Abney v. Amgen

RECOMMENDED FOR FULL-TEXT PUBLICATION

Pursuant to Sixth Circuit Rule 206

File Name: 06a0111p.06

UNITED STATES COURT OF APPEALS

FOR THE SIXTH CIRCUIT

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EDWARD ABNEY, BARBARA ALLEN, JAMES DAY,

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ROBERT GREEN, DELBERT JACKSON, JAMES PUGH,

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ROGER L. THACKER, and DANIEL HUNTER

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No. 05-6132

WEBSTER,

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Plaintiffs-Appellants, >

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v.

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Defendant-Appellee. -

AMGEN, INC.,

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Appeal from the United States District Court

for the Eastern District of Kentucky at Lexington.

No. 05-00254—Joseph M. Hood, Chief District Judge.

Argued: February 1, 2006

Decided and Filed: March 29, 2006

Before: MARTIN, NORRIS, and DAUGHTREY, Circuit Judges.

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COUNSEL

ARGUED: Alan C. Milstein, SHERMAN, SILVERSTEIN, KOHL, ROSE & PODOLSKY,

Pennsauken, New Jersey, for Appellants. Mark D. Gately, HOGAN & HARTSON, L.L.P.,

Baltimore, Maryland, for Appellee. ON BRIEF: Alan C. Milstein, SHERMAN, SILVERSTEIN,

KOHL, ROSE & PODOLSKY, Pennsauken, New Jersey, for Appellants. Mark D. Gately, Lauren

S. Colton, HOGAN & HARTSON, L.L.P., Baltimore, Maryland, Winston E. Miller, FROST,

BROWN, TODD, LLC, Louisville, Kentucky, Keith Moorman, Susan J. Pope, FROST, BROWN,

TODD, LLC, Lexington, Kentucky, Catherine E. Stetson, Michele W. Sartori, HOGAN &

HARTSON, L.L.P., Washington, D.C., for Appellee.

MARTIN, J., delivered the opinion of the court, in which DAUGHTREY, J., joined.

NORRIS, J. (p. 12), delivered a separate opinion concurring in the result.

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No. 05-6132 Abney, et al. v. Amgen, Inc. Page 2

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OPINION

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BOYCE F. MARTIN, JR., Circuit Judge. The plaintiffs in this case are eight individuals

involved in a clinical drug trial sponsored by Amgen, Inc. When the study was terminated, the

plaintiffs sued claiming that Amgen was legally required to continue providing them with the drug.

The plaintiffs filed a motion for a preliminary injunction seeking to require Amgen to provide them

with the drug immediately. The district court denied the motion and the plaintiffs appealed. For the

reasons discussed below, we AFFIRM the district court’s denial of the plaintiffs’ motion for a

preliminary injunction.

I.

The plaintiffs are all Kentucky residents that suffer from Parkinson’s disease, a

neurogenerative disorder characterized by the progressive loss of dopamine-producing neurons in

the brain, resulting in tremors, shaking, slow movement, and muscle stiffness and rigidity. The

current treatment for Parkinson’s disease focuses on replacing dopamine in the brains of Parkinson’s

disease sufferers, thus masking the symptoms of the disease. None of these current treatments are

curative, however, as none of them halt the loss of dopamine-producing neurons.

A Colorado biotechnology company named Synergen, Inc. designed a protein called gial

cell-line derived neutrotropic factor, commonly known as GDNF, which pre-clinical (non-human)

studies preliminarily indicated could protect and restore dopamine producing neurons. Believing

that GDNF could potentially provide a breakthrough treatment for Parkinson’s disease, Amgen

purchased Synergen in 1994 for approximately $150 million. Having acquired the drug, however,

Amgen was now faced with the problem of how to effectively deliver GDNF to the brain. In 1996,

Amgen sponsored two clinical studies of GDNF to determine whether a delivery method known as

intracerebroventicular administration (ICV), in which the drug is injected directly into the central

fluid-filled cavities of the patient’s brain, was effective. Unfortunately, these studies failed to prove

that ICV was safe or effective as a delivery method.

Subsequently, Dr. Steven S. Gill of Frenchay Hospital in Bristol, England developed a means

of delivering the drug directly to the brain known as bilateral intraputaminal (IPu) infusion. This

procedure involves implanting a pump filled with GDNF in the patient’s abdomen attached to

catheters which, when threaded through the patient’s check, neck, and head, deliver the GDNF

directly to the putamen region of the brain.

