Managing Clinical Trials

In a phase I trial, how many sites is ideal?

In the last few posts we’ve been talking about site selection criteria.  We've discussed looking for sites that have dedicated phase I oncology teams, private versus academic centers, and how to evaluate a site. The next question: how many sites is ideal?

The nature of the indication can dictate this number. If it’s a rare indication or one that’s not readily diagnosed by the patient’s primary oncologist, you might need 5 to 10 sites to get enough patients to complete your study within a calendar year. If the protocol is fairly standard, we typically prefer to use two sites.

Two sites = tighter control

With two sites, cooperation between the sites is pretty easy. Each site alternates enrolling a patient, making it easy to exercise tight control over data flow, monitoring, and the information sponsors are evaluating to make important decisions such as trial continuation.

While logic dictates that more sites = more patients = faster data collection, it’s not always the reality in phase I oncology trials. Sometimes, a third site (or more) can add complexities that slow down a trial.

"Three's a crowd"

Surprisingly enough, three sites can be a crowd in a standard phase I oncology trial. Sometimes sites will argue over whose turn it is to enroll a patient. This leads to unproductive complexity, and it’s prevalent enough that some phase I investigators will not conduct a study that involves more than two sites.

Another reason some investigators object to more than two sites is the ethical concern of delaying potentially critical treatments to terminally ill oncology patients because other sites are next in line to enroll patients.

It’s a good idea to match the number of sites to the sponsor’s priorities. If speed is important, remember that using more sites doesn’t always equal faster completion. Sometimes one or two private sites can produce faster results than three or more academic sites.

The decision tree

So to determine the number of sites you need for your next trial, here are the key criteria to evaluate:

1. If you're studying a rare cancer type, cast a wider net by engaging multiple sites.
2. The position of your trial's investigators on the number of sites needed.
3. Your timelines and expectations.

If your indication or investigators don't require a large number of sites, then two sites is often the ideal arrangement since it allows you to retain control while ensuring quality and safety measures are being followed at all times.

Evaluating a trial site's track record

This month we've been writing about selecting sites for phase I oncology trials.  Our first recommendation is to use a dedicated oncology team.  Then we provide pros and cons of academic versus private sites.  Now we'll move to evaluating potential sites.

Without a doubt, your direct experience with a site is the best predictor of future success. You know what type of service, results, and responsiveness to expect. But what if you haven’t worked with a site before? How do you evaluate them?

Thoroughly.

Step one:  Determine how many phase I studies the site has completed in the last 12 to 24 months. Look for the details such as the number of patients enrolled in each study, enrollment rates, and data collection.

You’re always looking for a dedicated phase I oncology team. But sometimes we’re given sites that don’t have a dedicated team, so we have to make the best with what we have.

Since phase I oncology studies typically follow a standard approach, site comparisons are pretty straightforward. Talk directly with the site’s nurse to validate her experience. If she has hands-on phase I experience, you can be more comfortable that she understands the fast-changing nature of a phase I oncology trial and will handle the curveballs that always appear. It’s a red flag a nurse isn’t familiar with the phase I oncology process or feels that certain steps or frequencies of meetings are excessive.

It’s also important to understand the investigator’s experience level. Senior investigators are great because of their experience. Inexperienced investigators might require more hands-on trial management.

Something we look out for is a senior investigator that likes to assign a junior faculty member to a study.  While the junior member might bring enthusiasm to the study and enroll patients ahead of schedule (which of course sponsors love), his/her lack of experience can sometimes lead to trial problems later on.

For instance, overshooting patient enrollment rates can backfire if the structure and site staff aren’t in place to handle the impending avalanche of data. An experienced investigator will know that pacing patients is critical for staying responsive and keeping data processing manageable.

If "over-enrollment" occurs, it can become a challenging situation for you as a sponsor. You’re excited about being ahead of schedule, which sends a positive signal to management. But you also know that the faster patients go on study, the harder it becomes to manage the future data — especially if the right site staffing infrastructure isn’t in place.

Data managers or monitors are the people that understand the volume of work involved with getting data collected, reviewed, and entered into the database. "Over-enrollment" often leads to later delays, which wipes out the previous gains and makes it difficult to continue work with that site on the next trial.

Assessing a site’s track record is important when determining if you’re going to select it for your study. It’s also important to understand what’s in store for you if the site has already been selected for your trial. Dive deep into the details. Understand the site’s true experience, the nurse’s hands-on experience level, the lead investigator, and the site’s ability to manage resources. It’s well worth it and will help you keep your trial on track and on budget.

Academic versus private sites

In our last post, we talked about the importance of having a dedicated phase I oncology team and support structure at your site. Another element to evaluate is the type of site to use — academic or private?

It’s important to match your sites to fit your protocol and trial goals. However, there are differences between academic and private centers that directly affect the success of your trial.

Academic sites

Let’s look at the academic center first. If the site is a comprehensive cancer center, it likely has a dedicated phase I team. This is great and suggests a level of expertise. There’s a common perception, though, that academic centers have greater credibility than private sites. Whether or not that’s true is anyone’s guess.

