A change of tack

By Victoria Houghton, assistant managing editor, July 1, 2016

During the mid-eighteenth century, sailors from all over Europe were dying at sea in droves. However, these shipmen weren’t succumbing to warfare, but rather, scurvy. James Lind, a British Navy surgeon, saw a number of sailors with clear signs of the disease bleeding gums, exhaustion, and general pain and set out to test the various anecdotal theories for treating scurvy on 12 sailors with similar cases aboard the Salisbury. Lind compared the patients who were given cider, an elixir of vitriol, vinegar, sea water, a hospital-recommended electuary, or citrus fruits. The sailors who were given citrus improved drastically and were ready to get back to work soon thereafter (Perspect Clin Res. 2010 Jan-Mar: 1(1): 6-10).

Lind’s experiment did more than highlight the link between Vitamin C deficiency and scurvy. His work is widely considered one of the first documented comparative clinical trials in history  — a game changer for the time, and a stepping stone for the future of research. Indeed, clinical trials have come a long way from sailors and citrus. Even within recent history, clinical trials are evolving in a number of ways, and are increasingly:

• International
• In private settings with central IRBs
• Focused on technology
• Complex

Researchers in dermatology profile these changes and how they reflect an increased focus on efficiency and safety. 

Testing on foreign soil

Like many industries that have dipped their toes in cross-border endeavors, researchers are establishing clinical trial sites overseas to take advantage of logistical benefits. Alice Gottlieb, MD, PhD, professor of dermatology at Tufts University School of Medicine, says that it’s easier for investigators to find treatment-nave patients outside of the United States — patients who are more likely to see response rates because they’ve never been treated before. “With psoriatic arthritis it’s very hard to recruit patients because many are not eligible for clinical trials anymore because either they’re better and they don’t need the care, or they’re excluded because of the drugs they are on already. So, increasingly, very high percentages of clinical trials in psoriatic arthritis are done in Eastern Europe and Russia. These patients have no access to treatment other than clinical trials and therefore they’re willing to do these kinds of studies,” Dr. Gottlieb said.

Some physicians attribute the move beyond the U.S. to the fact that trials have swelled over the years. “Certainly, trials are larger and recruiting for patients has become more challenging,” said Jeff Crowley, MD, dermatologist at Bakersfield Dermatology and Skin Cancer Medical Group in Bakersfield, California. “Canada has a huge clinical trial population. Clinical trials help defray health care costs —hundreds or even thousands of patients in long-term trials with biologic therapies is a significant cost savings for the government,” Dr. Crowley said.

However, there are regulatory considerations for conducting trials in different countries that have changed certain aspects of the process. “In Europe, regulations for approval of a new drug often require that the new drug be tested against their standard of care,” said Linda Stein Gold, MD, director of Dermatology Clinical Research at Henry Ford Health System. “For instance, if you’re coming up with a drug for psoriasis, you have to do a trial against methotrexate or some other standard of care. That’s part of the approval process,” Dr. Crowley said.

Additionally, some companies are champing at the bit to get into the Japanese market — the country with the second-largest pharmaceutical market — requiring specific changes to the population makeup of clinical trials. “In Japan, it is required that patients in Japanese populations undergo a clinical trial before the drug is approved,” Dr. Crowley said. David Pariser, MD, argues that incorporating patients with various cultural and lifestyle factors in trials can be useful. “There are some differences among populations. For example, one of the new biologics for psoriasis didn’t behave exactly the same way in Asian patients as it did with patients here in North America.” All told, while instituting these changes may be challenging for the investigator, Dr. Pariser says that doing so may open the door for more patients to be treated effectively. “If you’re a pharmaceutical manufacturer and you want to develop a drug that’s going to be sold throughout the world, you really want to know how it’s going to behave in other populations.”

Going private

While trials are occurring all over the world, in the U.S. there has been an upsurge in the number of private sites conducting trials, with fewer trials in the academic setting. The reason for this shift: efficiency.

“One of the difficulties of having a trial in an academic center is that they often have their own institutional review board (IRB),” Dr. Stein Gold said. Dr. Crowley agrees and adds, “When you’re dealing with an academic center you have to deal with their IRB which is highly variable in terms of efficiency when approving the trial for the site. Contracting is another major issue. [With the academic IRB] there’s a separate business unit that’s approving the contract. You’ll end up going back and forth on contract language and by the time all of those things are done the trial can often be almost completely enrolled.”

Additionally, when it comes to managing costs, some argue that private is the way to go. “Often, academic centers have more overhead that is attached to the clinical trials which may make them more expensive,” Dr. Stein Gold said. “When conducting a clinical trial, if all sites use a central IRB there is more control by the sponsor and costs can be contained.”

