deficient CGMP conditions is well documented."

We respectfully request that you order all current and/or pendini government contracts and drug

applications for anthrax vaccine adsorbed be disapprovti and the appropriate government

agencies informed in accordance with Sec. 400.200 Consistent Application of CGMP

Determinations (CPG 7132.12).

INFORMATION KNOWN WHICH IS UNFAVORABLE TO m,,PETITION:

There is no evidence through FDA Freedom of Information Act discovery that documel&:s any

regulatory waivers or acts of discretion concerning this government pohy.

26 IND 6847 should also be terminated in accordance with 21 C.F,R. $3 12.44 ef seq whereby an

processing, and pack&g of the investigational drug are ,ina$epate to establish and maintain

27 Any assertion that previous inspections do not apply to the anthrax vaccine manufacturing

23

The Congress, through the Secretary of Health and Human Services and the Federal Food, Drug

and Cosmetic Act, has given the Commissioner of Food and Drugs broad regulatory authority to

ensure that the drugs the public receives are safe, effective; and not misbranded. It is incumbent

upon the Commissioner to enforce the regulations such that the- public health is the primary

consideration in any action. The Federal Food, Drug and Cosmetic Act (the Act) addresses the

need to suspend, withdraw and revoke the licenses of those, drugs whose safety, efficacy or

labeling is in doubt.

a) The anthrax vaccine license was improperly issued

In 1906 Congress passed the Federal Food and Drugs Act to regulate drugs generally. In 1938,

Congress enacted the Federa! Food, Drug and Cosmetic Act (t&Act) to require, inter aha, that

all drugs marketed after 1938 be "stie". Any drug marketed after 1938 must have a license

known as an approved New Drug Application or be generally recognized as safe.

The Drug Industry Act of 1962 (often referred to as the Harris-.Ref$uver Amendment to the Act)

established a legal requirement’ for a demonstration of ef&ac’y in licensed drugs. To support a

finding of efficacy, the law required yinvestigations" that resulted in ‘Substantial evidence" of

. ef!Iicacy obtained through "‘adequate and well cornroIled investigations.". A claim of substantial

evidence could be rejected if it were found that the investigations were not adequate, were not

well controlled, or had not been conducted by experts qua@ied to evaluate the drug. The various

holders of the AVA license have yet to conduct a single adequate and well-controlled

investigation that demonstrates efficacy in humans. There ,is no substantial evidence of efficacy

with this vaccine. The Act’s requirement to demonstrate e@cacy was never met.

In May 1965, the U.S. Army contracted with the Department of Health, Education, and

Welfare’s Public Health Service Communicable Disease .Ce+er for;+ ._

"‘Development of a contract to obtain a rea& sulgply of anthrax vaccine for use

in industries where immunizqtion is important a~&$0 s&date a pharmaceutical

compny to prepare a protocol and a batch of vaccine for licensing by the PHS .

Division of Biologic Stmrdards. " IExhibit 91

24

A patent for a process to manufacture an anthrax ,vaccine w@ filed on May 19, 1965 and

awarded on September 28, 1965. An Investigational. New Drug @ND) application was approved

in January 1966 (DBS IND-180). The Michigan Department of Public Health (MDPH)

submitted a Product License application in July 1967 (Ref. # 67-70). The investigational study

was conducted in goat hair processing mills in ,Talladega. Correspondence between the

investigators conducting the study and the National Institutes of Health indicate problems with

the study. As an example, in January 1968 the study’s Acting Chief, Dr. Philip Coleman, wrote

"As t0 the efficacy of the vaccine, we have no real method of determining the

protection a~rd&i. " [Exhibit IO]

A Feb 6 February 1969 memorandum Tom the licensing oversight committee to Dr. Margaret

Pittman, of Department of Health, Education, and Welfare, critiques the study efforts by stating:

"The lack of cases of anthrax in an uncontro&dpoplation of approximately 600

persons in the Tall&ga miil can hardly be accepted as scientific evidence for

ef#cqy of the vaccine. " wxhibit l]

On January 22, 1969 Dr. U. Pentti Kokko, Director, Laboratory Division, National

Communicable Disease Center wrote Dr. Roderigk: Murray, Director, Division of Biologics .

