Collaboration underway to advance future of biologics
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As advancements in musculoskeletal biologic therapies have grown in the past decade, so has clinical use of these therapies despite insufficient evidence for widespread clinical application.
Currently, peer-reviewed clinical literature on orthobiologic therapies and efficacy of these is in its infancy with more to be learned on the exact formulation of each biologic treatment, the conditions for which these show promise and the setting in which optimal application is achieved. However, sources who spoke with Healio/Orthopedics Today said there is a lot of potential for the use of biologics in orthopedics.
Source: C. Shapiro
“I see a future in the use of biologics in orthopedics where precision medicine principles will allow us to restore and preserve musculoskeletal health after injury or disease by using the appropriate biologic at the correct time for the right patient,” Constance R. Chu, MD, professor of orthopedic surgery at Stanford Medicine, said.
Although there are currently a number of injectables that can be minimally manipulated and used in the treatment of orthopedic conditions, Kenneth R. Zaslav, MD, director of the Center for Regenerative Orthopedic Medicine at Lenox Hill Hospital, Northwell Health and professor of orthopedic surgery at Hofstra University, said there is not enough control of these therapies “to say that we are doing anything regenerative at this point.”
“That is certainly our hope that we would get to a point where, someday, we could personalize these injectables, make sure we know exactly what is in them and what the important factors are that could stimulate the body’s own healing potential, but we are not there yet,” Zaslav, who is co-chair of the Biologic Association, told Healio/Orthopedics Today.
Understand the biologic process
Although there have been exciting laboratory findings that support new cellular, proteomic and molecular treatment strategies for musculoskeletal conditions, according to Chu, she said the biologics studied in the laboratory differ from what is available clinically in several respects.
“Clinical preparations tend to be minimally manipulated, whereas new treatments being studied in the laboratory are highly manipulated to ensure uniformity, purity and potency,” Chu told Healio/Orthopedics Today. “Thus, we are still in early stages with harnessing the clinical therapeutic potential of biologics,” she said.
Chu said the latest laboratory findings still need systematic preclinical testing followed by FDA approval for initial clinical trials in humans.
“These are iterative processes that frequently require return to the bench to optimize treatments followed by additional preclinical testing,” Chu said. “Only the most promising strategies that show safety and effectiveness in early stage human studies can then progress to larger-scale human studies.”
Bert R. Mandelbaum, MD, professor of orthopedic surgery at Cedars-Sinai and of the department of orthopedic surgery and co-chair of clinical affairs for Cedars-Sinai Kerlan-Jobe Institute, said one way to identify where biologics fit in orthopedics is to understand the harmonization between what is happening on a molecular level, tissue level and cellular level.
“We have to understand these processes because they have negative and positive consequences on this harmonization,” Mandelbaum, who is past chair of the Biologic Association, said. “So, it is important that we learn more, that we understand more and we get better at our research and education for orthobiologics.”
To achieve a better understanding of biologics throughout the orthopedic field, the American Academy of Orthopaedic Surgeons and Biologic Association are collaborating with the ultimate goal to scientifically and clinically validate biologic therapies, according to Shane A. Shapiro, MD, co-chair of the Biologic Association, associate professor of orthopedics and a sports medicine physician in the department of orthopedic surgery at the Mayo Clinic campus in Jacksonville, Florida.
“We want to take [biologic] treatments for orthopedic conditions that have been shown to work or will be shown to work and we want to advance those therapies into the clinic and into the operating room, essentially, into routine practice,” Shapiro told Healio/Orthopedics Today. “For those [biologics] that have promise, but have not been demonstrated to be effective, we want to make sure practitioners, clinicians and surgeons are not utilizing those therapies until more research has been conducted.”
Use of a registry, biorepository
One way this integration of orthobiologics into orthopedic practice can be accomplished is through clinical validation of biologic therapies, which Shapiro said is generally collected and done through randomized controlled trials and longitudinal prospective cohorts of large groups of patients over time.
“We know that biologic therapies injected into a knee joint for knee arthritis can relieve pain as well as, if not better than, comparator injection therapies for a finite period of time,” Shapiro said. “What we do not know is whether that prevents progression of knee degeneration or people end up continuing to get worsening OA. You cannot know that until you study large populations of patients over a longer period of time, [for] 5 and 10 years.”
To gather this information, Shapiro said it is crucial to create a registry to collect patient-reported outcomes for different biologic therapies, how those therapies were used and whether a patient goes on to continue to be managed medically or whether they go on to need surgery.
The Biologic Association is focused on the creation of a biologic outcomes registry and biorepository that will be known as the Biologic Association Registry and Biorepository (BARB), where samples of biologic therapies will be stored for analysis at a later time. The AAOS and Biologic Association are working together to evaluate a potential companion registry that would further collect data on biologic therapies to help understand the variation and efficacy of biologic treatments approved for use in the U.S.
