Clinical Trials in Practice: The Business of Drug Approval

Participating in clinical trials can be advantageous to both clinicians and their patients.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

As most retinal physicians are aware, no drug requiring a prescription or new medical device can be marketed without approval of the Food and Drug Administration. The process involves a series of phases, from animal testing for safety and toxicity through the 2 successful phase 3 trials required by the FDA to make the drug available by prescription to consumers. These trials are carried out by the doctors themselves, in both private and academic practices.

Retinal Physician spoke with physicians at a large, urban practice, a smaller private practice, and a university medical center to gain insights into how the clinical trials process unfolds and what challenges investigators face, as well as how clinical trial results are incorporated into the management of retinal diseases — even before the FDA approves a particular treatment.

THE LARGE, URBAN PRACTICE

Jeffrey S. Heier, MD, a vitreoretinal surgeon at Ophthalmic Consultants of Boston and president of the Center for Eye Research and Education, also in Boston, is a participant as an investigator in several ongoing clinical trials, including the VIEW studies, which are looking at the efficacy and safety of VEGF Trap-Eye (Regeneron and Bayer HealthCare AG, Leverkusen, Germany) in the treatment of exudative age-related macular degeneration (AMD). He is also an investigator on the head-to-head CATT trial, which is comparing the efficacy of bevacizumab (Avastin, Genentech) vs. ranibizumab (Lucentis, Genentech). This is one of the most anticipated trials in recent memory, as use of bevacizumab for AMD is entirely off-label, while ranibi zumab was developed specifically to treat AMD.

"We are looking at several early phase trials of innovative agents for exudative AMD," Dr. Heier said, "such as integrin antagonism, which may offer antifibrotic activity, as well as antiangiogenic. Intraocular application of brachytherapy in combination with anti–vascular endothelial growth factor (VEGF) therapy has generated interest, and we are evaluating this therapy in patients who have experienced suboptimal anti-VEGF responses."

So, what are the advantages of running a clinical trial in the atmosphere of a large urban private practice? According to Dr. Heier, the advantages are largely the same as in an academic medical center. "The trials process is still dependent upon the interest and dedication to the trial of the principal investigator," he said. "Without these, recruitment, for instance, fails — whether at an academic or private practice." Having said that, Dr. Heier noted that the large majority of top-enrolling sites in the trials of the past several years are what are referred to as "academic private" practices; that is, practices that are heavily involved in clinical trials — possibly also with fellowship programs, as is the case with his practice — and a strong group commitment to clinical research.

However, a chief difference, Dr. Heier noted, is in the oversight process. All clinical trials are subject to approval and monitoring by institutional review boards (IRBs). These exist at virtually all university medical centers, but there are also private IRBs that can green-light a clinical trial and make sure that it maintains the highest standards.

"Private groups often utilize central [i.e., private rather than academic] IRBs, their own legal counsel for review, and internal contract and budget review processes," said Dr. Heier. He noted that practices familiar with this process can often be up and running a new trial in 4 to 6 weeks from beginning to end vs 4 to 6 months for similar processes in an academic setting. Depending on the recruitment objectives, they may have achieved their goal before most academic sites are even able to begin.

This is not to say, however, that private IRBs are less rigorous than those in academic settings. Private practices such as Dr. Heier's report to such IRBs as Western IRB, which operates out of Olympia, WA. Western IRB has posted its procedures and requirements online, and those for investigators can be viewed here: http://www.wirb.com/content/investigator_smo.aspx.

There are also financial advantages. "Well-run trials can be financially rewarding to a practice," Dr. Heier said. "They can help to cover overhead and new equipment and run a profit. However, this only occurs if trials are run efficiently and are well recruited." This can and does benefit the patients too. Dr. Heier's group doesn't undertake trials if they don't offer a significant benefit to the practice's patients, whether it be early access to a new treatment or involvement in an innovative treatment for a disease that doesn't currently have a treatment. As such, he said, both the clinicians and patients are motivated to participate.

SMALLER PRIVATE PRACTICES

Henry L. Hudson, MD, FACS, is a member of a 3-doctor retina-only practice in Tucson, AZ, that sees patients solely on the basis of referrals from general ophthalmologists or optometrists. Because smaller practices have fewer financial resources to put toward recruitment for clinical trials, practices such as Dr. Hudson's enroll the clinical trials in which they participate on a patient-by-patient basis. They are offered the opportunity to participate in a trial by a sponsor or a corporation, and generally they choose to participate if they know it will be useful for their patients.

"When you first see someone and they're a candidate for a clinical trial, they're offered it right up front, as opposed to a call center or something like that," Dr. Hudson said. "The doctor that sees them presents them that option."

Dr. Hudson sees this as a great advantage. His practice does not require the presence of a large administrative staff. Instead, there are fewer highly trained, multiskilled coordinators to handle enrollment, monitoring, and other issues that arise during clinical trials. "Thank God we don't have that," he said, "because that can cause a delay in patient recruitment and enrollment." Moreover, he pointed out the impact that a smaller practice can have on patient perception. "The patients want to know that their care is not being delayed by administrative issues," he said.

Trials being conducted at Dr. Hudson's practice include the VIEW trial, the RISE and RIDE trials for diabetic macular edema, and the CRUISE and BRAVO trials for the treatment of retinal vein occlusions (RVOs). All these trials are in phase 3, but Dr. Hudson's practice participates in both phase 1 and 2 studies as well.

