How do primary investigators (PIs) report promptly reportable information (PRI) in a blinded* study? How can they report unblinded information without unblinding themselves?

*While in ophthalmology studies the term “masked” is used, blinded will be used here as it is the most commonly used terminology.

Answer

For WCG’s Institutional Review Board (IRB), reporting protocol deviations are required if the deviation harmed a participant or placed a participant at risk of harm. You can review our list of events that require reporting, when disclosing through our portal, on our Promptly Reportable Information Form (HRP-204) or in our Guide for Researchers.

When reporting PRI in a blinded study, there are two issues to consider:

1. Unblinding the participant to see the randomization, e.g., whether they were assigned a placebo or the investigational product (IP).
2. Unblinding a blinded clinical study team member as a result of reporting the participant’s clinical information as a PRI.

For the first issue, WCG’s IRB doesn’t require universal unblinded reporting. In most cases, sufficient information is available without unblinding to allow the IRB to determine if the issue requires further follow up and action. If insufficient information is provided, we will follow up and ask for specifics. If unblinding is required, we will request that information with a rationale. For example, if an overdose occurs, unblinding is not necessary for reporting as the issue is the overdose. Overdosing is a problem because it’s the process that led to the overdose that is the risk. In this case, the most important information to provide is the Corrective and Preventive Action (CAPA) plan that identify and address the root causes of noncompliance and prevent future occurrences.

Unblinding the participant to manage an adverse event would only be necessary if the clinical information is required for corrective actions to address the immediate problem. If the participant or staff were unblinded, WCG’s IRB would need to be informed of this.

Out of respect for persons and to encourage trust through transparency in research, we believe it is important to inform participants about research errors. That does not require you to unblind to inform the participant. For example, if the site is aware that a participant in a double-blind, randomized study received the IP that was intended for another participant, unblinding isn’t necessary to tell the participant that they received the study drug intended for another participant. Instead, inform them of the importance of blinding to address the reason for not providing more detail.

For the second point, the issue is unblinding blinded study staff. This could occur either because of a blinded study team member being unblinded or unblinding themselves, or this could be due to the reporting of an event where the details or data included in the report could unblind a staff member. In the case where a staff member is unblinded, the act of unblinding them wouldn’t have to be reported unless the unblinding put a participant at risk or met one of the other reportable categories. If in doubt, the event can be reported that a blinded study staff was unblinded, without the specific data that would unblind others.

In the case where the reporting of the event details might unblind staff, this is best managed through reporting events in a way that doesn’t include the specifics which would unblind. There are very few and limited circumstances in which the site or sponsor would need to report an event to the IRB that would unblind the site where the site wasn’t already needing to be unblinded.  

In either situation, good communication with the IRB is important. If you have any questions, please don’t hesitate to contact us. Our experts are always ready to assist you with your questions. Whether you have additional questions about reporting PRI in a blinded study or other IRB inquiries, our team is here to provide the guidance you need. Submit your questions to our IRB experts here.

The post How Do PIs Report PRI in a Blinded Study Without Unblinding Themselves? appeared first on WCG.

The following Insight is a featured article from WCG’s 2025 Trends & Insights Report. If you would like to read more insights from this report, please click here.

Former U.S. President Obama called precision medicine, “Health care tailored to you.”¹ Nowhere is precision medicine more critical than in oncology, where life and death clinical decisions are based on an individual’s genetic or biomarker results. In the last decade, precision medicine approaches made a paradigm shift in the understanding and treatment of cancer.² From “one-size-fits-all” to an individual, biomarker-driven treatment, precision medicine improved treatment outcomes and patient survival rates, while reducing toxicity.³ 

Despite tremendous progress, much is left to do. The number of biomarkers is vast and complex. A disease biomarker may be a combination of factors, such as multiple genes and proteins barely detectable. Research study designs have been evolving to meet these needs, with the classic basket and umbrella master trial designs requiring biomarker validating components. Similarly, increased complexity with changing master trial designs may move science forward more efficiently. For example, NCI-MATCH has evolved into ComboMATCH to address the issues of tumors having more than one gene driver and cancers developing resistance to treatment.⁴ 

Furthermore, biomarkers and precision medicine approaches will evolve as disease treatments evolve. Next-generation, multi-gene DNA sequencing will grow into multi-RNA sequencing and multi-modal panels, including nucleic acid and other omics-based target testing. Precision medicine requires biomarker-driven targeted treatment, and with cancer’s heterogeneous nature, further profiling of patient tumor tissues will be required.  