“So, the registry would collect patient-reported outcomes, while the biorepository would be designed to collect patient samples. We will then look for associations in who does well with these treatments and what their patient-donated samples can tell us about that,” Shapiro said.
Identify biologic treatments
The registry and biorepository could be used to identify which biologics would be most ideal to be used for treatment of muscle, tendon, ligament, cartilage and bone injuries, Mandelbaum said.
With joint preservation through tissue regeneration as a main focus of the use of many biologics, Jason L. Dragoo, MD, professor at the University of Colorado and the Steadman Hawkins Clinic Denver and chair of the AAOS Committee on Devices, Biologics and Technology, said the first iteration of the biologics registry will be to preliminarily follow patients with OA. With each patient as their own control, Mandelbaum said the BARB is also being used to follow patients who received platelet-rich plasma to identify how the PRP is being produced, what are the different types of cells and proteomic arrays produced by different patients and how PRP uses correlates with responders and non-responders.
“This is a critical and important project, and, at the moment, I think we are in the mid-hundreds in terms of the number of patients entered in this study and we are well on our way,” Mandelbaum told Healio/Orthopedics Today. “We will continue to need to fund this big, but important, multicenter project, but it is a model of how best to look at some of these questions that we have asked and [how to look at] each answer.”
Another subset of patients being focused on are those with tendinopathy, Dragoo said. While OA was chosen as an area of focus due to it having the greatest amount of information available, the most clinical trials completed and being a condition that carries the most treatment cost, tendinopathy was also chosen because there are currently no good treatments for it, he said.
“We are collecting tendon samples from surgical patients, with and without tendinopathy, and are exposing the sample to an array of biologics in the hopes to identify what treatments can correct the abnormalities within the cells of abnormal tendons. This analysis of the cellular gene profile of abnormal tenon cells will give us the opportunity to craft more efficient biologics in the future,” Dragoo said.
Continued validation
However, once a biologic therapy is validated for a certain area of the body, Shapiro said the same scientific and clinical validation will need to be performed not only for other orthopedic conditions, but for the same orthopedic conditions that occur in different areas of the body.
“We cannot assume that if a treatment works in the knee to relieve the pain from OA that it must also work in the elbow, because I do not think that has necessarily been the case,” Shapiro said. “There is a lot of work to do, and that work is only going to get done by starting now with the longitudinal collection of data and patient outcomes and those biologic variables that are contained in the products that we are using to treat our patients.”
Not only can the biorepository help identify what different biologic therapies consist of, but it can allow researchers to identify what causes biologics to be effective, whether it be specific proteins or genetic markers, according to Zaslav.
In addition, Dragoo said the biorepository may help in establishing an appropriate dose for orthobiologic products, similar to the dosing used for medications.
“You always know if you are taking ibuprofen, it is 200 mg in that tablet, and, ... biologics need to be dosed in the same way,” he told Healio/Orthopedics Today. “We need to collect these biologics, calculate the amount of cells and the amount of growth factors, and also the amount of platelets in PRP. We can then understand the dose of these biologics that have a consistent therapeutic effect.”
Physician education
As this information is being collected, Dragoo said it is important that physicians, surgeons and researchers are all collecting the same information from patients.
“We need to be collecting the same information so then, at the end of the day, we can pool the information together and get more answers,” he said. “If we collect things differently, then we cannot compare them to one another. So, that’s the collaboration of deciding how are we going to collect this information together in the same manner so we can use collaborative data.”
The AAOS and Biologic Association are also looking to focus on educating physicians and surgeons on the use of biologics and the corresponding regulatory environment, sources said.
“We want to dispel the myths on the internet about what is real about biologics and what is not real,” Zaslav said.
Dragoo said the best way for physicians and surgeons to stay up to date on the world of biologics is to attend biologic courses and symposia. He noted the AAOS Biologics Dashboard is an online, interactive tool that aggregates the various types of orthobiologics products that are currently available in an easily searchable database.
“[Surgeons] need to be updated every year because things change so fast,” he said.
In November 2022, the AAOS held a symposium in Washington, D.C., that covered the necessity of real-world evidence of orthobiologic products and the need to collect this evidence using registries and biorepositories to deliver efficacious and safe orthobiologic therapies.
In 2023, the AAOS and Biologic Association will host a joint symposium on the topic of orthobiologics at the AAOS Annual Meeting in Las Vegas, Dragoo said, noting there will also be a town hall meeting held in conjunction with the FDA during the AAOS Annual Meeting.
“The Biologic Association has an annual meeting, which is an in-depth dive into biologics,” Dragoo said, noting this year’s meeting will be held in conjunction with the Arthroscopy Association of North America Annual Meeting May 5-7 in New Orleans.