Remarking on phase 2 studies currently under way, Dr. Hudson gave an example of the kinds of findings made. "When you run a phase 2 trial and look at the molecular biology of AMD," he said, "new molecules are being discovered that have a relationship to choroidal neovascularization (CNV)." Like a large percentage of other retinal physicians, Dr. Hudson sees the future of AMD treatment as being in combination therapy. He said, "In AMD, the use of 2 or more agents to achieve durable control over CNV is inevitable."

ACADEMIC MEDICAL CENTERS

Does the clinical trials process in an academic medical center differ from the process as it unfolds in private practices? "The conduct of the trial is similar, since all investigators must adhere to a study protocol," said Franco Recchia, MD, associate professor of ophthalmology and visual sciences and chief of the retina division at the Vanderbilt Eye Institute of Vanderbilt University in Nashville, TN. But he noted that getting the study started may take longer in universities, as IRB approval and contract negotiations are conducted separately by groups unconnected with the retina doctors. The processes may be conducted in parallel, but usually in series, which delays approval.

Another issue that academic medical centers deal with that private practices do not is the issue of where research fits into rank and tenure. "There exist different ‘tracks’ for promotion in university departments (i.e., clinician-scientist, clinician-educator, nontenure, tenure, etc.)," Dr. Recchia said. "Productivity and achievement in any or all of these areas are requisite for promotion. Clinical trials are generally considered research, though some investigators may provide ‘service’ as members of steering committees, protocol development, or manuscript review."

The benefits of clinical trials for patients are equivalent to those in private practice, particularly when those patients, by virtue of being enrolled in a trial, will have access to newer therapeutic options. But the physicians themselves also benefit. "Internal referring doctors can offer their patients the ‘newest thing’ and the institution can uphold its commitment to the academic mission of innovative patient care and research," Dr. Recchia said. "The investigator benefits from all of these as well."

Dr. Recchia believes that patients often look to the university medical center for the newest treatments, or for rescue when all other options have been exhausted. And having dedicated clinical trials coordinators and contract officers removes the administrative burden from the physicians.

But things are not perfect at academic medical centers. "There are delays because of the number of different people and offices involved, lengthy legal review because of the institution's concern over liability, lack of control over negotiations for reimbursement, and possible lack of compensation, as revenue from clinical trials may not always flow back to the investigators," Dr. Recchia noted.

The IRB process is also different. As in the private sector, the process involves submission of a proposed study for review (typically by the full committee, composed of both medical and lay members), followed by revisions until the study protocol is deemed appropriately safe. "Depending on the scope and potential side effects of a study," Dr. Recchia said, "this review process may be rapid or take several iterations. For example, an observational study within existing standard of care will be different from a study in which patients are randomized to surgery or a new medication. Delays may arise because of the large number of studies — often more than 1000 per year — that a university medical center runs, as well as the extra detail with which they are reviewed."

WHERE THE PATIENT FITS IN

Regardless of where a clinical trial is being conducted, the results are going to be implemented with patients at some step along the way and, as noted, often before final FDA approval is given. The manner in which clinical trial results are incorporated into management of retinal disease is complicated. David M. Brown, MD, FACS, who practices with Vitreoretinal Consultants in Houston, discussed this issue.

"If a patient is not responding to conventional standard of care therapy, then I consider what other options (such as an National Eye Institute [NEI] or FDA-monitored trial) could be available for that patient," Dr. Brown said. "For example, you may have a case of RVO that is not responding to the standard of care (grid laser as per the BRVOS) where I may consider whether enrollment into either the NEI-sponsored SCORE study or one of the pharmaceutical sponsored trials looking at anti-VEGF therapies or steroids might be an option for the patient's care."

However, as with any other aspect of medical care, physicians must proceed with caution when considering a patient for a trial. "With phase 1 or 2 trials, you generally have a lot less safety and efficacy data than with a phase 3 trial," asserted Dr. Brown. "This means that the potential risk is certainly higher for the patient and I reserve discussing these trials to only those patients with no other options and whom I really know can understand the risks they are undertaking by being in this type of trial."

He continued, "The Holy Grail is when you see the kind of results we saw in the MARINA and ANCHOR trials [both trials of ranibizumab for AMD] in a disease like wet AMD that had no effective treatment. Even though you're masked, if you see a particular therapy that does better than anything else, you encourage other patients to consider whether they want to be a potential study subject." Dr. Brown believes it is important that any potential study patient realize that clinical trial visits are more time consuming and more frequent, that most studies include a control arm, and even the best designed studies with the best drugs do not guarantee that the patient will end up with a better clinical result.

He noted that many retinal physicians had access, via clinical trials, to ranibizumab to treat patients with AMD years before its approval by the FDA. He also points out that it was the brave and dedicated patients who enrolled in the ranibizumab trials that led to approval so that all US patients are able to obtain anti-VEGF therapy for wet AMD. "When your heart breaks is when you can't get someone into a trial and there is nothing else for them," Dr. Brown said. Clinical trials tend to have exhaustive lists of inclusion and exclusion criteria, and these criteria exist first and foremost to prevent any harm to the patient.

As a reminder to physicians in any specialty in considering whether to encourage a patient to enroll in a clinical trial, Dr. Brown offered a useful rule of thumb: "Treat ’em like you would your mom." RP