Clinical investigators are responsible for protecting the rights, safety, and welfare of subjects under their care during a clinical trial (21 CFR 312.60 and 812.100). In many trials, the sponsor delegates some decisions regarding trial design and conduct to an entity such as a steering committee or contract research organization (CRO).
Patient safety has always been the industry’s focus during clinical trials. However, a recent spate of well-publicized patient safety issues has increased public scrutiny and the industry’s desire to improve study quality, resulting in larger, longer, more expensive trials.
In this issue of Peer Perspectives in Oncology, James T. Gourzis, M.D., Ph.D., talks with Medelis about issues affecting patient safety:
James T. Gourzis, M.D., Ph.D. is a member of Medelis’ Medical Advisory Board and has more than 30 years of experience in designing and leading clinical trials, implementing regulatory strategies and negotiating licensing transactions. Dr. Gourzis currently provides consulting services to a wide range of biotechnology and medical device companies with respect to scientific, strategic and regulatory considerations associated with drug and biologic development.
Previously, Dr. Gourzis was an executive with PAREXEL International Corp., a contract research organization that provides a range of services to pharmaceutical and biotechnology companies. He began his career in the clinical research groups of McNeil Laboratories, Inc. and Schering Corp. and is experienced in a broad range of therapeutic areas, including cardiology, immunology and infectious disease.
Dr. Gourzis received his bachelor’s degree in biology from Harvard University, his master’s degree in pharmacology from Boston University, and his M.D. from the University of Manitoba, Winnipeg, Canada. Dr. Gourzis also received a doctorate in pharmacology from the University of Manitoba.
Medelis: In clinical trials, patient safety has always been a cause for concern. But today it is under increased scrutiny, and CROs are bearing that scrutiny – rightly or wrongly – alongside sponsors. What forces have brought patient safety to the forefront of our industry?
Dr. Gourzis: There are two factors that have brought safety issues so prominently into the public radar. The first is the sheer volume of data required to conduct a trial and win FDA approval.
I started out in the pharmaceutical industry shortly after the Kefauver-Harris Amendments came into law in the 1960s. Before that time — the pre-CRO days — the medical staff of the pharmaceutical houses oversaw investigators. Until the late 70s, it was very difficult to go into an investigator’s office and scour case report forms and patient records for safety issues. CRFs, as we know them today, didn’t exist. Investigators weren’t as meticulous with data capture as they have to be today.
With new regulations and increased FDA oversight, sponsors are now required to generate exponentially more data for each trial, bringing more safety issues to light. In fact, Institutional Review Boards (IRBs) now complain that the increasingly large volume of individual adverse event reports — often lacking in context and detail — are actually inhibiting rather than enhancing their ability to adequately protect human subjects.
The second factor driving awareness of safety concerns is the fact that our industry is conducting more clinical trials now than ever before. Many trials relate to disease states that concern so many of us, such as oncology. Thus, the general public is much more aware of clinical trials, and primary care physicians are more likely to refer patients to investigators conducting trials for investigational drugs that may be of interest.
Medelis: In your mind, is there one patient safety tragedy that stands out as an early catalyst for publicizing clinical trial safety concerns?
Dr. Gourzis: Yes … around 2000, the University of Pennsylvania reported on the death of a subject in an ill-fated gene trial. The 18-year-old patient died after he was injected with an adenovirus carrying a gene to treat his liver disorder.
That incident sent shock waves through the field of study, and similar trials were quickly halted. After that fatality, individual cases suddenly came to light in the literature and the general media.
Medelis: On the topic of the media, a recent article in The New England Journal of Medicine (October 4, 2007) described a “CRO Boom” in the last decade. It explained that CROs have absorbed much of academia’s traditional role in drug development by offering greater speed and efficiency in conducting clinical trials. Has this “boom” affected patient safety?
Dr. Gourzis: By using independent CROs, pharmaceutical and biotech sponsors are bringing an objective third party into the study, which ideally increases visibility into problems so they can be remedied as quickly and safely as possible.
