Abstract
Progress of biologics in orthopaedic surgery faces a delicate balance of clinical application and technology development in the face of government regulations. While early development of orthobiologics was in the hands of basic scientists, the next steps will require the assistance of clinical researchers. Clinicians should understand how to use the governmental rules and regulations to judge emerging technologies and appropriately apply them to clinical practice and clinical trials. The Federal Food and Drug Administration (FDA) is the US governing body over the development and use of biologics in orthopaedic surgery. An understanding of the origin of the FDA and its current regulatory guidelines will help clinicians to avoid trouble from regulatory bodies and avoid malpractice risk when treating patients. This discussion of where we are today, how we got here, and where are we headed can be used to help further the work in the development and application of orthobiologics.
Keywords
Biologics, FDA, Orthobiologics, Orthopaedics, Regulation
Disclosure Statement
Anz: Consultant for Arthrex; Pinegar: no disclosures.
Introduction
Progress of biologics in orthopaedic surgery, or orthobiologics, currently faces a delicate balance involving providers sprinting to apply clinically and profit on unproven technologies and the marathon of technology development through translational medicine. Weighing the balance is the orthopedic community and government regulatory bodies, while aspiring to move the front lines of patient care forward in a safe and ethical manner. While early promising development of orthobiologics was in the hands of basic scientists, the next steps of translation require patient care and have stumbled upon regulatory hurdles and early clinical shortcomings, i.e., technologies not performing as well in clinical trials as they performed in laboratory and animal studies. These hurdles and shortcomings are part of the developmental process and should not be cause for concern. To overcome the hurdles, clinicians and scientists must develop a deeper understanding not only of cellular/molecular mechanisms but also of the entire development process, which requires regulation. One can consider the study and understanding of FDA regulation a lot like understanding the rules of a sport. Rules have been made, precedent has been set, and we as clinicians should understand how to use the rules to not only judge emerging technologies but also sort out how to use them in our clinical practice and clinical trials. As clinicians, we should consider ourselves the referees in this game, at times getting yelled at by industry on one sideline and our patients on the other. The more we know, the better we will perform at translational medicine and the more we can stay out of trouble from regulatory bodies and/or malpractice risk when treating our patients.
Orthobiologics to an orthopedic clinician represent any naturally derived product, which can be used to improve the biology of healing in an orthopaedic intervention, including procedures in clinic such as joint injections and surgical procedures in the operating room. To the Federal Food and Drug Association (FDA), biological products are a subset of drugs and “biological” refers to those medical products that are derived from living material, as opposed to chemically synthesized. The FDA does not consider everything that clinicians consider orthobiologics as biological products. However, the FDA applies the Federal Food, Drug and Cosmetic Act (FDC Act) for the monitoring and regulation of many orthobiologics especially those involving cells.
Monitoring and regulation of orthobiologics is a double edge sword, important for patient safety and proof of worth on one side but stifling to progress at times on the other. Loose regulation encourages clinical experimentation, but raises concerns for patient safety, and does not force products to prove their value before clinicians set prices, market, and use them for patient treatments. Although rigid regulation stifles progress, it ensures patient safety and forces technologies to prove themselves through a developmental process. The latter requires a significant investment of time and money but produces clear indications and evidence for care. Although there is not currently an answer (or agreement) to how much freedom or regulation should be established in the development of biologics, the following will be a discussion regarding where we are today, how we got here, and where are we headed.
History of the Federal Food and Drug Association
The Federal Food and Drug Association (FDA) is an entity that was created by the US government in order to protect the citizens of the United States from abuses in the consumer product marketplace. Prior to 1930, it was known as the Department of Agriculture, but it is origin and history begins almost 100 years earlier.
In 1848, the United States Patent Office appointed Lewis Caleb Beck to analyze agricultural products by means of chemical testing. This marked the beginning of product monitoring and consumer protection in the United States. By 1862, demand had grown such that an entire department was created, the Department of Agriculture. Near the turn of the 20th century, a chemist, Harvey Washington Wiley, worked within the department to prohibit the interstate trade of poor quality and misbranded foods and drugs. In 1906, 25 years of Wiley’s work led to the passage of the “Pure Food and Drugs Act.” The passage of this act set into motion the modern regulatory functions of the FDA, and it’s stated mission today continues to be to protect and promote public health.
It was nearly 30 years after the passage of the Pure Food and Drugs Act that the next bill regarding product safety was passed. This occurred after multiple products came onto the market that resulted in serious reactions and even death to consumers. The worst involved a sulfa drug targeted to pediatric patients, which contained a harmful substance similar to a component of antifreeze. Over 100 people died as a result of exposure to the harmful drug, including children. On June 25th, 1938, Franklin D. Roosevelt approved the “Food, Drug, and Cosmetic Act,” a law requiring product labels to include directions for safe use and premarket approval before a drug could be marketed and sold. This approval required that manufacturing companies provide evidence of a drug’s safety before marketing and sales could be initiated.
