Factor VIIa for ICH: Behind the Scenes of an Academic–Industry Collaborative Trial

Introduction

Improved treatment for common, serious diseases such as stroke, which have huge implications for public health, is the most important goal of both academic investigators and the pharmaceutical industry. There have been two primary funding sources for clinical trials in the United States: the National Institutes of Health (NIH), and the pharmaceutical and device industries. The model of NIH funding includes a principal investigator or an investigative team who develops a research idea and writes a grant proposal that is submitted for rigorous peer-review. Successful applications are eventually funded to complete a trial. In this model, the steering committee of investigators, with NIH oversight, controls the data, which are monitored by an independent Data and Safety Monitoring Board (DSMB) that is also appointed by the NIH. Drugs and devices may be provided by industry, but control is clearly in the hands of the investigators.

This NIH model of funding for clinical trials is responsible for the single greatest success story in stroke therapy to date: The National Institute of Neurological Disorders and Stroke rt-PA trial (1). Many other promising NIH-sponsored trials are also in the pipeline, including the Interventional Management of Stroke (IMS) trial, which is evaluating intravenous rt-PA as ‘bridging therapy’ to more definitive intra-arterial intervention, and the Albumin in Acute Ischemic Stroke (ALIAS) trial. However, the vast majority of phase III clinical trials for stroke over the past 30 years have been funded by the pharmaceutical industry. Pharmaceutical sponsorship of acute stroke trials, for instance, increased from 38% before 1970 to 68% in the 1990s, and this number is still on the rise (2, 3). Paradoxically, nearly all of the acute stroke trials sponsored by the industry have been negative to date.

Industry-sponsored clinical trials

Within the academic world, the pharmaceutical industry has been viewed somewhat warily (4, 5). An important concern is that in an industry-sponsored trial, the investigator does not have sole control over the scientific agenda, and may not have unlimited access to the data or data analyses. In some situations, this has been taken to the extreme of clinical trials that originate from completely within a company, which then are ‘endorsed’ by a paid steering committee that has had minimal or no involvement in the design or day-to-day conduct of the study. In some cases, companies have been known to recruit investigators and conduct trials without the involvement of any outside academic input. Concern has also been expressed about the financial relationships that exist between sponsors and investigators. Various levels of potential conflict have been identified, including consulting fees and honoraria, speaking engagements, direct profit through shares or share options, and nontrial research funding. Finally, it is well established that published drug company-sponsored trials are more likely to be positive than government or nonprofit agency-funded studies, a phenomenon that has been largely attributed to bias favoring nonpublication of negative studies (6).

Because ethical collaboration between academic investigators and industry is essential, these important concerns have led to published ‘rules of engagement’ for the conduct of trials (7), an internet-based registry (clinicaltrials.gov) of all prospective clinical trials, and strict rules in top medical journals for the publication of the results of randomized clinical trials, embodied in the widely endorsed CONSORT statement (consort-statement.org). These rules stipulate that industry-sponsored trials must be led by investigators who take full responsibility for the scientific integrity of the trial, are free to publish the trial results as they see fit, and have complete access to all of the data. Key quality criteria include an independent and actively engaged steering committee with full access to trial data, an arms-length data safety monitoring committee, independent statistical review, and a commitment to publish negative trial results (7–9).

Despite all of these concerns, industry brings several considerable advantages to the table, the most important of which are major financial resources, and very often an outstanding research infrastructure. The annual worldwide budget for drug development by the pharmaceutical industry is approximately $US 6 billion. In addition, the methodological quality of industry-sponsored trials tends to be superior to that of government or nonprofit-funded studies, which again most likely reflects vast resources available for site monitoring, safety surveillance, and other aspects of quality control (3). With financial resources that often exceed the funding available from public agencies such as the NIH, industry-sponsored clinical trials have tremendous potential to advance medical science and improve the public health. Nonetheless, most of the existing literature on academic–industry collaboration has been negative, emphasizing the perils, pitfalls, and problems inherent in this partnership (4–6). This has also been mirrored by negative reports of academic–industry collusion in the lay media.