The standard collection of tissue and blood samples for DNA will commonly add RNA sequencing, gene expression, mutation and deletion profiles, protein expressions, immune repertoires, tumor microenvironment, and metabolic changes to drive cancer treatment’s increased rate of success. The precision medicine approach works hand in glove with drug development. The biomarkers found in tyrosine kinases, EGFR, ALK, KRAS mutations, immune checkpoints, and T-cell targets resulted in the approval of products targeting those biomarkers. That trend will continue and mature.   

Ensuring biomarkers achieve their potential requires the assays to detect them are high quality, accurate and safe and effective. When used to identify patients who are most likely to benefit, be at increased risk, or need monitoring from a particular product, the assay to detect the biomarker is a companion diagnostic device (CDx). These CDx provide information essential for the safe and effective use of a corresponding drug or biological product. As of October 31, 2024, there are 168 FDA-cleared or approved CDx (In Vitro and Imaging Tools).⁵ Out of the 168 FDA-cleared or approved CDx, 164 (97.7%) are for oncology indications and only four (2.3%) are for non-oncology indications. (see Figure 1).  

The FDA, as always, will be advancing with the technology. This started with the 21^st Century Cures Act detailing the Oncology Center of Excellence.⁶ Bringing together the expertise across drug and device realms for the trials testing companion diagnostics and platform treatment approaches will require exemplary coordination. For example, developing the next decade of gene therapy products will mean testing off-the-shelf CAR-T products with biomarker-directed targets. Institutional Review Boards (IRBs) will also need to keep pace and realize last year’s exploratory objectives are next year’s companion diagnostics, staying current on the technology and regulatory components. Only in this way can we all support the true value of precision medicine. 

References:

1. The White House. “Precision Medicine.” The White House, https://obamawhitehouse.archives.gov/precision-medicine. 
2. Rulten, S.L.; Grose, R.P.; Gatz, S.A.; Jones, J.L.; Cameron, A.J.M. The Future of Precision Oncology. Int. J. Mol. Sci. 2023, 24, 12613. https://doi.org/10.3390/ijms241612613 
3. Nature. “Milestones in Cancer.” https://www.nature.com/immersive/d42859-020-00083-8/index.html  
4. ⁴National Cancer Institute. “New NCI Precision Medicine Trials.” Cancer Currents Blog, https://www.cancer.gov/news-events/cancer-currents-blog/2023/new-nci-precision-medicine-trials. 
5. U.S. Food and Drug Administration. “List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools).” https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. 
6. U.S. Food and Drug Administration. “Oncology Center of Excellence.” https://www.fda.gov/about-fda/fda-organization/oncology-center-excellence.

Related Insight:

Ethics in Clinical Research

Under the Microscope: Biomarker and Diagnostic Tests as FDA-Regulated Devices

Whitepapers

The post Advancing Precision Medicine in Oncology: From One-Size-Fits-All to Biomarker-Driven Treatments appeared first on WCG.

In this episode of WCG Talks Trials, host Kelly FitzGerald sits down with Dr. Currien MacDonald, medical chair director at WCG, and Sara Reed, a participant in two psychedelic clinical trials, to explore the evolving landscape of psychedelics research. Dr. MacDonald shares his expertise on the growing acceptance of psychedelics in clinical settings, recent FDA updates, and the inner workings of ongoing trials. Later, Sara provides a firsthand account of her experiences as a trial participant, offering unique insights into how psychedelics are being tested as potential therapeutic options. Tune in to learn more about aligning clinical practice with patient experience in this emerging field.

The post Have a Safe Trip: Clinical and Patient Alignment in Research with Psychedelics appeared first on WCG.

The Impact of Pioneering Research

Those were the days when we didn’t have many choices for hematology/oncology treatments for pediatric patients. Thankfully, treatments have advanced so much in the past 30 years. September is Childhood Cancer Awareness Month, and it is a time to remember children who died from childhood cancer, families who are still struggling with the aftermath, and those who are in the middle of the fight. It is also a reminder to clinical research stakeholders that we’ve worked hard, and we still have a lot of work to do against childhood cancer, which is the leading cause of disease death in children.¹

Over the past 50 years, treatments and therapies for pediatric hematology/oncology have undergone significant advancements, transforming the prognosis and quality of life for children with cancer. In the mid-1970s, 58% of children (ages 0 to 14 years) diagnosed with cancer survived at least five years.² However, with the introduction of new therapies and treatments, the overall survival rate has increased to over 80% today.² Moreover, targeted therapies, immunotherapies, and gene therapies have emerged as promising treatments for specific types of childhood cancers. For example, CAR-T cell therapy has shown remarkable efficacy in treating certain types of leukemia and lymphoma, offering new hope to families and children affected by these devastating diseases.

