FDA device regulations and approval process address safety and efficacy issues

The agency may subject new biologics to tissue rules regarding production and donor eligibility.

Issue: October 2006

The history of FDA regulation is marked with mishap and reform. As the markets for biologics and drugs grow, the agency is taking a tougher stance on safety.

"There are enough examples of tragedy in the history of drug, biologic and device introduction to warrant continued close examination of these new devices," Michael J. Yaszemski, MD, PhD, the former chair of the agency's orthopedic and rehabilitation device panel, said during the American Orthopaedic Association 119th Annual Meeting. He cited the Biologics Control Act, the Federal Food and Drugs Act and the distribution of unsafe medications as steppingstones to the FDA's current regulations.

The Biologics Control Act was signed in 1902 after 13 children contracted tetanus from contaminated diphtheria antitoxin and died. The act introduced government regulation of product safety and potency.

Upton Sinclair's work, The Jungle, about unsanitary meat packing sites helped pass the Federal Food and Drug Act in 1906. The law prohibited "adulterated or misbranded food and drugs," Yaszemski said.

Nearly three decades later, the Food, Drug and Cosmetic Act was passed after 107 people died from sulfanilamide elixirs containing ethylene glycol.

"These drugs, devices, [and] biologics were sold with no regulation as to whether they actually did what they said they could do," Yaszemski said. Paralytic polio cases contracted from inappropriately manufactured polio vaccines in the United States in 1955 led to tighter rules on safety; birth defects in the early 1960s caused by thalidomide led to the inclusion of efficacy in the FDA's mission.

Device classification

The FDA has stringent rules regarding product safety and efficacy. Devices, drugs or biologics under approval consideration fall into one of three classifications, based on complexity and health risks.

"Class I devices are subjected to a set of general regulations that apply to all devices," Yaszemski said. "Class II devices are usually those for which general controls are not sufficient to ensure safety, and for which special controls may be needed. Class III devices may require post-approval controls such as registries and postmarket surveillance at the discretion of the FDA."

Class II products must demonstrate substantial equivalence to another product that gained FDA approval prior to 1976. These devices go through a 510(k) regulatory process to gain marketing approval. The FDA defines Class III devices as life supporting or life sustaining. These products have the most challenging route to approval and require an investigational device exemption (IDE), investigational new drug (IND) or humanitarian device exemption (HDE), he said.

"There have been more than 1,000 Class II devices approved since 1976 and only 43 approved as Class III," Yaszemski said. "Class III poses a very difficult path to approval."

The FDA can categorize new orthopedic products as devices, drugs or biologics. Products deemed as biologics fall under the jurisdiction of the Center for Biologics Evaluation and Research (CBER). These undergo the approval process via the investigational new drug (IND) pathway, just as the Center for Drug Evaluation and Research (CDER) uses for new drug applications. Petitioners must demonstrate the biologic product's safety, efficacy, purity and potency and then they apply to CBER via a Biologics Licensing Application.

"And, not only is the biologic product regulated, as we're used to in the device approval pathway, but also the process that makes the product is regulated, and quality control of all intermediates toward that product have to be regulated," Yaszemski said.

Tissue rules

The FDA may also enact tissue quality and practice rulings for the approval process for a drug, biologic or device, detailing the establishment of a direct registration, meaning where the tissues are made, donor eligibility criteria and good tissue practice rules.

Investigational new drugs or biologics undergo three or four study phases. In phase 1 trials, researchers identify safe dosages and acute side effects in a group of 20 to 80 healthy volunteers. phase 2 studies include 100 to 300 people with the targeted illness. If the drug seems safe and effective and carries acceptable risks, investigators gather safety and efficacy research on 1,000 to 3,000 patients for the final phase.

"In a phase 3 trial, there's also a comparison to whatever the gold standard of treatment is to assess whether the new treatment could become an acceptable alternative to it," Yaszemski said.

For more information:
Yaszemski MJ. The difference between device and drug in FDA approval. Symposium 2. Presented at the American Orthopaedic Association 119th Annual Meeting. June 21-24, 2006. San Antonio.