Abney v. Amgen, Inc.

• Decision Date: 29 March 2006
• Docket Number: No. 05-6132.,05-6132.
• Citation: 443 F.3d 540
• Parties: Edward ABNEY, Barbara Allen, James Day, Robert Green, Delbert Jackson, James Pugh, Roger L. Thacker, and Daniel Hunter Webster, Plaintiffs-Appellants, v. AMGEN, INC., Defendant-Appellee.
• Court: U.S. Court of Appeals — Sixth Circuit

Page 540

443 F.3d 540

Edward ABNEY, Barbara Allen, James Day, Robert Green, Delbert Jackson, James Pugh, Roger L. Thacker, and Daniel Hunter Webster, Plaintiffs-Appellants, v. AMGEN, INC., Defendant-Appellee.

No. 05-6132.

United States Court of Appeals, Sixth Circuit.

Argued: February 1, 2006.

Decided and Filed: March 29, 2006.

COPYRIGHT MATERIAL OMITTED

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.

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

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

NORRIS, J. (p. 553), delivered a separate opinion concurring in the result.

OPINION

BOYCE F. MARTIN, 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.

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.

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...