In 2000, Amgen supported an open-label trial in the United Kingdom for the administration

of GDNF using IPu with five patients suffering from Parkinson’s disease. Although the study

yielded favorable results because the study was open-label, meaning study participants knew they

were receiving GDNF and no participants received a placebo, Amgen concluded that more research

was necessary. Another open-label study was also conducted at the University of Kentucky medical

center in which GDNF was administered via IPu to ten patients.1 All ten of these patients showed

benefits after six months of treatment but, it was unclear whether this improvement was the result

of the GDNF or a placebo effect as there was no control group in the study.

1

The study was originally designed and initiated by physicians at the University of Kentucky. In September

2002, however, Amgen became a sponsor of the study, meaning it funded the study and provided the study drug.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 3

Based on the result open-label studies, in 2003 Amgen sponsored a multi-center Phase II,

randomized, double-blind,2 placebo-controlled study of GDNF using the IPu method of delivery in

order to test its safety and efficacy. As part of this study, Amgen and the University of Kentucky

entered into a Clinical Trial Agreement. Under the Agreement, Amgen agreed to sponsor the

University as one of the study center locations and the University agreed to carry out Amgen’s

Protocol for the trial. Amgen’s Protocol, which was approved by the Institutional Review Board at

the University, indicated that the trial would begin with each participant having a pump inserted in

their abdomen and the catheter inserted through a hole drilled in their skull. The participants would

then receive treatment or a saline placebo solution for approximately thirty-three weeks. At the end

of the study, the Protocol indicated that the participants “may elect to continue treatment for up to

an additional 24 months.”

The plaintiffs in this case elected to participate in the clinical trial at the University. Each

plaintiff signed an Informed Consent Document, indicating that they were aware of the risks of the

clinical trial and agreeing to participate. Like the Protocol, the Informed Consent Document

indicated that study participants could elect to continue treatment for 24 months after the end of the

study. The Informed Consent Document also informed participants in the study that they might be

required to withdraw from the study “if they find that your being in the study is more risk than

benefit to you, if you are not able to follow the directions they give you, or if the agency funding the

study decides to stop the study early for a variety of reasons.” The Informed Consent Document

was signed by each participant and by the physician investigators leading the study.

Using the Unified Parkinson’s Disease Rating Scale,3 Amgen hoped to see a 25% increase

in motor scores relative to the placebo after six months of treatment. In June 2004, the study results

showed only a 10.01% increase in the group using GDNF and a 4.52% increase in the group being

administered the placebo. Seven of the thirty-four subjects demonstrated dramatic improvement,

but four of the seven were receiving the placebo.

Despite these less than stellar results, Amgen decided to continue with the clinical trial but

convert it into an open-label study with all thirty-four patients receiving GDNF. The plaintiffs

contend that after GDNF was administered, they experienced marked physical, cognitive, and

emotional improvement. The plaintiffs also have submitted affidavits from several patients from

other study locations attesting to similar improvements. Moreover, the plaintiffs have submitted

affidavits from all of the doctors participating in the University of Kentucky study and principal

investigators involved in the New York and Chicago studies that unanimously state that GDNF is

safe and effective.

Despite the plaintiffs’ belief that GDNF was working, in September 2004, Amgen

announced that it was terminating all clinical use of GDNF based on two scientific concerns. The

first was the discovery that several study participants had developed neutralizing antibodies.

Antibodies are proteins produced by the immune system that attack substances such as viruses,

bacteria, and in some cases, synthetic proteins like GDNF. Such neutralizing antibodies could clear

the drug from a patient’s system, neutralizing the effects of the drug. More worrisome to Amgen,

however, was that the antibodies could attack naturally occurring GDNF in the body. While it is

unclear what naturally occurring GDNF does, animal studies have shown that an absence of GDNF

during development causes irreversible damage to vital organs.

2

This means that neither the patient volunteers nor the physician investigators know which patients are

receiving the study drug and which patients are merely receiving the placebo.

3

UPDRS is a standard instrument widely used to determine the severity of a patient’s Parkinson’s disease. It

measures a patient’s behavior, mood ability to accomplish daily activities, and motor skills.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 4

The second disturbing discovery was that several primates used in a long-term toxicology

study of IPu delivered GDNF developed lesions in the cerebullum, an area of the brain critical for

movement and coordination. Based on these concerning scientific findings along with the lack of

efficacy shown by the study, Amgen made the decision to terminate the study. Amgen consulted

the FDA regarding discontinuation of the study and the FDA indicated that given the evidence

termination of the study was reasonable.

