Petition for Writ of Certiorari — Rempfer v. Hamburg

(1)

09-7 92 DEC 28 2009

OFFICE OF THE CLERK

In The . Wiliam. Suter, ler

Supreme Court of the United States

THOMAS REMPFER,

Petitioner

Vv.

MARGARET HAMBURG, M.D.,

COMMISSIONER, U.S. FooD & DRUG ADMINISTRATION,

ET AL.

Respondents

On Petition For Writ Of Certiorari To The United

States Court of Appeals for the District of Columbia

PETITION FOR WRIT OF CERTIORARI

LT. COL. THOMAS REMPFER

Pro Se

6058 South Jakemp Trail

Tucson, AZ 85747

(520) 869-6590

In The

Supreme Court of the United States

THOMAS REMPFER,

Petitioner

Vv.

MARGARET HAMBURG, M.D.,

COMMISSIONER, U.S. Foop & DRUG ADMINISTRATION,

ET AL.

Respondents

On Petition For Writ Of Certiorari To The United

States Court of Appeals for the District of Columbia

PETITION FOR WRIT OF CERTIORARI

LT. COL. THOMAS REMPFER

Pro Se

6058 South Jakemp Trail

Tucson, AZ 85747

(520) 869-6590

Questions Presented for Review

In 1998, the United States Department of

Defense (DoD) ordered members to receive the

anthrax vaccine. Many soldiers declined the order

because they believed the vaccine was not properly

licensed by the Food and Drug Administration

(FDA). The matter percolated in the lower courts for

the past decade as members challenged the legality

of mandatory vaccinations in civilian and military

forums. The 10-year history of lower court litigation

notably includes injunctions in 2003 and 2004 by the

District Court for D.C. The Court’s 2004 summary

judgment halted mandatory vaccinations on the

grounds that the vaccine was not properly licensed.

In 2005, the FDA completed the licensure process.

The Plaintiff in this matter contests the presumed

legality of the 2005 licensure based on a lack of

evidence that the vaccine is effective against inhaled

anthrax. This background presents the following

questions for the Court’s review:

First, when military orders hinge on the

legality of a final administrative action

of a non-military agency, can members

of the armed forces contest the propriety

of the non-military agency’s action?

Second, where ethical concerns preclude

adequate human clinical trials, what

level of evidence is necessary for the

FDA to license a biologic product, such

as a vaccine?

Parties to Proceeding

Petitioner: Lt. Col. Thomas Rempfer.

Respondents: Margaret Hamburg, M.D.,

Commissioner, U.S. Food & Drug Administration;

Robert Gates, Secretary of Defense; Kathleen

Sebelius, Secretary of Health and Human Services.

Table of Contents

Questions Presented for Review .................cceceeeeeeseeees i

inns saconuahbepnvniokenveorsanvoseseseseh ul

I. «..... . s ssuchaptnasescansvdesaessaniteesacdeeisis ili

III. 0. 1. so cacahoanepnnnbncventeesausasueneinten lv

I ol cc saeawsenanerneieuaaes 1

So Ol ce uanennenboannenl 5

Reasons for Granting the Petition......................45 13

a — RENNES AACE Se CD 15

II. Case Involves Urgent National Security

Problem That Will Recur, With Open Legal Issue

Ren PROG GE CPR vsecicccccccccveccconssesccesccsccecss 19

III. The Result Below Creates an Injustice.. 21

a. Scorecard: Pre-1998 v. Post-1998 .............. 23

b. Scorecard: Executive Branch v. Others..... 25

IV. Decisions Below Were in Error .............. 26

a. Judge Garland’s Unwitting Approach....... 27

i IIE... csansonccuedtcnssnbs present 33

GO ee CI BOD evn ncccccsscnccsccncccecccvcescess 35

SELES OI Oe Ee NN 36

| SRE RSE RE ie ee arte OO OPE es ea eR App.-1

Appendix 1 — Court of Appeals Opinion........ App.-1

Appendix 2 — District Court Opinion .......... App.-18

Appendix 3 — GAO Report: 02-181T............ App.-44

Appendix 4 — CT Att Gen Amicus Curiae... App.-58

-il-

Table of Authoriti

Cases

Doe v. Rumsfeld, 297 F.Supp.2d 119, 131 (D.D.C.

2003), appeal dis’d as moot, 172 Fed. Appx. 327

I a la ica & ti

Perry v. Wesely, No. NMCM 200001397, 2000 WL

1775249, at *3 n.2 (N-M. Ct. Crim. App. Nov. 29,

Sater ek ee 19

Ponder v. Stone, 54 M.J. 613 (U.S. Navy-Marine

SE Sek Gs FEI, MDa cacavesesecdusceseseedencesnvennes 20

Rempfer v. Sharfstein, 583 F.3d 860 (D.C. Cir. 2009)

s scinncainabsaea al nagliaeealace Saaiddioabaemene aabedausesdaniecduniasaiinns 1, 14, 16

Rempfer v. Von Eschenbach, 535 F. Supp. 2d 99

I aa eaashuedamesnennenennaal passim

United States v. Kisala, 64 M.J. 50 (C.A.A.F. 2006)

(nvenanbinesibiretnecsssenesessoocnseboenchsnscaaesernssnsccsesesessesnunnmne

United States v. New, 55 M.J. 95, 105 (C.A.A.F. 2001)

Laka at adednsicockdideusieitaseueaenidiaieniibudiacussiiamiseanione 19

United States v. Schwartz, 61 M.J. 567 (U.S. Navy-

Marine Corps Ct. Crim. App. 2005);..................... 20

Statutes

as sss cauebocvadabuehenmeeae passim

IIE ik csyciscebcrsvescisbenaasneessceesacesoonend passim

a ands ch adanunuunedaneemenenbaenen 2

iss sca bun nwnbbiennneveed inde nemmecaneat retbouel 2

ns. sineussesencnbvexaonsenoiibearanaumnenninnal 2

oa an aecaaia scab ealegeunsburasauenetseetal 2

is snide ca tclnicuieiniepcdledeansedcenhalenoneeeen 11

Other Authorities

Brachman, P., & Friedlander, A. (1994). Anthrax,

SIN: cs ssa vangendaduncusdeobeusronkenauanmbeeeseeonenia ns 25

o We

Brachman, P., & Friedlander, A. (1998). Anthrax,

I i age 25

Brachman, P., Gold, H., Plotkin, S., Fekety, F.,

Werrin, M., & Ingraham, N. (1962, April......... 6, 24

Chemical and Biological Weapon, RE DoD Letter to

| ae 25

Cohen, W. (1998). Implementation of the Anthrax

Vaccination Program for the Total Force. Retrieved

from

http://www.anthrax.mil/documents/902implementa

Ces oa ceahelatustnes 6

DoD-Request for Proposal (RFP) (see Admin Record).

(1985, May 16). Request for Proposals for new

anthrax vaccine by US Army Medical Research

Acquisition Activity. (No. DAMD 17-85-R-0078 ed.).

Fort Detrick, Frederick, MD........................c0006 ae

El-Ayyat Afaf A; Sayed Hanan A; El-Desoky

Howaida H., Pattern of water contact activities in

relation to S. mansoni infection in rural area in

Giza Governorate, Egypt, J. EGYPT PUBLIC HEALTH

ASSOC. 2003, 78 (6-6): 417-32........ccccccssssccesseresesees 31

FDA Backgrounder, The FDA Modernization Act of

es BT Ricintenitscscctbessccecesecsassdecnesscscssees 36

Improving Health Protection of Military Personnel

Participating in Particular Military Operations,

Executive Order 13139 (Sept. 30, 1999)................. 3

Ivins, B. (1988) The search for a new-generation

human anthrax vaccine. Clinical Immunology

Cee es ieee heahaeeséees 25

Reuters Health News, Factors associated with

persistence of hepatitis C viremia identified (April

ali ew aadeabeenkaunhad 31

Sharon M. Miller, About Time: A Chronobiological

Approach to Healthcare, 28 MEDICAL LABORATORY

OBSERVER, 26 (January 1, 1996)................:scceseeees 32

Takafuji, E., & Russell, P. (1990). Military

immunizations. Past, present, and future prospects.

Infectious Disease Clinics of North America, 4(1),

sbds ae badbenusubednbanthunendesheibuddbuincbvnnssvassnensepbeumauenttesenaeians 24

Regulations

Be Ne EE vii oc sscccavnenccscedcnscssacsssiions 38, 61, 69, 76

ee ee D sabeniiicecccncncensecssccsevessonsinicsocinene 9

BD FF ie Pe CRs By BED vn esce cc ccessccsscncccccsesscesrenee 10

Biological Products; Bacterial Vaccines and Toxoids;

Implementation of Efficacy Review; Anthrax

Vaccine Adsorbed; Final Order, 70 F.R. 75180

EES MEG SE: IIL. <n cs .avsnoncevesecavuenuierscuccsasiacnebios 1

1. Biological Products; Bacterial Vaccines and

Toxoids; Implementation of Efficacy Review;

Anthrax Vaccine Adsorbed; Final Order, 70

F.R. 75180 (FDA, Dec. 19, 2005).

4 Rempfer v. Von Eschenbach, 535 F. Supp. 2d

99 (D.D.C. 2008) (Appendix 1).

3. Rempfer v. Sharfstein, 583 F.3d 860 (D.C. Cir.

2009) (Appendix 2).

Jurisdiction:

Review is sought from the decision of the

Circuit Court of Appeals for the District of Columbia,

dated September 29, 2009 (Appendix 1). The District

Court for the District of Columbia filed its final

decision in this matter on February 29, 2008

(Appendix 2). The final agency action at issue was

published in the Federal Register by the U.S. Food &

Drug Administration on December 19, 2005.

This Court has jurisdiction pursuant to 28 U.S.C.

§ 1254. The Circuit Court had jurisdiction pursuant

to 28 U.S.C. § 1291. The District Court had

jurisdiction pursuant to 5 U.S.C. § 702, 28 U.S.C.

§§ 2201, 1331 and 1346.

Statutes

1. When a drug has not yet been licensed by the

FDA, the consent of the recipient is normally

aks

required before it can be administered. 21 U.S.C.

355(a)(4):

(i) Exemptions of drugs _ for

research; discretionary and

mandatory conditions; direct

reports to Secretary

(1) The Secretary shall promulgate

reguiations for exempting from the

operation of the foregoing subsections of

this section drugs intended solely for

investigational use by experts qualified

by scientific training and experience to

investigate the safety and effectiveness

of drugs. Such regulations may, within

the discretion of the Secretary, among

other conditions relating to the

protection of the public health, previde

for conditioning such exemption upon—

(4) Regulations under paragraph (1)

shall provide that such exemption shall

be conditioned upon the manufacturer,

or the sponsor of the investigation,

requiring that experts using such drugs

for investigational purposes certify to

such manufacturer or sponsor that they

will inform any human beings to whom

such drugs, or any controls used in

connection therewith, are being

administered, or their representatives,

that such drugs are being used for

investigational purposes and will obtain

the consent of such human beings or

their representatives, except where it is

not feasible or it is contrary to the best

a

interests of such human beings. Nothing

in this subsection shall be construed to

require any clinical investigator to

submit directly to the Secretary reports

on the investigational use of drugs. The

Secretary shall update such regulations

to require inclusion in the informed

consent documents and process a

statement that clinical trial information

for such clinical investigation has been

or will be submitted for inclusion in the

registry data bank pursuant’ to

subsection (j) of section 282 of title 42.

2. When the military seeks to use a non-licensed

drug, the military has the authority to administer it

to service members in connection with a particular

military operation, if the service members consent, or

if the president waives the consent requirement. ' 10

U.S.C. § 1107(f(1):

In the case of the administration of an

investigational new drug or a drug

unapproved for its applicd use to a

member of the armed forces in

connection with the member's

participation in a particular military

operation, the requirement that the

member provide prior consent to

receive the drug in accordance with

the prior consent requirement imposed

under section 505(1)(4) of the Federal

‘ The President issued an Executive Order in 1999 that

effectively embodies the same standard. IJ/mproving Health

Protection of Military Personnel Participating in Particular

Military Operations, Executive Order 13139 (Sept. 30, 1999).

Food, Drug, and Cosmetic Act (21 U.S.C.

355(01)(4)) may be waived only by the

President. The President may grant

such a waiver only if the President

determines, in writing, that obtaining

consent is not in the interests of

national security.

3. When the normally required two adequate,

controlled human clinical studies are not available, a

drug can be licensed based on only one such study, if

there is sufficient confirmatory evidence. 21 U.S.C. §

355(d):

(d) Grounds for refusing

application; approval of

application; “substantial evidence”

defined

If the Secretary finds, after due notice to

the applicant in accordance with

subsection (c) of this section and giving

him an opportunity for a hearing, in

accordance with said subsection, that

(7) based on a fair evaluation of ail

material facts, such labeling is false or

misleading in any particular; he shall

issue an order refusing to approve the

application. If, after such notice and

opportunity for hearing, the Secretary

finds that clauses (1) through (6) do not

apply, he shall issue an order approving

the application. As used in this

subsection and subsection (e) of this

section, the term “substantial evidence”

means evidence consisting of adequate

and well-controlled investigations,

including clinical investigations, by

experts qualified by scientific training

and experience to evaluate the

effectiveness of the drug involved, on

the basis of which it could fairly and

responsibly be concluded by _ such

experts that the drug will have the

effect it purports or is represented to

have under the conditions of use

prescribed, recommended, or suggested

in the labeling or proposed labeling

thereof. If the Secretary determines,

based on relevant science, that data

from one adequate and well-controlled

clinical investigation and confirmatory

evidence (obtained prior to or after such

investigation) are sufficient to establish

effectiveness, the Secretary may

consider such data and evidence to

constitute substantial evidence for

purposes of the preceding sentence.

Statement

In 1998 the military began its Anthrax Vaccine

Immunization Program (“AVIP”) to inoculate service

members in certain theaters against the threat of

aerosolized anthrax.” The only “approved” anthrax

vaccine available in the United States, then and now,

is called Anthrax Vaccine Adsorbed (“AVA,” or “the

vaccine”). AVA was tested in the 1950’s during a

Cohen, W. (1998). Implementation of the Anthrax

Vaccination Program for the Total Force. Retrieved from

http://www.anthrax. mil/documents/902implementationpolicy.pd

f

DoD sponsored field trial® for use by tannery workers

handling raw, potentially anthrax infected hides. Dr.

Philip S. Brachman executed this 1957 human

clinical trial for AVA for the DoD.* During the study

approximately 26 workers out of the 1,249 studied

were infected with anthrax; the great majority were

from cutaneous, or skin exposure, with only five or so

believed to have been infected by inhaled anthrax.

Though the government granted a license, during the

process regulators noted a failure to submit the

required “scientific evidence for efficacy of the

vaccine.” The Centers for Disease Control (CDC)

specifically challenged the licensing application at

that time due to the absence of proper efficacy data.

In the 1990s, the vaccine underwent “major,” DoD

coordinated manufacturing changes according to the

Government Accountability Office (GAO) (Appendix

3).° The manufacturing alterations were not

approved until over a decade later, and without

additional clinical trials. According to the GAO, the

alterations required prior approval and_ the

manufacturer failed to report some of the major

changes to the FDA. Regardless of the modifications,

the Brachman study remains the seminal source of

proof regarding efficacy of the new, altered vaccine,

° Brachman, P., Plotkin, S., Bumford, F., & Atchison, M.

(1960). An epidemic of inhalation anthrax: the first in the

twentieth century. II. Epidemiology. American Journal of

Hygiene, July (72), 6-23.

* Brachman, P., Gold, H., Plotkin, S., Fekety, F., Werrin, M.,

& Ingraham, N. (1962, April). Field Evaluation of a Human

Anthrax Vaccine. American Journal of Public Health, 52(4),

632-645.

° GAO-02-181T. (2001, October). Anthrax Vaccine: changes to

the manufacturing process. Appendix 2.

.

and serves as the prime basis for FDA licensure

under FDA Comparability Policy Guidance.°®

Significantly, following the aforementioned

unapproved manufacturing alterations, but before

the pivotal FDA licensure at issue in this filing,

earlier manufacturing quality control problems’

remained unresolved until “expedited” agency action

ensued following the “Amerithrax” anthrax letter

attacks. Only recently, the Federal Bureau of

Investigation (FBI) associated these known testing

irregularities of the existing vaccine to the 2001

anthrax letter attacks. The FBI alleged a DoD

scientist's motive stemmed from the fact that the

“anthrax vaccine he was working on was failing” due

to potency problems, which the scientist was

responsible for resolving.®» The GAO reported that

7 Comparability of Human Biological Products, Including

Therapeutic Biotechnology-derived Products. (1996). Retrieved

from

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfor

mation/Guidances/ucm 122879. htm

" FDA Notice of Intent to Revoke. (1997). In Food and Drug

Administration (Ed.), CBER Warns Michigan Biologic Products

Institute of Intention to Revoke Licenses. Retrieved from

http://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianc

eRegulatoryInformation/ComplianceActivities/Enforcement/defa

ult. htm; http://www.fda.gov/cber/infosheets/mich-inf. htm;

http://www.fda.gov/NewsEvents/Testimony/ucm114911.htm

® Note: The DoD scientist worried in the timeframe

preceding the letter attacks, “I think the **** is about to hit the

fan...bigtime. The final lot ... isn’t passing the potency test, and

now there’s nothing to back it up. Plus, the control vaccine isn’t

working ... It’s just a fine mess.” (2008, August 6). Federal

Bureau of Investigation, Amerithrax Court Documents.

Retrieved from http://www.usdo)j.gov/amerithrax/;

http://www.usdoj.gov/opa/documents/opa-080806. html;

http://www.usdoj.gov/opa/pr/2008/August/08-opa-697. html;

http://www.usdo}.gov/amerithrax/docs/07-524-m-01.pdf

. -

manufacturing changes might have resulted in up to

a “hundredfold increase” in potency attributes.”

As argued below, and as the District Court in

D.C. held in 2003, beyond the manufacturing

problems AVA was also never properly licensed for

use against inhaled anthrax before the 2005 Final

Rule. See Doe v. Rumsfeld, 297 F.Supp.2d 119, 131

(D.D.C. 2003), appeal dis’d as moot, 172 Fed. Appx.