Standards, Najiow Institute of Flea& Dr. Kokko st&qy ;

product &s was done by Dr. Phillip Bra&man ting the Merck, Sharp and Dohme

product. " pklliiit 111

On February ‘10, 1969, ad hoc‘ committee head Dr. Wgaret P&i&n confirmed the inadequacy

of the Talladega efficacy study of the licensed vaccine in a memorandum to Dr. Sam Gibson,

Director of Licenses and Inspections, concerning the a&hrax license application:

"On June 21, 196% the Ad Hoc Committee reqommer+e~‘t@t license be granted

following pub&a&m of A&tior& Stan&&: Anthrax V&%ine. It was noted also

that &a be requestedfiom NCDC . . . it is recommen&d that license be granted

and that NCDC @ND-180) be requested to obtain a&a with a view to determine

human e$?cacy of Hie prod&t. "

Regardless, Dr. Pittman recommended licensure of the.vaccine but wrote:

25

‘Is was noted also that clinical &ta est@ii~h@g eflcacy of the product had not

been submitted and that d&a be requestedfrom NCDC [National Commznticable

Disease Center]. "

Dr. Pittman supported licensure of the vaccine despite her acknowledgement that the legal

requirement of a valid human efficacy study had not b&n met. Instead, she based her decision on

guinea pig tests, which were, and still are, irrelevant to the standards required for product

licensure. Dr. Pittman a@rmed this in another memorandum $9, DIk, Gibson on-, September 30,

1969:

"The recent information submitted by NCDC ayld Ft. Detrick for DBS IND-180

was’ &cussed It was emphasized that the epidemio~ogical study did not provid:-,

contpol &a, whereby the eflectiveness of the vbccine could be evlrruated ?he fact

that the vaccine hax been used in a number of textile mills and that there has been

not cases ofAnt.hr&‘&as tibstantive but not‘6oncdirsivejSi&ce ofeficacy. "

At some point data fi-om an earlier study was submitted and accepted. The study, conducted by

Dr. Philip Bra&man and others, was used a difTerent va&ne. The ,"Bra.&rnan Study" was

published in 1962.28 On 2 November 1970 license approval was recommended by the

Department of Health, Education, and Welfare without any efficacy data. The License was

granted on 10 November 1970.

During Congressional hearings on the AVA in 1999 the General Accounting Office (GAO)

noted:

‘MDPH was granted a license for a similar vaccine that d#ered from the

original vaccine in three ways. First, the manufacturing process changed when

MDPH took over. Second, the strain of anthrax that M&k used to grow the

original vaccine was changed, and another strain was gsed to grow the MDPH

vaccine. Finally, to increase the yieid of the pflotective antipen (which is believed

make vaccine were changedfom the originai vaccine. " 2g

28 P.S. Brachman et al., Field evaluation of a human anthrax vaccine, American Journal of Public

Health, vol. 52 (1962), pp. 632-645.

29 Medical Readiness: Safety and Efficacy of the Anthrax Vaccine (C)4/29/1999), T-NSIAD-99-

148,29 Apr 1999.

26

AVA is a biologic product as defined in 42 USC. 6 262(i), and is subject to the provisions of

the Food, Drug, and Cosmetics Act (21 U.S.C. 6 301 et seq.), which applies to biological

products. On August 18, 1972 nine days after assuming responsibility for the regulation of

biologics, the Food and Drug Administration pubhshed a proposal in the Federal Register

establishing procedures for review of safety, efficacy, and labeling of biological products. This

notice reiterates that the applicability of the Act and the Harris-Kefauver amendment to the Act:

"Because ail biological products are dmgs.. . . "

The record reflects, however, that the license was granted without the legal standard having ever

been met. Despite requests to the manufacturer by the National Institute for Heal, I+ and Public

Health Service for evidence of efficacy, there is no record of any scientifklly valid human

efficacy data having ever been submitted in support of this specific anthrax vaccine.