The plaintiffs claim that the drug is effective and that Amgen has exaggerated the safety risks

of GDNF. The plaintiffs submitted to the district court an affidavit from the principal investigator

of the New York study suggesting that the primates’s legions were not a cause for alarm as the

primates received larger doses of GDNF than study participants received and because the primates,

unlike the study participants, were rapidly withdrawn from GDNF. The affidavit also disagreed with

Amgen’s placebo effect theory and asserted that the antibodies found in several study participants

were not harmful.

The plaintiffs assert that Amgen’s reasons for ending the study were financial rather than

safety and efficacy. They allege that because of the prolonged time it took Amgen to develop a

delivery method for GDNF, Amgen has little time left before its patent on the drug expires.

Moreover, based on the invasive means of delivering the drug, only those with severe Parkinson’s

disease would use the drug, leading to less profit. Finally, GDNF has a short shelf life and thus

Amgen would constantly be required to produce new proteins. The plaintiffs claim that all of these

considerations led Amgen to conclude that it was financially untenable to bring the drug to4market

and thus Amgen terminated the study. Amgen vehemently disputes the plaintiffs’ claims.

After deciding to terminate the study, several investigators and Amgen met with the FDA

to consider whether to permit “compassionate use,” meaning use of a drug even if the drug is proven

unsafe, of GDNF for the participants. The FDA stated that it would permit compassionate use of

GDNF but left the decision up to Amgen. After seeking advice of eight external experts (three

bioethicists and five Parkinson’s disease experts), seven of whom advised Amgen to terminate the

use of the drug, Amgen decided not to allow compassionate use of GDNF.

The plaintiffs filed suit on June 17, 2005, naming Amgen as the sole defendant. The district

court had jurisdiction based on diversity of citizenship, and none of the plaintiffs’ causes of action

arise under federal law. On June 24, the plaintiffs moved for a preliminary injunction requiring

Amgen to provide the physicians at the University of Kentucky with GDNF and to allow the doctors

to administer it to the plaintiffs. None of the plaintiffs have received GDNF treatment since

September 2004.

The plaintiffs advanced three legal theories to support their motion for a preliminary

injunction. First, they claimed that GDNF is beneficial to them, and that Amgen is contractually

obligated to supply them with GDNF. Second, they argued that Amgen is liable under a theory of

promissory estoppel as Amgen promised to continue to provide the plaintiffs with GDNF and the

plaintiffs detrimentally relied on this promise. Third, they asserted that Amgen owes them a

fiduciary duty, and that is has breached that duty by unreasonably denying them access to GDNF.

In response, Amgen denied that it made any such enforceable promises to the plaintiffs and denied

owing the plaintiffs any fiduciary duty.

The district court held a hearing on the plaintiffs’ motion on July 5 and on July 8 denied the

motion. The district court concluded that the plaintiffs had failed to demonstrate a strong likelihood

4

Amgen submitted evidencing disputing the plaintiffs’ claims regarding the safety and efficacy of GDNF.

Moreover, Agmen submitted evidence indicating that it would have been in the company’s best financial interest to bring

GDNF to market quickly.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 5

of success on the merits based on any of their claims. The district court also concluded that the

plaintiffs could not prove that they would suffer irreparable harm if they did not obtain a preliminary

injunction nor could they establish that public policy would be furthered by issuing the injunction.

Thus, the district court denied the plaintiffs’ motion for a preliminary injunction. This appeal

ensued.

The district court’s decision to deny the plaintiffs’ motion for a preliminary injunction relied

in part on a decision from the Southern District of New York in a nearly identical case, Suthers v.

Amgen, Inc., 372 F. Supp. 2d 416 (S.D.N.Y. 2005). In Suthers, two Parkinson’s disease sufferers

who participated in the Amgen study at the New York University site filed suit against Amgen in

the Southern District of New York and sought a preliminary injunction requiring Amgen to provide

them with GDNF. The plaintiffs in Suthers advanced nearly identical legal claims as this case:

breach of contract, promissory estoppel, and breach of fiduciary duty. The district court denied the

plaintiffs’ motion on grounds similar to the district court’s reasoning here. Specifically, the Suthers

court concluded that the plaintiffs “have shown neither a likelihood of success nor a sufficiently

serious showing of merits to warrant the extraordinary relief of a preliminary injunction.” Id. at 419.