The development and implementation of these groundbreaking treatments would not have been possible without the rigorous research and clinical trials that have taken place over the past several decades. Institutional Review Boards (IRBs) have played a crucial role in these advancements, ensuring that all research studies involving human subjects, particularly vulnerable populations like children, are conducted ethically. By overseeing the conduct of clinical trials, IRBs have supported researchers in pursuit of innovative treatments and therapies, which have significantly improved the outcomes for children with cancer.

Conclusion

In August 2024, the White House put out a proclamation, listing both obstacles and efforts to address childhood cancer.³ There is no better time than now to reenergize our work on childhood cancer. Basic genetic profiles, epigenetic driver discovery, and single-cell RNA sequencing have uncovered potential new avenues for research.⁴ We have encouraging success stories from the recent advances in pediatric cancer treatment such as CAR-T with Emily Whitehead and immunotherapy with Isabella Snow Frasier. ^{5, 6} As an industry, we’ve come a long way since my residency days, with so much more to do. By working together, we can help families have real hope in the face of a devastating diagnosis.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74(1): 12-49. doi:10.3322/caac.21820.
2. https://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-factsheet#:~:text=In%20the%20mid%2D1970s%2C%2058,least%205%20years%20(2). Accessed 9 Sept 2024.
3. https://www.whitehouse.gov/briefing-room/presidential-actions/2024/08/30/a-proclamation-on-national-childhood-cancer-awareness-month-2024/. Accessed 2 Sept 2024.
4. McEachron TA, Helman LJ. Recent Advances in Pediatric Cancer Research. Cancer Res. 2021 Dec 1;81(23):5783-5799. doi: 10.1158/0008-5472.CAN-21-1191. Epub 2021 Sep 24. PMID: 34561271; PMCID: PMC9725930.
5. https://www.chop.edu/news/emily-whitehead-first-pediatric-patient-receive-car-t-cell-therapy-celebrates-cure-10-years. Accessed 3 Sept 2024.
6. https://cancerprogressreport.aacr.org/report/survivor-journeys/isabella-snow-fraser-reclaiming-childhood-thanks-to-immunotherapy/. Accessed 2 Sept 2024.

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In this episode of WCG Talks Trials, we are joined by host Joanne Thomas, clinical reviewer and patient advocate at WCG, along with our guest Currien MacDonald, medical chair director at WCG. This episode covers the roles of IRB in ethical clinical research, frequently asked questions, and a general overview of the IRB’s role in clinical trials. 

The post Guarding Research Integrity: The IRB’s Essential Role appeared first on WCG.

While the topic of Legally Authorized Representatives (LARs) and their role in consent is complex and multifaceted, for the purposes of this discussion, an LAR is an individual who provides consent on behalf of an adult who lacks the mental capacity to make decisions for themselves. In other words, an LAR is only necessary when an adult’s mental capacity is impaired, rendering them unable to provide informed consent.

This is different from a parent or guardian, who provides permission for a child to participate in research. WCG makes a clear distinction between an LAR and a parent or guardian to highlight the differences between a child who cannot consent due to their age, versus an adult who lacks mental capacity. In some cases, a parent or guardian may also serve as an LAR for an adult, but this would be documented as an LAR, rather than a parent or guardian.

A witness is very different. They are an impartial person not related to the research study who is brought in to observe the consent process with the consent document. They are not an LAR, not a parent, and are not signing for anyone else. They are someone completely independent of the research. An example of an impartial individual who can undertake this role is a nurse who is not part of the research team and has no other involvement with the investigator. In contrast, a study coordinator working on the same study, even if they are not directly responsible for obtaining consent, would not be considered impartial and thus not an appropriate witness.

Per regulation, a witness is needed when you unexpectedly encounter a person who can’t read the consent form, or in some very rare cases, physically can’t document consent. The “short form” consent process is used in this case. In this process, a witness observes the verbal discussion and reviews the short form and long form documents. The witness then signs both the short and long form documents, attesting to what they observed. Meanwhile, the participant signs the short form, and the person obtaining consent signs the long form to formally document the consent. It’s essential to note that this process, including the requirement for a witness, is distinct and separate from the involvement of an LAR.

