Emily Cantrell, Senior Director Operations, has ten years of experience managing Phase 1-3 trials and utilizes her experience and customer service background to ensure seamless communication throughout the life of a trial. Her focus has been in pain management, including successful management of six full-service Phase 2 and 3 pain trials from study start through NDA submission.
Ben Vaughn,Principal Statistical Scientist, has participated in over 25 marketing applications and is an expert on CDISC implementation and standards. His work has included coproducing the ISS/ISE for multiple analgesic products; and statistical consultation, display generation and submission work for several chronic and acute pain products. In the past three years, he has supported five opioid sponsors at DAAAP advisory committee meetings, both back room and bullpen.
Pain trials are unique among clinical trials, and it is important to select a clinical research partner that understands and embraces the many differences. There are several key factors to consider when choosing a CRO to work with on your next pain trial.
In any pain study, enrollment may present a challenge. For example, in acute pain model studies, sites tend to enroll quickly and sponsors can find themselves in an over-enrollment situation. Some overage can be helpful to account for subjects withdrawing early from the study, but too much overage can significantly impact exceed the trial’s budget. Sponsors must work with the CRO to set a reasonable cap on the overall number of subjects enrolled to minimize overages while allowing sites to continue to enroll without undue restrictions. For example, for a phase III bunionectomy study, we were able to complete enrollment seven weeks early while managing the enrollment cap by using experienced CRAs and maintaining strong relationships with high performing sites.
Chronic pain studies present the opposite challenge. Enrollment is usually much slower than what sponsors hope for, as chronic pain studies can be a tough sell for subjects. Why enter a trial if your current medication is already working and risk receiving a placebo, a rescue medication offering little analgesic control, or an experimental new drug which may or may not work? Naturally, this presents challenges when meeting predetermined time
lines. During a recent osteoarthritis study, we were able to complete enrollment early by expanding advertising programs across all sites, closing underperforming sites while increasing enrollment caps at high enrolling sites, and continuing to run advertisements throughout the entire enrollment period.
In both situations, transparency with your CRO is key. Understanding a realistic budget and timeline will help keep your trial running smoothly. Your CRO should be able to provide data to support budget and timeline projections. At times, sponsors may be reluctant to approve advertising expenses upfront. For one particular sponsor, we were able to provide them with a comparison of the advertising costs versus the cost of extending the timeline if enrollment targets weren’t met. This comparison encouraged them to move forward with early advertising, and, as a result, their enrollment target was met.
During site identification for another study, it became apparent to us that some of the sites provided by the sponsor were likely to enroll few, if any, patients. We recommended dropping these sites in favor of higher enrolling sites or adding a couple of additional sites to make sure that enrollment rates met their expectations. The sponsor declined because the investigators at those sites were key opinion leaders (KOLs) and they didn’t want the additional expense of adding more sites. In the end, it took an additional 2 months to complete enrollment. Sometimes it is a choice between paying more upfront to reduce the risks of slow and costly enrollment period extensions.
Another obstacle we see is that some sponsors estimate site budgets too low rather than market value for site payments. While we do our best to negotiate the best site agreements we can on behalf of sponsors, unreasonable budget expectations can lead to a study not being able to initiate enough (or the right) sites. The costs in timeline extensions often exceed the costs of offering market-based site payments upfront. Your CRO should be able to provide you with market-based estimates for site payments based on your study design and their experience in similar studies.
2. Subject Reported Data
Pain is not usually a visible condition. A health care professional cannot look at a subject and objectively determine how much pain that person is in. The only way to gather data during pain trials is to ask the subjects to report the information themselves. Any time subjects must provide their own data from a trial, site staff must be educated to work with subjects to better standardize subjective data collection. Similarly, subjects must receive training from site staff on how to report the information, whether electronically or on paper.
If an abnormal value entered by the subject is discovered in your data, the site cannot go back and request a clarification. For example, a subject reporting only to one extreme – all 10s say, or all 1s – is not considered clean data. In an acute pain trial, it would need to be determined how to best represent these outlier data. In a chronic trial, the study team and CRAs must revisit the site for retraining purposes.
3. Data Monitoring
Because there is generally a great volume of data collected in any pain trial, it is important that a CRO monitor these data regularly. This requires a keen eye and can be quite time consuming, particularly in acute pain trials because subjects may leave the clinic before data is available to the study team. However, frequent visits to a site can help catch errors and irregularities before they become a major concern. The study team should look for outliers in the data to identify sites that may need more frequent monitoring visits or additional training for site staff. It is also important to have an experienced CRA capable of monitoring the large amount of data while visiting sites.
To manage this, many sponsors require that CRAs for pain trials have a certain level of experience. As a result, sponsors should be mindful to ensure their selected CRO can meet these expectations for staffing purposes.
4. Drug Preparation
For many pain trials, the investigational product (IP) or rescue medication may be a controlled substance scheduled by the DEA. CROs must be familiar with both DEA and state licensing requirements and forms and must also have an understanding of how to ship, move, and monitor scheduled drugs.
5. Diversion & Misuse
Diversion and misuse of medications can be an issue in pain trials, particularly for chronic subjects. If IP counts appear incorrect, sponsors need to determine if it was a mistake or something more. The CRAs should work closely with sites to ensure IP accountability is performed on a very regular basis.
Because pain, is not necessarily a visible condition, site staff need to be diligent in recognizing suspicious behavior and detecting drug-seeking individuals. This is another area where a well-trained site can make all the difference. It is imperative to consider these points during the site selection process.
6. FDA Approval
A final point to consider when selecting your CRO is the experience of the team in supporting submissions for Food and Drug Administration (FDA) approval. DEA-scheduled drug trials not only need to demonstrate safety and efficacy, but must also address the human abuse liability/potential (HAL/HAP). Additionally, FDA’s Division of Anesthesia, Analgesia and Addiction Products (DAAAP) has been quick to enforce the recommendations of a 2010 FDA position paper on missing data, so sponsors must be extremely precise in their treatment of missing data or risk rejection.
Ultimately, there are many considerations a sponsor must make when selecting a CRO for a pain trial. Trained and experienced project staff are key in keeping trials moving forward with ease, detecting potential issues and monitoring vast quantities of data quickly. Any CRO seeking work on pain trials should also be prepared to demonstrate positive relationships with study sites, which can help ensure good subject recruitment and produce clean data.