The court found that the plaintiffs’ breach of contract claim was unlikely to succeed because the

plaintiffs could not show any contract between the plaintiffs and Amgen. While their Informed

Consent document arguably gave them a right to GDNF, the court concluded that this agreement was

between the plaintiffs and New York University rather than the plaintiffs and Amgen, and that the

principal investigators did not have the authority to bind Amgen. The court also concluded that the

plaintiffs’ promissory estoppel argument had little chance of success as Amgen had made no direct

promises to the plaintiffs. Finally, the court held that under the facts of the case, Amgen did not

have a fiduciary duty to continue treatment. As a result of these determinations the district court did

not address whether the plaintiffs or the defendants would suffer irreparable harm based on the

district court’s decision. The plaintiffs in Suthers initially appealed the district court’s decision but

later withdrew their appeal.

II.

The plaintiffs assert that the district court erred in denying their motion for a preliminary

injunction. We review a district court’s grant of a preliminary injunction for an abuse of discretion.

Tucker v. City of Fairfield, 398 F.3d 457, 461 (6th Cir.2005). “A district court abuses its discretion

when it relies on clearly erroneous findings of fact, improperly applies the law, or uses an erroneous

legal standard.” Id. A district court errs “only if it incorrectly applied the law, or relied on clearly

erroneous findings of fact.” Ramsey v. Formica Corp., 398 F.3d 421, 423 (6th Cir. 2005). We

review the district court’s conclusions of law de novo and its findings of fact for clear error. Golden

v. Kelsey-Hayes Co., 73 F.3d 648, 653 (6th Cir.1996).

To determine whether to grant a preliminary injunction, a district court must consider: “(1)

the plaintiffs’ likelihood of success on the merits; (2) whether the plaintiff may suffer irreparable

harm absent the injunction; (3) whether granting the injunction will cause substantial harm to others;

and (4) the impact of an injunction upon the public interest.” Deja Vu of Nashville, Inc. v. Metro.

Gov’t of Nashville & Davidson County, 274 F.3d 377, 400 (6th Cir.2001). “None of these factors,

standing alone, is a prerequisite to relief; rather, the court should balance them.” Golden, 73 F.3d

at 653. Thus, even though a finding of no likelihood of success “is usually fatal[,]” Gonzales v.

Nat’l Bd. of Med. Exam’rs, 225 F.3d 620, 625 (6th Cir. 2000), a district court should ordinarily

analyze all of the factors. Leary v. Daeschner, 228 F.3d 729, 739 n.3 (6th Cir. 2000). We will

review the district court’s analysis as to each of these factors in order to ensure that the district court

did not abuse its discretion in denying the plaintiffs’ motion for a preliminary injunction.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 6

A.

The first factors to be considered is whether the plaintiffs have demonstrated a likelihood of

success on the merits. The plaintiffs identify three grounds on which they allege that Amgen is

legally obligated to provide them with GDNF — breach of contract, promissory estoppel and

fiduciary duty. The district court concluded that the plaintiffs had little chance of success on any

of these grounds. We find nothing in the record that suggests the district court abused its discretion

in reaching such a conclusion.

i.

Turning first to the plaintiffs’ breach of contract claim, the district court concluded that there

was no breach of contract by Amgen because no contract ever existed between the plaintiffs and

Amgen that required Amgen to continue to provide the plaintiffs with GDNF. The court found that

the Informed Consent Document that the plaintiffs rely upon as evidence of a contract between them

and Amgen did not directly bind Amgen because neither Amgen nor any agent of Amgen signed the

Informed Consent Document. We find no abuse of discretion in the district court’s conclusion on

this point.

Under Kentucky law, “in order to recover in any action based on breach of a contract, a

plaintiff must show the existence and the breach of a contractually imposed duty.” Lenning v.

Commercial Union Ins. Co., 260 F.3d 574, 581 (6th Cir. 2001) (citing Strong v. Louisville &

Nashville R. Co., 43 S.W.2d 11, 13 (Ky. 1931)). Thus, the plaintiffs must show by clear and

convincing evidence proof of an actual agreement between them and Amgen. See Auto Channel,

Inc. v. Speedvision Network, LLC, 144 F.Supp.2d 784, 790 (W.D. Ky. 2001).

