By Stacy Freeburg, FACT Accreditation Coordinator
Programs monitor adverse events for patient safety and report events to third party organizations (FDA, Trial Sponsors), who consider the implications of single adverse events and compile the data to identify potential trends. Management of adverse events within an organization related to the administration of cellular therapy products is required by the FACT Standards.
FACT defines an adverse event as any unintended or unfavorable sign, symptom, abnormality, or condition temporally associated with an intervention that may or may not have a causal relationship with the intervention, medical treatment, or procedure. An adverse reaction is classified as a type of adverse event. In the standards, references are made to adverse events that encompass required detection, investigation, documentation, reporting, corrective and preventive action, and the responsibility to report incidents to different entities.
If an unexpected or serious adverse reaction occurs due to cellular therapy product collection or administration for which there is a reasonable possibility that the response may have been caused by the product, the report of the adverse reaction and its outcome and investigation should be communicated to all facilities associated with collection, processing, and/or administration of the product.
Organizations must comply with FACT Standards and policies throughout their accreditation cycle, including submission of the Annual and Renewal Report within 30 days of receipt (refer to the FACT Maintaining Accreditation Policy). The Annual Report is sent on the 12-month anniversary of current accreditation, whereas the Renewal Report is sent 14 months prior to expiration.
These reports allow organizations to update FACT regarding their demographics, changes in key personnel, facilities, or services, and submit required documentation of corrective action, as applicable. The report also requires programs to provide an explanation of any serious or unexpected adverse event that occurs during the reporting period. As defined by the FDA, serious adverse events have a severe impact on an individuals’ health, potentially leading to life-threatening consequences, permanent damage, or extended hospital stays (refer to the FDA, “What is a Serious Adverse Event?”).
When reporting an adverse event, organizations must include an explanation and supporting documentation that demonstrates compliance with the FACT Standards and includes the following:
- A description of relevant patient details. Do not include Protected Health Information (PHI).
- A description of relevant product details, if applicable.
- A summary of how the event was identified and investigated, corrective action(s) implemented, and that appropriate follow-up of implemented corrective action(s) was performed to ensure the corrective action(s) were effective.
- 3.4.8 Management of complications related to the administration of cellular therapy products.
- B/C/D220.127.116.11 Occurrences shall be reported to other facilities performing cellular therapy product functions on the affected cellular therapy product and to the appropriate regulatory and accrediting agencies, registries, grant agencies, sponsors, IRBs, or Ethics Committees,
The Importance of Both Hope and Information when Battling Disease: A FACT Accreditation Coordinator’s Experience
By: Dina Becirovic, MPH, FACT Accreditation Coordinator
I lost a loved one to testicular cancer. At the time of his death two years after diagnosis, my cousin was more alive than most living people. He was an example of someone willing to try different treatments and travel far in the hopes of a cure. He was in his early 40s and living in Bosnia when he was diagnosed early enough that the tumor could be removed. The follow-up scans showed the involvement of the lymph nodes, which were also removed. Subsequent scans showed elevated cancer markers, with additional scans showing nodules in the right lung and kidneys. He remained hopeful that he could still be cured. Holding onto hope, he turned to herbal supplements and cocktails. He would drink fluids that would “boost his immunity.”
With a poor prognosis, his last resort was coming to the United States. The cancer was inoperable at this point as it metastasized close to the walls of the aorta. With the condition that far advanced, his treating physician indicated the stem cell transplant would yield a 10% chance of recovery and cancer remission. He passed away a week after receiving an autologous transplant, two years after his diagnosis. Even in his worst days, he was full of life, unscathed, hoping to see his son again. His experience showed the perseverance, hope, and desperation of someone who wanted to live.