327 (D.C. Cir. 2006). It is critical to understand that

in the decades following the Brachman study, its

deficiencies (principally but not wholly related to

small sample size and the insignificant number of

inhaled anthrax cases) were consistently noted by

those who considered the matter, including

government scientists. Repeated comments were

made, including by Brachman himself, that the 1957

study did not sufficiently establish the efficacy of

AVA against inhaled, vs. cutaneous anthrax

infection. In fact, with the assistance of the DoD, the

vaccine manufacturer’ in 1996 filed an

Investigational New Drug (“IND”) application to seek

licensure for “inhalation anthrax.” Yet, during this

timeframe, the 1985 Proposed Rule for licensure

languished un-finalized, while comments critical of

the AVA in general, and specifically as a treatment

for inhaled anthrax, continued to mount.

As demonstrated above and further below, the

most significant new development driving the

vaccine’s ultimate licensure for inhaled anthrax in

2005 was political and bureaucratic, rather than new

scientific or medical evidence. These dynamics

included the advent of the AVIP in 1998, and were

further motivated by the post-2001 anthrax letter

attack atmosphere. After the 1998 to 2001 moment

* Ibid at 5, nn. 5-13.

of pivot, the executive branch of the USS.

Government, notably the Department of Defense

(“DoD”) and the Food and Drug Administration

(“FDA”), purported to reexamine the Brachman data

and claimed to find therein new evidence for efficacy,

specifically for inhaled, aerosolized or inhalation

anthrax. As part of the about-face, the government

apparently altered its previous official position, one

identical to that of the present petitioner, i.e., that

the DoD needed a new vaccine due to the efficacy

limitations of AVA. The DoD published this

requirement in a Request for Proposal (RFP) for a

new vaccine as early as 1985.’° Also published in

1985, the FDA’s Proposed Rule’! for anthrax vaccine

similarly expressed the fundamental position of this

petitioner, i.e., that “no meaningful assessment of

[AVA’s] value against inhalation anthrax is possible.”

Following implementation of the DoD AVIP, and the

anthrax letter attacks, the government asserted that

the older 1970 NIH licensure, promulgated prior to

© DoD-Request for Proposal (RFP) (see Admin Record).

(1985, May 16). Request for Proposals for new anthrax vaccine

by US Army Medical Research Acquisition Activity. (No. DAMD

17-85-R-0078 ed.). Fort Detrick, Frederick, MD. The RFP

stated, “There is an operational requirement to develop a safe

and effective product which will protect US troops against

exposure from virulent strains of Bacillus anthracis.” The RFP

added, “There is no vaccine in current use which will safely and

effectively protect military personnel against exposure to this

hazardous bacterial agent.” The RFP clarified that the current

vaccine is, “highly reactogenic [reactive], requires multiple

boosters to maintain immunity and may not be protective

against all strains of the anthrax bacillus.”

‘' A 1985 FDA Advisory Panel published a proposed rule in

the Federal Register in order to finalize the anthrax vaccine’s

license. The Proposed Rule noted the “efficacy against

inhalation anthrax is not well documented.” 50 F.R. 51002

(Dec. 13,1985).

>

FDA's assumption of vaccine responsibilities in 1972,

sufficiently included the use of the vaccine for

inhalation anthrax. The FDA altered the earlier

understood limited use of the vaccine for at risk

individuals against cutaneous anthrax, which had

stood for some 30 years, instead broadening the

license for all routes of exposure.

When the D.C. District Court agreed in late 2003

that the vaccine had never been licensed for inhaled

anthrax, the government eight days later in January

2004, finally acted on the pending 1985 Proposed

Rule, granting the license for AVA and added efficacy

for inhalation anthrax. Doe v. Rumsfeld, 297

F.Supp.2d at 131. The District Court then stepped

in, holding that the 2004 licensure was inadequate

under the Administrative Procedures Act, 5 U.S.C.

§§ 511-99, enjoining the AVIP unless and until a

license based on proper procedures was issued. In

2005, the government issued a new Final Rule

following a comment period, again relying in large

part on the Brachman study. Notably, Dr.

Brachman, in_ post-licensure writings, cites

government conclusions that AVA is effective against

inhaled anthrax, whereas the FDA relies primarily

on his study.” Dr. Brachman’s reluctance to assert

directly the efficacy of the vaccine based on his 1957

clinical trial, as relied upon by the FDA, exemplifies

an unsuitable circular chain of reasoning that

renders the FDA decision arbitrary and capricious.

While the government was preparing to issue its

final licensure order in 2005, it simultaneously

‘2 Brachman, P., Friedlander, A., & Grabenstein, J. (2008).

Anthrax Vaccine, Chapter 8. In S. Plotkin, W. Orenstein & P.

Offit (Eds.), Vaccines (5th ed., pp. 111-124). Philadelphia, Pa.:

Saunders/Elsevier.

-10-

appealed the District Court’s injunction. FDA

ultimately issued a new Final Rule in December

2005, and because of this new Final Rule, the court

dismissed the appeal on grounds of mootness in

February 2006. Therefore, the Court of Appeals

never reviewed the merits of the vaccine’s final

licensure for inhalational anthrax in 2005; that

question is the gravamen here. With the injunction

dissolved, DoD Undersecretary Dr. David Chu

tod ‘oe 13

ordered renewed mandatory military vaccinations.

Ironically, Dr. Chu previously recommended DoD

“minimize” AVA use immediately prior to the

controversial anthrax letter attacks in 2001.'* DoD

recommendations to minimize use of the anthrax

vaccine, rely on antibiotics, and develop a new

vaccine placed the old vaccine in jeopardy. The

anthrax letter attacks apparently were motivated to

resolve this previous “failing” status of the program,

and essentially led to the current dispute over

licensure and continued reliance on AVA.”

** Chu, D. (2005, April 29). DoD Implementation of

Resumption of the Anthrax Vaccine Immunization Program.

'* Chu, D., & Aldridge, P. (2001, August 10). In Rumsfeld D.

Technology Development for Force Health Protection Against

Biological Threat, RE minimizing anthrax vaccine. Retrieved

from ht tp://www.fda.gov/ohrms/dockets/dockets/80n0208/80N-

0208_emc-000192-07.pdf. Available in docket & Admin Record.

'© Ibid at 8, p. 15. AVA’s use significantly expanded to

include over $1 billion in procurement for the nation’s Strategic

National Stockpile after the letter attacks. The procurements

represented a major leap compared to the vaccine’s problems

revealed through FBI released emails. The DoD scientist’s

admitted that the vaccine “isn’t passing the potency test.” The

emails stated, “If it doesn’t pass ... the program will come to a

halt.” The FBI confirmed, the FDA “had suspended further

production” because the “same vaccine was having problems in

the production phase.” Ultimately, the DoD awarded the DoD

x

As with this Petitioner, many similarly situated

service members in all branches of the armed forces

were disciplined for refusing the vaccine, based on

orders issued both before and after the district court

injunction. It is worth noting that many members

were disciplined before the 2003 court order

confirmed that the vaccine was not properly licensed;

those punishments were never lifted or ameliorated,

even after the mandatory vaccination program was

enjoined by a court finding that the vaccine was not

properly licensed exactly as these service members

had argued. This is in the face of clear statutory

requirements, discussed further below, that consent

(or a presidential waiver of consent) is required when

the military seeks to administer an unlicensed

treatment to its members. Also of note, during this

entire period, the Court of Appeals for the Armed

Forces (CAAF) periodically faced the identical issue

of the legitimacy of the vaccine licensure by FDA.

The CAAF essentially accepted at face value the

government’s assertion that the vaccine had been

properly licensed at all times since 1970. United

States v. Kisala, 64 M.J. 50 (C.A.A.F. 2006).

This is contrary to the decisions of the D.C.

District Court, the same opinion the D.C. Court of

Appeals declined to vacate. The CAAF also held that

military orders were presumed legal. The practical

result in this case being that so long as government

makes a colorable assertion that a drug is properly

licensed, service members cannot question the final

administrative action of a non-military agency (such

as the drug’s licensure here), even if their military

scientist, Dr. Bruce Ivins, the highest honor for “getting the

anthrax vaccine back into production.” The FBI found, “with

respect to the motive” and the “troubled nature of Dr. Ivins”

related to “concern about the end of the vaccination program.”

~

orders are based on such a final administrative

action. The CAAF noted this conflict with the

approach taken in the federal courts in D.C. Kisala,

64 M.J. 50.

In the matter at bar, where service members

contest the vaccine’s 2005 licensure, the Court of

Appeals carried through with the 2003 District

Court’s different approach to the issue of proper

licensing; that is to say, the Court of Appeals

completed a full merits review of the FDA’s licensing

process without questioning the service member's

right to contest an agency action, even when that

agency action underpins military orders. See

Rempfer v. Sharfstein, 583 F.3d 860 (D.C. Cir. 2009).

ranting t etition

The Petitioner’s basic legal claim relies on the

official documented position previously held by the

DoD and its scientists involved with anthrax vaccine

prior to the advent of the politically charged AVIP

and the letter attacks. Those attacks were allegedly

launched to overcome the fundamental failings of the

vaccine, its potency and efficacy problems, and make

for the premise of the Petitioner’s claim for review.

The resultant arguments supporting this claim

borrow from scholarly’ articles, logic and

commonsense in asserting the necessity to resurvey

the entire scheme:

First, the anthrax vaccine is not FDA-

approved because of alterations in its

chemical formula and a change in its

intended use from the original vaccine.

As such, the FDA must consider it an

IND [“Investigational New Drug” per 21

U.S.C. § 355()(4)]. Second, since the

7,

vaccine is an IND, it requires informed

consent of the service member under

federal law and a_ Presidential

Executive Order. Third, since the

current vaccine is Ulegal to administer

and was administered without consent,

the order directing the service member

to become vaccinated was iilegal.”®

Fourth, Dr. Brachman’s study historically was

not considered a reliable means of proving efficacy

for inhalation anthrax according to the author

himself. Instead, today Dr. Brachman points not to

his earlier study, but to the government’s

conclusions, in asserting the efficaciousness of AVA.

Circularly though, those government conclusions by

the FDA and the National Academies of Science

Institute of Medicine (IOM) point back to Dr.

Brachman’s study for proof of efficacy. IOM

acknowledges AVA is “far from optimal” and advises

a “new vaccine, developed according to more modern

principles of vaccinology, is urgently needed.” *”

'PRANDALL J. KATZ, Friendly Fire: The Mandatory Military

Anthrax Vaccination Program, 50 Duke L.J. 1835, 1852-53

(2001) (citations omitted). Additional scholarly analysis on the

AVIP exists in peer-reviewed literature: Corrigan, S. (2001).

Total Force Anthrax Vaccine Immunization Program:

Controversy and Conflagration. Harvard Law School. Retrieved

from http:/leda.law.harvard.edu/leda/data/365/Corrigan.pdf;

'7 1OM. (2002, April). The anthrax vaccine: Is it safe? Does it

work? Institute of Medicine (U.S.). Committee to Assess the

Safety and Efficacy of the Anthrax Vaccine. Washington, D.C:

National Academy Press, p. 208. Earlier IOM reports

cautioned, “There is a paucity of published peer-reviewed

literature on the safety of the anthrax vaccine.” IOM. (2000,

March 30). An assessment of the safety of the anthrax vaccine

{electronic resource]: a letter report. Committee on Health

Effects Associated with Exposures during the Gulf War.

-14-

Each of the abovementioned reasons stand

contrary to the DoD’s planned August 2001

minimization of anthrax vaccine use due to its

“failing” status and the “political problems” related to

“Gulf War Syndrome.””® The Petitioner reasons that

the reversal resulted from AVA’s illegal use and the

anthrax letter attacks plan to “save” the AVIP,

leading directly to improper agency action and

unwarranted court acquiescence in the matter at bar.

I. Circuit Split

The two most important courts in the nation for

determining the validity of military orders that hinge

on the legality of an underlying final administrative

action of a non-military agency are divided in that

the CAAF has in effect stated that when a military

order is based on an administrative order from a non-

military agency, the legality of the underlying

administrative action is entitled to the same heavy

presumption of legality that applies to military

orders. In contrast, the civilian federal courts in the

District of Columbia, as exemplified in the matter at

bar, have moved directly to a review of the merits of

the civilian agency’s actions on the arbitrary and

capricious standard of review, without any

consideration of the presumption of legality of

military orders. Compare Rempfer, 583 F.3d 860,

with Kisala, 64 M.J. 50.

Institute of Medicine (U.S.). Washington D.C: Institute of

Medicine, p. 6. Retrieved from

http://ocoks. nap.edu/openbook.php?record_id=9811&page=R1

'8 Thid at 14, and Rove, K. (2001, April 25). In Deputy

Secretary of Defense Wolfowitz P. (Ed.), Gulf War Syndrome

and Anthrax (See Appendix 9). Retrieved from

http://www.mvrd.org/rovememo. pdf

a. P

The CAAF’s approach at bottom is that if a

civilian agency so much as colorably asserts that it

has taken a ~al, legal action on which a subsequent

military order aepends, the CAAF needs conduct no

further review of the propriety of the agency’s

actions, but rather moves straight to an analysis

based on the presumption of legality of military

orders. In contrast, civilian courts in the matter at

bar have addressed the merits of the question

whether the 2005 licensure (or any earlier iteration

thereof) is valid. The CAAF has instead stated in

effect that since the FDA has asserted that the

anthrax license has been in place since 1970, the

CAAF can presume that the agency action is legal

and need not inquire into the merits of the agency

action, either as to the original licensure in the

1970’s for cutaneous anthrax, or the latest licensure

in 2005 for inhaled anthrax. The practical question

is should civilian courts apply the presumption of

legality of military orders when they review

challenges to the legality of civilian agency

administrative actions by members of the military

who assert they are subject to illegal orders? Or,

should the courts under the Armed Forces

jurisdiction review the validity of a civilian agency

order before they apply the presumption of legality of

military orders?

The Court of Appeals for the D.C. Circuit is the

nation’s leading administrative law forum outside of

this Court, while the Court of Appeals for the Armed

Forces is the nation’s foremost lower court authority

on military matters, exercising worldwide appellate

jurisdiction over members of the armed services on

active duty and others subject to the Uniform Code of

Military Justice in a wide variety of civil and

criminal matters. It is highly undesirable for these

-16-

two crucial forums to disagree on an important issue

at the intersection of their zones of expertise and

influence — the proper weight, if any, to be given to

final orders of a non-military administrative agency

when military orders hinge on the legality of such

final orders. Kisala, 64 M.J. 50.

The court with administrative law expertise did

not address the issue of the presumed legality of

military orders, while the court with military

expertise relied on the presumption of legality of

military orders to the exclusion of an appropriately

rigorous review of the legality of the administrative

action. This may be a case of ships passing in the

night, unaware of each other’s presence, mission and

import — and thus presents an opportunity for this

Court to exercise its responsibility to draw together

and unify two disparate legal approaches to the same

fundamental and important problem: to what extent,

if any, can members of the military contest the

validity of final non-military agency decisions when

such decisions underpin a military order.

The CAAF itself acknowledges this important

difference in approach, wherein the federal courts in

D.C. did not examine the presumed legality of the

military orders that the petitioners were subjected

to:

The federal district court's evaluation of

the civil remedies differs from our

evaluation of the criminal charges that

arise in the military context of

Appellant's willful disobedience of a

presumed lawful order. The linchpin of

this case is the presumed legality of the

military order to receive the Vaccine.

The district court opinions neither

ms

recognize nor address this critical

presumption.

Kisala, 64 M.J. at 53.'°

This presents a grave anomaly that only this

Court can remedy: It is inconsistent for one service

member, who is not facing criminal charges, to be

able to contest the legality of a final agency action in

civilian court, while another service member who is

being criminally prosecuted for disobeying an

identical military order does not have the

opportunity to contest the exact same agency action.

See United States v. New, 55 M.J. 95, 105 (C.A.A.F.

2001) (the “word ‘lawful’ [in the provision regarding

the presumed legality of military orders] simply

reinforces the opportunity for the accused to

challenge the validity of the regulation or order with

respect to a superior source of law without

establishing a separate and distinct element of the

offense”).”°

‘® One court has gone even further, and declared that the

Dob'’s assertion that the anthrax vaccine was properly licensed

constitutes a nonjusticiable political question. See Perry uv.

Wesely, No. NNMCM 200001397, 2000 WL 1775249, at *3 n.2 (N-

M. Ct. Crim. App. Nov. 29, 2000) (“Complicating the inquiry in

the petitioner's case is his effort to contest the lawfulness of the

commanding officer's order by litigating the legality of the DoD

anthrax vaccination program itself, a nonjusticiable political

decision”).

” The standard of review of final agency administrative

actions, such as the anthrax licensure here, is arbitrary and

capricious. A military order hinging on an arbitrary and

capricious agency action would seem to be patently illegal.

Therefore, at this petition for certiorari stage, consistency is

desirable in the various forums when service members assert

that a military order is not lawful because it is premised on an

illegal administrative agency action, such as the FDA’s final

anthrax vaccine licensure decision here.

- 18 -

This disparity in the two forums’ handling of

alleged violations of similar military orders is

rendered all the more urgent and ripe for review by

the fact that the court using the more restrictive

approach, here the CAAF, is using the more

stringent standard in criminal cases. This is akin to

a state’s allowing speeders who are facing merely

civil sanctions such as driver’s license suspensions to

contest the inspection and calibration of the state

police radar guns, while imposing a presumption that

the radar guns are accurate on speeders who are

charged criminally. This Court should accept this

matter for review to resolve the inconsistency

, . 21

between these two courts on an important issue.

Il. Case Involves Urgent National Security

Problem That Will Recur, With Open

Legal Issue In Need of Clarification

This Court needs no reminding that a new

century has dawned with terrorism and

unprecedented national security threats presenting

hitherto unseen challenges to the legal system,

including threats posed by Weapons of Mass

Destruction (“WMD”) — biological, chemical and

nuclear threats that can be levied against both

military and civilian targets. Anthrax is clearly one

such weapon — and the national security and legal

challenge posed when the government tries to protect

its military and its citizens against threats such as

*) For other examples of the military courts’ consistent

approach of not reviewing the vaccine’s licensure on the merits,

see [/nited States v. Schwartz, 61 M.J. 567 (U.S. Navy-Marine

Corps Ct. Crim. App. 2005); Ponder v. Stone, 54 M.J. 613 (U.S.