.,.

. ‘.

27

b) Even with a newly renovated production facility, BioPort is incapable of complying with

CGMP or of producing an AVA of consistent safety, purity, potency.and quality.

BioPort Corporation is now solely focused on the production of anthrax vaccine adsorbed and

the approval of its renovated facility. BioPort continues to be unable to meet current good

manufacturing practice standards as illustrated by the following Form FDA 483 observations:

October 1998:

"Stab&y testing has not alwqs been pe.r$ormed in .accordmce with stabi&

protocols, for example... "

"CBER has not been not$ed in accordance with Error and Accident reporting of

the following.. . "

"On 6/30/98, the$rm instadled a new reaction tank mix& on Tank (redactted).

Yhere is no d&a domspnenting that the new mixer is equivalent to the old mixer,

change. "

October 2000:

incomplete.. . I’

3o Thirty observations were noted. The inspection report ends with this comment: "X4e

28

"lizvestigations are incomplete, inaccurate, or not conducted "

"There is no assurance equipment is operatingz as designed "

Biologic products can be marketed only with a license issued under the Public Health Service

Act. The Food and Drug Administration Modernization Act of 1997 amended the Public Health

Service Act to state specifically that biological products are subj+ to the drug provisions of the

Federal Food, Drug and Cosmetic Act. The Center for BiolQgics Evaluation and Research

(CBER) licensing powers dbminate its law enforcement approach &ward these products.

CBER‘ need not iely on po&narkeGng enforcement actions Such as seizure and injunction

because FDA regultitions authorize immediate suspension of a biological product’s license. The

FDA may summarily suspend the AVA license if the Agency bklieves that grounds for license

revocation exist that create a danger to health (21 C;F.R. 0 601.6). FDA enforcement policies

(inadequare manufacturing con&oh, failure to report require< information, or submission of

false information) " AVA has met the threshold for suspension for multiple reasons in both

,categories.

. . . ." ,

The scientific threshold is &inned in Weinberger Y H@zson 412 U.S; 609 622 (1973). Studies

conducted, and data presented, for the &ensure of AVA have not met the most cursory standards

of scientific validity and the license must therefore be immediately suspended for the public

health.

The regulatory threshold for immediate suspension has also been’ met. John LX Copanos & Sons,

Inc. v FDA 854 F.2d 510 (D.C. Cir. 1988) and American Public He&h Association v Veneman

394 F. Supp 1311 (1972) a%rm the Agency’s authority to im&diately withdraw a license. In

Veneman the court states:

"%s it could not be clearer that the Secretary must begin Gze procedures to -i

efk4x-y. "

29

the statute and regulations and the Congressiokxal intent to rid the marketplace of

ineffective drugs. "

The Agency may immediately suspend a product or establishment license for failing to: 1) report

a change in manufacturing procedures and: 2) for changing manufacturing methods to the extent

that the company needs to show its new methods meet applicable standards.

BioPort may argue that Notice is required prior to suspension of the license. FDA enforcement

policies anticipate this contingency:

"Nurmaliy the FDA will not withdraw an appkoved product application without

providing the opportunity for a hearing. However, in pracfice, the agency has

grartted fav hearing requests. Most o$2en, #he agency concludes that . . . no

genuine issue of material fact warranting a hearing and, consequevttly, denies the

request . . . "

In the case of BioPort though, prior notice has been given in the form of multiple Form FDA 483

List of Observations (discussions of objectionable conditions by FDA investigators), as well as

Warnings and a Notice of Intent to Revoke (NOIR) their license. Regardless, the FDA has the

authority to ‘szqend biologkal prod&t approvals wit~?ut ,giving, companies the .epportunity to

requc7st a hearing ",

If the IDA Commissiorier believes the product is an "imminent hazard" the Secretary of the

Department of Health and Human Services may also act (Tab 701). 21 C.F.R. 6 2.5 defines the

Commissioner’s authority to exercise judgment in the ,event of an "imminent hazard" as welL

The regulation refers to a "chain of events" and "‘vccwrences" which may ultimately result in a

"harm to the public he&h. " Such a chain of events is extensively documented in this petition.