A couple of months ago, I had the opportunity to attend a webinar on the topic of stem cell tourism (Gulera, 2020). This presentation reminded me of what I had already personally seen regarding the extent people are willing to go out of desperation, hope, and a desire to live. My cousin’s experiments with outside remedies did not touch the surface compared to the extreme examples shown during the webinar. Stem cell tourism is often presented to patients as having the ability to treat or cure conditions and diseases such as diabetes, stroke, paralysis, or cerebral palsy (ISSCR, 2014). For example, because of a stem cell treatment in this setting, an individual lost an eye. Perhaps the most gruesome example of stem cell tourism was that of a man with an aggressive growing mass of someone else’s cells in the lower portion of his spine. For treatment and in hopes of finding a cure for quadriplegia post-stroke, that man paid $300,000 for injections (Kolata, 2016).
The International Society for Cell & Gene Therapy (ISCT) describes stem cell tourism as “any unproven or insufficiently proven cell therapies proposed to patients as “treatments or therapies” for a specific financial cost and without recognized biological and medical proofs of safety and efficacy (i.e., without a positive benefit-risk assessment in place)” (ISTC, 2015, p.9). These therapies are often offered to patients in clinics locally and worldwide. Most therapies are not part of the domain of conventional clinical trials, and no regulatory monitoring or information about risks or benefits is available. Furthermore, unproven cell therapies are characterized by the inability to confirm product quality and efficacy due to unclear scientific foundation or experimental procedures or consistency in cell manufacturing, inadequate consent forms, and failure to support clinical use due to incomplete research on action mechanism and biological function (ISCT, 2015).
The International Society for Stem Cell Research (2014) developed a Patient Handbook on Stem Cell Therapies, including stem cell tourism. This resource provides a set of questions one might ask of the clinic or their provider. It also includes the warning signs a patient should look for should they ever find themselves in this situation.
FACT Standards require independent oversight by appropriate agencies, such as an Internal Review Board, ethics boards, and regulatory agencies; the disclosure of risks and benefits; and the disclosure of the cell source and how the cells will be collected, manufactured and administered. Additionally, FACT Standards reinforce training and continued annual competence of stem cell transplant physicians, advanced practice providers, and staff that are providing patient care in the stem cell transplant field. These requirements would mitigate the risks of stem cell tourism of clinics that voluntarily comply with them.
For a list of patient-related resources on Stem Cell Tourism and similar topics, visit the FACT website. Whatever you do for yourself or a loved one, be informed.
Gulera, I. (2020). Stem Cell Tourism [Webinar]. AABB Spanish Subsection.
Kolata, G. (2016, June 23). A Cautionary Tale of ‘Stem Cell Tourism’. https://www.nytimes.com/2016/06/23/health/a-cautionary-tale-of-stem-cell-tourism.html.
International Society for Cellular Therapy. (2015). ISCT Presidential Task Force on the Use of Unproven Cellular Therapies: Reference Guide. https://isctglobal.org/page/PTF2015 .
Mummery, C. L., Stolpe, A. van de, Roelen, B. A. J., & Clevers, H. (2014). Chapter 11. In Stem cells: scientific facts and fiction. Elsevier/AP, Academic Press is an imprint of Elsevier. https://doi.org/https://doi.org/10.1016/B978-0-12-411551-4.00011-8
Comments due by September 11, 2020
The Society for Immunotherapy of Cancer (SITC) announced a public comment period on its upcoming clinical practice guideline, The Society for Immunotherapy of Cancer consensus statement on immune effector cell-related adverse events. Comments are due by the end of September 11, 2020.
This manuscript is part of the SITC Cancer Immunotherapy Guidelines program, which is a collection of clinical practice guidelines available in the open-access, peer-reviewed online journal, Journal for ImmunoTherapy of Cancer (JITC). It was written by an expert panel that included representatives from the American Society of Hematology (ASH), the American Society for Transplantation and Cellular Therapy (ASTCT), and the Foundation for the Accreditation of Cellular Therapy (FACT).