The goal of this article is to fully disclose the inner workings of the recombinant activated factor VII (rFVIIa) testing program for acute intracerebral hemorrhage (ICH). This drug development program began in 1998 with the submission of an investigator-initiated research proposal to the manufacturer of rFVIIa (NovoSeven®, Novo Nordisk A/S, Bagsvaerd, Denmark). This year the announcement of the phase III FAST trial, which is the largest trial of a medical therapy for ICH ever conducted, was made. This trial was highly anticipated given the tremendous unmet clinical need related to this disease, and the robust mortality and functional outcome benefits seen with rFVIIa in an earlier phase IIB ‘proof-of-concept’ trial (10). Unfortunately, this trial failed to meet the primary endpoint of a reduction in death or severe disability. However, the rFVIIa ICH testing program can serve as a valuable example of how each side of the academic–industry partnership can provide synergistic complementary strengths, hopefully resulting in a whole that is greater than the sum of the two parts.

The idea and the pitch

In 1996 rFVIIa (NovoSeven®), a novel biological pro-hemostatic agent, was approved for use in the European Union for the treatment of life-threatening bleeding in hemophilia patients with antibodies to factor VIII and IX. Largely at the urging of the agent's principal developer, Dr Ulla Hedner (a Novo Nordisk employee), the company was just starting to explore the potential utility of rFVIIa as a general hemostatic agent for high-risk conditions such as variceal bleeding, massive traumatic injuries, intracranial aneurysm rebleeding, and prostate and liver transplant surgery. In 1997, data from an NIH-sponsored population-based study first demonstrated using prospective serial CT imaging that substantial ongoing bleeding occurs during the first 3–4 h after ICH onset, and that early hematoma growth is associated with clinical worsening (11). Based on this scientific observation, Dr Stephan Mayer first proposed the concept of using rFVIIa to halt early bleeding in patients with ICH in 1998.

Dr Mayer approached Novo Nordisk, which led to a series of mutually informative meetings with two Novo Nordisk employees (First Professor Ulla Hedner, and later Dr Elizabeth Erhardsen). In these meetings the industry scientists from Denmark learned about the epidemiology, natural history, and pathogenesis of ICH, while Dr Mayer learned about hemostasis, the pharmacologic properties of rFVIIa, and the fundamentals of phase I/II trial design. The end result of this collaboration was an investigator-initiated proposal for a 24-patient single-center phase IIa trial evaluating the feasibility and safety of rFVIIa for ICH. The protocol included several design innovations, such as linking treatment to the baseline CT scan that arose from the data that had been originally funded by the NIH (12). Of note, a key factor in getting this proposal completed was the requirement that the proposal arrive by a specific deadline. A strong emphasis on timeliness and execution is a major theme that pervades the culture of the pharmaceutical industry, and in this case the admixture with academia proved to be beneficial.

By early 2000 the final protocol and request for free drug was approved by Novo Nordisk management; no other support had been requested. An investigator-initiated Investigational New Drug (IND) application was submitted to the Food and Drug Administration (FDA), at which point a number of helpful trial design changes were requested. The IND was approved and the study was ready to begin. At the time, Dr Mayer's plan was to collect preliminary data for a proposal for a phase IIB trial to be submitted to the NIH.

A change in game plan

In the fall of 2000 however, a dramatic change in Novo Nordisk's plans was in the works. A new research and development scientist in the company's hemostasis division, Nikolai Brun, was assigned to further investigate the potential application of rFVIIa for ICH. This led to a series of ‘due diligence’ meetings with international experts, most notably Marku Kaste, Thomas Brott, and Joseph Broderick. For the most part, these experts confirmed the scientific rationale supporting ultra-early hemostatic therapy for ICH with rFVIIa, although the lack of conventional preclinical testing in animals was repeatedly cited as an important concern (interestingly, the laboratory experiments that would have fulfilled the classic translational paradigm have since been performed) (13).

Novo Nordisk had in fact decided to initiate major phase II testing programs of rFVIIa in four new indications outside of hemophilia, at a cost of several million US dollars each. Although their main business was insulin, hemostasis was viewed as the company's best potential growth driver, and the stated goal was to establish rFVIIa as the world's first general hemostatic agent. After reviewing the science and judging the feasibility of a large number of different bleeding emergencies, the four indications that were selected by the rFVIIa management team for phase II testing were (1) hemorrhage associated with blunt and penetrating trauma, (2) oral anticoagulant therapy associated bleeding, (3) bone marrow transplantation, and (4) ICH. Nikolai Brun had been convinced that ICH was a compelling potential indication for rFVIIa, won approval for the phase II testing program senior management within the company, and was given responsibility within the company to carry it out.