The improper licensure and adulterated nature of anthrax vaccine adsorbed represents an

"imminent hazard" and warrants an immediate license suspension,

30

The importance of expeditious enforcement once a problem h& been identified was recently

articulated by the FDA’s top en&cement officer, Associate ‘Commissioner for Regulatory

Ai%irs Dennis Baker:

"‘I believe in a strong enforcement program that is tied to:e&cution and outreach

[efjorts]. I also believe in a strong enforce@ent pro&.zm once a problem is

identijfied. Certainly, I believe in not@ing thesrm of the problems and giving it

time to correct them, but ly the violations, are not corrected, I believe in

proceeding with enforcement straight away Too often we tend to talk these things

to death and we need to move things along. "

The problems have been identified. The manufacturer, has had J3p years to gather valid efficacy

data and it has not. The mant&acturer has had ample opportunity to notify FDA of equipment and

process changes and it has not. The manufacturer has endangered the public health by producing ..*,*,.

other biologic products in the equipment dedicated for the manufacture of AVA The . .I,‘

manufacturer has had at least 13 years to rectify current! ‘good manufacturing practice 1 1 .+

deficiencies and it has not. It is time to stop talking about these problems and "move things

along. "

We therefore respectfully request you immediately suspend the’ AV’A license (License #1260), .

and move expedmously to’ &draw &d revoke this license ip, wrdance. with. the Federal

Food, Drug and Cosmetic Act. The Commissioner’s prompt a&ion and prioritization of FDA

resources on this Ciiizen’s petition is in the best interest of the public health.

TNFORMATION KNOWN WHICH IS UNFAVORMjLE TO T-l@ PETITION:

We are unaware of any provisions in the Federal Food, Drug and Cosmetic Act that allow such a 2

product to continue in interstate commerce or be placed in interstate commerce.

31

Prepared by:

Russell E. Dingle

7 1 Shaughnessy Drive

East Hartford, CT 06 118

860-568-8767

And

Thomas L. Rempfer

3 8 I 1 P helps Road

West SufIidd, CT 06093

860-668-l 513

Supported bv:

.John Michels, Jr.

McLean, VA

John Richardson

Pittsboro, NC

James Turner

Washington, D. C .

Sammie Young

Silv;er ‘Sprin& MD

Very respectfklly, fl

Russell E. Dinglkj

Thomas L. Rempfer

Note: Please use Russell E. Dingle for any and all contact regarding this Citizen Petition.

Exhibit 1

.

-.

Ref. No. 67-70

FROM : Ad Hoc Committee

Clinical Data submitted under TNB-180 on 3anuary 22, 1969

As zequested, we have reviewed the cJ&ical data contained in Dr.

Kokko's letter of January 22, 1969 and its attached report. Our

couunents are as follows:

of approetely 600 persons: in the' TaUad+a mill c&n hardly-

There is no iadication of t& frequea& or t&e detailwitb which

the bacteriological studies cnt goat hair were conducted during

this period, W'e do tiolr‘.que&iou thti& %%er&@.ght be up ‘to 10

cases of expected authrax peI$ 600 workers; but without evidence

of actual exposure 5n this @.I.1 duri&g thfs time, and the

apparently unpredictable lnckdence ana cUstz%bution of authrax

in various nrLlls (see Fig. l', Brachm&u~& aI. Am. .T. Pub. Hlth --s

i

l$gher, presumably due to closer folXo%p. The nature and

degree of reactions is nor w&l defiized.