For the short form process, a person who speaks and understands English, but does not read and write, can be enrolled in a study by “making their mark” on the consent document, when consistent with applicable state law.

While a person not being able to read the consent form is the baseline for when a witness is required by regulations, WCG IRB has the following policy regarding the use of a short form consent process to enroll participants. This policy, which may be more restrictive than federal requirements, limits the use to the situation when both of the following are true:

1. A full-length version of the consent form in language understandable to the participant is not available or is not appropriate for the participant. Situations that generally meet this condition include:
   1. Unexpected translations
   2. Low literacy
   3. Visual impairment
2. It is in the participant’s best medical interest to be enrolled in the research, and for unexpected translations, before a translated consent form can be obtained.

In both circumstances — the participant cannot consent or cannot read — the key component is consent. Consent involves understanding what the research is about and agreeing to participate. A consideration often conflated with consent in total is the documentation of consent. For example, an adult able to consent who has a broken arm might have a different way of documenting their consent, such as a larger or non-dominant hand signature. If someone has the capacity to consent but has physical impediments to signing a form, there’s almost always a way to have them make a mark to legally document their consent. This can include with assistance of another person who doesn’t have to be an LAR or witness but someone who is helping them do every other activity of daily living, such as helping a person with spasticity make a thumbprint. For a very rare case, such as complete paralysis, the witness process would be used, with additional documentation like a note to file. This would include the specifics of why this process was used, how agreement was indicated by the participant, and related details. 

In circumstances where you need a signature, but one does not exist on the IRB-approved consent form, there are two very different cases.

1. If you need a witness and you don’t have a signature line on your form, you can use one of the pre-approved templates from WCG’s IRB & IBC Resource Center, under the Template Consents tab in the IRB Forms section. Access the form here.
2. If you are planning on consenting a person who needs an LAR or parent/guardian, but there are no signature lines on the consent form for an LAR or parent/guardian to sign, then stop and talk to your IRB.

Do you have questions about your informed consent form?

Consult WCG’s experts by completing the form below.

The post What Is the Role of a Legally Authorized Representative in Informed Consent? appeared first on WCG.

The FDA plays a crucial role in overseeing the development, manufacturing, and distribution of devices, which includes in-vitro and other diagnostic assays. This is not a recent development. In 1976, the Medical Device Amendments to the Food, Drug, and Cosmetic Act made explicit that FDA’s responsibility includes devices. At that time, FDA carried over a risk-based framework in use at the time and put certain in-vitro diagnostic assays into the category of laboratory developed tests (LDT). Specifically, these are in-vitro diagnostic assays intended for clinical use, designed, manufactured, and used within a single certified laboratory that meets the regulatory requirements under Clinical Laboratory Improvement Amendments of 1988 (CLIA) to perform high complexity testing. LDTs at that time were manufactured in small volume and used in a local population or for rare diseases. They also used simple technology with manual methods and without automation.[ii] Within that risk environment, FDA took an enforcement discretion approach.

Since that time, and most notably over the past 15 years, technological and global use of assays have expanded into the open prairies of assays. LDT’s were a gold rush of information, providing important medical information. Complex instrumentation, computerized and automated devices, immunologic and DNA-based testing have stampeded into the market. While run in a single laboratory, these are not for a local population. These tests are much different than the LDTs from the 1970s, and FDA has oversight responsibility. FDA’s previous attempts at less burdensome oversight and gentle regulation proved untenable. After about a decade of waiting, the FDA is preparing to implement its plan for the oversight of laboratory developed tests.  

Like the federal marshals riding into a gold-boom town or cattle rancher’s territory, the FDA announcement that it will fully embrace its responsibilities in regulating the assay area was met with resistance. The first draft guidance published in 2014 described a framework for addressing the oversight for these tests. There was no distinction for assays made by conventional device manufacturers and those manufactured by laboratories.[iii] An avalanche of comments poured in response. On November 16, 2015 FDA published the public health evidence for the need for FDA oversight of laboratory developed tests, which included 20 case studies that specifically highlighted the need for effective oversight.[iv] Then, in 2017, FDA announced they would not issue a final guidance, ostensibly to allow “congressional authorizing committees the opportunity to develop a legislative solution.”[v] Since that time, FDA has been working with industry, academia, and other stakeholders to address the issues. Finally, almost a decade since its first announcement, FDA will phase out enforcement discretion. The plan is to do so in five stages over the next four years. Key dates include premarket review requirements for high-risk assays not before October 1, 2027, and for low-risk assays not before April 1,2028.[vi]