The plaintiffs admit that Amgen did not sign the Informed Consent Document, which the

plaintiffs point to as the primary basis for their breach of contract claim. Moreover, there are no

other documents that create a contractually enforceable duty for Amgen to continue to provide

GDNF to the plaintiffs. The Clinical Trial Agreement was not signed by the plaintiffs but rather was

signed by Amgen, the University of Kentucky, and the principal investigators. Thus, the plaintiffs’

claim that Amgen is directly contractually obligated to provide the plaintiffs with GDNF is unlikely

to succeed on the merits because “it is axiomatic that courts cannot bind a non-party to a contract

because that party never agreed to the terms set forth therein.” EEOC v. Frank’s Nursery & Crafts,

Inc., 177 F.3d 448, 460 (6th Cir. 1999).5

Moreover, the principal investigators in the University of Kentucky study were not in a

position to enter into a binding contract with the plaintiffs on Amgen’s behalf, as the district court

correctly concluded that the principal investigators were independent contractors rather than

Amgen’s agents. Under Kentucky law, whether a principal/agent relationship is created rather than

merely a principal/independent contractor relationship is determined by examining the following

factors:

(a) the extent of control which, by the agreement, the master may exercise over the

details of the work;

(b) whether or not the one employed is engaged in a distinct occupation or business;

5

Even if the Informed Consent Document or the Clinical Trial Agreement created a contract between Amgen

and the plaintiffs, Amgen would still have no duty to provide the plaintiffs with GDNF. As the district court correctly

noted, the Informed Consent Document allows Amgen to terminate the study for scientific reasons, which is at least

arguably what occurred in this case. In addition, the Clinical Trial Agreement specifically allowed Amgen to terminate

the agreement “immediately upon written notice.”

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 7

(c) the kind of occupation, with reference to whether, in the locality, the work is

usually done under the direction of the employer or by a specialist without

supervision;

(d) the skill required in the particular occupation;

(e) whether the employer or the workman supplies the instrumentalities, tools, and

the place of work for the person doing the work;

(f) the length of time for which the person is employed;

(g) the method of payment, whether by the time or by the job;

(h) whether or not the work is a part of the regular business of the employer; and

(i) whether or not the parties believe they are creating the relationship of master and

servant.

Sam Horne Motor & Implement Co. v. Gregg, 279 S.W.2d 755, 756-757 (Ky. 1955). Of these

factors, the most critical element in determining whether an agency relationship exists is whether

the alleged principal has the right to control the details of the agent’s work. Grant v. Bill Walker

Pontain-GMC, Inc., 523 F.2d 1301, 1305 (6th Cir. 1975); Bottled Gas, Inc. v. Borg Warner Corp.,

56 F.3d 726, 736 (6th Cir. 1995).

Here, the above factors suggest that the district court did not abuse its discretion in

concluding that the plaintiffs had little chance of success based on their agency theory of contract

liability. As the district court properly pointed out: “The [Clinical Trial] Agreement provides that

the ‘Institution agrees to act as an independent contractor without the capacity to legally bind

Amgen and also agrees that it is not acting as an agent or employee of Amgen.’ Because the

Kentucky doctors were employees of the University of Kentucky, they too were independent

contractors lacking the power to bind Amgen.” Abney v. Amgen, Inc., No. 5:05-CV-254-JMH, 2005

WL 1630154 (July 8, 2005 E.D.Ky.) (citing Berry v. Delta Airlines, Inc., 260 F.3d 803, 812 (7th Cir.

2001), for the proposition that “an employee of an independent contractor typically cannot be

considered an agent of the employer”).

Other factors also indicate that the principal investigators were independent contractors and

not agents of Amgen. The set up of the Kentucky study, consistent with federal regulations, left the

principal investigators in charge of the details of the work. See 21 C.F.R. § 312.60 (indicating that

in a clinical drug trial “[a]n investigator is responsible for ensuring that an investigation is conducted

according to the signed investigator statement, the investigational plan, and applicable regulations;

for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the

control of drugs under investigation.”). Furthermore the principal investigators drafted and

implemented the Protocol for the study themselves, not Amgen. Moreover, the doctors were highly

specialized professionals with extensive experience in their field. The study took place at the

University of Kentucky, not at an Amgen facility. The University also received a set amount of

money from Amgen as a result of the study. Finally, as the documents regarding the study indicated,

the study was structured such that Amgen’s sponsorship of the study would be independent of

control over the study. Thus, the above factors indicate that the district court did not abuse its

discretion in concluding that it was unlikely that any direct agency relationship existed between

Amgen and the University of Kentucky or its physicians.

Moreover, the record suggests that the district court was similarly correct in concluding that

it was unlikely that the principal investigators had any apparent authority to bind Amgen. Apparent

authority, which may be possessed by an independent contractor, is “the authority the agent is held

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 8

out by the principal as possessing. It is a matter of appearance on which third parties come to rely.”