Navy-Marine Corps Ct. Crim. App. 2000); see also, Katz, 50

DUKE L.J. at 1852.

-19-

anthrax can unfortunately be expected to be repeated

as new WMD threats emerge. It is appropriate and

desirable for the nation in facing such threats to have

clear legal guidance from this Court in place when

future threats arise from some unexpected quarter —

an unknown pathogen or other WMD developed by

terrorists. In this instance, the government’s

attempt to prepare for and protect against the

anthrax threat relies on an old medication, one that

languished without final agency action for decades

because of its seeming obscurity, limited scope or use,

and obsolescence. As well, administrative inertia

appeared to prevail, caused by the understanding of

all concerned about the inadequacy of the scientific

evidence of the vaccine’s efficacy, its potency

problems, and the failure to synthesize long sought

alternatives to this inadequate vaccine.

The next time, the unlicensed treatment might

not be an old and forgotten one, but rather a new one

developed using the most modern methods, but

perhaps created on the fly to meet an urgent need.

In either case, the legal issue that will be presented

when the military once again needs to use unlicensed

treatments on its members is the same: from a legal

standpoint, what requirements must be met before

the military can administer an unlicensed treatment

without .seeking the recipients’ consent or a

presidential waiver of consent?

The question is made all the more proper for this

Court’s attention and current clarification because of

the special concern that these issues may arise in the

future on an emergency, urgent basis as the nation

and its military, medical and regulatory institutions

scramble to address an unforeseen threat. It will be

far better for this Court to have considered these

-20-

matters in the more deliberate manner presented by

this case, rather than on a crisis basis.

This Court should exercise its discretionary and

supervisory authority to hear this matter in order to

provide a solid, clear and workable legal framework

for the nation’s civil and military commanders.

Additionally, individual members of the armed

forces, who serve patriotically, deserve to know with

clarity what legal rights they do — and do not — have

with respect to unlicensed drugs or other treatments

that might be mandated.

This problem raises important issues of national

security and personal liberty that are within the

historic purview of this Court, and currently the

civilian and military justice arenas are taking

different, yet universally deferential approaches.

The question of course has broader applicability

than just the particular FDA and drug licensure

order at issue here; it rather applies whenever a final

administrative decision of a civilian agency underlies

military orders, and affected service members contest

the legality of the civilian agency’s final action.

III. he Resul low Creates an Injustice

Without suggesting that the injustice being

worked against is alone enough to merit a grant of

certiorari, it is nevertheless important for the Court

to understand that petitioner here belongs to a class

of honorable, hard-working, honest and in many

cases distinguished members of the armed services

who suffered consequences including discipline,

transfers (voluntary and involuntary), delayed or

denied promotion, and other personal, professional,

and emotional harms as a consequence of attempts to

oe

honor the highest and most difficult traditions of

duty in military service — questioning in good faith

the legality of an order received. These injuries have

not been remedied or alleviated in any way — despite

the indisputable fact that the fundamental claim

that this vaccine was not properly licensed at the

outset of the mandatory vaccination program in 1998

was accepted by no less of an authority than the

District Court for D.C. Moreover, the federal

government, since the time of that District Court

decision, has proceeded as if it were in full agreement

that the vaccine was never properly licensed for

inhalational anthrax exposure until late 2005.

That is to say, to this day many service members

continue to be injured based on their refusal of orders

to take the vaccine — while the government can and

does argue that post-2005 refusals are not

appropriate, it is hard to make a fair case for any

disciplinary or other sanctions based on pre-2005

refusals. This assessment is validated not just by the

District Court’s decision in unrelated Doe uv.

Rumsfeld matters in 2003 and 2005, but also by the

behavior of the Defense Department, who punished

the plaintiffs for arguing that the vaccine was not

licensed for inhaled anthrax. Meanwhile, the DoD

and FDA at the same time proceeded to secure a

license for the anthrax vaccine for inhalational

indications. The bottom line is that this country has

punished, and continues to punish, certain of its

faithful warriors for a dutiful stance they took at a

time when even the government (i.e., as illustrated

by its own subsequent actions of pursuing and

securing a final license) now concedes the vaccine

was not properly licensed for the purpose the

military wished to use it for. This injustice alone

a a

may not make this case worthy of certiorari, but it is

a fair point to mention.

a. Scorecard: Pre-1998 v. Post-1998

Before the military’s anthrax vaccination

program launched in 1998, the scientific and

administrative commentary on the safety and

efficacy of the vaccine was consistently negative.

The pre-program commentary also consistently

recognized that the vaccine was not proven

effective against inhaled anthrax.” After the

” Examples of pre-1998 commentary regarding AVA:

> “When inhalation anthrax is considered, the limited

experience with this form of the disease makes the data less

significant in showing effectiveness of the vaccine” (Brachman,

P., Gold, H., Plotkin, S., Fekety, F., Werrin, M., & Ingraham, N.

(1962, April). Field Evaluation of a Human Anthrax Vaccine.

American Journal of Public Health, 52(4), p. 642.;

> “No data on MDPH-PA [anthrax vaccine] efficacy in

humans” existed (Ivins, B. (1992, October 6). In Deputy

Commander, MDPH-PA vaccine efficacy in humans. p. 2);

> DOD scientists described the vaccine as an

“experimental,” “limited use vaccine” (Takafuji, E., & Russell, P.

(1990). Military immunizations. Past, present, and future

prospects. Infectious Disease Clinics of North America, 4(1),

p.156;

> “Current vaccines, particularly the anthrax vaccine, do

not readily lend themselves to use in mass troop immunization

[because of], in some cases, lack of strong enough efficacy

against infection by the aerosol route” (Congress - S.Hrg. 101-

744. (1989, February 10). Hearing on the Global Spread of

Chemical and Biological Weapon, RE DoD Letter to Sen. Glenn,

(Aug. 24,1989));

> Anthrax vaccine “drawbacks, including the need for

frequent boosters, the apparent inability to protect adequately

against certain strains of B. anthracis, and occasional local

reactogenicity” (Ivins, B. (1988) The search for a new-

generation human anthrax vaccine. Clinical Immunology

Newsletter, 9(2), 30-32);

20.

anthrax vaccine was made the center of a military

initiative in 1998, the government dramatically

changed course, and began arguing that no

separate licensure for inhalational anthrax was

needed, regardless of the fact an unapproved IND

application existed. This sea change was

captured in an amicus brief filed by the

Connecticut Attorney General in the D.C. Circuit

in 2005 in the Doe v. Rumsfeld litigation

discussed elsewhere (Appendix 4):

Before the federal government decided

to “cut corners” and violate the

requirements of 10 U.S.C. § 1107,

everyone agreed that there was

insufficient data on the safety and

efficacy of the anthrax vaccine with

respect to inhalation anthrax. The

FDA, the author of the study, the DoD,

the CDC and the manufacturer all

agreed and acted on the basis that the

vaccine was an [Investigational New

Drug, that is to say, unlicensed] with

respect to inhalation anthrax.

Amicus Brief of the Connecticut Attorney

General, dated August 11, 2005 at 6 (hereafter,

“AG Brief) (Appendix 4).

It is likely that the government in its responsive

filing will marshal examples of favorable

commentary on AVA’s effectiveness, and perhaps

> “Unsatisfactory” nature of the current product due to

unknown purity, undefined nature, undesirable constituents

and efficacy issues (Brachman, P., & Friedlander, A. (1994).

Anthrax, Chapter 26. In S. A. Plotkin, & E. A. Mortimer (Eds.),

Vaccines (2nd ed., pp. 773-996). Brachman, P., & Friedlander,

A. (1998). Anthrax, Chapter 24. In S. Plotkin, & W. Orenstein

(Eds.), Vaccines (3rd ed., pp. 629-636).

-24-

statements supportive of the judgment that no

separate licensure for imhalational anthrax is

needed. The Court should keep a scorecard when

reading the respondents’ (or Judge Garland’s) list of

positive AVA comments: how many of the

government’s positive scientific citations come from

before 1998 vs. how many come in or after 1998?

That, of course, being the year when the anthrax

vaccine program was launched, and also the year

when the government ceased being a neutral,

sideline observer, adjudicator, and regulator of AVA,

and rather became the first large user of the anthrax

vaccine ever, with a huge vested interest in having

the vaccine legalized.

This Petitioner asks the Court to consider what

happens when the government stops being the

regulator — and becomes the applicant?

b. orecard: Executiv ranch ther

Another important metric the Court should keep

its eye on: both before and after 1998, institutions

other than the executive branch of the U.S.

Government have consistently criticized the vaccine’s

efficacy and/or the adequacy of the purportedly

seminal Brachman study. This includes strong

criticism of the vaccine and its fitness for mandatory

administration from both other branches of the

federal government, as _ well as_ from state

governments. ~° This is not to say that in the exercise

*° Critical commentary from outside the executive branch:

> In 1994, a Senate Committee Report found, “the

vaccine’s effectiveness against inhaled anthrax is unknown,”

and therefore should be “considered investigational when used

as a protection against biological warfare.” (Congress - SR 103-

97. (1994, December 8). 103-2. Js Military Research hazardous

-

of diligence the government will not reveal positive

commentary from credible institutions outside the

executive branch, or not funded or otherwise linked

to the executive branch; but we predict a lopsided

score, with positive comments coming principally

from the executive branch or its dependents and

connections.

IV. Decisions Below Were in Error

to Veteran’s Health?: Lessons Spanning Half a Century, p. 35.,

see Admin Record).

> Later Congressional reports concurred stating, “use of

the current anthrax vaccine for force protection against

biological warfare should be considered experimental and

undertaken only pursuant to FDA regulations governing

investigational testing for a new indication.” Congressional

investigations also revealed DoD awareness that the “potency

test required for the present vaccine has not been well

correlated to efficacy in humans and it is doubtful that it can

be” (Congress - HR 106-556. (2000, April 3). Unproven Force

Protection, pp. 4, 52, 62. fn. 269. Washington, DC: GPO.

> GAO reports also confirmed that the “the vaccine and

the manufacturing process were changed;” that the “ingredients

used to make vaccine were changed from the original vaccine,”

and thet “prior to the time of licensing, no human efficacy

testing of the MDPH vaccine was performed” (GAO T-NSIAD-

99-148. (1999, April). Medical readiness: safety and efficacy of

the Anthrax vaccine, p. 1-3.

> CT Att. Gen.: “Suddenly in 1997, DoD and the FDA,

with no change in the facts or the law, reversed themselves and

with the stroke of a pen wiped out the protections afforded our

members of the Armed Services by clearing the way for DoD’s

mandatory miss inoculations.” (Blumenthal, R. (2001, March

22). In Rumsfeld D., Schwetz B. (Eds.), Letters from the

Connecticut Attorney General to DoD and FDA “RE: ANTHRAX

VACCINE.” Retrieved from

http://www.ct.gov/ag/cwp/view.asp?A=1776&Q=283330;

http://www.ct.gov/ag/lib/ag/press_releases/200 1/health/dod.pdf;

http://www.ct.gov/ag/lib/ag/press_releases/200 1/health/fda.pdf)

- 26 -

Both the FDA and Judge Garland premise their

finding that the anthrax vaccine here was properly

licensed on the hypothesis that the vaccine is as

effective against inhaled anthrax as it is against

cutaneous anthrax. The scientific evidence,

including much evidence’ produced by the

government itself (FDA, CDC and DoD) prior to the

initiation of the government’s own use of the vaccine

in 1998, does not support this hypothesis, and if

certiorari is granted here, close scrutiny will show

that any such finding is arbitrary and capricious.

This is not a case involving the adequacy of a

drug license against a private party; here, the entity

seeking to declare the licensure valid, and seeking to

use the vaccine, is the licensing authority: the FDA.

Normally, when a drug license is in question, the

federal government and the FDA are in a position

something like a neutral referee between two non-

government parties; but here, the government itself

is the entity asserting that it should be allowed to

use this drug because its licensing process was valid.

This Court should view this matter in the context of

FDA and DoD, perhaps understandably, fighting to

save an executive branch initiative in which they

played an intimate role.

a. Judge Garland’s Unwitting Approach

Again, while the errors may not alone merit this

Court’s attention, they bear mention. We do not take

issue with Judge Garland’s statement that:

At bottom, the plaintiffs’ claim that the

Brachman Study establishes nothing in

regard to “inhalational anthrax” relies

on the proposition that route of exposure

is scientifically relevant. But the FDA’s

2] -

contrary determination is a scientific

judgment within its “area of expertise,”

the kind of judgment to which this court

gives a “high level of deference.”

(Decision at 12.)

However, here the FDA’s errors are fundamental;

and they were moreover perpetuated and magnified

by Judge Garland. Judge Garland repeatedly

revealed a fundamental misunderstanding of the

judiciary’s appropriate role in reviewing the validity

of the FDA’s finding that the vaccine here was

proven to be effective as a matter of scientific

evidence. Specifically, Judge Garland, rather than

simply assessing the adequacy of the evidence relied

on by FDA, repeatedly — and apparently in all good

faith and unwittingly — relies on his own scientific

judgments en route to his conclusion that the FDA’s

decision was not so unmoored from scientific basis as

to be arbitrary and capricious.

For instance, when Judge Garland states:

But this simply directs us to the

underlying issue: should “inhalational

anthrax” be analyzed separately? That

question cannot, as appellants

assume, be answered as an abstract

question of statistical method. Rather,

it must be answered as a matter of

scientific judgment. To illustrate: if the

route-of-exposure distinction were

replaced with a__ time-of-exposure

distinction, no one would insist that

“morning anthrax’ must be analyzed

separately from “afternoon anthrax.”

Yet categorizing cases by time seems

arbitrary not because time of exposure is

>.

any less measurable a distinction than

route of exposure, but because time

seems unlikely -- as a scientific matter -

- tc be relevant to vaccine effectiveness.

(Decision at 10), he has based his thinking on a

scientific assumption of his own creation — the idea

that time of exposure is “unlikely to be relevant.”

(Ibid.) The point here is not whether or not Judge

Garland’s (or FDA’s) scientific assumption that time

of exposure does not matter is incorrect — FDA’s

judgment if well-grounded is entitled to “high

deference.” Rather, Judge Garland’s _time-of-

exposure thought experiment is not based on any

evidence in the record — it is a scientific assumption

or hypothesis (as it turns out an incorrect one, see

footnote) by a lawyer who is in all good faith trying to

exercise what he takes to be common sense; it is

P -_ 24

arbitrary and capricious.

” Judge Garland’s hypothesis — that time of exposure is

never relevant — is incorrect when considering bacterial and

viral infections generally, and probably incorrect regarding

anthrax. Substantial evidence exists that the time of exposure,

levels of sunlight, and ambient temperature may impact

infection rates. Scientific literature includes references to such

variables as a factor in infection with respect to many

pathogesn. See, e.g., Cyril William Holmes, Black’s Medical

Dictionary (Harvard 1990) at 71 (tuberculosis); El-Ayyat Afaf A;

Sayed Hanan A; El-Desoky Howaida H., Pattern of water

contact activities in relation to S. mansoni infection in rural

area in Giza Governorate, Egypt, J. EGYPT PUBLIC HEALTH

Assoc. 2003, 78 (5-6): 417-32 (schistomiasis); Reuters Health

News, Factors associated with persistence of hepatitis C viremia

identified (April 1, 1999) (hepatitis C) (discussing Patrick G.

Quinn, AM. J. GASTROENTEROLOGY 1999;94:668-673 (April 1,

1999)). With specific reference to anthrax, the scientific

literature from its beginnings has noted sunlight’s role in

impeding anthrax., e.g., “In subsequent experiments with

sunlight, Arloing found that two hours of exposure to the July

a. 2

Judge Garland’s assertion that “no one would

insist that ‘morning anthrax’ must be analyzed

separately from ‘afternoon anthrax” shows at once a

serious lack of understanding of the scientific

method, as well as a failure to grasp the scientific

specifics of the matter at hand. Judge Garland’s own

conclusion, that “categorizing cases by time seems

arbitrary not because time of exposure is any less

measurable a distinction than route of exposure, but

because time seems unlikely -- as a scientific matter

-- to be relevant to vaccine effectiveness” does more

than any skilled advocate ever could to demonstrate

an unwitting abdication of the proper prudentially

limited role of the judicial system in reviewing the

FDA’s scientific judgment.

A judge’s role is not to decide whether or not time

of exposure, or route of exposure, is likely or unlikely

to be relevant. It is not for him, or this Court, to

judge what factors are, or are not, arbitrary or

unlikely to be relevant as a scientific matter; it is

rather for the judiciary to satisfy itself that the

government reviewed the scientific evidence and

literature in a way that was not arbitrary and not

capricious — that is, the proper subject for court

review is whether or not the government followed the

sun sufficed to destroy the vitality of anthrax spores ...

Cultures which were weakened in their reproductive energy by

exposure to sunlight were also ‘attenuated’ as to their

pathogenic power ....” GEORGE MILLER STERNBERG, A MANUAL

OF BACTERIOLOGY, (William Wood & Co. 1893) at p. 152; accord,

Holmes at 71. Other complex factors play into whether or not a

pathogen is successful in penetrating the body, for instance

body temperature, recent stress, having other infections, and

normal circadian rhythms. An entire field called chronobiology

has emerged in recent years. Sharon M. Miller, About Time: A

Chronobiological Approach to Healthcare, 28 MEDICAL

LABORATORY OBSERVER, 26 (January |, 1996).

- 30-

science without being misleading or dishonest, and

also without falling into Judge Garland’s own more

innocent mistake of unconsciously relying on

subjective assumptions in reviewing the FDA's

analysis.