When a pharmaceutical or biotech sponsor contracts with a CRO, it’s the CRO’s responsibility to ensure that each study site adheres to good clinical practices and safety guidances. The CRO collects the data from the sites and reports back to the sponsor.
It’s also critical for the CRO to illuminate data that may be prejudicial or suspicious, protecting the sponsor from getting blindsided by problems such as false data, improper study procedures, or failure to report adverse reactions at the study site.
Once that data is submitted to the sponsor, the CRO has discharged its responsibility. It is now the sponsor’s responsibility to clarify any safety issues with the FDA and to ensure that the health status of the patient or trial subject is protected.
In 99% of the cases, this system works. But the few times it doesn’t, it’s like a shark attack. Forty million people swim in the ocean and four get attacked by sharks. What do you read about? The four attacks.
Medelis: A number of well-publicized cases have revealed inadequate conditions and minimal oversight at phase I and II clinical trials being conducted by CROs. What criteria should medical officers apply in assessing CRO competency?
Dr. Gourzis: It’s important to identify a CRO that balances quality data monitoring with speed. If speed is emphasized at the expense of quality, it can be a set up for an expensive failure.
Whether a sponsor is using a CRO or conducting a trial with in-house CRAs, employee turnover will also directly impact the quality of the data gathered during a trial. Studies, especially phase IIIs, tend to last for at least two years. Cleanup and site closure often takes nearly as long as the trial itself. As patients complete their study period, study monitors must record, double-check and fill in the blanks in the data – all of which can add another year or two to the study.
Throughout this process, employee turnover – whether by attrition or promotion – can result in a lack of continuity of monitoring at each site, which adds to the potential for things slipping through the cracks.
Medelis: How does this employee turnover directly affect patient safety?
Dr. Gourzis: Much of the study data comes from patient questioning. When the medical monitor changes during the study, there is greater room for error due to subjective variability.
For instance, a monitor needs to evaluate whether a patient complaint is due to a disease state or the investigational drug. Site coordinators are very rigorous in questioning patients, but some may not be quite as thorough as others. The same is true for monitors.
If you have changes at the site, it’s hard to ensure data is real and correct. The ultimate responsibility rests with the investigator to make the final assessment. The CRO can only dig into the data so far.
Medelis: To sum up, ideally a CRO has minimal employee turnover, helping to ensure relatively consistent reporting. Any other qualifications a CMO should be looking for in a CRO as it pertains to patient safety?
Dr. Gourzis: A CMO should evaluate the CRO’s site experience, relationships and selection criteria. Just as a sponsor may select a CRO based on previous experience and relationships, a CRO will use similar criteria for selecting trial sites. And appropriate site selection and management is absolutely paramount to achieving the sponsor’s goals for the trial.
A CRO will have established relationships with sites and will continue to work together when the last trial has gone well. But the CRO must also step back and assess a site for each new trial. For example, at a particular time, the site staff may have changed or may be overcommitted with other trials, limiting the scope of the site’s staff activities. The CRO needs to have the relationships and controls to ensure that a sponsor’s study is conducted with experienced, appropriate sites.
Medelis: Sponsors lean heavily on CROs to get trials done quickly. If the CRO ultimately hires the investigator, and ‘the buck stops with the investigator,’ doesn’t that automatically put the CRO on the front-line to protect patient safety?
Dr. Gourzis: Like a lawyer during jury selection, the sponsor can pre-empt the CRO in an investigator recommendation. The CRO provides the short list of investigators and the sponsor makes the final selection. So the sponsor has the ultimate ‘yea or nay’ on an investigator, and thus the ultimate responsibility.
At the same time, though, the sponsor depends on the CRO to provide a list of highly qualified, experienced investigators with whom the CRO has direct experience or good rationale for recommending.
Medelis: What are the more progressive CROs doing to support or improve patient safety in this changing landscape?