Mill St. Church of Christ v. Hogan, 785 S.W.2d 263, 267 (Ky. Ct. App. 1990) (emphasis added).

Nothing in the record nor in the plaintiffs’ brief demonstrates any representations made by Amgen

to the plaintiffs that could have led the plaintiffs to believe that the principal investigators were

agents of Amgen for purposes of the study. Nothing suggests that Amgen even had any contact with

any of the plaintiffs as it was the principal investigators who controlled the study and were in charge

of the plaintiffs’ care. Thus, the district court did not abuse its discretion in concluding that the

plaintiffs’ claim based on apparent authority had little chance of success on the merits.

ii.

The plaintiffs’ second claim is that Amgen is legally required to provide them with GDNF

based on promissory estoppel. The plaintiffs’ promissory estoppel argument is premised on their

claim that the principal investigators informed them that they would make decisions based upon the

patients’s best interests and that if GDNF proved to be safe and effective, study participants could

continue to receive the medication following termination of the study. The district court concluded

that “the plaintiffs have not shown a strong likelihood of success on the merits because the plaintiffs

have not submitted any evidence of a clear promise by Amgen.” The district court did not abuse its

discretion in reaching such a conclusion.

Promissory estoppel requires “(1) a promise; (2) which the promisor should reasonably

expect to induce action or forbearance of a definite and substantial character on the part of the

promisee; (3) which does induce such action or forbearance; and (4) injustice can be avoided only

by enforcement of the promise.” Bergman v. Baptist Healthcare Sys., Inc., 344 F. Supp. 2d 998,

1003 (W.D.Ky. 2004) (analyzing Kentucky law). Where there is no evidence of a promise,

promissory estoppel cannot be established.

In this case, there is no evidence of a promise by Amgen to continue to provide the plaintiffs

with GDNF following the termination of the study. The plaintiffs do not assert that Amgen directly

promised to continue to provide them with GDNF. Instead, they assert that the principal

investigators promised that the plaintiffs would continue to receive the medication and that

subsequently Amgen is bound by those promises. This theory is untenable, however, because, as

discussed above, neither the University of Kentucky nor the principal investigators were agents of

Amgen. There is also no evidence that the University or the principal investigators had the apparent

authority to bind Amgen via their promises to the plaintiffs. As a result, the district court did not

abuse its discretion in concluding that there is little chance that the plaintiffs will succeed on the

merits of this claim.

iii.

The plaintiffs’ final claim is that Amgen, working through the principal investigators,

breached its fiduciary duty to ameliorate their pain and treat their illness with the best medicine

available. The district court held that Amgen had no fiduciary duty to continue to supply the

plaintiffs with GDNF. The district court did not abuse its discretion in concluding that the plaintiffs’

likelihood of success on this claim is minimal.

Under Kentucky law, while there is no set formula for determining whether a fiduciary duty

exists, “as a general rule, [courts] can conclude that such a relationship is one founded on trust or

confidence reposed by one person in the integrity and fidelity of another and which also necessarily

involves an undertaking in which a duty is created in one person to act primarily for another’s

benefit in matters connected with such undertaking.” Steelvest, Inc. v. Scansteel Serv. Ctr., 807

S.W.2d 476, 485 (Ky. 1991); Layne v. Bank One, Ky., N.A., 395 F.3d 271, 281 (6th Cir. 2005).

While “[f]iduciary relationships can be informal, [] they must evidence circumstances showing both

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 9

parties agreed that one party would be acting in the interest of the other.” In re Sallee, 286 F.3d 878,

892 (6th Cir. 2002).

In this case, the record does not demonstrate that Amgen and the plaintiffs agreed that

Amgen would be acting primarily for the benefit of the plaintiffs. Amgen had various reasons for

the undertaking sponsorship of the University of Kentucky study. While benefitting the plaintiffs

could arguably be described as one of those reasons, there is nothing to suggest that the parties

agreed that this would be the primary reason for Amgen’s sponsorship of the study. Thus, the

district court did not abused its discretion in concluding that there is no evidence Amgen has a

fiduciary duty to the plaintiffs.