The FDA repeats Judge Garland’s fundamental

errors of method at several crucial junctures. For

instance, Judge Garland highlights the FDA Final

Rule’s conclusion that, “Jhus, AVA elicits an

antibody response to disrupt the cytotoxic effects of

toxins produced by anthrax bacteria, regardless of the

route of infection. 2005 Final Rule, 70 Fed. Reg. at

75,187 (emphasis added),” and adds his explanation:

“lfiln other words, AVA responds to anthrax in the

same way regardless of how the disease enters

the body.”

The assumption underlying Judge Garland’s

and the FDA’s reasoning in that instance is that

because “toxins produced by anthrax bacteria do not

vary based on the route of exposure,” and it is

demonstrable that the AVA vaccine attacks

toxins, it is valid to conclude that route of

exposure does not matter. That is incorrect. The

FDA in this passage cites two measurable pieces

of scientific data: 1. that the toxins produced by

anthrax which enters the body through the skin

are the same as the toxins produced by anthrax

which enters the body through the lungs; and 2.

that the vaccine attacks those toxins. This is an

analysis on the cellular/molecular level, and is

fine as far as it goes. What is missing is any

evidence comparing the course of the disease

outside of the level of the toxins produced by the

bacteria, at the level of the infected individual's

body. For instance, are there differences in toxin

dispersal and distribution throughout the body,

o Sie

based on the route of infection? Or, in dispersal

and distribution throughout the human body of

the bacteria itself (not the toxin)? Or in the rate

of the anthrax organism’s reproduction and

proliferation in different host tissues? Or, in the

amount of toxin produced by anthrax hosted in

different types of tissues?

Even the FDA does to an extent acknowledge

issues of this sort, stating “We agree that the route

of exposure to an infectious agent may potentially

have an impact on the effectiveness of a vaccine. The

impact likely depends on the nature of the infectious

agent in terms of its mechanism of virulence and the

pathophysiology of infection and disease, and the

mechanism of protection afforded by the vaccine” 70

F.R. at 75187. But then the FDA, in its usual

post-1998 pattern, goes on to declare that the

Brachman study provides sufficient answers for

this. Jd.

Before turning to a brief review of other flaws in

the FDA’s reasoning and processes, a word needs to

be said about the unusual context in which the FDA

was forced to conduct its review, followed by the final

licensing in 2005 of a drug that had languished

virtually unused on the dusty back shelves of the

nation’s apothecary for the better part of half a

century — with a corresponding lack of regulatory

activity or oversight by FDA and its predecessors.

The Court needs to be aware that unusual outside

pressures have seriously impacted the normal, low-

key scientific process here. The FDA and the DoD at

all times since 1998 have been on an urgent mission

to “save” the anthrax vaccine program, and to protect

presidents from both parties from the need to sign a

declaration waiving the consent requirement.”

Clearly, any president from 1998 forward could have

definitively halted the controversy, anxiety and

professional difficulties imposed on thousands of

government scientists, administrators, military

commanders, and service members, not to mention

halted an enormous body of unnecessary litigation

including this case, by simply declaring that a waiver

of the personal consent pursuant to 10 U.S.C. § 1107

was in the nationa! interest. *° This petitioner and

many others would have understood and obeyed the

president’s invocation of the proper legal process to

mandate inoculation of military personnel with an

unlicensed vaccine. Instead, the executive branch

never chose to follow the lawful procedure laid down

by Congress to address such exigencies.

The motivation of the FDA and the DOD in many

regards here is commendable: to protect the military

and the nation against a serious threat that has

emerged in recent years. But the scramble to save

the vaccine has led to short-cuts, unsound scientific

evaluations, and unhealthy rulemaking precedents.

b. Circular Reasoning

*° Defense Secretary Rumsfeld, at an October 18, 2001 news

conference, commented on the AVIP & AVA: “We're going to try

and save it. ... it may or may not be savable.” Retrieved from

http://www.defense.gov/Transcripts/Transcript.aspx?Transcript

[D=2130

*° Ibid. at 8. The unusual pressure government scientists

were under is illustrated by the FBI] report concluding that the

2001 anthrax-by-mail killer was most likely one of the

government's leading anthrax scientists, possibly driven in part

by concerns that the critics of the anthrax vaccine’s safety,

efficacy, and licensing shortcomings were gaining traction.

ie

The government, in its attempts to seize a final

licensure after the setbacks and injunctions imnosed

by the D.C. district court between 2003-05, tries to

argue that it has much more evidence than just the

flawed Brachman study. But a cimse review does not

bear that out; rather, the FDA’s supposedly non-

Brachman evidence itself relies on Brachman’s 1957

epidemic study. Here are the steps: later work by

Brachman and his colleagues, in order to overcome

the «challenge posed by the District Court’s 2003 and

2004 decisions and injunctions, point to FDA and

IOM; but those supposedly additional sources of

evidence both explicitly and heavily rely on the

results of Brachman’s 1957 study. FDA procedures

and federal statutes require two adequate, controlled

human studies.”” If we assume for a moment that

the Brachman study with its shortcomings even

qualifies as one adequate human study, the FDA

would still need to meet the requirement in 21 U.S.C.

§ 355(d)(7) for substantial “confirmatory evidence,”

to bolster the results of the one study. It defies logic,

and the FDA’s rules, to aliow the confirmatory

evidence to be itself substantially based on the single

available study. The law allows the FDA to deviate

from the normal drug-licensure requirement of two

clinical trials; but wisely requires confirmatory

evidence. That evidence should not stem from a

single human clinical trial questioned by its own

author, or perhaps from studies published by the

27 The FDA states, “as a general rule, two adequate and

well-controlled studies are needed to prove the product’s

safety and effectiveness.” FDA Backgrounder, The FDA

Modernization Act of 1997 (Nov. 21, 1997). The statutes allow

FDA to rely on only a single human controlled study in some

instances, but requires substantial confirmatory evidence when

only one human clinica! trial is available. See, e.g., 21 U.S.C.

§ 366(d)(7).

—' 2

alleged letter attack perpetrator as cited in the

FDA’s 2005 Final Rule for AVA.”®

c. FDA’s Other Errors

It is not the intent of this document to contest

the merits on an item-by-item basis. The two

preceding subsections (a.) and (b.) rather seek to

raise errors of fundamental methodology. In this

subsection, we note very briefly a number of other

errors by the FDA. Judge Garland’s propensity to

bake unexamined (and possibly incorrect) hypotheses

and assumptions into his review of the FDA’s

decision making is replayed throughout his decision,

as well as the FDA’s own review.

Ignored are the FDA improperly approved

major manufacturing changes to the vaccine, as

well as the DoD’s orchestration of a 1996 license

application for inhaled anthrax. Other serious

failings exist that could be developed in depth

during a merits review of this matter, any one of

which might support a finding that the FDA order

was arbitrary and capricious. They include

changes to AVA’s dosage schedule and the route

of administration (i.e., subcutaneous _ vs.

intramuscular), see, e.g. 21 C.F.R. § 312, again

triggering the consent provisions of 11 U.S.C. §

1107.

In sum, over the years the FDA and DoD

significantly altered the vaccine, its manufacturing

process, the dosage schedule, and the route of

administration as they saw fit or found convenient,

without regard for the regulations that trigger IND

status and potentially new clinical trials, thus

8 Ivins cited in AVA 2005 Final Rule70 F.R. at , nn. 3-5.

=. ee

requiring consent of military recipients. The sum

effect of these actions, and the lower court’s

misplaced deference, represents a clear indication of

arbitrariness and caprice that warrants review.

Conclusion

The Court should grant review in order to

resolve a significant split in the lower courts:

criminal defendants in the CAAF who refused

anthrax vaccine are subject to conviction and

penalties up to and including incarceration with

no opportunity to contest the legality of the FDA

licensing rule that underpins the military

command to take the vaccine; whereas plaintiffs

in the civilian courts who contest the legality of

the same rule are afforded the opportunity to

contest the agency action on its merits. This

appears unjust and unwise when evaluating

challenges to military orders.

A second issue worthy of the Court’s review

concerns the level of evidence needed before the

FDA can license a drug where ethical concerns

preclude adequately controlled human clinical

trials. Here, only one half-a-century old human

clinical trial exists, using a different vaccine, after

major subsequent manufacturing alterations.

Moreover, the licensure review must be viewed in

the unusual context where the Executive Branch

of the government had a vested interest in this

vaccine’s license, instead of acting in its normal

role as a neutral administrative arbiter. Here, the

entity evaluating the legality of the license also

defended its licensure and significantly expanded

its use through the civilian Strategic National

Stockpile following the 2001 bioterrorism events.

~” =

This Petitioner respectfully requests the Court

review AVA’s license based on the abovementioned

arguments, as well as the prescient relevancy of

the anthrax letter attacks and the DoD’s

deleterious affect on FDA approval methodologies.

Respectfully submitted,

/s/

Lt. Col. Thomas Rempfer

6058 South Jakemp Trail

Tucson., AZ 85747

(520) 869-6590

DECEMBER 28, 2009

endixe

Appendix 1 - Court of Appeals Opinion

United States Court of Appeals

For the District of Columbia Circuit

Argued April 20, 2009

Decided September 29, 2009

No. 08-5117

THOMAS REMPFER,

U.S. AIR FORCE, ET AL., APPELLANTS

V.

JOSHUA M. SHARFSTEIN, MD, ACTING

COMMISSIONER, FOOD AND DRUG

ADMINISTRATION, ET AL., APPELLEES

Appeal from the United States District Court for the

District of Columbia

(No. 1:06-cv-02131-RMC)

John J. Michels Jr. argued the cause for

appellants. With him on the briefs was Mark S. Zaid.

Melissa N. Patterson, Attorney, U-5S.

Department of Justice, argued the cause for

appellees. With her on the brief were Michael F.

Hertz, Acting Assistant Attorney General, Jeffrey A.

Taylor, U.S. Attorney, and Mark B. Stern, Attorney.

R. Craig Lawrence, Assistant U.S. Attorney, entered

an appearance.

Before: HENDERSON, TATEL, and

GARLAND, Circuit Judges.

App. - | -

Opinion for the Court filed by Circuit Judge

GARLAND.

GARLAND, Circuit Judge: Pursuant to the

Department of Defense’s Anthrax Vaccine

Immunization Program, members of che armed forces

may be ordered to submit to inoculation against

anthrax disease. Eight servicemembers brought suit

in district court to challenge the Food and Drug

Administration’s approval of the anthrax vaccine and

to enjoin the Defense Department from

administering it. The district court dismissed three

counts of the complaint on the merits and dismissed

a fourth count because the plaintiffs lack standing to

make it. We affirm.

I

Anthrax is an acute bacterial disease caused

by infection with spores of Bacillus anthracis. It can

be contracted throug three routes of exposure: by

skin contact (cutaneously), by inhalation, and by

ingestion. From 1954-1959, a clinical study led by Dr.

Philip Brachman tested an anthrax vaccine produced

by the Department of Defense (DOD). See Philip S.

Brachman et al., Field Evaluation of a Human

Anthrax Vaccine, 52 AM. J. PUB. HEALTH 632

(1962) [hereinafter Brachman Study]. Dr. Brachman

studied 1249 textile workers exposed to imported

goat hair, dividing the population into a vaccine

group, a placebo group, and an observational (no

treatment) group. Id. at 634, 638.

During the study, 26 cases of anthrax

" As the FDA explained: The Brachman Study’s “selected

population was at risk because the mill workers routinely

handled anthrax-infected animal materials. Prior’ to

App. - 2 -

occurred: 21 contracted cutaneously and 5 by

inhalation. Id. at 638. Three of the cutaneous cases

occurred in the vaccine group; the remainder, and all

inhalation cases, occurred in the placebo and

observational groups. Id. The study calculated that

the vaccine was 92.5 percent effective (lower 95

percent confidence limit = 65 percent). Id. at 644. The

study noted, however, that the small number of

inhalation cases “makes the data less significant in

showing effectiveness of the vaccine” with respect to

that “form of the disease.” Id. at 643.

DOD subsequently contracted with Merck,

Sharpe, & Dohme to develop a new version of the

vaccine for large-scale production. See Food and

Drug Administration (FDA), Biological Products;

Bacterial Vaccines and Toxoids; Implementation of

Efficacy Review; Anthrax Vaccine Adsorbed; Final

Rule, 70 Fed. Reg. 75,180, 75,192 (Dec. 19, 2005)

(hereinafter 2005 Final Rule]. Later, it entered into a

similar contract with the Michigan Department of

Public Health (MDPH), the relevant division of

vaccination, the yearly average number of human anthrax

infections among workers in these mills was 1.2 cases per every

100 employees.” Biological Products; Bacterial Vaccines and

Toxoids; Implementation of Efficacy Review; Anthrax Vaccine

Adsorbed; Final Order, 70 Fed. Reg. 75,180, 75,186 (Dec. 19,

2005). By the mid-1980s, this industrial setting was “vanishing,

precluding any further clinical studies.” Biological Products;

Bacterial Vaccines and Toxoids; Implementation of Efficacy

Review, 50 Fed. Reg. 51,002, 51,058 (Dec. 13, 1985). Today, “due

to the significant health risks associated with exposure to

anthrax spores, it would not be ethical to actively expose human

study subjects to B. anthracis spores in order to assess the

effectiveness of an anthrax vaccine in a controlled clinical trial.

Furthermore, naturally occurring anthrax is now so rare that a

field study of vaccine effectiveness is no longer feasible in the

United States.” 70 Fed. Reg. at 75,192.

App. -3-

which is now operated by the BioPort Corporation.

Id. at 75,181, 75,182, 75,192, 75,197. MDPH/BioPort

produced and continues to produce the current

generation of the vaccine, known as Anthrax Vaccine

Adsorbed (AVA). Id. at 75,192.

Prior to 1972, the National Institutes of

Health (NIH) was the agency responsible for the

licensing of biological products. See 2005 Final

Order, 70 Fed. Reg. at 75,181. In 1970, NIH issued a

license for AVA. As labeled, the vaccine was to be

administered in a six-shot sequence, with specified

intervals between each inoculation. Id. at 75,184.

In 1972, responsibility for licensing biological

products was transferred from NIH to the FDA. Id.

at 75,181. The FDA then issued procedures for

determining that products previously licensed by

NIH “are safe, effective, and not misbranded.”

Procedures for Review of Safety, Effectiveness and

Labeling, 38 Fed. Reg. 4319, 4321 (Feb. 13, 1973)

(codified as amended at 21 C.F.R. § 601.25). Under

those procedures, the FDA appoints an independent

advisory panel to report on covered products. See 21

C.F.R. § 601.25(a), (e). After reviewing the panel’s

recommendations, the FDA makes its own

det“rmination, which it publishes as a Proposed

Order along with the panel’s report. See id. §

601.26(f). After receiving and reviewing comments,

the FDA publishes a final order. See id. § 601.25(g).

In 1973, the FDA announced that advisory

panels would review the safety and effectiveness of

several vaccines previously licensea by NIH,

including AVA. Biological Products; Bacterial

Vaccines and Toxoids with Standards of Potency,

Single or in Combination; Safety, Effectiveness and

App. - 4-

Labeling Review; Request for Data Information, 38

Fed. Reg. 5358 (Feb. 28, 1973). In 1980, an advisory

panel submitted a report finding that the “best

evidence for the efficacy of anthrax vaccine comes

from [the] placebo-controlled field trial conducted by

Brachman.” Biological Products; Bacterial Vaccines

and Toxoids; Implementation of Efficacy Review, 50

Fed. Reg. 51,002, 51,058 (Dec. 13, 1985). Although

the panel concluded that “inhalation anthrax

occurred too infrequently [in the Brachman Study] to

assess the protective effect of vaccine against this

form of the disease,” it recommended categorizing

AVA as “safe and effective under the limited

circumstances for which [it] is employed.” Id. at

51,058, 51,059. In 1985, the FDA issued a Proposed

Order classifying AVA as “safe and effective and not

misbranded,” id. at 51,104, but it did not issue a final

order, see 2005 Final Order, 70 Fed. Reg. at 75,182.

In 1998, DOD implemented the Anthrax

Vaccine Immunization Program (AVIP), which

subjected members of the Armed Forces at risk of

anthrax exposure to mandatory administration of

AVA. See id. at 75,183. Thereafter, Congress directed

DOD to support an independent examination of AVA

by the Institute of Medicine of the National Academy

of Sciences. Id.; see H.R. Rep. No. 106-371, at 256

(1999) (Conf. Rep.). A committee convened by the

Institute conducted the study, examined “all

available data,” and concluded that, “[a]s indicated

by evidence from studies in both humans and

animals,...AVA, as licensed, is an effective vaccine to

protect humans against anthrax, including

inhalational anthrax.” COMM. TO ASSESS THE

SAFETY AND EFFICACY OF THE ANTHRAX

VACCINE, INSTITUTE OF MEDICINE, THE

App. - 5-

ANTHRAX VACCINE: IS IT SAFE? DOES IT

WORK? 1-2 (2002) (@J.A. 140-41) [hereinafter

Institute of Medicine Report].

Meanwhile, in July 2000, a shortage of the

vaccine resulted in a temporary suspension of DOD’s

vaccination program, causing servicemembers who

had begun the six-dose regimen to miss scheduled

shots. First Am. Compl. 94 58, 59, 61; Rempfer v.

Von Eschenbach, 535 F. Supp. 2d 99, 111 (D.D.C.

2008). According to the plaintiffs, when the

suspension ended in 2002, DOD announced that

personnel whose vaccination series had been

interrupted would not repeat any doses already

received but would instead continue with the next

dose in the series. First Am. Compl. 9 63-64.

Six servicemembers sought to enjoin the

vaccination program in 2003. Doe v. Rumsfeld, 297 F.

Supp. 2d 119, 123, 130 (D.D.C. 2003). Although they

did not dispute that AVA had been approved as safe

and effective against cutaneous anthrax, they argued

that it was not a licensed vaccine for inhalational

anthrax. Id. As a consequence, they maintained, 10

U.S.C. § 1107(f)(1) barred administration of the

vaccine without either informed consent or a

. , . 2

Presidential waiver.