By Sherry Adkins, RN, MSN, ANP-C and Kara Wacker, MBA, RAC
The CARTOX Mobile App for iPhone and Android, created by MD Anderson Cancer Center, is now available to assist clinicians with accurate and timely grading and treatment of toxicities associated with immune effector cellular therapy (IEC). The app is intended for physicians, nurse practitioners, physician assistants, nurses, and pharmacists who treat patients receiving IECs.
Sherry Adkins, RN, MSN, ANP-C, Advanced Practice Provider Supervisor, Lymphoma Research at the MD Anderson Cancer Center developed the idea of an app to allow for safer and more efficient care of the rapidly expanding population of patients receiving IECs. “We recognize that the app has helped our group improve the safety and efficiency of care for this group of patients,” explains Adkins. “We hope it will help other clinicians, particularly those who are just beginning to administer this therapy.”
Ms. Adkins led the implementation strategy with coding assistance from Darren Skeete and his team from the center’s Informational Technology (IT) department. Members of the MD Anderson CARTOX Committee, including Drs. Sattva Neelapu and Elizabeth Shpall, reviewed and tested the app. The process started in the Fall of 2017, and MD Anderson clinicians had access by August of 2018.
The app is based on published guidelines, and will continue to be updated as science evolves to reflect the most current practice guidelines. The initial version of toxicity grading was based on the MD Anderson’s CARTOX program guidelines, but has since been updated to reflect the ASTCT (formerly known as ASBMT) consensus grading. (Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. Review.)
Toxicity management is based on the CARTOX program’s guidelines, which were developed by a multidisciplinary, multi-institutional group of clinicians (Nat Rev Clin Oncol. 2018 Jan;15(1):47-62. doi: 10.1038/nrclinonc.2017.148. Epub 2017 Sep 19. Review). Toxicity management guidelines are currently being updated and the mobile APP will be updated to reflect those changes in the near future.
To download the app, search for CARTOX in the Apple Store or Google Play.
FACT Standards require reporting of adverse events related to cellular therapy product administration. FACT does not dictate the process or timing of such reporting, but requires that the reporting meets the requirements of applicable laws and regulations. We have fielded many questions via workshops, emails, and telephone calls regarding the reporting of adverse events related to commercial cellular therapy products (e.g., Kymriah, Yescarta).
Many stakeholders in the field are working on initiatives to make data reporting, including adverse event reporting, a more streamlined process. In the meantime, the FACT Immune Effector Cell Task Force recommends that programs define a reporting process and document it in a Standard Operating Procedure (SOP). The following are some tips for creating the process:
- Know, understand, and comply with the reporting requirements outlined in the Risk Evaluation and Mitigation Strategies (REMS) for the specific product(s) you administer. List these requirements in the SOP.
- For remaining gaps in the process, define your program’s reporting elements and frequency of reporting, including:
- The types of adverse events that your program will report immediately (e.g., all events, specific grades of cytokine release syndrome) and to what source (e.g., MedWatch, manufacturer).
- The types of adverse events that your program will collate for future reporting, the frequency of reporting such adverse events, and to whom the information will be reported.
- Maintain documentation of all adverse events and reporting records.
- Develop an audit plan and schedule for monitoring compliance with REMS requirements and the program-defined process.
- Regularly check in with your manufacturer contacts for any updates to their adverse event reporting requirements.
For additional information regarding adverse event reporting, visit the REMS websites of Kymriah and Yescarta, review FDA requirements for manufacturer reporting in 21 CFR 600.80 Postmarketing reporting of adverse experiences, and Standard B4.10 and its substandards in the FACT-JACIE HCT Standards and the FACT IEC Standards.
On-site inspections are understandably stressful experiences. Organizations essentially invite others to come to their sites, look through their documents, watch their work practices, and record observations. Organizations that voluntarily pursue FACT accreditation want to do well, and it is natural to feel nervous about what inspectors may find while assessing their programs.