The plaintiffs cite Grimes v. Kennedy Krieger Institute, Inc., 782 A.2d 807 (Md. 2001), in

support of their fiduciary duty claim. Grimes, however, is distinguishable from this case as the

district court correctly decided. The manner in which the district court in Suthers distinguished

Grimes from Amgen’s GDNF study is helpful:

In Grimes, the Maryland Supreme Court found that medical researchers owed a duty

sounding in tort to children whose parents had been induced to live in homes

containing lead paint so that the paint’s effects could be measured against a control

population without such exposure. The researchers in Grimes designed the study,

recruited the subjects, and obtained their consent. Understandably, the Maryland

Supreme Court was concerned about a “vulnerable research subject” who may have

been provided information to induce consent that was “incomplete in a material

respect.” Grimes concluded that there was a duty to the research subject independent

of the consent, and that a consent form could not be utilized to immunize the

researchers from liability. The Grimes court did not characterize the duty as that of

a fiduciary or offer any other characterization.

The dissimilarities between this case and Grimes are many. Here, a therapeutic

treatment was tested in a manner so that the tests would comply with FDA

regulations. To avoid the potential that a pharmaceutical company with a financial

interest in the outcome would place participants at risk of needless harm,

independent research institutions and their physicians conducted the clinical trials.

In Grimes, the participants were in direct contact and privity with the party who was

found to have owed them a duty. Here no claim is asserted against the principal

investigator [] with whom plaintiffs had their dealings.

Suthers, 372 F.Supp.2d at 427. This analysis applies with equal force to this case. Neither the

Grimes case nor Kentucky case law suggests that Amgen had a fiduciary duty to the plaintiffs.

Thus, the district court did not abuse its discretion in concluding that the plaintiffs had little chance

of success as to this claim.

Although we express no ultimate view, it appears that the plaintiffs might have considered

suit against the University of Kentucky’s Institutional Review Board and the physician investigators

involved in the clinical trial. It was the University that was legally bound by the Informed Consent

Document and thus arguably legally obligated to continue to administer the treatment to the

plaintiffs. Moreover, as discussed above, under the FDA’s regulatory scheme it is not the

pharmaceutical companies that are charged with ensuring trial participants’ well being. Rather, it

is the Institutional Review Board that is meant to “protect the rights and welfare” of trial participants

during a clinical trial. 21 C.F.R. § 56.101 (requiring university conducting clinical trials to establish

institutional review boards for the purpose of “protect[ing] the rights and welfare of human subjects

involved in” clinical trials); see also 21 C.F.R. § 56.103 (requiring institutional review boards to

approve all clinical trials before initiation and requiring continuing review of clinical trials while

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 10

they are being conducted). Thus, while the plaintiffs’ arguments have little merit against Amgen,

they may have merit against the University and its Institutional Review Board.6

B.

The second factors under the preliminary injunction test is whether the plaintiffs will suffer

immediate and irreparable harm absent injunctive relief. The plaintiffs assert that absent a

preliminary injunction they would suffer immediate, irreparable harm because without GDNF they

allege that their health will continue to deteriorate as a result of their Parkinson’s disease. The

district court concluded that “the plaintiffs [] failed to meet their burden in proving that they would

suffer immediate, irreparable harm if an injunction is not granted.” While there is evidence in the

record that supports the plaintiffs’ claim, the district court did not abuse its discretion in concluding

that the plaintiffs failed to show irreparable harm absent a preliminary injunction.

To demonstrate irreparable harm, the plaintiffs must show that unless GDNF treatments

resumed immediately, they will suffer “actual and imminent” harm rather than harm that is

speculative or unsubstantiated. See Monsanto Co. v. Manning, 841 F.2d 1126, 1998 WL 19169, at

*6 (6th Cir. Mar. 8, 1998); Heideman v. South Salt Lake City, 348 F.3d 1182, 1189 (10th Cir. 2003)

(citing Wisconsin Gas Co. v. FERC, 758 F.2d 669, 674 (D.C. Cir. 1985)). Here there is no question

that the plaintiffs’ health will continue to deteriorate as a result of their Parkinson’s disease.

Nonetheless, there is no guarantee that the plaintiffs’ condition will improve or at least deteriorate

at slower rate if they are prescribed GDNF. Admittedly, the plaintiffs have provided evidence

suggesting that GDNF is effective. There is evidence in the record that the plaintiff subjectively felt

an improvement in their symptoms after being administered GDNF. In addition, there is evidence

in the record that the principal investigators believe GDNF to be a safe and effective treatment for

the type of severe Parkinson’s disease that the plaintiffs are afflicted with.