* The statute provides:

In the case of the administration of an

investigational new drug or a drug unapproved for its

applied use to a member of the armed forces in

connection with the member’s participation in a

particular military operation, the requirement that the

member provide prior consent to receive the drug in

accordance with the prior consent requirement imposed

under section 505(i)(4) of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 355(i)(4)) may be waived only

App. - 6-

Finding a likelihood of success on this claim,

the district court issued the requested preliminary

injunction in December 2003. Doe, 297 F. Supp. 2d at

135. Days later, the FDA finalized the order it had

proposed in 1985, but revised it to specify that AVA

was safe and effective “independent of the route of

exposure.” Biological Products; Bacterial Vaccines

and Toxoids; Implementation of Efficacy Review, 69

Fed. Reg. 255, 260, 257-59 (Jan. 5, 2004). The district

court vacated that order for failure to comply with

the notice-and-comment requirements of the

Administrative Procedure Act (APA), 5 U.S.C. § 553.

Doe v. Rumsfeld, 341 F. Supp. 2d 1 (D.D.C. 2004).

The court then issued a permanent injunction --

“unless and until FDA follows the correct procedures

to certify AVA” as safe and effective -- against

“involuntary anthrax vaccinations absent informed

consent or a Presidential waiver.” Id. at 16. The

government filed an appeal in this court.

In December 2004, the FDA issued a new

proposed order for comment. Biological Products;

Bacterial Vaccines and Toxoids; Implementation of

Efficacy Review, 69 Fed. Reg. 78,281 (Dec. 29, 2004).

After reviewing the comments, the FDA issued a new

final order on December 19, 2005, again classifying

AVA as safe and effective in the prevention of

anthrax regardless of the route of exposure. 2005

Final Order, 70 Fed. Reg. 75,180. In February 2006,

a panel of this court concluded that, because issuance

of the new order caused the permanent injunction to

by the President. The President may grant such a

waiver only if the President determines, in writing, that

obtaining consent is not in the interests of national

security.

10 U.S.C. § 1107(f)(1).

dissolve “[b]y its own terms,” the government’s

appeal was moot. Doe v. Rumsfeld, 172 Fed. Appx.

327, 328 (D.C. Cir. 2006). In October 2006, DOD

announced resumption of the mandatory

immunization program. First Am. Compl. 4 8.

Thereafter, the plaintiffs in the case now

before us — eight servicemembers subject to

mandatory inoculation orders -- initiated new

proceedings in the district court challenging the

FDA’s 2005 final order. First Am. Compl. 94 1-8.

They also sought to enjoin DOD from deviating from

the recommended six-shot schedule for

servicemembers whose vaccinations DOD had

suspended between 2000 and 2002. The plaintiffs

alleged that any such deviation would violate 10

U.S.C. § 1107(H(1). Id. 94] 102-12; see supra note 2.

The district court resolved the only issue raised by

the plaintiffs’ three claims against the FDA --

whether the agency’s reliance on the Brachman

Study to establish the vaccine’s effectiveness against

anthrax was arbitrary or capricious under the APA --

in favor of the agency. Rempfer, 535 F. Supp. 2d 99.

It also dismissed the plaintiffs’ claim against DOD

for lack of standing based on the plaintiffs’ failure to

allege that they had been or would be subjected to

off-schedule inoculations. Id.

We review the district court’s APA ruling de

novo, “as if the agency’s decision ‘had been appealed

to this court directly.” Gerber v. Norton, 294 F.3d

173, 178 (D.C. Cir. 2002) (quoting Dr. Pepper/Seven-

Up Cos. v. FTC, 991 F.2d 859, 862 (D.C. Cir. 1993)).

We also review de novo the district court’s dismissal

of the claim against DOD for lack of standing. Muir

v. Navy Fed. Credit Union, 529 F.3d 1100, 1105 (D.C.

Cir. 2008).

App. -8 -

Il

The plaintiffs’ principal challenge is to the

FDA’s determination that the anthrax vaccine is

effective.’ More specifically, they fault the FDA’s

reliance on the Brachman Study in making that

determination. They argue that reliance on that

study was improper because: 1) it cannot support-a

finding of effectiveness against anthrax contracted by

inhalation; and 2) it cannot support a finding of

effectiveness for the current generation of the

anthrax vaccine. The plaintiffs do not contest the

vaccine’s safety.

We will consider both arguments, but first

pause to correct the plaintiffs’ misperception

regarding the nature of the district court’s review,

and of ours, under the APA. The plaintiffs repeatedly

insist that the district court was obliged to deny the

government's motion to dismiss because they had

raised genuine issues of material fact and hence were

entitled to discovery to flesh out their claims. But

“when a party seeks review of agency action under

the APA [before a district court], the district judge

sits as an appellate tribunal.” Am. Bioscience, Inc. v.

Thompson, 269 F.3d 1077, 1083 (D.C. Cir. 2001).

“The entire case on review is a question of law,” and

the “complaint, properly read, actually presents no

factual allegations, but rather only arguments about

the legal conclusion to be drawn about the agency

* “Effectiveness means a reasonable expectation that, in a

significant proportion of the target population, the

pharmacological or other effect of the biological product, when

used under adequate directions, for use and warnings against

unsafe use, will serve a clinically significant function in the

diagnosis, cure, mitigation, treatment, or prevention of disease

in man.” 21 C.F.R. § 601.25(d)(2).

App. -9-

action.” Marshall County Health Care Auth. v.

Shalala, 988 F.2d 1221, 1226 (D.C. Cir. 1993).*

Consequently, challengers are “not . . . ordinarily

entitled to augment the agency’s record with cither

discovery or testimony presented in the district

court,” and there is “no inherent barrier to reaching

the merits” at the motion to dismiss stage. Id. Our

review, like that of the district court, is based on the

agency record and limited to determining whether

the agency acted arbitrarily or capriciously. See 5

U.S.C. § 706.

A

The plaintiffs first object that, because the

Brachman Study included few cases of anthrax

contracted by inhalation, it cannot support a

conclusion of effectiveness against that route of

exposure. We grant the plaintiffs’ premise but

disagree with their conclusion.

The FDA does not dispute that, if “the cases of

inhalation anthrax reported in the course of the

Brachman study [are] analyzed separately, [they] are

too few to support a meaningful statistical

conclusion.” 2005 Final Order, 70 Fed. Reg. at

75,183. But this simply directs us to the underlying

issue: should “inhalational anthrax” be analyzed

separately? That question cannot, as appellants

assume, be answered as an abstract question of

* See Am. Bioscience, 269 F.3d at 1083 (noting that, “when

reviewing agency action[,] the question of whether the agency

acted in an arbitrary and capricious manner is a legal one

which the district court can resolve on the agency record,

regardless of whether it is presented in the context of a motion

for judgment on the pleadings or in a motion for summary

judgment”).

App. - 10 -

statistical method. Rather, it must be answered as a

matter of scientific judgment. To illustrate: if the

route-of-exposure distinction were replaced with a

time-of exposure distinction, no one would insist that

“morning anthrax” must be analyzed separately from

“afternoon anthrax.” Yet categorizing cases by time

seems arbitrary not because time of exposure is any

less measurable a distinction than route of exposure,

but because time seems unlikely -- as a scientific

matter -- to be relevant to vaccine effectiveness.

Of course, in comparison to time of exposure, it

is not as self-evident that route of exposure is

unlikely to be relevant. After all, Dr. Brachman did

flag the route-of-exposure distinction half a century

ago. Moreover, the FDA agrees that, as'a general

matter, “the route of exposure to an infectious agent

may potentially have an impact on the effectiveness

of a vaccine.” Id. at 75,187.

But in the case of the anthrax vaccine, the

FDA’s scientific judgment is that route of exposure is

not relevant to the vaccine’s effectiveness. The

reason, the agency explains, is as follows:

With regard to the known pathophysiology of

anthrax, the signs and symptoms of disease arise due

to the production of toxins by anthrax bacteria

growing within the infected individual. The toxins

produced by anthrax bacteria do not vary based on

the route of exposure. The antibodies produced in

response to vaccination contribute to the protection

of the vaccinated individual by neutralizing the

activities of those toxins. Thus, AVA elicits an

antibody response to disrupt the cytotoxic effects of

toxins produced by anthrax bacteria, regardless of

the route of infection.

App. - Ll -

2005 Final Order, 70 Fed. Reg. at 75,187

(emphasis added). In other words, AVA responds to

anthrax in the same way regardless of how the

disease enters the body. Thus, for purposes of

establishing AVA’s effectiveness, the inhalational

versus cutaneous distinction is one without a

difference, and there is no need to treat them

separately in interpreting the Brachman Study. This,

the FDA explains, is why it disagrees with the 1980

advisory panel’s statement that inhalation anthrax

occurred too infrequently in the Brachman Study to

provide a basis for assessing the efficacy of AVA

against that form of the disease. Id. at 75,183; see 38

Fed. Reg. at 4321 (stating that “the report of each

panel is advisory to the Commissioner, who has the

final authority to accept or to reject the conclusions

and recommendations of the panel”).

As the FDA further notes, its judgment in this

respect is in accord with the report of the committee

of experts charged by the Institute of Medicine with

conducting an independent review. 2005 Final Order,

70 Fed. Reg. at 75,183. The committee found that

“laboratory experiments indicate that AVA provides

effective protection against inhalational challenge in

rabbits and macaques, the animal models in which

the disease is most reflective of the disease in

humans.” Institute of Medicine Report, at 10. And

the committee concluded that, “[a]s indicated by

evidence from studies in both humans and animals,

...AVA, as licensed, is an effective vaccine to protect

humans against anthrax, including inhalational

anthrax.” Id. at 2.”

* The FDA found additional support for the effectiveness of

the vaccine in epidemiological data “on the occurrence of

App. - 12 -

At bottom, the plaintiffs’ claim that the

Brachman Study establishes nothing in regard to

“inhalational anthrax” relies on the proposition that

route of exposure is scientifically relevant. But the

FDA’s contrary determination is a_ scientific

judgment within its “area of expertise,” the kind of

judgment to which this court gives a “high level of

deference.” A.L. Pharma, Inc. v. Shalala, 62 F.3d

1484, 1490 (D.C. Cir. 1995); see Serono Labs., Inc. v.

Shalala, 158 F.3d 1813, 1320 (D.C. Cir. 1998).

Moreover, as the plaintiffs themselves concede, there

is no scientific evidence in the administrative record

to contradict that judgment. See Oral Argument

Recording at 35:03.° In the absence of such evidence,

we must defer to the FDA’s judgment that AVA is

effective regardless of the route of exposure.

B

anthrax disease in at-risk industrial settings collected by the

[Centers for Disease Control and Prevention] and summarized

for the years 1962 to 1974.” 2005 Final Order, 70 Fed. Reg. at

75,183. The FDA noted that unvaccinated persons within the

at-risk populations had been infected by anthrax during that

period, but that “no cases have occurred in fully vaccinated

subjects while the risk of infection has continued.” Id.

® At oral argument, plaintiffs’ counsel pointed to one piece of

evidence purportedly contradicting the FDA’s judgment — a

declaration the plaintiffs filed in the district court. See J.A. 212.

The declaration was not submitted to the FDA during the

administrative proceedings and was not mentioned in the

plaintiffs’ appellate briefs. It is therefore outside the scope of

our review on two accounts. See Citizens to Preserve Overton

Park, Inc. v. Volpe, 401 U.S. 402, 420 (1971) (holding that

review is generally limited to the “record that was before the

[agency] at the time [it] made [its] decision”); Ark Las Vegas

Rest. Corp. v. NLRB, 334 F.3d 99, 108 n.4 (D.C. Cir. 2003)

(holding that arguments raised for the first time at oral

argument are waived).

App. - 13 -

The plaintiffs’ other principal contention is

that, because the Brachman Study used an earlier

generation of the anthrax vaccine, it cannot establish

the effectiveness of the current version. We again

grant the premise but reject the conclusion.

The fact that manufacturing changes occur

during the course of vaccine production is not unique

to AVA, and the FDA has an established protocol for

analyzing such changes: “{[A] manufacturer may

make manufacturing changes in a product without

performing additional clinical studies to demonstrate

the safety and effectiveness of the similar product if

data regarding the manufacturing changes support

the conclusion that the versions are comparable.”

2005 Final Order, 70 Fed. Reg. at 75,184. The

plaintiffs maintain that “there is no evidence within

the Administrative Record that the FDA ever

compared the different anthrax vaccines and efficacy

data to reach the conclusion that the vaccines are

comparable.” Appellants’ Br. 43. But that is simply

incorrect, because the FDA did make the requisite

comparability determination.

As the FDA explained in its 2005 Final Order,

it “reviewed the historical development of AVA and

conclude[d] that DOD directed the development of

the vaccine, including its formulation § and

manufacturing process, from the vaccine used in the

Brachman study .. . to the vaccine that was

ultimately licensed and manufactured by BioPort.”

2005 Final Order, 70 Fed. Reg. at 75,184. “All three

versions of anthrax vaccine,” the agency determined,

“were tested in animals and demonstrated to protect

test animals .. . against challenge with virulent

[anthrax] spores.” Id. In addition, “clinical data

comparing the safety and immunogenicity of [AVA]

App. - 14 -

with [the DOD] vaccine...reveal that the serological

responses to [AVA] and [the DOD] vaccine were

similar with respect to peak antibody response and

seropositivity.” Id. That is, human blood serum

showed similar antibody production in response to

the different versions of the vaccine. Id. at 75,184,

75,192-93. The FDA also found that the two versions

were “comparable in their ability to protect test

animals.” Id. at 75,184. On this basis, the agency

concluded that the two vaccines were comparable

and that the Brachman Stud~ could therefore be

used to approve AVA. Id.

Once again, we are presented with a scientific

judgment by the FDA to which we owe considerable

deference. And once again, the plaintiffs fail to

proffer any scientific evidence to rebut it. Our

conclusion must therefore be the same as above: the

FDA did not act arbitrarily or capriciously in resting

a finding of effectiveness on the results of the

Brachman Study.’

III

Finally, we address the plaintiffs’ claim that

DOD is subjecting military personnel to mandatory

immunization on an unapproved schedule of

inoculations. The district court dismissed this claim

on the ground that the plaintiffs lack standing to

” Scattered throughout the plaintiffs’ briefs are a number of

additional arguments criticizing the Brachman Study. Because

those arguments are raised “only summarily, without

explanation or reasoning,” they are waived. City of Waukesha v.

EPA, 320 F.3d 228, 251 n.22 (D.C. Cir. 2003). In any event, we

agree with the carefully considered opinion of the district court

that those additional challenges lack merit. See Rempfer, 535 F.

Supp. 2d at 108-11.

App. - 15 -

raise it. “To establish constitutional standing, a

plaintiff must show an injury in fact that is fairly

traceable to the challenged conduct and that will

likely be redressed by a favorable decision on the

merits.” Muir, 529 F.3d at 1105 (citing Lujan v.

Defenders of Wildlife, 504 U.S. 555, 560-61 (1992)).

The district court concluded that the plaintiffs have

not alleged the constitutionally requisite injury in

fact, and we agree.

The plaintiffs’ complaint alleges that DOD

began its program of mandatory inoculation in 1998,

suspended it for some period during 2000-02 due toa

supply shortage, and then resumed the program

without correcting for the interruption in the

recommended six-shot dosage schedule. First Am.

Compl. {| 10, 58-64. The plaintiffs do not allege that

servicemembers who were or will be inoculated for

the first time under the post-2002 regime will have

their inoculations interrupted and restarted off

schedule. Nor do they claim that DOD is otherwise

stopping and resta ting the shot sequences. Rather,

they allege that “[p]lersonnel whose vaccination

series was interrupted during the p[re]vious AVIP

slowdown....will just continue with the next dose in

the series.” First Am. Compl. § 63 (emphasis added)

(quoting an Air Force statement).

As the district court noted, the plaintiffs have

“not alleged that they themselves have been, or

imminently will be, subjected to such [an

interrupted] vaccination schedule.” Rempfer, 535 F.

Supp. 2d at 111. The complaint does not allege that

the inoculation sequence of any of the plaintiffs was

actually interrupted by the 2000-02 AVIP

suspension. Nor have the plaintiffs filed an affidavit

te that effect. At oral argument, the plaintiffs

App. - 16 -

insisted that they are under no obligation to make

such an allegation. See Oral Argument Recording at

15:35-48.

The plaintiffs are wrong. “[I]t is the burden of

the party who seeks the exercise of jurisdiction in his

favor clearly to allege facts demonstrating that he is

a proper party to invoke judicial resolution of the

dispute.” FW/PBS, Inc. v. City of Dallas, 493 U.S.

215, 231 (1990) (internal quotations and citations

omitted). Thus, the plaintiffs “must ‘allege...facts

essential to show jurisdiction. If [they] faiflj] to make

the necessary allegations, [they have} no standing.”

Id. (quoting McNutt v. Gen. Motors Acceptance

Corp., 298 U.S. 178, 189 (1936)) (alterations and

omissions in original). Plaintiffs have failed to make

the necessary allegation here, and they therefore

lack standing to raise this challenge.

IV

For the foregoing reasons, the judgment of the

district court is

Affirmed.

App. - |7 -

A ndix 2 — District Cour inion

UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF COLUMBIA

)

THOMAS REMPFER, et al.,

Plaintiffs,

v.) Civil Action No. 06-2131 (RMC)

)

ANDREW C. VON ESCHENBACH,

Commissioner Food and Drug

Administration, et al.,

Defendants.

MEMORANDUM OPINION

Plaintiffs’ are military personnel subject to

orders to take Anthrax Vaccine Adsorbed (“AVA”),

the only vaccine in the U.S. licensed as a

prophylactic against anthrax. They brought this suit

against the Food and Drug Administration (FDA),

the Department of Health and Human Services

(HHS), and the Department of Defense (DoD)?

' Plaintiffs are: Thomas Rempfer, Joshua Cohen, Gareth

Harris, Kevin Ferrara, Shameka Edwards, Eric Gearhart,

Michael Palmer, and James Hailstone.

* The complaint names, in their official capacities, the

following: Andrew Von Eschenbach, Commissioner, FDA; Mike

Leavitt, Secretary, HHS; and Robert Gates, Secretary, DoD.

The FDA is an agent of HHS.