Regulatory pathways for biologics
In addition to educating physicians and surgeons on what biologics are, Shapiro said courses and symposia on this topic usually also address regulatory pathways for biologics.
“Essentially, there are three main regulatory pathways that you will commonly see for orthobiologics in the field of orthopedics and sports medicine,” Shapiro said.
The first pathway is one that therapeutic drugs manufactured by a pharmaceutical company undergo, which involves the traditional FDA approval pathway of phase 1, 2 and 3 trials before receiving a biologics license application, he said.
“Many manufacturers will seek approval for a device instead of a drug, and that goes through the 510(k) predicate approval pathway,” Shapiro said. “If you have a device that, say, centrifuges blood or bone marrow or processes fat and those devices have been approved in the past, there is a 510(k) pathway to get approval for devices that can process biologics.”
In addition, there are also a subset of biologics that are allowed to be applied within the practice of medicine, according to Shapiro.
“These are not necessarily products the FDA has taken through their approval process, but physicians and surgeons can apply patient’s own cells and tissues in a graft-like situation within the same surgical procedure,” he said. “So, taking patient’s own cells or tissues — whether [the cells are from] tendon, muscle, ligaments, processed fat, processed bone marrow — those are allowed to be utilized therapeutically in the procedural environment as long as you are not manipulating those products in any significant way and you are not adding anything to them.”
Stronger treatment recommendations
However, Dragoo said additional regulatory pathways are needed for biologic products that do not fit into the traditional investigational new drug pathway to allow for an easier and more efficient process to be used by companies that develop biologic products.
“We have not had a biologic product that has been authorized since autologous chondrocyte transplantation (ACI),” Dragoo said.
Since then, there have been no other biologic product approvals in the United States. “That is because there is not an applicable pathway, and the investigational new drug pathway is a tough pathway to be able to get a product through and it has been an obstacle that has been insurmountable for companies,” he said.
In addition to the FDA providing information on regulatory pathways for biologics, sources who spoke with Healio/Orthopedics Today said the FDA also issued a list of biologic products that should not be used, including stem cells other than hematopoietic stem cells, Wharton’s jelly, amniotic fluid, placental fluid, exosomes or biologic products from donors.
“[The FDA has] become more of the policer of what is being done, what is given to patients, to minimize the harm,” Mandelbaum said.
As physicians, surgeons and researchers begin to better understand how biologics work and the manufacturing process for producing biologics, Shapiro said they will be able to provide patients with stronger recommendations about the biologic treatments they should receive for orthopedic conditions.
“It is hard to recommend a therapy to a patient if we are not 100% certain how it works, how long it will work for and what the future holds for the patient,” Shapiro said. “So, as we understand these therapies better, that allows us, as clinicians, more confidence to use the therapies in our medical and surgical practices.”
- References:
- Biologic Association. www.thebiologicassociation.com/. Accessed Jan. 10, 2023.
- Biologics. www.aaos.org/quality/biologics/. Accessed Jan. 10, 2023.
- Chu CR, et al. J Am Acad Orthop Surg. 2019;doi:10.5435/JAAOS-D-18-00305.
- Cole BJ, et al. Orthop J Sports Med. 2021;doi:10.1177/23259671211002296.
- Frank RM, et al. Orthop J Sports Med. 2021;doi:10.1177/23259671211015667.
- Murray IR, et al. Bone & Joint 360. 2018;doi:10.1302/208-0105.76.360648.
- Murrell WD. Bio Ortho J. 2021;doi:10.22374/boj.v3i1.23.
- Noback PC, et al. J Am Acad Orthop Surg Glob Res Rev. 2021;doi:10.5435/JAAOSGlobal-D-20-00185.
- Obana KK, et al. Am J Sports Med. 2022;doi:10.1177/03635465211037343.
- Shapiro SA, et al. Br J Sports Med. 2022;doi:10.1136/bjsports-2021-104887.
- For more information:
- Constance R. Chu, MD, can be reached at 450 Broadway St., Pavilion A, 2nd Floor MC 6120, Redwood City, CA 94063; email: likim@stanfordhealthcare.org.
- Jason L. Dragoo, MD, can be reached at 175 Inverness Drive West, Suite 200, Englewood, CO 80112; email: killackey@aaos.org.
- Bert R. Mandelbaum, MD, can be reached at 2020 Santa Monica Blvd., Suite 400, Santa Monica, CA 90404; email: melissa.vizcarra@cshs.org.
- Shane A. Shapiro, MD, can be reached at 4500 San Pablo Road South, #378, Jacksonville, FL 32224; email: shapiro.shane@mayo.edu.
- Kenneth R. Zaslav, MD, can be reached at 210 E. 64th St., New York, NY 10065; email: kzaslav@northwell.edu.
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