Dr. Gourzis: Proper management of patient safety depends on effective communication between the CRO and the study site. The CRO can only report what is recorded and/or reported by the site.
Safety issues must be captured, recorded and communicated back to the sponsor, and it is essential to minimize turnover during these long, complex trials. So a progressive CRO will be very proactive in identifying good, diligent monitors and finding ways to keep them in engaged for continuity of service and consistency of quality. Much of the success of the monitoring visit has to do with the relationship of the monitor with the site staff and patients.
Medelis: Until now we’ve been discussing general patient safety issues. What about oncology trials – are there unique considerations for sponsors and CROs?
Dr. Gourzis: Yes, oncology trials have more complex patient safety issues. First, patients in a phase I or II oncology trial almost always have the disease and have usually exhausted other treatment alternatives. The disease may not be stable, so there are issues with disease progression — increased symptoms and/or adverse events not related to the drug.
In addition, you’re often dealing with patients who don’t have much more than six months to live, and these patients are often willing to take greater risk for a potentially positive therapeutic effect.
These factors create additional complications for maintaining patients on study, which makes enrollment, schedule/timing compliance, budgets and data all more complex.
Medelis: Given that oncology trials usually involve smaller numbers of patients, is the monitoring burden lower than trials for other indications?
Dr. Gourzis: Oncology trials don’t require as many patients; however, given the nature of oncology disease, those patients must be monitored more intensively. In addition, medical records are often extensive, requiring time for proper scrutiny.
Unless the FDA changes their criteria for efficacy, a lot of oncology compounds will be approved even though they have been tested in relatively few patients, which can lead to serious patient issues after the drug has gone to market.
Medelis: What’s a medical officer’s worst safety monitoring nightmare?
Dr. Gourzis: Promising results from at the end of an oncology phase II are can be exciting even though the drug has been tested on very few patients. Word may reach Wall Street; people start salivating.
The nightmare is a severe toxicity occurring in phase II or III — either that or a lack of sufficient efficacy.
A severe toxicity in phase II usually kills the compound unless it has tremendous lifesaving potential in a disease that is uniformly lethal. If the compound moves into phase III involving a larger number of patients, there is greater probability for an adverse event, especially one of low frequency. Sites and monitors have to be extremely alert for such an occurrence in a single site or the entire patient population. If a toxicity or adverse event is properly documented and analyzed, the compound may still be viable as a targeted therapeutic.
The nightmare can be magnified when an event isn’t properly documented and analyzed. With poor analysis, a highly targeted therapeutic may never make it to market. Or the drug may make it to market, only to be pulled later because of major safety concerns with substantial costs to the sponsor.
Medelis: The FDA requires that clinical studies are reviewed and approved by an Institutional Review Board. How effective is the IRB in enforcing safety?
Dr. Gourzis: The IRB is involved before the study is initiated and then during the study at intervals appropriate to the degree of risk for patients. In addition, the IRB must be notified of unanticipated problems and changes in research activity.
In the years since the FDA regulations were issued, there have been a lot of changes in clinical trial reporting due to, for example, multi-center studies and international trials. These changes have exponentially increased the volume of data generated by clinical trials.
Today, IRBs are also receiving increasingly large volumes of individual adverse event reports. These reports often lack the context and detail that the IRB would need to fully analyze the data. Thus, the IRB’s ability to assure the protection of human subjects is limited.
Medelis: How can a Data Monitoring Committee / clinical safety committee improve the safety of a trial?
Dr. Gourzis: DMCs are objective, arm’s length arbitrators and represent an important safety measure.
A DMC typically consists of three to four members who are identified up front to the IRB and FDA. They meet at specified intervals to review data from one or more ongoing clinical trials according to a pre-determined protocol.
DMC members are familiar with the disease state under study but they do not participate in the study. Instead, they advise the sponsor on two major issues: one, the continuing safety of trial subjects and two, the continuing validity and scientific merit of the trial itself.