3.~Theresults%romthe. . '---- .-.--__ _

details for perforr&xg and iuterpret+ug the test.

earlier study with the Met& S&&p SX%me ptioduct could'be

compared by the ---- ;e&uique with s&5 from persons xeceiting

the Michigan product. Since no simu$t&eous animal potaucy

comparison of the MSD and Mchigan p&ducts .has been possible,

this would provide at lea&some ev&&ice of'a &mparab%5 response

in man.

eph'P. O'Malley, M. aY,

HELP ELIMINATE WASTE

R'obert.W. Kolb

Exhibit 2

PUBLIC HEALTtf SERVICE

F---Y

---.

FROM :

SUBJECT:

DATE: February 10,

Chief, LBP and

Chairman, Ad Hoc Committee

Michigan Department of Health; Application for license for Anthrax Vaccint

On June 21, 1968 the Ad Hoc Committee recommended that license be granted . .,,-. -c.G,T,.. . . ,. z__ I,, ,._ .._,j

following publication of Additional Standa?$p: Asthrw Vacc&ee. .I&

noted also that cliukcal data establi@hin& 'efficaq of the product had

been subm3.tted and that data be requested from NCDC.

Decembti 14, 1968, and St ie understood th&.theee st.ar?pa@n_haye-beep

forwarded with request for publioation in the Federal Register.

Safety data appear to be satisfactory.

Michigan has filed

for license except

investigatioa that

with the Q$yiqiqq, @&.~~$u%red information and material

the results of an adequately controlled clin5cal

establ.i@hes eijficaoy. No cases of anthrax have occurrec

product does have specifk ability to.pt6tect guinea pigs. Therefore,

reco&nended.- that l&exwe be,.granted aad.tbjit.NCDC~(X@D-180) be requested

to obtain data with a v$eu to; de&er&.ne ti&.@ efficacy of the product.

Exhibit 3 "

L .

UNITED STATES GOVERNlM. .l" DEPARTMENT- OF HE .TH. EDUCATIOX,

Memra&um .’ ‘I -p,, HEALTH s&VICE

PROM : Margaret Pittman, Ph. D., Ch$ief, LBP ‘ '

Chairman, Ad EIOC Committee

and Dr. J. R. Mitchell

Anthrax Vaccine

(DBS personnel: Drs. J. C. Feeley and M. P&man)

The recent information subm+e&by NCDC and Ft. Detrick for DBS-MD-180

was discussed. It was qjphasfzed that the epidemiological study did

provsde control data, whereby the effectSF.eness of the vaccfne could

evaluated. 'ifhe fadt that the vaccine has been u&d in a number of

conclusive evidence of efffcacy.

,,

It was also noted that Michigan .Lot 3 was mire reactive than one lot

prepared by Ft. Detrick and one lot prepared by Merck, Sharp & Do&e;"

With gel diffusion tests it.was demonstrated that the first Tao lots . +m.m..,-.. .

induced antfbodies that were lower in titer an&of shorter d&&&than

,did the MSD praduct.

.l_VI. . .L. .I,. "_,, Eowwer, tbe &--;-y--; y&& were $bymt+d

and a true comp)lrison could not be made.

. .

:.

Michigan Lot 2 now in current use was less reactive than Lot 3. Lot ,._/ I.".,

., _. .,

Dr. Anderson‘was &formed.thaf ar‘l requirements for 'ri$$n& the applfcation

for Anihrax Vaccine had-been ful‘fill‘ed but that I- - .

until the Add%tlonal Standards: ~'%,&th$~~~a$<&e~

nontechnical block wa,s.delaying their!.$ublftitior

appreciative of the information. . .1

Lzcen8e c0u.m not 'Siid $;,a :$dbsishdd.