App. - 18 -

(collectively “Defendants”), challenging (1) the FDA’s

Final Order, see 70 Fed. Reg. 75,180 (Dec. 19, 2005),

which determined that AVA is safe and effective and

not misbranded,’® and (2) the DoD’s decision to

reinstate mandatory AVA inoculations. Plaintiffs do

not contend that AVA is unsafe or misbranded;

instead they allege that there is insufficient evidence

that AVA is effective to prevent anthrax infection

acquired through inhalation. Defendants move to

dismiss. Upon reviewing the pleadings and the

administrative record and in deference to the FDA’s

evaluation of scientific data, Defendants’ motion will

be granted.

I. BACKGROUND

Anthrax is a bacterial disease caused by

spores of Bacillus anthracis. Anthrax spores can

cause infection through three routes: skin contact

(cutaneous), ingestion, and inhalation. Without

antibiotic treatment, inhalation anthrax has the

* Plaintiffs’ counsel here instituted prior litigation, Doe v.

Rumsfeld, Civ. No. 03-707 (D.D.C.), related to AVA. In that suit,

six John and Jane Doe plaintiffs sought to challenge the DoD’s

immunization program. The court enjoined DoD from

inoculating service members, finding that the vaccine was not

properly licensed since the FDA had not made a final decision

regarding the investigational status of AVA. Doe v. Rumsfeld,

297 F. Supp. 2d 119, 131 (D.D.C. 2003). Soon after, the FDA

issued a final order classifying AVA as safe and effective; as a

result the injunction was stayed. Doe v. Rumsfeld, 297 F. Supp.

2d 200, 201 (D.D.C. 2004). The Doe plaintiffs then amended

their complaint to challenge the FDA’s final order. The Court,

on cross motions for summary judgment, then determined that

the FDA had issued the final order without proper notice and

comment. The FDA withdrew the final order and proceeded

with notice and comment. The FDA then issued a new Final

Order, 70 Fed. Reg. 75,180, the one at issue here.

App. - 19-

highest fatality rate — estimated to be 45% to 90%.

A.R. at 639 (04 AR, Vol. 3).* Cutaneous anthrax has

an estimated 20% fatality rate, and gastrointestinal

anthrax has an estimated fatality rate of 25% to 60%.

Id. at 638-39. In the U.S., there were eighteen cases

of inhalations anthrax from 1900 to October 2001,°

mostly occurring in textile mill workers. Jd. at 639.

Sixteen of those cases were fatal. Then, from October

4, 2001 to December 5, 2001, there were eleven cases

of inhalation anthrax, five of which were fatal. Jd.

The 2001 cases were all linked to intentional

dissemination. Jd. Regardless of the route of

exposure, anthrax is toxic to the body in the same

way. The “virulence components” of anthrax include

an anitphagocytic capsule and three proteins:

protective antigen, lethal factor, and edema factor.

The combination of protective antigen with lethal

factor causes the formation of cytotoxic lethal toxin,

and the combination of protective antigen with

edema factor results in edema toxin. Jd.

In 1965, DoD contracted with the Michigan

Department of Public Health (“MDPH”) to produce

an anthrax vaccine. A.R. 3647-52 (04 AR, Vol. 13).

Before the MDPH contact, DoD had contracted with

Merck Sharpe & Dohme to produce an anthrax

vaccine and prior to that the Army had produced a

vaccine (the “original vaccine” or the “DoD vaccine”).

* “AR.” refers to the Administrative Record consisting of

4209 pages originally filed in 2004, see Doe v. Rumsfeld, Civ.

No. 03-707 (D.D.C.), plus an additional 20,000 pages. The

record first filed in 2004 has been refiled here in 15 volumes on

a single CD; these documents are secondarily cited as “(04 AR,

Vol. __)”. The additional 20,000 pages were filed here in 3

volumes on 3 CDs.

° The last case reported in this period occurred in 1976.

App. - 20 -

In 1966, the Center for Disease Control (“CDC”) filed

with the National Institute for Health (“NIH”) a

“Notice of Claimed Investigational Exemption” for

the anthrax vaccine. Under this investigational new

drug application, the CDC began an “open label

study” to collect safety data on the MDPH vaccine;

the study continued from year to year and the CDC

provided annual progress reports to the NIH. The

next year, MDPH filed a product license application

with the NIH for the vaccine it was producing for

DoD. During the licensing process, the MDPH

vaccine was named AVA.

The NIH licensed AVA in 1970.° The NIH-

approved package insert recommended AVA

immunization for individuals with a risk of exposure

to anthrax, those who come into contact with animal

hides, bonemeal, and fur, especially goat hair. A.R.

3291 (04 AR, Vol. 12). The 7 059 labeling did not

recommend immunization be limited to any

particular route of exposure. A.R. 3291-92 (04 AR,

Vol. 12). AVA was licensed to be given in a six dose

regimen: three inoculations, each two weeks apart,

and then three more given at six, twelve, and

eighteen month intervals thereafter.

®° The committee from the NIH that recommended g 6

ranting the license application based its recommendation on the

following: the CDC safety data, potency data from lab tests

using AVA in guinea pigs, and additional standards relating to

production and potency testing. While the committee noted that

MDPH’s vaccine had not been used in a controlled field trial,

the original vaccine was used in a controlled study. Because the

original vaccine and the MDPH vaccine were comparable, the

FDA determined that the controlled study could be relied upon

for proof of AVA’s effectiveness. See text infra regarding Count

III of the First Amended Complaint.

App. - 21 -

In 1973, the FDA announced a safety and

effectiveness review for various vaccines, including

AVA, and solicited data and information. 38 Fed.

Reg. 5,358 (Feb. 28, 1973). The Panel that conducted

the review issued a report in 1980. See A.R. 0001-

0600 (04 AR, Vol. 1-2). In 1985, the FDA published

the Panel’s report and a proposed order relating to

matters in the report. See 50 Fed. Reg. 51,002, (Dec.

13, 2005). As to AVA, the FDA agreed with the

Panel’s recommended that AVA be categorized as

safe, effective, and not misbranded. 70 Fed. Reg. at

75,182; see 50 Fed. Reg. at 51,059."

To determine whether AVA was effective, the

Panel considered: (1) a controlled human field study

conducted by Drs. Brachman, Gold, Plotkin, Fekety,

Werrin, and Ingraham in the 1950s (the “Brachman

Study”), see A.R. 3732-3745 (04 AR, Vol. 13), and (2)

surveillance data collected by the CDC. See 50 Fed.

Reg. at 51,058. The Brachman Study involved 1,249

workers in four textile mills that processed raw

imported goat hair, a group at risk for anthrax

infection.® See AR 3732-33 (04 AR, Vol. 13). The

" There is a two-stage process for reviewing biological

products licensed prior to July 1, 1972, such as AVA. See 21

C.F.R. § 601.25. First, the FDA Commissioner appoints a Panel

of experts to review the safety, effectiveness, and labeling of the

biological product at issue and to produce an advisory report. Id.

§ 601.25(a) & (e). Second, the Commissioner publishes the

report and a proposed order in the Federal Register and solicits

comments. Id. § 601.25(f). After reviewing the comments, the

FDA publishes a final order, which constitutes final agency

action from which appeal may lie to the courts. Id. § 601.25(g) &

(i).

* In order to conduct a study of the effectiveness of the

vaccine, the study required a “well defined, exposed, susceptible

population among whom cases of anthrax were reported with

App. - 22 -

workers were divided into three groups: one received

the anthrax vaccine; one received a placebo; and one

was simply monitored for anthrax infection. Jd. at

3732; 50 Fed. Reg. at 51,058. There were 26 cases of

anthrax during the study period, five of which were

individuals infected through inhalation. See AR 3734

(04 AR, Vol. 13); id. at 3736 (Table 4). None of the

individuals with inhalation anthrax had taken the

vaccine, two were in the placebo group, and three

were in the observation group. The remaining

twenty-one infected workers contracted cutaneous

anthrax. Of those, three had taken the vaccine

(although two had not been fully inoculated), fifteen

were in the placebo group, and three were in the

observation group. Jd. Based on these facts, the

Brachman Study concluded the effectiveness of the

vaccine at 92.5%, comparing the vaccine group with

the placebo group and combining the inhalation and

cutaneous cases. Id. at 3737. The rate of effectiveness

did not include data from the group that was simply

monitored. Jd.; A.R. 1381 at n.9 (04 AR, Vol. 6).

Although the Panel relied on the Brachman

Study, the Panel found that the study demonstrated

effectiveness only against cutaneous anthrax because

the inhalation cases “occurred too infrequently to

assess the protective effect of [the] vaccine against

this form of the disease.” Fed. Reg. at 51,058.

“Anthrax vaccine poses no serious special problems

other than the fact that its efficacy against

inhalation anthrax is not well documented. This

some regularity.” See A.R. 3732 (04 AR, Vol. 13). This type of

population could only be found in the U.S. in certain types of

textile mills. Id. When the Panel submitted its report in 1980,

this type of industry was “vanishing, precluding any further

clinical studies.” 50 Fed. Reg. at 51,058.

App. - 23 -

question is not amenable to study due to the low

incidence and sporadic occurrence of the disease.” Jd.

Even so, the Panel found the vaccine to be safe and

effective for the limited circumstances for which it is

employed. Jd. Further, the Panel did not recommend

any change in the “recommendations for use” section

of the AVA label, which recommended AVA for

immunization against anthrax, without § any

specification regarding route of exposure.®

In addition to the Brachman Study, the Panel

relied on the CDC surveillance data as evidence of

effectiveness as follows:

{The data] were summarized for the

period between 1962 to 1974. Twenty-

seven cases were identified. Three cases

were not mill employees, but worked in

or near mills; none of these cases were

vaccinated. Twenty-four cases were mill

employees; three were partially

immunized (one with 1 dose, two with 2

doses); the remainder (89 percent) being

unvaccinated. Therefore, no cases have

occurred in fully vaccinated subjects

while the risk of infection § has

continued. These observations lend

further support to the effectiveness of

this product.

* In the Final Order, discussed infra, the FDA found that the

Panel’s conclusion that the Brachman study demonstrated

effectiveness only against cutaneous anthrax due to the low

incidence of inhalation cases was in error, and that in fact the

Brachman Study calculated the vaccine’s effectiveness against

cutaneous and inhalation anthrax. See A.R. 3736 (04 AR, Vol.

13 (Table 4); id. at 3740-41 (Table 8).

App. - 24 -

Id. Thus, based on the CDC surveillance data and

the Brachman Study, the Panel found “substantial

evidence of safety and effectiveness for this product

[AVA].” Jd. at 51,059.

In March of 1998, DoD implemented the

Anthrax Vaccine Immunization Program to protect

service personnel at risk of contracting anthrax.

Congress then directed DoD to contract with the

National Research Council to study the safety and

effectiveness of AVA. A.R. 3324 (04 AR, Vol. 12). As a

result, the Institute of Medicine’s Committee to

Assess the Safety and Efficacy of the Anthrax

Vaccine (the “IOM Committee”) conducted an

independent study over the course of two years. A.R.

3303-583 (04 AR, Vol. 12). The IOM Committee’®

sought, reviewed, and weighed “[a]ll available data.”

Id. at 3309. The Committee issued a report finding,

“As indicated by evidence from studies in both

humans and animals, the committee concluded that

AVA, as licensed, is an effective vaccine to protect

humans against anthrax, including inhalational

anthrax,” and it is “reasonably safe.” Jd. at 3323.

In its 2005 Final Order, the FDA agreed with

the report of the IOM Committee and its finding that

AVA was effective. 70 Fed. Reg. at 75,183. The FDA

disagreed with the Panel’s 1985 opinion that the

Brachman Study did not have sufficient data to

'° The IOM Committee was composed of ten experts from

respected institutions such as Harvard University and the

University of Pennsylvania School of Medicine. Their collective

knowledge included expertise in microbiology, epidemiology,

biostatistics, immunology, and health surveillance, as well as

vaccine research, development, manufacture, evaluation, and

post - marketing surveillance of adverse events. A.R. 3325 (04

AR, Vol. 12).

App. - 25 -

demonstrate the effectiveness of AVA against

inhalation anthrax. The FDA explained:

We do not agree with the Panel’s

statement that the protection [provided

by AVA] was limited to cutaneous

anthrax cases. The Brachman [S]tudy’s

comparison between anthrax cases in

the placebo and vaccine groups included

both inhalation and cutaneous anthrax

cases. Accordingly, the calculated

effectiveness of the vaccine to prevent

both types of anthrax disease combined

was 92.5 percent (lower 95 percent

confidence interval = 65 percent) as

described in the Brachman, et al. report.

Id. See also A.R. 3736 (04 AR, Vol. 13 (Table 4)); id.

at 3740-41 (Table 8). The FDA noted that the CDC

surveillance data supported the Brachman Study’s

findings regarding the effectiveness of AVA.’

The FDA _ received numerous comments

relating to its Order. Comments supportive of AVA

licensure included a submission by a researcher who

discussed in detail “how the pathology of cutaneous

and inhalation anthrax at the cellular level is

fundamentally the same, i.e., dependent on the

actions of anthrax toxin, such that cytotoxic activities

are blocked by antibodies produced in response to

AVA in the same manner despite the route of

'' The FDA also agreed with the Panel that the safety of

AVA was demonstrated by the CDC open label safety study

(described supra) that was initiated in 1966. 70 Fed. Reg. at

75,183 & 75,188. The CDC open label safety study should not be

confused with the CDC surveillance data which corroborated

the Brachman Study’s findings regarding AVA’s effectiveness.

App. - 26 -

exposure.” 70 Fed. Reg. at 75,185. Comments

against licensure included the same objections that

Plaintiffs raise here. The FDA concluded, “After

review of the comments and finding no additional

scientific evidence to alter the proposed

categorization, FDA accepts the Panel’s

recommendation . . . and determines AVA to be safe

and effective and not misbranded.” Jd. at 75,182.

Counts I, II, and III of the First Amended

Complaint challenge the FDA’s Final Order.

Plaintiffs seek temporary and permanent injunctive

relief from DoD’s anthrax vaccination program,

alleging that the FDA’s finding that AVA was

effective against inhalation anthrax was arbitrary

and capricious in violation of the Administrative

Procedure Act (“APA”), 5 U.S.C. §§ 701 et seq. In

Count IV, Plaintiffs seek a declaratory judgment that

AVA is being administered in violation of 10 U.S.C. §

1107. Defendants seek dismissal of Counts I, II, and

III based on failure to state a claim and on Count [V

based on lack subject matter jurisdiction due to lack

of standing. Plaintiffs oppose.

Il. STANDARD OF REVIEW

A. Failure to State a Claim

A motion to dismiss pursuant to Federal Rule

of Civil Procedure 12(b)(6) challenges the adequacy of

a complaint wn its face, testing whether a plaintiff

has properly stated a claim. Although a complaint

“does not need detailed factual allegations, a

plaintiffs obligation to provide the ‘grounds’ of his

‘entitle[ment] to relief requires more than labels and

conclusions, and a formulaic recitation of the

elements of a cause of action will not do.” Bell Atl.

Corp. v. Twombly, 127 S. Ct. 1955, 1964-65 (2007)

App. - 27 -

(internal citations omitted). The court must treat the

complaint’s factual allegations — including mixed

questions of law and fact — as true, drawing all

reasonable inferences in the plaintiffs favor,

Macharia v. United States, 334 F.3d 61, 64, 67 (D.C.

Cir. 2003); Holy Land Found. for Relief & Dev. v.

Ashcroft, 333 F.3d 156, 165 (D.C. Cir. 2003), and the

facts alleged “must be enough to raise a right to relief

above the speculative level,” Twombly, 127 S. Ct. at

1965. But the court need not accept as true

inferences unsupported by facts set out in the

complaint or legal conclusions cast as factual

allegations. Browning v. Clinton, 292 F.3d 235, 242

(D.C. Cir. 2002).

B. Lack of Subject Matter Jurisdiction

Federal courts are courts of limited

jurisdiction and the law presumes that “a cause lies

outside this limited jurisdiction.” Kokkonen v.

Guardian Life Ins. Co. of Am., 511 U.S. 375, 377

(1994). Because subject matter jurisdiction is an

Article III as well as a statutory requirement, “no

action of the parties can confer subject-matter

jurisdiction upon a federal court.” Akinseye vu. District

of Columbia, 339 F.3d 970, 971 (D.C. Cir. 2003). On a

motion to dismiss for lack of subject-matter

jurisdiction pursuant to Rule 12(b)(1), the plaintiff

bears the burden of establishing that the court has

subject matter jurisdiction. Evans v. B.F. Perkins

Co., 166 F.3d 642, 647 (4th Cir. 1999); see also

McNutt v. Gen. Motors Acceptance Corp., 298 U.S.

178, 182-83 (1936)). Because subject matter

jurisdiction focuses on the court’s power to hear the

claim, however, the court must give the plaintiffs

factual allegations closer scrutiny when resolving a

Rule 12(b)(1) motion than would be required for a

App. - 28 -

Rule 12(b)(6) motion for failure to state a claim.

Macharia v. United States, 334 F.3d 61, 64, 69 (D.C.

Cir. 2003). To determine whether it has jurisdiction

over the claim, the court may consider materials

outside the pleadings. Herbert v. Nat'l Acad. of Scis.,

974 F.2d 192, 197 (D.C. Cir. 1992).

C. APA Review

The APA requires a reviewing court to set

aside an agency action that is “arbitrary, capricious,

an abuse of discretion, or otherwise not in accordance

with law.” 5 U.S.C. § 706(2)(A); Tourus Records, Inc.

v. Drug Enforcement Admin., 259 F.3d 731, 736 (D.C.

Cir. 2001). In making this inquiry, the reviewing

court “must consider whether the [agency’s] decision

was based on a consideration of the relevant factors

and whether there has been a clear error of

judgment.” Marsh v. Oregon Natural Res. Council,

490 U.S. 360, 378 (1989) Gnternal quotation marks

and citation omitted). At a minimum, the agency

must have considered relevant data and articulated

an explanation establishing a “rational connection

between the facts found and the choice made.”