As long as the DMC determines that there are no safety issues, the study proceeds. However, if they see something that requires additional scrutiny, they may request further review of the data. In some cases they may even stop a study pending that further review of data.
For the DMC to be effective, however, it’s up to the CRO and the sponsor to ensure that the DMC gets the information they need in a timely fashion.
Medelis: Is a DMC mandatory?
Dr. Gourzis: In big studies, particularly if there is either an important efficacy end point, or safety end point, or a safety monitoring issue, the FDA will insist on it. For example, DMCs have generally been established for large, randomized multisite studies that evaluate treatments intended to prolong life or reduce risk of a major adverse health outcome, such as a cardiovascular event or recurrence of cancer.
In addition, DMCs are generally recommended for any controlled trial of any size that will compare rates of mortality or major morbidity.
Working closely with the sponsor and the CRO, the DMC adds another set of eyes focused on safety and trial validity and helps prevent the nightmare scenario we discussed earlier.
Medelis: What’s the single most important recommendation for medical officers concerned about improving patient safety?
Dr. Gourzis: A DMC should be considered in every study, both for safety and an objective voice to the sponsor. For example, if interim data suggest a negative efficacy or side effect profile, the DMC may recommend the study be terminated to avoid needless patient exposure and potential costs to the sponsor.
I would also recommend bringing the DMC into the loop quickly – ideally in the planning stage of the study.
Medelis: How about recommendations regarding trial budget and operations to optimize patient safety?
Dr. Gourzis: While a medical officer may be tempted to shave time off site monitoring to control costs, I’d highly recommend against it. If it’s a rare disease where patient enrollment is monthly, the standard monitoring interval is typically once every four to five weeks. But if it’s a condition where enrollment is fast and furious, it may be prudent to increase that monitoring frequency in order to keep on top of the data.
More frequent monitoring can get very time intensive in oncology studies since these patients typically have voluminous medical records. Effective monitoring may require up to 16 hours per patient. A pushback on time to reduce costs may be false economy.
Medelis: It seems that the responsibility for patient safety is spread across the board — the sponsor, the CRO, the IRB, the FDA, the DMC, if there is one. And that a mechanism for improved patient safety is greater monitoring and thorough real-time analysis of that data—all of which means rising costs.
Dr. Gourzis: Given the complexity of oncology studies, costs are a substantial concern. In this regard, I think the CRO will play a greater and greater role in patient safety given the sheer volume of trials that are now underway. A CRO whose monitors have deep experience in an indication, particularly oncology, are the best hedge against rising costs. Experienced, objective monitors who can properly review the files can generate higher quality data for sponsors and DMCs. Of course, patient safety will always continue to be the responsibility of the sponsor and study site.
Medelis: What’s on the horizon at the FDA?
Dr. Gourzis: The FDA has talked about mandating post-marketing studies but nothing has been done so far except in very select cases, such as pediatric safety trials. Post-marketing studies obviously involve a much larger patient population than a clinical trial; the goal is to bring rare toxicities to light more quickly.
Most of the issues with safety post-marketing have been with new state-of-the-art drugs. Powerful patient advocacy groups are increasingly demanding access to emerging novel compounds outside of clinical trials. As they push for expedited approval of these drugs, there may be greater political will to push through required post-marketing monitoring since these novel compounds are more likely to be associated with hidden toxicities.
If post-marketing studies are mandated, a sponsor may have to shoulder the costs of collecting more rigorous safety data on the patients who are, for example, in the first cohort of 15,000 new users.
Medelis: Do you believe that post-marketing requirements will become a reality? Are there any other changes you see ahead?
Dr. Gourzis: Yes, I do think the formal post-marketing studies and reports will be our next major regulatory change. In addition, patients are demanding full disclosure and access to trial results and, more specifically, to their data.
Trials have become exponentially more complex since the first regulations emerged in the 1960s. It’s like comparing a Model T to a Mercedes SLK. As our industry evolves, regulations will evolve as well.
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