I- ./ ..,. "". ,."a :

1. Dr. Anderson was.

a

Exhibit 4

-. DATE TiMf CWXK C&llNG

&z UTfjOlNC

a MEE~iNt

I CWTERRbPR

iT~iEiHONE NO. - -1 ----

3500 North lUarth Luther Xing Jr. ]Jhd., BaiSkUag CWc, 3"’ Float, biitsiag,

Te~(517]33~-9934E*-rul:(5f7]335-911~

Mic- 48906

"*-‘-- -. - .- --. .- .,

January 14,1999

Division Director

Division bf Manx&acturing and Product Quality

. Center for Biologics Ex&ation and Research

RECEh'ED

I I

’ Food and Drus Administration. : *

1401 Roctille Pike, HFM-99

Rockville, MID 20852

Attn: I-IF?&205

Dear Mr. Eltermaxm:

In our recent telephone convetition oq J~WUY 14,1999, MS. Fl?~nce Kaltovich, SAX,

VaccineAdsortKd(AVA)werenevff~~tedfbr3~~O~to~.~~~~~:"~~ *-

’ were i&&&d in 1993 in the.AyA.facility on &e, -aid 0% of.%i@in~ I&, As we

d&used, we have w@en an Infom.&@n &@zr thai b;iiefly &%&z what @es we.

have reviwed,tg ~certain the safety of the affected AVA lots -. .i _.I. _ .,i_ including lot nunhers ,_ ‘:.I’

FAV023 and higher. As you requested, we will prep? a "Category II"’ supplemknt that

describes Fermentation Trains 3 and 4.@c&d&g retrospective valiidatjon info+on and

data.

. . -. . . .

If you have any.questions, or require more i&x&ion, -please do not hesitate to contact

me at 5 17335~8096.

Sincerely,

. ’

Exhibit 6

. .

. t.3’. *

To: Tckcon File

Date: OK@&‘8 1 O:33 AM

2

I .

I

i

Date:

Fruat:

P

Michigan Biologic Products Institute

11/~8-2?/56;PaK/tPN/PR~~

Lansing, HI 48909

Fbf~X/73886??36.N27

This was a compliance followup inspecticm of a J&z@gics

manufacturel:, according to a 3;0/31/96 CRRR Off&e of Cqapliaxxce

memo and IXT-Do wurkplans (WATS #103826), The 'g%=%< 'i&cq.qd

. .

Public HeaLth, Bio&&‘&%iuots M&s&o;; lice&3e.fOO99. The

also held a xaeettig with CBERon 6/15/95 &o dis~ygs- planned

_

renovatZons to.the vaccipe production bQ$lcU.q lL6;

has an active val5da;rcion program fn place. XowqYer, ti&$ lack an

adequate quality assurance 'program for.au+mi iit 'of aZztiviti$s;

The .

-'I*

Exhibit 7.

.

SGRD-UIZ-S(70-lz) Trip Report

Dep Cdr for Development

OATE 26 September 1988

Dep Cdr for Research

Kuehne/bjm/73

MI. Date of visit:

Michigan State Department of Public Realth, Lansing,

22 Sept 1988. Travel order #RR1 9-27.

2. Purpose of trip: To visit and inspect the anthrax vaccine production ant

assess adequacy to fulfil requirements at HRDC contract as specified in the

CDC/NIH Biosafety Guidelines.

3. Persons contacted: Dr. John Mitchell, ,Chief,,Division of Biological

Pxoducts, Dr. Harvey Burgoyne,

Mr. Richard Hoort,

Chief, Vaccine Pro?uction, Ms. Judy Boice, and

all from Michigan State Oepartment of Public Health.