As this new law was enforced and direct-to-consumer marketing emerged, it became evident that not all products could be safely marketed to and used by the public. It was decided that certain products would require a prescription from a physician for individual consumer use. Over ensuing years further legislation was required and evolved as the regulations demanded change to accommodate the growing marketplace of new products and developing technology. For example, as the available supply of nutritional supplements and medications flooded the consumer markets, the control of these products was challenged at the judicial level. Some manufacturers challenged the need for government regulation of their products, and in 1976, the FDA was prohibited from controlling the potency of dietary supplements after being challenged within the court system.
In that same year (1976), medical devices began to receive added attention under the jurisdiction of the FDA after an intrauterine device injured thousands of women. The “1976 Medical Device Amendments” demanded that new devices be placed into three classes, each of which required a different degree of control to ensure both safety and efficacy. The most regulated, Class III, are devices that support or sustain human life, associated with high risks of use. Class II are devices with moderate risk to humans. Class I are considered low-risk items and are not used in supporting or sustaining human life.
Over the last 20 years, many advancements in the regulation and duties of the FDA have been made, and today the FDA is an agency within the US Department of Health and Human Services. Currently this department consists of the Office of the Commissioner and four directorates that specifically monitor the four core functions of the agency : Medical Products and Tobacco, Food and Veterinary Medicine, Global Regulatory Operations and Policy, and Operations (see Fig. 2.1 ). While monitoring these core functions the FDA also has specific responsibilities. These responsibilities have been described in five basic categories: protecting the public health by assuring that foods are safe and properly labeled (a shared duty with the US Department of Agriculture) and ensuring that drugs, vaccines, and other biological products and medical devices intended for human use are safe and effective; protecting the public from electronic product radiation; assuring cosmetics and dietary supplements are safe and properly labeled; regulating tobacco products; advancing the public health by helping to speed product innovations (see Fig. 2.2 ).
Safety and Efficacy
One of the FDA’s most important roles (yet sometimes questioned in the realm of orthobiologics) is to ensure product safety and efficacy prior to marketing. “Safety” involves ensuring that in the course of administering a product in appropriate fashion the product does not cause harm, injury, or loss by the recipient in a direct or indirect manner. For safety, the FDA most concerns itself with the possible introduction, spread, and/or transmission of infectious disease as well as ensuring that treatments do not cause undue adverse events. Adverse events for which the FDA has raised concerns include the possibilities of immune reactions to biologic treatments, infections, the potential for neoplasms, and/or increasing the likelihood of a venous thromboembolic event. “Efficacy” generally involves the power of a treatment to produce a claimed effect. As new biologic treatments are emerging, the due diligence of safety and efficacy should preceed marketing and/or making claims regarding biologic treatments. If the medical community is not willing to police itself regarding safety and efficacy prior to making claims and marketing unproven treatments, the FDA was founded upon a responsibility to protect the public and likely sees this as their charge. Since 2008, the reach of the FDA has extended into both industry and the practice of medicine regarding stem cells and orthobiologics. For this reason, it is important to understand the approval process and demands requested of these therapies.
Layered Regulation: 351 Versus 361 Products
The FDA derives its authority to regulate biologic products from the Public Health Service Act (PHSA), a federal law enacted in 1944, which outlines the federal government’s duties to protect the health of the public. Section 351 of the PHSA (PHSA 351) addresses biological products defined as “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product,…applicable to the prevention, treatment, or cure of a disease or condition of human beings.” PHSA 351 established the authority for the FDA’s oversight in the development of these products. Section 361 of the PHSA (PHSA 361) granted the FDA the authority to prevent the spread of communicable diseases.
As biologics have emerged in medicine, the FDA developed layered regulations, based upon perceived risk to the US public, which set the mechanisms of control and oversight established in PHSA 351 and PHSA 361. These regulations are set forth in the Code of Federal Regulations. The Code of Federal Regulations is a document produced yearly that depicts the rules published in the Federal Register. These rules are established by the executive departments and other agencies within the federal government. This document depicts the policies of the FDA and contains specific instructions to manufacturers, healthcare providers, and sponsors in the development/manufacture of products. Title 21 specifically focuses on the rules of the Food and Drug Administration. Part 1271 of Title 21(21CFR1271) is titled: Human Cells, Tissues, and Cellular and Tissue-based Products, or HCT/Ps for short, and addresses “articles containing or consisting of human cells or tissues that are intended for implantation transplantation, infusion, or transfer into a human recipient.”
21 CFR 1271 states that an HCT/P is regulated solely under 361 of the PHSA and must be manufactured to meet the requirements of 21 CFR 1271 alone if it meets four criteria: (1) the HCT/P is minimally manipulated; (2) the HCT/P is intended for homologous use only; (3) the manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and (4) either the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function or if the HCT/P does have a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, it is autologous or allogenic in a first-degree or second-degree blood relative (see Fig. 2.3 ). HCT/Ps that meet these four criteria are often termed “361 products.” Although these HCT/P’s are not subject to premarket FDA review requirements, 1271 does set forth clear requirements within six domains: (1) registration and listing with the FDA, (2) donor screening and testing, (3) current good tissue practices, (4) labeling, (5) adverse-event reporting, and (6) inspection and enforcement. HCT/Ps that are harvested, processed, and reinjected in the same surgical procedure are exempt from the requirements of CFR 1271; however, they are not exempt from overall regulation under PHSA 361 and/or 351.