Bowen v. Am. Hosp. Ass’n, 476 U.S. 610, 626 (1986);

see also Pub. Citizen, Inc. v. Fed. Aviation Admin.,

988 F.2d 186, 197 (D.C. Cir. 1993) (“The requirement

that agency action not be arbitrary or capricious

includes a requirement that the agency adequately

explain its result.”). An agency action usually is

arbitrary or capricious if

the agency has relied on factors which

Congress has not intended it _ to

consider, entirely failed to consider an

important aspect of the problem, offered

an explanation for its decision that runs

App. - 29 -

counter to the evidence before the

agency, or is so implausible that it could

not be ascribed to a difference in view or

the product of agency expertise.

Motor Vehicle Mfrs. Ass’n of U.S. v. State Farm Mut.

Auto. Ins. Co., 463 U.S. 29, 43 (1983); see also County

of Los Angeles v. Shalala, 192 F.3d 1005, 1021 (D.C.

Cir. 1999) (“Where the agency has failed to provide a

reasoned explanation, or where the record belies the

agency's conclusion, [the court] must undo its

action.”).

As the Supreme Court has explained, “the

scope of review under the ‘arbitrary and capricious’

standard is narrow and a court is not to substitute its

judgment for that of the agency.” Motor Vehicle

Mfrs. Ass’n, 463 U.S. at 43; see Henley v. FDA, 77

F.3d 616, 621 (2d Cir. 1996) (“we might not have

chosen the FDA’s course had it been ours to

chart...[b]ut that is hardly the point.”). Rather, the

agency action under review is “entitled to a

presumption of regularity” and the court must

consider only whether the agency decision was based

on relevant factors and whether there has been a

clear error of judgment. Citizens to Pres. Overton

Park, Inc. v. Volpe, 401 U.S. 402, 415 (1971),

abrogated on other grounds by Califano v. Sanders,

430 U.S. 99 (1977).

In cases involving scientific or technical

decisions within the agency’s area of expertise, the

agency is entitled to a “high level of deference.”

Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1320

(D.C. Cir. 1998). When confronted with subject

matter characterized by scientific and technological

uncertainty, courts “ must proceed with particular

App. - 30 -

caution, avoiding all tempta‘*ion to direct the agency

in a choice between rational alternatives.” Alliance

for Bio-Integrity v. Shalala, 116 F. Supp. 2d 166, 177

(D.D.C. 2000). Judges are not “scientists

independently capable of assessing the validity of the

agency’s determination”; instead of making an

independent assessment, courts must hold the

agency to the standards of rationality required by the

APA. Serono Labs., 158 F.3d at 1327; accord Troy

Corp. v. Browner, 120 F.3d 277, 283 (D.C. Cir. 1997)

(“we review scientific judgments of the agency [the

EPA] not as the chemist, biologist, or statistician

that we are qualified neither by training nor

experience to be, but as a reviewing court exercising

our narrowly defined duty of holding agencies to

certain minimal standards of rationality.”). The

determination of whether a drug is_ effective

“necessarily implicates complex chemical and

pharmacological considerations.” Weinberger uv.

Bentex Pharms., Inc., 412 U.S. 645, 654 (1973). The

FDA’s judgments regarding efficacy fall within the

FDA’s expertise and thus such judgments merit

deference from the courts. Bristol-Myers Squibb Co.

v. Shalala, 923 F. Supp. 212, 220 (D.D.C. 1996).

Further, the “FDA’s policies and its interpretation of

its own regulations will be paid special deference

because of the breadth of Congress’ delegation of

authority to FDA and because of FDA’s scientific

expertise.” Berlex Labs., Inc. v. FDA, 942 F. Supp. 19,

25 (D.D.C. 1996).

In reviewing an administration action such as

the FDA’s Final Order at issue here, the role of the

district court is to “sit as an appellate tribunal” and

review the case as a matter of law. Marshall County

Health Care Auth. v. Shalala, 988 F.2d 1221, 1226

App. - 31 -

(D.C. Cir. 1993). Such review is limited to the

administrative record, and “not some new record

made initially in the reviewing court.” Camp v. Pitts,

411 U.S. 138, 142 (1973); accord Alliance for Bio-

Integrity v. Shalala, 116 F. Supp. 2d 166, 177 (D.D.C.

2000). Thus, here the Court reviews the pleadings

and the administrative record; the Court may not

review any new materials submitted by either party.

III. ANALYSIS

Counts I through III each challenge the FDA’s

finding that AVA is effective. The standards for the

FDA and its Panels to apply in evaluating safety,

effectiveness, and labeling are set forth in 21 C.F.R. §

601.25(d). Effectiveness is defined as follows:

Effectiveness means a_ reasonable

expectation that, in a_ significant

proportion of the target population, the

pharmacological or other effect of the

biologic product, when used under

adequate directions, for use and

warnings against unsafe use, will serve

a clinically significant function in the

diagnosis, cure, mitigation, treatment,

or prevention of disease in man.

21 C.F.R. § 601.25(d)(2). Proof of effectiveness “shall

consist of controlled clinical investigations” as

defined in 21 C.F.R. § 314.126, unless this

requirement is waived or alternate methods are

adequate to substantiate effectiveness. Jd. Such

controlled clinical investigations “may be

corroborated by partially controlled or uncontrolled

studies, documented clinical studies by qualified

experts, and reports of significant human experience

during marketing.” Jd.

App. - 32 -

A. Counts I and II

Plaintiffs’ allegations in Counts I and II of the

First Amended Complaint are overlapping. In Count

I, Plaintiffs assert that the FDA relied on flawed

scientific studies, the Brachman Study and the CDC

safety surveillance data, to find that AVA was

effective. First Am. Compl. 94 69-75. In Count II,

Plaintiffs assert that there were too few incidents of

inhalation anthrax in the Brachman Study to

substantiate the vaccine’s effectiveness.’” Id. 94 90-

92.

First, Plaintiffs allege that the FDA’s reliance

on the Brachman Study was improper because the

study was not “well-controlled” as required by 21

C.F.R. § 601.25(d)(2). The FDA, in its scientific

judgment, has found that the Brachman Study was

well-controlled. See 70 Fed. Reg. at 75,182. This

judgment is supported by the record. The Brachman

Study was a field study that compared the results in

an inoculated group against the results in a placebo

contro] group, and thus by its very definition was a

controlled study. AR 3734 (04 AR, Vol. 13); id. at

3736 (Table 4). Plaintifis argue that in 1969 when

the NIH reviewed the effectiveness of AVA (the

MDPH vaccine), the NIH noted that the studies “did

? In Count II, Plaintiffs also assert that at the time AVA

was licensed in 1970 under the Public Health Service Act

(“PHSA”), 42 U.S.C. §§ 201 et seq., it was found to be “potent”

as required by the PHSA and it was not found to be “effective”

as was required starting in 1972 under the Food, Drug, and

Cosmetic Act (““FDCA”), 21 U.S.C. §§ 301 et seq. The fact that in

1970 there was no finding of effectiveness is not relevant

because in 2005 the FDA in its Final Order did find that AVA is

effective. See 70 Fed. Reg. 75,180. It is this finding of

effectiveness that Plaintiffs challenge in this lawsuit.

App. - 33 -

not provide control data whereby the effectiveness of

the vaccine could be evaluated.” A.R. 3629-30 (04 AR,

Vol. 13). In fact, the NIH did not refer to the

Brachman Study at all, as the Brachman Study used

the earlier version of the vaccine (the DoD vaccine),

not the MDPH vaccine that the NIH was reviewing

at the time.'* The NIH documents that Plaintiffs cite

discuss data generated from uncontrolled studies of

the MDPH vaccine. The NIH was referring to the

“Talladega” non-controlled epidemiological data and

other uncontrolled studies listed at A.R. 3607-16 (04

AR, Vol. 13). See A.R. 3634 (04 AR, Vol. 13) (“The

lack of cases of anthrax in an uncontrolled population

of approximately 600 persons in the Talladega mill

can hardly be accepted as scientific evidence for the

efficacy of the vaccine.”). In a 1969 letter from the

CDC to the NIH, the CDC director indicated, “[t]here

have been no controlled evaluation studies with the

Michigan [MDPH] anthrax product as was done by

Dr. Philip Brachman using the [original/DoD]

vaccine.” A.R. 1375 (04 AR, Vol. 6).

Second, Plaintiffs allege that the FDA should

not have combined statistics regarding cutaneous

anthrax cases with inhalation anthrax cases when it

evaluated the Brachman Study data. They argue

that “modern statistical analysis of Brachman data

reveals that there is no statistical correlation

between vaccination with AVA and_ inhalation

anthrax protection.” Pls.’ Resp. at 15. Plaintiffs, in

essence, argue that cutaneous and _ inhalation

anthrax are different outcomes and must be tested

'? The FDA concluded in its Final Order that these versions

of the vaccine in fact are comparable. See discussion of Count

III, infra.

App. - 34-

for separately. If inhalation anthrax had been tested

separately in the Brachman Study, the numbers

would not have been sufficient for a statistical

analysis — the two cases in the placebo group

compared to no cases in the vaccinated group were

just too few to be statistically significant.

However, the FDA, again in its scientific

expertise, determined that the contraction of the

anthrax disease was the proper outcome to be tested,

regardless of the route of exposure. The Brachman

Study compared the incidence of anthrax in a control

group with the incidence in an inoculated group and

determined that the vaccine was 92.5% effective

against anthrax, combining both cutaneous and

inhalation anthrax cases. The FDA determined that

this type of statistical analysis was appropriate

because the vaccine counteracts the anthrax bacteria

in the same manner, no matter how the anthrax was

contracted. Regardless of the route of infection, the

anthrax bacteria produces the same toxins and the

vaccine acts against those toxins in the same

manner. The FDA fully explained its analysis:

The inclusion of both cutaneous and

inhalation cases of anthrax in the

analysis of the Brachman [S]tudy was

appropriate because it was not possible

to predict the route of exposure

(cutaneous versus inhalation) that

would occur within the environmental

setting of the woolen mills. With regard

to the known pathophysiology of

anthrax, the signs and symptoms of

disease arise due to the production of

toxins by anthrax bacteria growing

within the infected individual. The

App. - 35 -

toxins produced by anthrax bacteria do

not vary based on route of exposure. The

antibodies produced in response to

vaccination contribute to the protection

of the vaccinated individual by

neutralizing the activities of those

toxins. Thus, AVA elicits an antibody

response to disrupt the cytotoxic effects

of toxins produced by anthrax bacteria,

regardless of the route of infection.

70 Fed. Reg. at 75,187.

Third, Plaintiffs contend that the fact that

inhalation anthrax is more deadly than cutaneous

anthrax shows that the bacteria acts differently

depending on the route of infection. Pls.’ Resp. at 7.

Plaintiffs cite no support for this proposition. FDA

has explained that inhalation anthrax has a higher

fatality rate than cutaneous anthrax because it

generally results in a systemic infection whereas

cutaneous anthrax generally results in a localized

infection. See, e.g., A.R. 3363-64 (04 AR, Vo. 12).

Fourth, Plaintiffs contend that the FDA

improperly relied on (1) the CDC surveillance data

and (2) animal studies. In making a finding of

effectiveness, the FDA can rely on a controlled

clinical study such as the Brachman Study, and the

controlled clinical study may be “corroborated by

partially controlled or uncontrolled _ studies,

documented clinical studies by qualified experts, and

reports of significant human experience during

marketing.” 21 C.F.R. § 601.25(d)(2). “Isolated case

reports, random experience, and reports lacking the

details which permit scientific evaluation will not be

considered.” Jd. Under this regulation, the FDA

App. - 36

considered the CDC surveillance data as “reports of

significant human experience during marketing.”

Similarly, the FDA found that studies in human and

animal models cited in the IOM report supported the

conclusion that AVA was effective against anthrax

regardless of the route of exposure. 70 Fed. Reg. -at

75,183. For example, the [OM Committee noted that

the pathology of anthrax in macaques “best mimics

that seen in humans after inhalation exposure,” A.R.

3385 (04 AR, Vol. 12), and concluded that AVA is

effective in protecting macaques from inhalation

exposure to the strains of anthrax tested. /d. at 3389.

Pursuant to section 601.25(d)(2), the FCA cited the

LOM’s conclusions from animal studies to corroborate

the Brachman Study. The FDA’s interpretation of its

own regulation, as permitting corroboration by the

CDC surveillance data and animal studies, was not

plainly erroneous and must be afforded deference.

Berlex Labs., 942 F. Supp. at 25 (the FDA's

interpretation of its own regulations should be paid

special deference because of its scientific expertise).

Accordingly, the FDA’s reliance on the CDC

surveillance data and animal studies’ as

corroborating evidence was proper.

B. Count III

In Count III, Plaintiffs assert that the current

AVA vaccine, manufactured by the MDPH, was

never tested and thus the FDA cannot attest to its

efficacy; the Brachman Study tested the original DoD

vaccine manufactured by the Army. The FDA may

base its approval on studies done with a prior version

of a vaccine if it finds that the two versions are

comparable in terms of safety and effectiveness.

Products may be comparable, so long as the

manufacturers have shared critical manufacturing

App. - 37-

process information. A.R. 1399-1406 (04 AR, Vol. 6)

(FDA comparability policy).

Here, the FDA found that AVA and the

original vaccine were comparable under “FDA's long-

standing approach to comparability,” which permits

a manufacturer to make manufacturing changes in

producing a product “without performing additional

clinical studies to demonstrate the safety and

effectiveness of the similar product if data regarding

the manufacturing changes support the conclusion

that the versions are comparable.” 70 Fed. Reg. at

74,184. Applying this approach and after reviewing

the development of AVA, the FDA found AVA and

the original vaccine were comparable. /d. “[Cjlinical

data comparing the safety and immunogenicity of

[AVA] vaccine with [the original] vaccine

reveal[ed] that the serological responses to [AVA]

and [the original] vaccine were similar with respect

to peak antibody response and seropositivity.” Jd.

The FDA concluded that the two versions of the

vaccine “are comparable in their ability to protect

test animals .. . and their ability to elicit similar

immune responses in humans” and thus the data

from test studies of the original vaccine could be used

to approve AVA. Id.

Plaintiffs argue that the FDA may not

compare AVA and the original vaccine because the

comparability policy only applies to products made

by a single manufacturer and AVA and the original

vaccine were made by different manufacturers. First

Am. Compl. 4 99. The FDA comparability policy does

not state that it is limited to products made by a

single manufacturer.

App. - 38 -

Further, Plaintiffs claim that the FDA simply

“declared” AVA and the original vaccine to be

comparable as part of this litigation, that the FDA

did not make a legitimate finding of comparability.

This claim is not borne out by the record. As quoted

above, the FDA reviewed the development of the

anthrax vaccine and examined the clinical data

comparing the safety and immunogenicity of AVA

and the original vaccine. See A.R. 3698-3705 (AR 04,

Vol. 13) (clinical data). As the FDA noted in its Final

Order, “after a manufacturing change, a

manufacturer may use data gathered with a previous

version of its product to support the effectiveness of a

comparable version of the same product.” 70 Fed.

Reg. at 75,184; see also A.R. 1383-84 (04 AR, Vol. 6)

(the FDA’s 2002 statement that the DoD vaccine is

comparable to the BioPort [aka AVA] vaccine). In

sum, the FDA’s determination of comparability,

based on its review of scientific data, is supported by

the record.

C. Count IV

In March of 1998, DoD implemented the

Anthrax Vaccine Immunization Program (“AVIP”) to

protect service personnel at risk of contracting

anthrax. Pursuant to this Program, DoD has

inoculated active duty and reserve members of the

armed forces against anthrax with AVA, via the

recommended the _ six dose_ regimen: three

inoculations, each two weeks apart, and then three

more inoculations at six, twelve, and eighteen month

intervals thereafter. See First Am. Compl. {4 10 &

25. In July of 2000, DoD suspended the AVIP due to

a shortage of AVA. Jd. § 58. Thus, immunization was

interrupted for those military personnel who had not

completed the six dose regimen at the time the AVIP

App. - 39 -

was suspended. On October 16, 2006, DoD

announced the resumption of the AVIP for military

personnel and “emergency-essential” DoD civilians

and contractors. Id. | 48. Plaintiffs allege:

As part of this suspension, DoD

announced that members of the Armed

Forces who had received at least one of

the sequences of six vaccinations

required by the AVA product license

would be _ subject to a modified

vaccination schedule that is inconsistent

with the vaccination schedule required

by the AVA license. Specifically, DoD

announced that members who had

received one or more vaccinations, but

who had not completed the six shot

sequence of vaccinations, would not be

required to restart the inoculation

sequence as long as they received a

subsequent shot within two years of

their last vaccination.

Id. 4 59; see also id. J 61 & 63 (DoD requires

individuals who had their doses deferred must

continue with the next dose in the series when

directed.) Jd. J 61.

Thus, Plaintiffs claim that some military

personnel will be subject to mandatory immunization

under a modified drug regimen schedule that was not

approved by the FDA. Because DoD intends to follow

a vaccination schedule (for personnel whose vaccine

regimen was interrupted) which is inconsistent with

AVA’s FDA-approved inoculation schedule, in those

cases AVA is a drug allegedly unapproved for its

applied/intended use. /d. § 107. Under 10 U.S.C. §

App. - 40 -

1107, drugs unapproved for their applied uses may

not be given. to members of the Armed Forces without

their informed consent except in the case of a

Presidential waiver. Plaintiffs allege that they have

not consented to unapproved anthrax inoculation by

the DoD. Id. J 111.

Although Plaintiffs allege that for certain

military personnel DoD approved a _ vaccination

schedule inconsistent with product instructions,

Plaintiffs have not alleged that they themselves have

been, or imminently will be, subjected to such a

vaccination schedule and thus they lack standing to

bring this claim. To withstand a motion to dismiss

for lack of standing, a plaintiff must allege facts

“demonstrating that he is a proper party to invoke

judicial resolution of the dispute.” FW/PBS, Inc. v.