4, Findings:

f'

a. Background

This facility has been making anthrax vaccine for the US Army since

1970. The vaccine has been used, in addition, by various textile manufacturer:

been made every, 3-4 years and the largest run has.been' 7,500'doses. The

100 liter batch fermentor in a very small area consisting of a small room

housing the fermentor and holding tank, andjan average sized adjoining

laboratory in part of the second floor of a.buildfng which is used for other

purposes {Bldg 12). The building was constructed in 1939. The fermentor is

used between anthrax runs to produce botulinum toxoid which is licensed by the

USDA for animal use only. For anthrax vaccine production, the V-770-NPI-R

non-encapsulated strain of Bacillus. anthracis is .u.@d which was originally

supplied by Dr. George Wright of Fort Detriok.

extracellular soluble protective antigen.

This strain produces an

during the fermentation, exhaust

then ducted to the outside.

then through a filter and

At the end of the run, the liquid passes through

sequential filters to remove the cells and enters'a'holding tank. The

fermentor is then self-steam-sterilized.

are autoclaved in toto.

Filters .in stainless steel housings

adjacent buildi=.-

All filling and packaging operations are done in an

about 10,000 or more doses will have been produced with the current fermentor.

(A new production facility is planned, but groundbreaking will not occur until

mrhaps 1991, so is not apropos to this initial &o$tr&t. The new facility

vi11 sequentially produce anthrax vaccine, botulinurn toxoid, and tetanus

toxoid).

Exhibit 8

t

DEPARTMENT OF- THE AR

U S. ARMY MEOlCAt RESEARCH ~COU1StTION+.TTIVITY

FORT OETRICK. FREbERtC)(, MD lf702-JgJ?

19 October $995

Special Projects Branch

Michigan Department of Public Health

ATTN: Dr. Robert C. Myers

3500 North Martin Luther King Blvd.

Lansing, Michigan 48909

SUBJECT: Facilities Contract No. DAMD17-92-E-2001

Dear Dr. Myers:

It has come to my attention that the facilities for the

above subject contract were used for purp&es not authorized

in accordance with Se&ion C.l of the contract. ". .I,. ,

Please provide me the details df the &e of the

unauthorized use of the facilities (&hat‘&gs'produced, period

of usage, disposition of product, etc.). After I review this

information, 1 will make a determination ab'to what needs to

be done to compensate the Government: for tha,*use of the

facilities and what actions'ghouid he t&ka,:""tio that this

will not happen in the future.

'Mr. .B.C. Ba$er.f??, at Q(rl1 6,9-2035;. -Ii,. .._ . .I :: /

Michael A. Younkgi s

Contracting t Offic. r ,* . . .,

COR

I /

i :

MICHIGAN DEPARTMEW

Cd506 NbRW Mann I.

lANSl~C, Mlcllla

5 I 7-335-t

FAX: 5 I 7-33!

To: B.C. Baker III Da

COMMENTS:

This @ywz$ffai r4qx-nds to Mr. You&ins letter of 1

located on the second ffoor of Building I2 at the Mi

other than those specified to be in accordance with i

The facility is not only used for de@nse vaccines pi

eff&&s otthe MDPH with respect to &se facilities j - --

the veterinary product were ex$austed. Since it was time to.requaiifj &e f8ciIiti& in any event,

inventories of the veterinary product.

1

The specific usage of these facilities over the period of time.in question is summarized in the

table on the foIlOwing-page.

During and immediately after the conflict, MDPH was informed that the Army would assist

Army to purchase this vaccine from someone else to maintain a &pply for use in horses in the

United States, but there is no other manufacturer of the vaccine. ‘We did&ter into discussions in

this regard for the use of Type B toxoid generated by the SaIk in&itute.’ !& the end, such use was

not feasible for the veterinary product. We are at this time reqt&ting th& you approve our use of

these facilities for the stated purpose without charge as such use &as the direct result of our

eiTixts to sem your needs over the last five years.

If firther information is needed Lease fet me know.

.

0 ,, ?"

of Type B Toxoid for Veterins~‘ike

Deco-on and minor repair ,,_ ,, .~ .