Some argue there are better ways to regulate these tests, including CLIA or the College of American pathologist (CAP) accreditation. However, even these arguments support awareness of the problems with unregulated testing and that additional regulation or oversight is needed and merely propose other ways to do it. Arguments for CLIA-only oversight are undermined by the overt support for FDA’s proposed rulemaking by the Centers for Medicare and Medicaid Services (CMS), who regulate laboratories through the CLIA standards.[vii] The 2015 testimony by the Chief Medical Officer of CMS specifically notes that they do not have the expertise to assure that tests work while FDA does.[viii] Proposals for amendments to CLIA to require further CAP oversight belabors that argument. Adding additional layers to an existing framework would require resources that are already being given to FDA.

The idea that innovation would be stifled, or necessary tests would be unavailable for patients and participants is a real concern. Additionally concerns about smaller companies not being able to produce the results FDA requires, or shoulder the burdens needed to produce the evidence for tests of rare diseases also need careful consideration.[ix] At the same time, arguing for the need of such testing and the imperative importance of its impact on health care only further underlines the need for accurate and reliable tests in those spaces. FDA’s phase-out plan includes provisions to address both concerns. Further mechanisms in place to both effect quick and specific review include expanded access[x] and the humanitarian use device pathway.[xi] Pre submission review and predicate device (e.g., 510K) pathways should also further decrease the burdens over time.

The pandemic provided good evidence of FDA’s ability to address the issues directly. The need for COVID tests right after the pandemic started and the processes for addressing the need prior to FDA approval showed that there are mechanisms to address concerns even in the worst case. The number of COVID molecular tests that applied to obtain Emergency Use Authorization (EUA) and the subsequent number that were identified as having major issues shows FDA can rapidly deploy tests and that FDA can quickly and effectively work with those that have issues. For example, in 2020, FDA reviewed 125 EUA requests for COVID tests. Of those, 82 (66%) had major issues while 43 had no issues and moved forward. Notably, of those 82 that had major issues, there was no clear distinction between hospital or commercial laboratories. Of the 82 that had major issues, six were withdrawn and FDA worked with the submitters until all but 28 were able to successfully manage to produce the data necessary to show that they were effective enough for the specific EUA requirements for their test.[xii]

FDA oversight instills confidence and trust in diagnostic assays among healthcare providers, patients, and other regulatory agencies. FDA evaluation encompasses the assessment of both analytical and clinical performance, including accuracy, precision, sensitivity, specificity, and potential risks associated with assays’ use. By establishing clear regulatory pathways, the FDA helps support accurate diagnoses and mitigate the harm to patients from inaccurate or unreliable diagnostic results. These assays are part of modern healthcare, and ever-increasing in importance. Other solutions are not tenable. Furthermore, even if those solutions might work, FDA still has the responsibility to oversee these tests. Those and similar arguments are just as irrelevant as arguing if cowboys actually needed the assistance of federal marshals in keeping the peace. The railroad has come through. Enforcement of regulation is overdue.

References:

[i] FDA’s Proposed Rule Regarding Laboratory Developed Tests. https://www.fda.gov/media/173457. Accessed 24 Mar 2024.

[ii] FDA’s Proposed Rule Regarding Laboratory Developed Tests.  https://www.fda.gov/media/173457. Accessed 24 Mar 2024.

[iii] Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs). October 2014.

[iv] https://wayback.archive-it.org/7993/20171115144712/https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf. Accessed 20 Mar 2024.

[v] Discussion Paper on Laboratory Developed Tests (LDTs). January 13, 2017.

[vi] FDA’s Proposed Rule Regarding Laboratory Developed Tests. https://www.fda.gov/media/173457 Accessed 24 Mar 2024.

[vii] https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-and-cms-americans-deserve-accurate-and-reliable-diagnostic-tests-wherever-they-are-made. Accessed 20 Mar 2024.

[viii] https://democrats-energycommerce.house.gov/sites/evo-subsites/democrats-energycommerce.house.gov/files/Testimony-Conway-LDTs-2015-11-17.pdf

[ix] JR Caldera, Hannah K. Gray, Omai B. Garner, Shangxin Yang, “FDA trial regulation of laboratory developed tests (LDTs): An academic medical center’s experience with Mpox in-house testing,” Journal of Clinical Virology,

Volume 169, 2023. https://doi.org/10.1016/j.jcv.2023.105611.