City of Dallas, 493 U.S. 215, 231 (1990). The facts

alleged “must be enough to raise a right to relief

above the speculative level.” Twombly, 127 S. Ct. at

1965. To assert standing, an Article III jurisdictional

requirement, a plaintiff must allege: (1) an actual or

imminent injury in fact; (2) fairly traceable to the

challenged action of the defendant; (3) likely to be

redressed by a favorable decision. Lujan v. Defenders

of Wildlife, 504 U.S. 555, 560-61 (1992). Because

Plaintiffs have not alleged that they have suffered, or

imminently will suffer, an injury due to an off-label

inoculation schedule, they lack standing to bring this

claim and the Court lacks jurisdiction over it. Count

IV will be dismissed.**

'* Although none of the Plaintiffs is a civilian, Plaintiffs

assert that civilian DoD employees and DoD contractors should

be covered by 10 U.S.C. § 1107. Pls.’ Resp. at 22. Section 1107

expressly applies only to members of the armed forces. 10

U.S.C. § 1107 (this section applies when “the Secretary of

App. - 41 -

IV. CONCLUSION

For the reasons explained above, the Court

will dismiss Counts I, II, and III, Plaintiffs’ APA

challenge to the FDA’s Final Order. After examining

the available scientific data and interpreting the

data pursuant to its regulations, the FDA applied its

expertise and found that AVA is effective for

immunization against anthrax, whether the infection

was acquired by inhalation or cutaneously. The FDA

did not act arbitrarily or capriciously. It considered

the relevant data and articulated an explanation

establishing a “rational connection between the facts

found and the choice made.” Bowen, 476 U.S. at 626.

The Court will not substitute its own judgment when

the FDA made no clear error of judgment. See

Overton Park, 401 U.S. at 415-16 (the court must

consider only whether the agency decision was based

on relevant factors and whether there has been a

clear error of judgment). In addition, the Court will

dismiss Count IV because Plaintiffs lack standing to

make a claim of off-label use under 10 U.S.C. § 1107.

Accordingly, Defendants’ motion to dismiss'®

will be granted. Counts I, II, and III will be

dismissed for failure to state a claim, and Count IV

will be dismissed for lack of standing. A

Defense requests or requires a member of the armed forces to

receive an investigational new drug or a drug unapproved for

its applied use”). Even if a civilian were a named plaintiff in

this suit, no claim could be stated under section 1107 on behalf

of a civilian.

'® Defendants’ motion to dismiss fl5 Dkt. # 15) was

dismissed without prejudice by Minute Entry Order on August

3, 2007. Defendants renewed their motion to dismiss without

amendment by filing a notice of such renewal [Dkt. # 29] on

September 17, 2007.

App. - 42 -

memorializing order accompanies this Memorandum

Opinion.

Date: February 29, 2008

Is/

ROSEMARY M. COLLYER

United States District Judge

App. - 43 -

Appendix 3- GAO R : -

United States General Accounting Office

Tuesday, October 23, 2001

ANTHRAX VACCINE:

Changes to the Manufacturing Process

Statement of Nancy Kingsbury, Ph.D.,

Managing Director, Applied Research and Methods

Mr. Chairman and Members of _ the

Subcommittee:

We are pleased to be here today to contribute

to your hearing on biological warfare defense vaccine

programs. This topic is of considerable urgency today

in light of the terrorist attacks of September 11) and

the exposures to anthrax in recent weeks. Our

testimony today is limited to the work we have done

in response to your October 2000 request to review

the changes to the manufacturing process for the

anthrax vaccine that has been produced by the

BioPort Corporation and its predecessor entities. As

you know, BioPort is the sole facility in the U.S.

currently capable of producing anthrax vaccine.

My testimony today will address the changes

that occurred in the manufacturing process for

anthrax vaccine since 1989, and the status of the

approval of those changes by the Food and Drug

Administration (FDA). It is, of course, FDA’s

responsibility to determine that the anthrax vaccine

is safe and efficacious, and it is our understanding

that FDA officials will be undertaking a review in

the near future to determine if vaccine production

App. - 44 -

can be resumed. We appreciate the opportunity to

provide information that may be relevant to that

determination.

A brief summary of our scope and methodology

is provided in appendix I. A list of related GAO

products is presented in appendix II.

Background

The original anthrax vaccine was developed by

George Wright and others in the 1950s and was first

produced on a large scale by the pharmaceutical

company Merck Sharp & Dohme (Merck).

' A clinical study in 1962 evaluated the safety

and effectiveness of the Merck vaccine in mill

workers.” The results of this study formed the basis

for subsequent licensure of the vaccine in 1970. The

original license for the production of anthrax vaccine

was issued to the Michigan Department of Public

Health by the Division of Biologics of the National

Institutes of Health.® In 1995, the facility changed its

name to the Michigan Biologic Products Institute. In

1998, the facility was sold, and its name was changed

to BioPort Corporation.

* Merck Sharp and Dohme is currently known as Merck and

Co., Ine.

* The most common occurrence of anthrax infection has been

in industrial settings like wool mills where workers may be

exposed to infected animal products.

3 Prior to the establishment of FDA as the licensing

authority for vaccines, the National Institutes of Health was

responsible for licensing.

Avo. - 45 -

Today, FDA, through the Center for Biologics

Evaluation and Research (CBER), licenses biological

products (that is, biologics) and the facilities in which

they are produced. The manufacturer is required to

comply with current Good Manufacturing Practices

(CGMP) regulations, which regulate personnel,

buildings, equipment, production controls, records,

and other aspects of the vaccine manufacturing

4

process.

When there is a major change in the

manufacturing process—defined as a _ change

determined by FDA to have a substantial potential to

adversely affect the identity, strength, quality,

purity, or potency of a product in relation to safety or

effectiveness—the manufacturer must’ submit

evidence to FDA demonstrating that the change does

not have any such adverse effects. This requirement

is particularly important for vaccines since the

quality of biologics cannot be ensured solely from

final tests on random samples. Instead, the quality of

biologics can be determined only by a combination of

strict control of the entire manufacturing process, in

process tests, and end-product tests. When

significant process changes are made, the onus is on

the manufacturer to ensure that the quality of the

product is maintained after such changes are

introduced. Depending on the changes made, this

may require trial studies (with animals or humans)

* cGMP embodies a set of scientifically sound methods,

practices, or principles that are implemented and documented

during development and production to ensure consistent

manufacture of safe, pure, and potent products. Such principles

apply to the manufacturing process as well as to the facilities in

which products are manufactured. (21 C.F.R., parts 600

through 680.)

App. - 46 -

to evaluate the impact of the new process, followed

by comparison of pre and post-change lots before

releasing the pcest-change lots for use.”

As our testimony today reports, in the case of

the anthrax vaccine, the Michigan facility did not

notify FDA of a number of changes made in the

manufacturing process in the early 1990s and no

specific studies were undertaken to confirm that

vaccine quality was not affected. FDA inspectors did

not inspect the Michigan (facility’s anthrax

production room until 1993. According to FDA,

access was not granted because its inspectors had not

been vaccinated against anthrax. FDA inspectors

were able to perform some aspects of inspection—for

example, reviewing records—but not equipment and

production.°®

The inspections that FDA ultimately was able

to conduct over time found a number of deficiencies,

many of which were not corrected in a timely

manner. For example, the deficiencies that FDA

identified it its February 1998 inspection fell broadly

° FDA guidance states that, if significant changes to the

manufacturing or formulation of a vaccine are made after the

original clinical trial, bridging studies may be used to

demonstrate that immunogenicity and the occurrence of

common adverse events have not been affected adversely by

these changes. Anthony, B.F. and A. Sutton, “The Role of the

Food and Drug Administration in Vaccine Testing and

Licensure,” New Generation Vaccines, New York, Marcel

Dekker, Inc., Ch. 73, p. 1191.

° The purpose of FDA’s inspection is to determine that the

products are manufactured in compliance with cGMP as

described in the license application. Manufacturers who fail to

meet product standards or who make unreported or

undocumented changes in manufacturing methods may have

their license suspended or revoked.

App. - 47 -

into two categories: (1) those that, although serious,

might affect only one or a limited number of batches

that were produced when the deficiency was extant

and (2) those of a generic nature that could

compromise the safety and efficacy of any batch or all

batches. Vaccine production was suspended after

these findings, and BioPort has been attempting

since then to bring the facility and manufacturing

process into compliance. We understand from recent

testimony by the Secretary of Health and Human

Services that BioPort has recently submitted an

application for an FDA inspection to approve its

facility and manufacturing process.

Changes to the Fermenters and Filters in the

: T e

Beginning in 1990, the Michigan state-owned

facility (the Michigan facility) that was later sold to

BioPort changed both the fermenters and the filters

it used in manufacturing the anthrax vaccine.’ With

regard to fermenters, it replaced the original glass

fermenter with two 100-liter stainless steel

fermenters in 1990, and installed two similar

fermenters in 1993. With regard to filters, the facility

changed from ceramic to nylon filters in 1990. After

the 1990 change, the facility changed the types of

filters two more times, in 1996 and 1997. According

to Michigan facility officials, changing the filters

reduced processing time for the production of a single

lot of anthrax vaccine, while changing and adding

additional fermentors increased its production

” A fermenter is used to grow the bacteria. A filter is one of

the processing stages after the fermentation. The filter removes

whole bacteria and other biochemical components.

App. - 48 -

volume. We were informed that both changes were

made to increase production before the onset of the

Gulf War.

Under FDA regulations, changes to a vaccine

manufacturing process are to be reported to FDA and

significant changes may require the manufacturer to

submit a license application amendment.® In

December 1990, FDA was notified of the replacement

of the original glass fermenter with two 100-liter

stainless steel fermenters. FDA approved that

change in 1993. Although the Michigan facility

installed two additional stainless steel fermenters in

1993, it did not notify the FDA about the additional

fermenters at that time. Inspection records indicate

that FDA was aware of the additional fermenters

and encouraged the facility to submit a license

amendment application for them in 1993” and again

in 1995."° In January 1999, BioPort submitted a

° Prior to 1997, FDA regulations required that “important”

proposed changes in the vaccine manufacturing process be

reported to FDA at least 30 days prior to implementation. Since

1997, FDA regulations have required that “major” changes be

reported to FDA at least 30 days prior to implementation and

that FDA approve such changes prior to distribution of vaccine

made using them.

* The FDA inspection report (May 26, 1993) stated that “any

changes to the manufacturing [process] that have the potential

to affect the safety, purity, or potency of a biologic must be

submitted and approved by CBER prior to implementation.”

’ In April 1995, Michigan facility officials told FDA that the

additional fermenters installed in 1993 were similar, although

not identical, to those installed in 1990 and approved in 1993.

In response, FDA officials explained that “a different fermenter

may cause change in the product, even if the fermenter is

similar to the existing fermenter, and would most likely require

App. - 49 -

license amendment application with supporting

documentation to FDA concerning the two additional

fermenters. In May 2001, FDA approved these

additional fermenters.

Because we could find no evidence in BioPort

or FDA records that the filter changes had been

reported to FDA, we contacted FDA officials in

December 2000 to discuss the filter changes. They

told us that they had not been notified and were not

aware of changes to any filters used to produce

anthrax vaccine. In February 2001, FDA wrote to

BioPort, raising questions about the changes to the

filters. In April 2001, BioPort submitted

documentation, primarily in-process tests and lot

release data, to FDA to demonstrate that the filter

changes had not had a significant impact on vaccine

quality. FDA reviewed and accepted the data and

approved the filter changes in July 2001. Although

the lot release data included lots produced

immediately before and after the filter changes, the

data submitted did not include the type of data that,

according to FDA officials, would normally have been

required if a license amendment application had

been filed contemporaneously with the changes, that

is, a direct biochemical] analysis of vaccine samples

from before and after the changes. FDA officials told

us that such a direct comparison is not possible now,

because appropriate pre-1990 vaccine samples no

longer exist.

agency approval.” (FDA/CBER Conversation Record, Apr. 21,

1995.)

App. - 50 -

Studies Suggest Possible Changes to the

Anthrax Vaccine After the 1990 Manufacturing

Changes

Because it is not now possible to definitively

resolve the question of whether the anthrax vaccine

produced after the filter changes is the same as that

produced before the changes (a demonstration that is

normally required in a_ license amendment

application), we have reviewed other studies to see if

evidence suggests that the question may need to be

further examined. We have found two types of such

evidence.

First, in an unpublished study performed in

1990, the Department of Defense (DOD) found up to

a hundredfold increase in the protective antigen

levels in lots produced after the filter change that

year.’ (Anthrax toxin is composed of protective

antigen, lethal factor, and edema factor. The

individual toxin components are not toxic. A

protective antigen and lethal factor combination

produces lethality, and a combination of protective

antigen and edema factor cause swelling.)

'* J.W. Ezell and T. Abshire, “In Vitro Analysis of Michigan

Department of Public Health Human Anthrax Vaccine”, U.S.

Army Medical Research Institute of Infectious Diseases,

Bacteriology Division, Fort Detrick, MD, Oct. 25, 1990. This

unpublished study applied a then-new methodology to measure

protective antigen that had not been separately validated at the

time but is widely used today, and Dr. Ezell told us that the

results should be interpreted cautiously as a result. We have

had the study reviewed by two experts in anthrax vaccine

issues who did not see any evident reasons to question the

study methodology. We believe at best, however, it is an

indicator that protective antigen levels may have changed after

the filter changes. Since it cannot be replicated, it is the only

evidence available on this point.

App. - 5} -

In a subsequent article published in 1994,

DOD researchers, referencing the earlier study,

hypothesized that the filter change altered the

composition of the vaccine by increasing the level of

protective antigen in the finished product.”

According to the authors of this article, when DOD

questioned the Michigan facility about this increase

in 1990, the responsible Michigan facility official

attributed it to the change in the filter from ceramic

to nylon.

There are no studies to show what the effect of

a significant increase in protective antigen may be on

safety or efficacy of the vaccine. However, because

the tests that could have demonstrated that the

product was not changed in a material way in the

context of a timely license amendment application

were not done, and cannot now be done, there is

potential merit in evaluating the findings of the 1990

DOD study further. We discussed the DOD study

further with FDA officials on October 15, 2001, and

they told us that they had not evaluated the study

because they did not have it. At their request, we

have provided the study to them.’®

Second, we have reported several times in

earlier work that, before 1990, anthrax vaccine was

used by a small number of at-risk individuals (for

'* B.E. Ivens [sic, “Ivins”] and others, “Efficacy of a Standard

Human Anthrax Vaccine Against Bacillus anthracis Spore

Challenge in Guinea Pigs,” Vaccine, vol. 12 (1994), pp. 872-874.

'’ Because we had earlier discussed this study with both

DOD and BioPort, we had assumed that one or both of them

had referred the information to FDA. We had also asked FDA

about the study in December 2000 but they did not request a

copy from us at that time

Apo. - 52 -

example, wool mill workers), and FDA did not have

any system to report adverse reactions associated

with drugs and vaccines. Safety data, as reported in

the product insert, were limited to the information

from studies done in the 1960s, long before the

fermenter and filter changes discussed here.

Published and unpublished data on anthrax vaccine

use during the Gulf War and since 1998 show a

significantly greater incidence of both local and

systemic adverse reactions compared with rates

reported in the product insert. For example, the

product insert says that the following should be

expected: (1) 30 percent of recipients should

experience a mild local reaction; (2) 4 percent should

experience a moderate local reaction; and (3) 0.2

percent should experience systemic reactions

characterized by malaise and lassitude with chills

and fever reported in only a few cases. This indicates

that some reaction should be experienced by a total

of 34.2 percent of recipients. By comparison, in a

survey we conducted in calendar year 2000, 85

percent of National Guard and reserve forces in our

survey who were given the anthrax vaccine reported

some reactions, with local reactions experienced by

76.2 percent of recipients and systemic reactions

experienced by 23.8 percent. Chills and fever were

reported by between 9 and 11 percent of our

surveyed vaccine recipients.'* These results are

consistent with unpublished DOD studies and other

published epidemiological work we are aware he

'* The full results of our survey will be reported in the near

future.

‘> We reported on the results of several DOD studies in

Anthrax Vaccine: Safety and Efficacy Issues (GAO/T-NSIAD-00-

48, Oct. 12, 1999.) See also Lea Steele, “Prevalence and

App. - 53 -

Because there are no data to evaluate the

effect of the filter change on the characteristics of the

vaccine product, it is difficult to determine whether

these greater levels of adverse reactions could be

related to changes in the vaccine associated with the

filter changes. Ceramic filters (used before 1990)

absorb proteins more than nylon ones, and the

change to nylon filters in 1990 could theoretically

have resulted not only in more protective antigen

coming through but also other proteins. The end-

product and in-process tests that BioPort submitted

to FDA in 2001 in support of the filter changes may

lack the capability to evaluate this possibility.

Additional biochemical tests would have been

required. For example, a filter change could have

allowed more edema factor to pass through. The

Michigan facility did not routinely test for edema

factor in the product. We note that, since 1997,

United Kingdom (U.K.) regulations have required

the anthrax vaccine produced by the U.K. Center for

Applied Microbiology and Research to be tested for

both protective antigen and edema factor.'®

Obser ion

General public health vaccines are produced

according to cGMP and are in constant, routine use

worldwide. This use permits real-time monitoring of

whether the vaccines are performing properly. In

Patterns of Gulf War Illness in Kansas Veterans: Association of

Symptoms with Characteristics of Person, Place, and Time of

Military Service.” American Journal of Epidemiology, Vol. 152,

No. 10, 2000, pp. 992-1002.

‘© The Center for Applied Microbiology and Research is the

manufacturer of the U.K.’s only licensed anthrax vaccine.

Ann - 54-

contrast, bio-defense vaccines have no such ongoing

reality check because of the absence of natural

disease and relatively limited use. Thus, only in

emergency situations are bio-defense vaccines

subjected to the evaluations that public health

vaccines undergo all the time. Accordingly, the

stringent application of cGMP by FDA in its approval

of the resumption of vaccine manufacture at BioPort,

as well as subsequent monitoring of the

manufacturing process, is vital to ensure that

vaccines produced are safe, pure, and of high quality.

In view of the increasing importance that will

be given to the anthrax vaccine in the current

environment and whether or not the anthrax vaccine

is approved for production in the near future, it is

important to ensure that studies continue to evaluat

This text is long and has been trimmed here. Open the source document for the complete record.