Dechminate and requalify fti%G . _ . . . . _

July 1995 ., .., . , _ ..- ,-. a*

August and September 1995

October, I&Minber and December 1995

* I Resume man~acture ofAnthrax vaccine I January 1996 I

FAX TRANSMIS#~V -= ’

3500 NORM bfAFt7lN LWI-EN KINCJ EWAj

LuauQ. MICI-IIQAN 48909

5 17-335-8 i 20

_

Fw: 5 I 7-335-9486

This transmittal r-ponds to Mr. You&ins letter of Qctobq 19,19%.oti the use of the fkciiities

&ated on the second ‘ff oor of BuiIdii 12 at t&e Micbigas&Jepar&~tit of Public %a& for uses

other than those specified to be in accordance with Section C. 1 of &&tract DAMD 17-92-E-200 1.

The facitity is not only used for defense va&ines fnupijses;%ut alsq is qtikzed for the

man- of the USDA k&sed ~~~‘~+t$it&~ Bot-ulinti T$k+ Ij Tokoid. Th&entire ,_ a:,+ y*;.-y ""."" _ _

efforts ofthe’WFtiw* %i$i+i io these iixilities, has beq to seyve the needs of the U.S. Army

for defense vaccines since t&e Persian GuXfconfIict beg= Be&&‘of&is ‘focus, inventories of

the veterinary product were exhausted. Since it was time to ~qual$y tie &$i&s iir any ei%nt,

the opportunity that this production break &&d&d w$s’d%&ted’k%&$&e establishment of new

inventories of the veterkqr product.

The specific usage of these fadilities over the period of time in question is summarized in the

table on the following page. A

MDPH in meeting other commitmepts not met during that tie p61Z&X&ause of the alniost

complete diversion of resources to th;: defense vaccine su@por# effo$ We would have asked the

Amy to purchase this vaccine f&m someone dse to makitain~ supply for use in horses in the 1

United States, but there is no other mazmfkctuzr of the vaccinq~. I@‘?(id en&r intO d&cussions in

this regard for the use ofTypk B toxoid generated by the Salk In&$+. in the end, such use was

these faciiities for th& stated pu$ose without charge as such usq tiL +6 direct result of our

. .

MCM&PLD (70) 2 April 1996

MBMORANDUM FOR $hnng&x, U.S. Army Medical Reg&$i Acquisition Activity,

ATTR Mr. B,C, Baker, Fort Detrick,;‘MD 21702-5014

SUBJECT: Contract DAMDL7-92-E-2001

1. This is in referewe to &he encloseqi contractofs let&s dated 1~9.m 1995 regard&

unautho~ use ofthe f&ilitieg. ; .

3. It is alsg my txnddg that admid.don of this;wntra%~ wigned to IKMN.

Please contac% the DC&$&0 pr+ert$ admi&Wtor and ex#n~‘$twtion regarding the

unauthorized use of equipmat and find but ifit is wit&@i$r &j&&y to ewabte the situation

and reccgng~cj eppropriate acti&. Also ask them iftbe$ can hi 0~ ifthe, contractor .bas

incurred any costi for m&t- ‘ax, ‘&r this equip& ti G&&w the ‘co* have been

cluuged to c-1 139,or to any &her Governm~ co-

4. Please ceil me on exte&pn 7439 ifthct_re ate any que&ons.

Bllcl

,

Activity, ATTN: SGRD-UMB (LTC Balady), Fort

Detrick, Frederick, MD 217'02-5009

SUBJECT: Contract DAMD17-92-E-2001

contract.

xact file +r,.the..~,ubject

The, equipment identified under,Se&$gn E was purchased

under contract DAF4D17-88-C-824?.,-?'.;~.~. ~ur3?en,tly being used for

production of anthrax vaccine. No costs fsr mqintenancq have

yet

Government contraf$x, I,

you deem it necessary. I would suggest a meeting at the Michigan

Department of Public Health sometime in the near fgture to -, x. -, I ,"_% ,