An international advisory board was organized during the US autumn 2000 to review Dr Mayer's phase IIA trial protocol; additional changes were made to enlarge the sample size and the range of doses tested. This was the first time that any of the investigators was paid anything by the company – a standard consulting fee for attending this 1-day meeting in Frankfurt, Germany. Two parallel phase IIA dose-escalation studies were subsequently designed, one in Europe and Australasia, and one in the United States to satisfy specific dosing requested by the FDA. These studies would come to involve 30 sites and enrolled a total of 88 patients (14, 15). At the time, Dr Mayer had already prepared the trial plans and proposed endpoints for a phase IIB dose-ranging ‘proof of concept’ trial, and a phase III trial.

Before proceeding however, Novo Nordisk requested that Dr Mayer's investigator-initiated IND filing with the FDA be rescinded so that it could be re-submitted by Novo Nordisk. This request reflected the critical role that interactions with regulatory agencies such as the FDA play in drug development. From the academic's point of view, once you convince FDA regulators to approve an IND application, you are finished with the agency and can proceed with the primary task at hand: carrying out the research. For a drug company, the ultimate goal is to eventually obtain licensing approval. Accordingly, every single interaction with the FDA is a high-stakes strategic interaction, with important downstream consequences. The stakes are too high to leave to the investigator alone: this is the job of their regulatory division.

A steering and data monitoring committee needed to be organized to proceed with the phase II trial program. This is where it got interesting, because at that point Novo Nordisk had possession of all of Dr Mayer's and others' ideas, as well as the original protocol. They could easily have recruited a more experienced stroke trialist to serve as the principal investigator, or even proceeded without an academic steering committee (which in fact is customary with the company's diabetes research), but they did not. It was decided that Dr Mayer would chair the steering committee. Dr Mayer also negotiated an agreement with Novo Nordisk at that time to reimburse him retroactively as a scientific consultant for the many hours of work that he had committed to designing and writing the trial protocols. At this point, the future of the rFVIIa ICH trial program would hinge on a few additional decisions made by Drs Brun and Mayer: the composition of the steering committee.

Building the team

From a company's perspective, a steering committee is formed primarily to provide expert input to the company's own team of scientists who have been given the responsibility of executing the trial. Moreover, in many industry-sponsored clinical trials the members of the steering committee are chosen exclusively by the sponsor. This may discourage criticism on the part of the steering committee members because of unstated pressure to remain in the ‘good graces’ of the company. In addition, this may hinder the selection of members who are truly the most knowledgeable about a given disease, or who are the most collaborative in their views. The company may receive contradictory views from its outside experts, leading to protocols that are not internally consistent, and internal power struggles can lead to unpleasant distractions. In our opinion, it is critical that industry-sponsored trials not only rely on outside leadership from an independent steering committee; it is also crucial that this committee have self-determination in terms of its membership. The same applies to membership on a Data and Safety Monitoring Committee (DSMC).

In the case of the rFVIIa ICH testing program, Drs Brun and Mayer selected and recruited the members of the academic steering committee. That was the last decision they made independently. Moving forward, our steering committee has functioned as a collaborative group that is charged with providing ‘independent scientific and academic leadership’ for the rFVIIa ICH testing program in partnership with Novo Nordisk. Rather than serving as an advisory group to a Novo Nordisk employee who was in effect acting as principal investigator, or as a body that had the final authority to make all decisions, the steering committee was given the charge of providing independent scientific leadership while working in close collaboration with employees of the sponsor. Collectively, all of us, on both sides of the academic–industry divide, have been responsible for the ultimate conduct and integrity of the trial. No side can do it without the other.

To function effectively, a trial steering committee needs members who are highly collaborative and work well together. Stability is also important. Both the steering committee and the DSMC, which is chaired by Dr Thomas Brott, have remained intact with minimal change over the past 6 years. This stability is in sharp contrast to the frequent turnover of individuals working on various operational aspects of the testing program for Novo Nordisk. In our view the stability of the steering committee, DSMC, and key leadership personnel representing the sponsor has been critical to the successful execution of the trials.