[x] Expanded Access for Medical Devices. https://www.fda.gov/medical-devices/investigational-device-exemption-ide/expanded-access-medical-devices. Accessed 24 Mar 2024.

[xi] Humanitarian Device Exemptionhttps://www.fda.gov/medical-devices/premarket-submissions-selecting-and-preparing-correct-submission/humanitarian-device-exemption. Accessed 24 Mar 2024.

[xii] Memorandum from Elizabeth Hillebrenner, Associate Director for Scientific and Regulatory Programs Center for Devices and Radiological Health (CDRH). Summary of 2020 Assessment of the First 125 EUA Requests from Laboratories for Molecular Diagnostic Tests for SARS-CoV-2. https://www.regulations.gov/document/FDA-2023-N-2177-0121.

The post Sunsetting FDA Enforcement Discretion of Laboratory Developed Tests appeared first on WCG.

Regulatory Restrictions on Charging for Investigational Products

FDA: Charging for an Investigational Drug

For a clinical investigation of a drug under an IND, the FDA released updated guidance in February 2024.^[i] The guidance details questions and answers about the regulatory requirements. For an investigational drug in a clinical trial, including an investigational use of an approved drug, a sponsor must do all of the following to obtain authorization from FDA to charge for the drug:^[ii]

• Provide evidence that the drug has a potential clinical benefit that would provide a significant advantage over available products.
• Demonstrate that the data to be obtained from the clinical trial would be essential to establishing the drug is effective or safe or would support a significant change in the labeling of an approved drug.
• Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor.^[iii]
• Provide documentation to support its calculation for cost recovery accompanied by a statement from an independent certified public accountant.

The FDA decides if a sponsor may charge but does not decide who receives the bill — a third-party payor or the trial participant — or if a third-party payor should pay the bill. The guidance recommends consulting with the third-party payor. FDA’s guidance does advise sponsors to ensure that charging for investigational drugs does not create barriers to a ccess that may exacerbate disparities in clinical trial participants or expanded access patients.

In contrast to non-expanded access, for individual patient expanded access, the sponsor may only charge for direct costs associated with acquiring an investigational drug, such as shipping and handling fees.^[iv] The requirement for FDA authorization to charge does not extend to administrative costs in a clinical trial, such as pharmacy, nursing, or equipment costs.

FDA: Charging for an Investigational Device

Similar to the drug regulations, the Investigational Device Exemption (IDE) regulations allow FDA to authorize sponsors of a clinical investigation under an IDE to charge for the investigational device. To do so, the sponsor must provide in the IDE application:^[v]

• The amount to be charged.
• A justification for the proposed charges as not more than necessary to cover the costs of manufacture, research, development, and handling of the investigational device.
• An explanation for why the charge does not constitute commercialization.

For devices, there is a clear pathway for that cost to potentially be covered at least in part by Medicare insurance. FDA has a Memorandum of Understanding with the Centers for Medicare and Medicaid Services (CMS). With an approved IDE comes a risk-based FDA assignment to one of two categories: Experimental/Investigational (Category A) or Non-experimental/Investigational (Category B).

A Category A device is one for which “absolute risk” of the device type has not been established. That is, initial questions of safety and effectiveness have not been resolved, and the FDA is unsure whether the device type can be safe and effective. CMS will provide no coverage for a Category A device but may approve coverage of routine care and services in the study. If FDA determines the device is a Category B device, Medicare may provide coverage for the device. Category B devices are those where the underlying questions of safety and effectiveness of that device type have been resolved, or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA approval for that device type.^{[vi] [vii]} For Category A devices and all uncovered costs for Category B devices, the cost is passed directly on to participants.^[viii]

These regulations provide, for studies under an IND or IDE, a way to have participants pay for participation. While allowed by regulation, the underlying message is that even then, pay-to-participate trials should require clear and substantive justification.^[ix]

WCG’s Policies and Guidance on Participants Paying for Research

Many studies are not under an IND or IDE, so they have no requirement to have FDA review for a clear and substantive justification. Even if FDA has reviewed and authorized charging, the practice still has ethical and separate IRB issues to address. For those reasons, WCG has an expanded and more protective policy.