There are purists who believe that unless a site is tied into an established academic group—in other words, a non-profit setting—the data does not carry weight. Purists might argue that results presented at ASCO, for example, might be dismissible because the study wasn’t done at a Harvard or an MD Anderson-caliber center. This is an important issue for some sponsors and a non-issue for others.

Private sites

In some parts of our industry, private sites suffer from a perceptual lack of credibility. However, a growing number of private sites have created the dedicated team and infrastructure to efficiently and effectively collect high-quality data for your study. These sites are typically headed up by physicians who have implemented an academic-type structure in a private setting.

One example is Premiere Oncology of California and Arizona. Dr. Lee Rosen and Dr. Michael Gordon created Premiere Oncology by combining rigorous academic-like processes with a more entrepreneurial pace. (Note: Dr. Gordon is one of the medical founders of Medelis, and we often recommend Premiere Oncology to sponsors.)

Other private sites might not have a fully dedicated phase I team but could have a dedicated research nurse or study coordinator instead of a complete team. Still other private sites have a single staff that handle all trials (phases I through III), which can create challenges if the entire team didn’t cut their teeth on phase I trials.

Advantages of private sites

If you’re able to find the right private site, you’ll probably find that they can ramp up faster (typically 6 to 8 weeks) compared with 4 to 6 months for academic sites. The bureaucracy from the many institutional levels at academic sites are the main reason for this lengthy timeframe.  (Note:  We have had great experience and rapid, efficient start-ups at Scottsdale HealthCare's Virginia G Piper Cancer Center, where the experienced staffs from TGen Clinical Research Centers and the Scottsdale Clinical Research Institute collaborate on over 20 cancer studies.)

The other benefit you’ll find from most private sites is that they’re often less expensive. Academic centers add what they call their indirect, or overhead, rate and it adds anywhere from 25% to 35% to costs.

Balance your needs

The decision regarding what kind of site to use should balance the need for rapid start-up with the need for high quality, accurate data. A high-quality academic center can raise the profile of your trial, but are you able to wait six months for the first stream of data?

If your main concern is getting clinical data as fast as possible because of budget concerns, private sites are probably your best bet. If budget and time aren’t much of an issue and you have a potential blockbuster, academic sites will suffice. Most sponsors we talk to fall into both categories – they want high quality data fast, are focused on driving down clinical trials costs, and desire the top investigators.

For them, we recommend using one of each. Use the private site to get the study launched, enrolling patients in the first 8 weeks to gain quality data at an affordable price. Then enroll the later patients at the academic center to add the credibility (whether it’s real or not) that satisfies the academic world and the investors looking for names like Johns Hopkins, MD Anderson, Vanderbilt etc. for your trial.

Clinical Trial Site Selection - The Importance of a Dedicated Team

Site selection is a key decision at the start of any phase I oncology trial. Good sites start your trial off right; early site challenges put you behind schedule and over budget.

When investigating sites, we look for a site that has

1. Specific experience running phase I oncology trials
2. The ability to get up and running quickly
3. A proven track record for identifying, screening, and enrolling a patient on study in a systematic manner
4. The capabilities and resources to handle the pharmacokinetics/ pharmacodynamic and other correlative laboratory or radiological studies supporting the trial, and
5. The ability to generate timely, high quality data.

Over the years we’ve evaluated and selected many investigative sites for phase I oncology trials.  We have found that the most effective sites have dedicated phase I oncology teams. In many cases, they also have a dedicated phase I clinical research space within the cancer center or clinic.

Dedicated team benefits

A dedicated team provides the structure to efficiently facilitate these key activities:

• Patient enrollment, patient screening, and placement on study according to protocol
• Collection of biospecimen samples and/or radiological images for correlatives studies
• Generating timely, high quality data.

The smoothest-running sites have a specialized team that includes experienced study coordinators, research nurses, data managers and other personnel dedicated to running the phase I trials at the site. With the intense biospecimen collections and safety monitoring, the collective efforts and experience of a dedicated phase I team increase the chance of protocol compliance and quality data.

A dedicated phase I team typically uses a system to support regular patient toxicity review meetings with investigators, sub-investigators, and research nurses. This is critical for accurately monitoring patient responses and making dose escalation decisions. Also, these routine patient review meetings ensure that all appropriate team members, especially the principal investigator, are engaged in patient monitoring. 

Another key consideration is how the team manages the logistics of the serial biospecimen collections and additional radiographical studies.  A dedicated phase I team is usually better prepared to handle the special sample collection, processing and shipping requirements, especially for the collection of samples after clinic hours. They’re also better at working with in-patient hospital staff, or GCRC staff, to ensure the collection of key samples throughout the night.

We believe that the structure brought by a dedicated team is a better qualifier for a site than, say, the number of years of experience.  A dedicated phase I study coordinator with only a few years of research experience may have handled ten phase I studies in twelve months. That’s a strong experience base. Another study coordinator might have ten year’s experience but only completed one phase I trial. We always feel more comfortable with the former coordinator.

The ultimate benefit of a dedicated phase I oncology team is focus. Focus ensures familiarity, precision and efficiency. Look for it when evaluating sites for your trial, and feel confident that they’ll handle all the nuances that occur.