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Breaking down the phases of FDA clinical studies
Many practitioners choose to be involved in the approval process of new drugs and devices.
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An 8-year-old boy living in a town outside Glasgow, Scotland, experienced a frightening bacterial meningitis epidemic in which five of his best friends died, one of his friends lost his hearing in both ears, and the young boy lost his sight completely in one eye and partially in the second eye. This young boy was why I became an ophthalmologist and why I continually participate in clinical trials to find new ways to improve care for our patients both medically and surgically. This young boy was my father, who in the 1940s persevered to become a well-established attorney and judge before Parkinson’s disease took his life.
Although I became an anterior segment surgeon and do not treat optic neuropathies on a daily basis, my obligation to my patients and my field is to participate in clinical studies to help discover new therapies. Each and every surgeon will most likely have the opportunity at some point in his or her career to participate in clinical study, but weaving through the maze of clinical research can be a bit daunting at first glance.
There are many phases of clinical research as defined by the U.S. Food and Drug Administration: preclinical and phases 0, 1, 2, 3 4 and 5. These phases apply to both pharmaceutical drugs and surgical devices, with the latter also having the well-known 510(k) approval.
Mitchell A. Jackson
Preclinical involves in vitro (cell culture/test tube) and/or in vivo (animal) experiments to gather preliminary efficacy and safety data.
Phase 0 was a recent addition primarily used in pharmaceutical testing of oral drugs in microdosing to determine bioavailability and half-life data in no more than 10 humans.
Phase 1 is the usual first stage of testing a drug or device in approximately 20 to 100 human subjects. This phase determines safety and, if a drug, what dose or range of doses is safe to move to the next phase of testing.
Phase 2 testing, performed on larger groups of 100 to 300 people, is to determine whether a device or drug has any efficacy. Phase 2 studies sometimes are divided into 2a to assess dosing requirements and 2b to determine how well the drug works at the prescribed dose, and sometimes they are combined into one study. Phase 2 trials are typically randomized, in which some patients receive the drug/device and some receive placebo/standard treatment.
Phase 3 occurs when a drug/device is presumed to be safe and to have a therapeutic effect. It is performed on a much larger group of patients, from 300 to 3,000 people, over a longer time period. Phase 3 includes randomized controlled multicenter trials with the primary aim of determining how effective the drug/device is compared with the current “gold standard” treatment. The recent phase 3 data submission on the corneal inlay Kamra (AcuFocus), despite its clinically insignificant adverse event data in phase 3, was compared with reading glasses as the gold standard for presbyopia, and unfortunately this “unfair” comparison has delayed its approval process. In my opinion, this comparison feature of phase 3 needs to be modified by the FDA to help expedite the approval of great drugs/devices needed for our patients.
Phase 4 is known as postmarketing surveillance on an already FDA-approved drug/device. Phase 4 data help the sponsoring company determine other uses or side effects for its product for marketing purposes to the public.
Phases 1 through 5 are usually conducted under the guidance of a contract research organization (CRO), which then helps select the appropriate investigational review board (IRB) to oversee safety and efficacy in the clinical trial. IRBs can be central through the sponsoring company/CRO and/or local, such as through the hospital conducting the study. Nevertheless, the entire process for a drug or device to go from the lab to full FDA approval could take 10 to 18 years, often costing up to a billion dollars in some instances.
Section 510(k) approval by the FDA involves a manufacturer to notify the FDA of its intent to market a medical device at least 90 days in advance, known as premarket notification. If the device is equivalent to a device already approved by the FDA, the manufacturer can typically avoid the lengthy process described above to have its device available for commercial use sooner than expected. Many of the ophthalmic surgical devices we use on a daily basis are 510(k) approved.
No matter what part of this process you as the premium surgeon decide to participate in, pharmaceutical or device, phase 2 or 3, it is our duty to give back to the community, discover new therapies, remain ethical throughout the process, provide proper informed consent, and hopefully be proud to have participated in the process that ultimately gives better and safer outcomes for our patients.
Stay tuned for next month’s column on the proper balancing act as a premier surgeon.
References:
Adams CP, et al. Health Aff (Millwood). 2006;doi:10.1377/hlthaff.25.2.420.
U.S. Food and Drug Administration. www.fda.gov.
For more information:
Mitchell A. Jackson, MD, can be reached at Jacksoneye, 300 N. Milwaukee Avenue, Suite L, Lake Villa, IL 60046; 847-356-0700; email: mjlaserdoc@msn.com.
Disclosure: Jackson has no relevant financial disclosures.