 WCG requires sponsors and investigators to notify the IRB if participants will be required to pay to participate in a study. The IRB will then review the research and the information provided about the context of the participant payment. Assuming there are no questions regarding the scientific basis of the risks and benefits or the research design, during review, the following factors are considered:

• Charging for approved products being used for their approved indications is generally acceptable. In as much as possible, those costs should be sent to third party payors including in advance of study enrollment (prior authorization).
• Charging for approved products being used as part of participant care as research procedures may be acceptable. Factors that are considered include:
  • Are the costs substantial? For example, the implantation of a device requires surgery and long-term follow up compared to a short-term use of a low-risk product.
  • If the costs are likely to be or are covered by third party payors.
  • The proximity of the research procedures to an accepted standard care. For example, a commonly used treatment, but in the context of research, it is an investigational use.
• Charging for the administration of the study product when the investigational product is provided at no cost may be acceptable. For example, site costs for administration of the investigational product when it is used as standard care for the participant’s treatment. Charging for administration or other ancillary costs of investigational products when the investigational product is not provided as part of a standard treatment is almost never acceptable.
• Charging for investigational products where the cost is solely borne by the participants is almost always unacceptable.

Despite FDA’s authority to allow charging for investigational products as noted above, FDA also advises sponsors to ensure that charging for drugs in clinical trials or expanded access use does not create barriers to access that may exacerbate disparities in clinical trial participants or expanded access patients. Considering the financial situation of many potential clinical trial participants, and the IRB’s requirement to ensure equitable selection, the requirement to pay for investigational products would almost invariably restrict those with limited financial means from participating. This could further exacerbate disparities, including those for which economic status are proxy. Any significant, uncovered charges could exacerbate disparities and result in a failure of equitable selection for that study. Third-party payor coverage of an investigational device may mitigate this impact and be acceptable, for example, if the sponsor has obtained CMS coverage assurance in a study under an IDE.

Some may incorrectly argue that equitable selection is achieved overall when charging for participation as those with more money will bear the burdens of research and once the intervention is proven, the benefits accrue to those who were not able to participate as they could not pay. However, the data collected from studies with limited diversity of participants are not necessarily relevant to the wider population. In fact, another study with those populations who were not included due to their inability to pay could be needed to prove the benefit of the intervention. Similarly, the argument that the direct benefit from participation is sufficient to balance the burdens of costs also fails. Research studies are done prior to establishing benefit, and participation in a trial is a burden unto itself with the additional burden of risk. Because the risks of research must be reasonable in anticipation of the benefits, overcoming the weight of risk and participation burdens leaves little room for the weight of potential benefit to also outweigh the burden of costs.

WCG’s Process for Review of Participant Payment

If either WCG as a company or the IRB determine that the study is not acceptable as proposed, we will work with sponsors to try to reach a mutually acceptable outcome.

In all cases, all costs to participants — both investigational product and the administration procedures — are required to be disclosed in the consent form. This includes providing clear information regarding costs that may be considered by participants to be part of their care that third party payors may not cover. The consent form has a related requirement which includes clearly describing which procedures are research procedures as compared to which would occur regardless of the research. The clarity of this requirement directly relates to the need for clarity in the costs of the research to participants.

As noted above, FDA regulations allow for certain studies with clear and substantive justification to have the sponsor be authorized to bill for costs of the investigational product. Even in that case, and for all other studies that include participants paying for research participation, WCG will carefully review the research and proposed charges to participants to assure their rights and welfare are protected.

References

[i] Charging for Investigational Drugs Under an IND Questions and Answers Guidance for Industry. February 2024.

[ii] 21 CFR 812.8(b) & (d).

[iii] The costs that are extraordinary are relative to the sponsor. A cost that is considered extraordinary to a small start-up company may not be considered extraordinary to a large, established company.

[iv] 21 CFR 312.8(d)(1)(ii).

[v] 21 CFR 812.7(b).

[vi] https://www.cms.gov/medicare/coverage/investigational-device-exemption-ide-studies Accessed March 5, 2024.

[vii] FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions. December 2017.

[viii] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/charging-investigational-products Accessed March 6, 2024.

[ix] DHHS, Secretary’s Advisory Committee for Human Research Protections. Charging Subjects for Clinical Trial Participation. Attachment A to Letter to the HHS Secretary, November 20, 2019. https://www.hhs.gov/ohrp/sachrp-committee/recommendations/november-20-2019-attachment-a/index.html. Accessed March 6, 2024.

The post Pay to Participate in Research: Regulations and WCG’s Position appeared first on WCG.

