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After 20-plus years of experience bringing multiple ophthalmic products to market, I understand that the large-scale clinical trials required for regulatory approval of new drugs and devices in the United States can be time-consuming, expensive, and often frustrating. However, as a clinician and patient advocate, I am also grateful for what we learn from these trials.
The rigorous process of moving a new product from preclinical studies through phase 1, 2, and 3 human clinical trials is the foundation for evidence-based medicine. The results of these clinical trials provide the guideposts for medical decision making: the gains to be expected, the populations in which a treatment is effective, the contraindications to its use. What the investigators get out of a study is highly dependent on how well it is designed in the first place.
Ultimately, a pivotal phase 3 clinical trial—the large studies designed to lead to approval of a new drug or device—must satisfy three very different audiences. First is the US Food and Drug Administration (FDA), which must be satisfied that the product is safe and effective. Without the regulatory body’s approval, needless to say, the drug or device will never reach the US market to be able to help patients. Second, treating physicians and their patients must also see clinical value in the study. Potential partners, investors, and distributors in the business community are the third significant audience.
As the chief technical officer of Allegro Ophthalmics, the company developing the investigational drug Luminate (formerly known as ALG-1001), I know that for this therapy to be successful in the marketplace, it will have to be not only very effective but also be either safer or better tolerated or longer lasting than current therapies. These factors will be important to all three of those audiences.
A fundamental feature of a prospective clinical trial is that the endpoints, or measures of success, must be predefined. Defining trial endpoints that meet the FDA’s exacting standards while also being clinically relevant and cost-effective can be quite challenging, especially for a drug with a new mechanism of action or a treatment for a disease process that is not well understood.
One can cite cases in which the benefits identified in a trial did not match the predefined endpoints. For example, Ohr Pharmaceutical agreed to measure the success of its squalamine drops for wet age-related macular degeneration by reduction in the number of as-needed ranibizumab (Lucentis; Genentech) injections. It turned out that, although the drops improved vision over ranibizumab alone, they did not reduce the number of injections.1 Had that been in a phase 3 trial, the drug would likely not have been approved despite its clinical benefits. Because it was only a phase 2 trial, the company and the FDA agreed on a different endpoint—a 3-line or greater gain in visual acuity—for the pivotal trial now underway.
It is important to keep in mind that when an investigational drug or device fails to meet the endpoints of a trial, this does not necessarily mean the product doesn’t work. It may just be that it doesn’t work in the scenario in which it was tested. Unfortunately, other scenarios in which it would work may never come to light if retesting is too costly or time-consuming.
Even a relatively small trial takes much longer than many people expect. My rule of thumb is that each clinical site will enroll approximately 0.75 patients per month. That means if you want to test an intervention in 100 subjects and complete enrollment within 6 months, you need at least 22 sites. With fewer study sites, a larger test population, or very narrow inclusion criteria, it could take much longer. Also, you cannot begin to analyze the data until the last patient enrolled reaches the last follow-up visit. A 1-year study can easily take 2 years or more to complete (Figure). That is why it is so important to design clinical trials carefully.
TRANSLATING SCIENCE INTO PRACTICE
From the point at which clinical trial data become public information in a peer-reviewed journal, proceedings from an FDA panel hearing, or product labeling, clinicians must use their own judgment to apply the lessons from a tightly controlled clinical trial to real-world practice.
The patients in a trial, for example, may have only the disease being studied, with otherwise healthy eyes and unremarkable medical histories. Also, every effort is taken to make sure patients are not lost to follow-up. In clinical practice, things are not so neat and tidy. Patients miss appointments and can be noncompliant with therapy. They have multiple concomitant conditions and/or prior surgeries.
There is so much a clinical trial does not tell us: What was the reason for treatment failures? Why do some patients progress faster than others with the same treatment regimen? Will a given drug have synergies with other therapies? What are the relative risks and benefits in patients who are older or sicker than those in the study?
But clinical trials give us data that are a more reliable starting point than personal experience alone. Clinicians can be biased by what they have seen in their exam chairs recently. The aggregate data that clinical trials provide is crucial to add to those anecdotal impressions.
Clinical trial data also enhance the clinician’s ability to educate patients about their conditions and proposed treatments. With chronic, slow-moving diseases such as diabetic eye disease, macular degeneration, and glaucoma, it is important to be able to share with patients the evidence that supports the burdensome daily drops or regular injections with which they are asked to comply.
At the end of the day, clinical trials provide the scaffolding on which to base our treatment plans.
We have to take the evidence of benefit they provide and apply that to each of our complex, individual patients to the best of our ability as physicians.
- Ohr Reports Positive Interim Data from Phase II Trial with Squalamine in Wet AMD. LifeSci Advisors newsletter, June 27, 2014, page 1. http://www.lifesciadvisors.com/clientinfo/ohr/Ohr__Interim_Phase_2_Data_6-27-14__clientinfo.pdf. Accessed March 5, 2015.
Vicken Karageozian, MD
• Partner, Clarity Eye Group, Huntington Beach, California
• Chief technical officer, Allegro Ophthalmics
• (949) 940-8130 x724; firstname.lastname@example.org