Nonetheless, there is also evidence in the record that rebuts the plaintiffs’ claim that GDNF

is safe and effective. Amgen has submitted clinical evidence indicating that there may be scientific

reasons to be concerned about the safety of GDNF based upon: (1) cerebullum lesions developed

by primates on GDNF and (2) neutralizing antibodies found in some patients taking GDNF. More

importantly, there is evidence in the record suggesting that even if the plaintiffs were provided with

GDNF their health might not improve. The clinical data submitted by Amgen suggests that GDNF

adminstered via IPu proved ineffective in clinical trial. The data can arguably be read as indicating

that any improvement in study participants was based merely on a placebo effect. Thus, in the

record there is simply conflicting evidence as to whether GDNF would really prevent irreparable

harm to the plaintiffs if immediately administered. Therefore the district court did not abuse its

discretion in concluding that the plaintiffs failed to establish they would suffer irreparable harm

absent a preliminary injunction.

C.

The third factor we must consider is whether substantial harm to others will occur if the

injunction is granted. As to the third factor of the preliminary injunction test the district court

concluded that “on balance, the court would side with the plaintiffs on this prong.” Like the second

6

Moreover, the litigation in this case indicates that the University, through its Informed Consent Document,

and its other representations to the plaintiffs did a poor job informing the plaintiffs as to the grounds upon which the

study would terminate and their access to GDNF would be denied. We urge the University’s Institutional Review Board,

and other review boards throughout the Circuit, to take additional measures to ensure that patients fully understand that

even if they or their physicians believe an experimental treatment to be safe and efficacious there may circumstances

under which they will be denied continued access to treatment. If this fact had been properly explained to the plaintiffs

in this case prior to the outset of the clinical trial (and spelled out clearly in the Informed Consent Document) perhaps

the litigation in this case could have been avoided.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 11

factor, there is conflicting evidence on the record as to whether others would be harmed if the

plaintiffs’ motion for a preliminary injunction was granted. On the one hand, Amgen asserts several

harms that it would face if a preliminary injunction was awarded, including: (1) exposing Amgen

to future civil liability; (2) undermining Amgen’s role as the sponsor of clinical trials under federal

regulations requiring Amgen to terminate trials found to present unreasonable and significant risk

to patients. On the other hand, these concerns are at least partially obviated by the plaintiffs’

assertions that they will assume all risks of taking GDNF and the fact that the FDA informed Amgen

that it would permit compassionate use of Amgen. Given that there is conflicting evidence in the

record, we conclude that the district court did not abuse it discretion in finding that this factor

weighed in the plaintiffs’ favor.

D.

The final factor is whether the public interest would be served by granting the plaintiffs’

motion for a preliminary injunction. Before the district court, the plaintiffs asserted that the public

interest weighed in favor of granting the preliminary injunction because it should be physicians (who

in this case the record suggests were in favor of compassionate use of GDNF) who decide whether

a drug should be given to their patients and not pharmaceutical companies. The plaintiffs also

claimed that a denial of their motion for an injunction would cause them unnecessary suffering

thereby disrepecting human subjects and deterring other patients from participating in clinical trials.

In response, Amgen claimed that forcing them to provide GDNF to the plaintiffs is contrary to the

FDA’s regulatory scheme and that it is up to the FDA, and not doctors or their patients, to determine

whether a drug is safe and effective. The district court found that public interest was not served by

granting an injunction in this case.

The district court’s opinion made several insightful points regarding this prong. The district

court acknowledged that there may be some deterrent concern as to patient participation in clinical

trials if the plaintiffs are not provided with compassionate use of GDNF. The district court was

quick to point out, however, that granting the plaintiffs’ motion for a preliminary injunction could

also deter pharmaceutical companies from sponsoring clinical trials as clinical trial sponsors might

be required to continue to produce and distribute a drug they believed to be dangerous.

Additionally, the plaintiffs’ claim that physicians should be the sole arbiter of patient care wholly

undermines the purpose and value of the FDA. The public has a strong interest in ensuring that the

FDA rather individual doctors has the power to decide what drugs meet baseline levels of safety and

efficacy. Thus, the district court did not abuse its discretion by concluding that the public interest

would not be served by granting the plaintiffs’ motion for preliminary injunction.

III.

Based on the analysis above, the district court did not abuse its discretion in the denying the

plaintiffs’ motion for a preliminary injunction. We therefore AFFIRM the district court’s ruling.

No. 05-6132 Abney, et al. v. Amgen, Inc. Page 12

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CONCURRENCE

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ALAN E. NORRIS, Circuit Judge, concurring in the result. I agree with the majority

affirming the district court’s denial of the plaintiff’s motion for a preliminary injunction, with the

exception of the inclusion in the opinion of the last paragraph of section A iii and footnote 6.