However, while efficiency and cost containment may be drivers behind the shift to central IRBs, concerns remain. “The academic dermatologists who are willing to do clinical trials are basically being driven out of academics because there’s not enough clinical trial business to keep them engaged in the academic endeavor. This leads to a dearth of clinician investigators in academia,” Dr. Gottlieb said. “Who teaches the future? Academic dermatologists. With these people in private practice, who’s going to teach the next generation either about clinical research or how to take care of complicated patients? There are fewer doctors available to do that.”

Tackling technology

Regardless of whether the IRB is central or within the academic setting, sites are being inundated with a massive influx of technology devoted solely to improving methods for collecting, evaluating, and reporting data in clinical trials. “As we increase our understanding about the underlying biology of diseases such as cancer, we believe clinical trials also need to evolve to help advance research and accelerate the development of medicines for people who need more options for their diseases,” said a Genentech spokesperson.

“The technology piece is so prevalent now,” said Laurie Halloran, president and CEO of the Halloran Consulting Group in Boston, which assists medical device, biotech, and pharmaceutical companies in developing strategies for their clinical, quality, and regulatory compliance projects. “With the advent of cloud-based technology and the quest for a greater level of efficiency, the industry has followed the general trend toward smartphones and online business processes. You can say it’s very similar to the way we do anything from airplane reservations, to banking transactions, to ordering groceries or supplies.”

For example, according to Halloran, patients enrolled in clinical trials can utilize apps on their phones to schedule an appointment. Additionally, “There are portals to exchange all of the day-to-day updates in communication, regulatory documents, and safety documents. In virtually every area, there’s often a quest to find that technology-based solution.” Halloran says that there are many advantages to incorporating advanced technology in clinical trials. “When you think about clinical trials, most of what you’re dealing with is documentation. Technology can be used anywhere there’s an immediate feedback loop with a person who sits on the other end of the process — whether it’s data entry or uploading a document. It all goes to the bottom line of time efficiency.”

However, when it comes to drawbacks, “anything that’s done in the clinical trial space that contains data is protected by regulations. In this industry there needs to be a level of security for all technology where there is a password-protected sign-in, and an audit trail. Anything in that space can be very expensive to implement,” Halloran said. Additionally, when it comes to improving efficiency, some physicians aren’t convinced yet. “Wouldn’t that be wonderful if it was true?” Dr. Crowley said. “We have hundreds of site tablets and all of them work differently on different platforms. All of them go down and have technical glitches.”

For Dr. Pariser, the increased focus on electronic health records for trials hasn’t eased the administrative workload. “It forces the investigator site — the doctor and their staff — to do the key punching of data into the computer. The electronic case-record form really doesn’t save time and effort. Also, there are a number of studies that will use different forms of electronic records, and keeping 25 different passwords and learning multiple systems for me is a big hassle.” Indeed, while emerging technology holds enticing promise, Dr. Crowley says that it’s simply not there yet. “Definitely, there’s a big push to integrate more technology in clinical trials and I think eventually the data that’s collected may actually be better than paper data. But right now I would say that’s not the case. It’s an ugly process.”

Managing complex data 

For many physicians, a fully functioning electronic health record system would be welcomed as clinical trials are collecting an increasing amount of complex data. “If you look back at the trials upon which etanercept achieved approval for psoriasis, there were several hundred patients in those two trials. If you look at the latest biologics that are being approved, there are several thousands of patients in clinical trials,” Dr. Crowley said. For Dr. Crowley, this is in part because the U.S. Food and Drug Administration (FDA) is simply asking for more information before granting approval of a treatment.

“For instance, a lot of sub-analyses are done within the trial. Patients are withdrawn from treatment to see if there’s going to be any flare or rebound in diseases such as psoriasis. Patients are often treated with different dosing regimens in phase 3 trials and often have to have dosing de-escalation where the doses are spread out to see where the breaking point is for patients to maintain their response.” Additionally, Dr. Crowley has noticed an uptick in the amount of monitoring required in a clinical trial. “There are multiple layers of monitoring. There’s the regular monitoring of the data. Oftentimes, there’s monitoring of the monitor internally. Then there’s an external validator of the monitoring process,” Dr. Crowley said.

The additional monitoring may in fact be a product of what Dr. Pariser says is the number-one change he has noticed in clinical trials over the years: an increased emphasis on safety. “I think what has changed the most is the focus on gathering adequate scientific data on the safety and efficacy of new drugs and treatments, but particularly on the patient safety aspects of performing clinical trials. There’s a whole body of knowledge and literature on proper use of human beings and experimentation,” Dr. Pariser said. “I would say that properly designed, well-controlled clinical trials that are the standard of today are not only designed to gain efficacy information on treatments, but information on the safety of treatments.”

Undoubtedly, like many facets of modern life, clinical trials have changed — bringing opportunities and headaches alike. Yet, despite all of these changes, for Dr. Gottlieb, one element of clinical trials has remained constant. “It is extremely rewarding to make somebody better for the first time in their life with a drug that you researched and they’re using. Can you imagine how good that feels? Every day I hear, 'you’ve changed my life.' That’s rewarding.” 

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