The steering committee also includes three nonvoting Novo Nordisk employees who have played an invaluable role in contributing to the testing program, Brett Skolnick, PhD, and Kamilla Begtrup, MSc, who have served as the primary trial statistician. Novo Nordisk readily agreed to our request to fund two additional independent statistical consultants (including Dr George Howard) appointed by us to externally review (and in some cases independently re-run) her work.

Activities of the steering committee

The factor VIIa ICH steering committee meets monthly via teleconference to review and troubleshoot all aspects of the drug development program. Enrollment, problems and important protocol violations at particular sites, key quality indicators (i.e. the proportion of patients treated within two hours of onset), and adverse events of special interest are reviewed on a monthly basis on these calls, and weekly by the principal investigator.

From the academician's perspective no matter who you are dealing with, a notable aspect of collaboration with industry is the ubiquitous and mysterious entity called ‘senior management’. Nikolai Brun and Brett Skolnik have served as the critical link between the rFVIIa management team and trialists, facilitating the flow of information, and advocating on behalf of the steering committee within the company. Throughout the six years that we have been involved with the rFVIIa testing program, the majority of specific decisions made by the steering committee have been endorsed by the company and incorporated into the trial protocol. These have ranged from safety testing procedures, modifications of endpoints and statistical analysis plans, and adjustments in sample size and discussions of critical safety endpoints among others. In many cases useful recommendations have also arisen from employees of the company, particularly regarding contingency plans for adjusting sample size during the course of the trials. The Steering Committee has been responsible for a series of secondary academic papers based on the data from the rFVIIa ICH trial program, aimed at expanding our understanding of the causes and impact of hematoma growth, the effects of rVIIa on intraventricular hemorrhage and edema, and of the factors that influence both the efficacy and risks of rFVIIa treatment (16–20). Finally, we have been closely involved with many of the more pragmatic ground-level details of trial conduct, including monitoring of key safety and performance indicators, including troubleshooting the performance of individual centers, and communicating directly with investigators to encourage recruitment or investigate quality issues.

Sometimes there have been points of contention. In these cases we have found that articulating the unanimous position of the steering committee has been essential for getting our point across. Examples of the give-and-take between the steering committee and sponsor have included decisions regarding adequate powering, safety testing that we felt was essential, and feedback regarding the extent to which company employees are involved in manuscript preparation. The company has been remarkably responsive to all of these points, and to date all have been resolved to everyone's mutual satisfaction.

The financial arrangements

The committee meets face-to-face twice a year, primarily to work out study protocols, draft protocol revisions and statistical analysis plans, review key trial data, and to write and edit draft publications. Interim work also involves assisting in the preparation of supporting documents such as the trial newsletter, and preparing all trial-related publications and presentations, including the coordination of sub-analyses initiated by the trial investigators themselves.

These activities and responsibilities were specifically delineated in a contract that we collectively presented to Novo Nordisk, which includes stipulations that we have full access to all of the trial data, and have the sole and final responsibility for publication of all trial results. Although we are certain that we would be willing to perform these duties for free, it is obvious that the activities of the steering committee have inherent value to Novo Nordisk, which is a privately and publicly held company with a primary motive of executing on what they call their ‘triple bottom line’ – remaining economically viable, environmentally sound, and socially responsible (Novo Nordisk is the second largest company in Denmark). In return for our activities related to the trial, the members of the steering committee are paid for approximately 6 h a month at a standard industry rate. As chair of the steering committee, Dr Mayer is reimbursed for approximately 12 h of work each month. In addition, Dr Mayer receives partial salary support (60% effort) in the form of a coordinator's agreement for a coordinator who provides logistical support to the steering committee. None of the members of the steering committee (or their families) are employees or own publicly traded stock in Novo Nordisk.

Lessons learned

Although the FAST trial was negative, we view the program as a successful model of academic—industry collaboration. We set out to answer a question; can rFVIIa reduce hematoma growth and improve outcome? In 2007 we accomplished this goal. We were able to negotiate these challenges successfully because of the collective efforts of a strong and empowered steering committee and DSMB, working in partnership with a corporate organization that shares a common goal. We agree that the alliance between academia and industry, despite its inevitable tensions, is a valuable one that should be nurtured and perfected (5).