When preparing documentation for inspector review, it may be instinctively enticing to avoid showing inspectors everything. Limiting what inspectors see limits the amount of deficiencies they find, right? Wrong. Although it seems counterintuitive, more citations result from inspectors not able to find evidence of compliance.
Do not think of an inspection as a day to avoid doing anything wrong. Think of it as a day to proudly show all that your program has accomplished! The easier it is for inspectors to find and review documents, the easier it is for them to check “Compliant” on that ubiquitous inspection checklist. Showing documentation upfront on the day of inspection will avoid extra time and effort to describe the documentation when responding to deficiencies afterward.
Therefore, be ready to show inspectors audits, adverse event investigations, and urgent medical need documentation for ineligible donors. The purpose is not to show the inspectors any shortcomings; the purpose is to show inspectors your approach to quality management and continuous improvement. Organizations that act like they have something to hide will appear to have something to hide. Confidently showing inspectors your quality documents, procedures, and investigations demonstrates a commitment to quality.
FACT and its inspectors want organizations to do well, and that does not end with an accreditation certificate. The ultimate goal of FACT accreditation is to continuously improve. The more you show us, the more we will be able to help you and the better value you gain from the accreditation process.
Throughout the past few months, the FDA has released numerous final and draft guidances that are pertinent to cellular therapy. The following are summaries of recent documents.
Final Guidance on Testing for Treponema pallidum (Syphilis)
The FDA published updated recommendations concerning donor testing for evidence of Treponema pallidum (T. pallidum) infection, the etiologic agent of syphilis. As required under 21 CFR 1271.80(a) and (c) (§ 1271.80(a) and (c)), testing must be performed using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer’s instructions, unless an exception to this requirement applies under 21 CFR 1271.90. This guidance clarifies that the FDA does not consider cleared or approved diagnostic tests or pre-amendment devices (which have not been licensed, approved, or cleared) to be adequate for use in donor testing for T. pallidum infection under the criteria specified in § 1271.80(c).
Draft Guidance on Testing for West Nile Virus
The FDA also announced the availability of a draft document entitled “Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry.”
The FDA recommends the use of an FDA-licensed nucleic acid test (NAT) to test living donors of HCT/Ps for evidence of infection with West Nile Virus (WNV) to reduce the risk of transmission to recipients.
Draft Guidance on Deviation Reporting
The Food and Drug Administration announced the availability of a draft document entitled “Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR part 1271; Draft Guidance for Industry.”
The draft guidance document provides certain establishments that manufacture non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps), regulated solely under the Public Health Service Act (PHS Act) and under FDA regulations, with recommendations and relevant examples for complying with the requirements to report HCT/P deviations.
Final Guidance on Investigating and Reporting Adverse Reactions
The FDA published finalized guidance entitled, “Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR part 1271; Guidance for Industry.” The guidance document provides establishments that manufacture HCT/Ps for which no premarket submissions are required with recommendations for complying with the requirements for investigating and reporting adverse reactions involving communicable disease in recipients of these HCT/Ps. The guidance also provides updated information specific to reporting adverse reactions related to HCT/Ps to supplement the general instructions accompanying the MedWatch mandatory reporting form, Form FDA 3500A.
Draft Guidance regarding Homologous Use of HCT/Ps
The FDA announced the availability of, “Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and FDA Staff.” The draft guidance document provides human cells, tissues, and cellular and tissue-based product (HCT/P) manufacturers, health care providers, and FDA staff with recommendations for applying the criterion of “homologous use” as it applies to HCT/Ps. Comments must be submitted by September 27, 2016.
Draft Guidances Reopened for Public Comment
The FDA is again accepting comments for the following draft guidance documents. Comments must be submitted by September 27, 2106.
- Human Cells, Tissues, and Cellular and Tissue-Based Products From Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry
- Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff
- Same Surgical Procedure Exception: Questions and Answers Regarding the Scope of the Exception; Draft Guidance for Industry