Building Partnerships Toward Single IRB

On September 28, 2022, FDA published a proposed rule that if implemented would require any institution located in the United States to rely on review and approval of a single IRB for FDA-regulated cooperative research¹. If the proposed rule is implemented, having smooth processes for managing reliance agreements will become more important than ever. At WCG, we value our relationships with institutions, and recognize the difficulty in managing multiple IRB reliance agreements whether WCG is acting as a central or local IRB. SMART IRB is an NIH-funded initiative to facilitate IRB reliance agreements for multi-site studies². WCG has been a signatory to versions 1 and 2 of the SMART IRB agreement. WCG’s experience with SMART IRB is that it reduces the time and effort to establish an IRB reliance agreement. Participating in the SMART IRB community is one of the ways WCG has built partnerships with institutions as first NIH, then the Common Rule moved toward a single IRB model^3,4.

WCG Policy Changes to Support Rule Harmonization of Informed Consent Regulations

SMART IRB has proposed a revised version 3.0 of the SMART IRB agreement for which comments closed on February 15, 2024. One of the proposed requirements for signatories of SMART IRB is to apply the Common Rule standards to the review of all research, not just research subject to the Common Rule due to federal funding unless a different standard is agreed to by both parties. WCG is supportive of this proposed requirement and has already taken steps to align our policies with it. One impact WCG wishes to highlight for sponsors and institutions is the requirement for consent forms to include a key information section at the beginning of the informed consent document and to include additional disclosures in the consent form. We discuss the elements of the concise summary in more detail in the podcast below.

Revised Common Rule Consent Requirements

WCG has included the Common Rule informed consent requirements in our publicly available sample informed consent document since the revised Common Rule was implemented in 2019 because their inclusion facilitates understanding of the research by participants⁵. At that time, WCG made the decision not to require these additional sections unless it was specifically required. Since 2019, WCG has seen an increasing number of institutions and sponsors reflecting the revised Common Rule requirements in the informed consent documents submitted for review by WCG in all research, regardless of funding source. 

On September 28, 2022, proposed changes to FDA informed consent requirements were published in the Federal Register. The changes incorporate the requirement to include a key information section in the informed consent document, to include similar new elements of consent as required by the Common Rule, and to include new definitions to support the new required elements. The policy changes WCG is making now will allow for a smooth transition for sponsors and institutions once the proposed rule is finalized.  

On February 29, 2024, FDA and OHRP published a draft guidance, Key Information and Facilitating Understanding in Informed Consent Guidance for Sponsors, Investigators, and Institutional Review Boards⁶. It notes FDA’s proposed regulations would require consent information to “begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research”, identical language as in the Common Rule.

Waiver of Informed Consent

On December 21, 2023, a final rule was issued by FDA to amend its regulations to allow for a waiver of consent for certain types of minimal risk research⁷. FDA had previously published its plan to exercise enforcement discretion for waivers of consent for minimal risk research in 2017. That guidance stated that FDA does not “intend to object to an IRB approving a consent procedure that does not include, or that alters some or all the element of informed consent set forth in 21 CFR 50.25,” as long as the IRB finds and documents that:

• The clinical investigation involves no more than minimal risk (as defined in 21 CFR 50.3(k) or 56.102(i)) to the subject.
• The waiver or alteration will not adversely affect the rights and welfare of the subjects.
• The clinical investigation could not practicably be carried out without the waiver or alteration.
• And whenever appropriate, the subjects will be provided with additional pertinent information after participation.

WCG has been following that guidance since 2017. With the publication of the new final rule on waivers of informed consent, the previous guidance is no longer valid, and FDA harmonized with the revised Common Rule criteria for a waiver of consent for minimal risk research. We discuss the criteria for a waiver of consent in the podcast below.

Summary

While change can be difficult to manage, the goal of harmonizing federal regulations for research with human subjects is to reduce the burden on institutions and sponsors to ensure valuable research developments reach the public efficiently and safely. Institutions and sponsors may have concerns about how the single-IRB mandate and the evolving informed consent requirements affect their research programs. We encourage you to reach out to ask questions. Our regulatory experts are ready and willing to provide guidance to you.

References:

1. https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research
2. https://smartirb.org/
3. Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research Notice Number: NOT-OD-16-094.  Release Date:  June 21, 2016. Effective Date: New Date – January 25, 2018 as per issuance of NOT-OD-17-076.
4. Title 45 Subtitle A Subchapter A Part 46  § 46.114 Cooperative research.
5. https://www.wcgclinical.com/wp-content/uploads/2020/08/WCG-Consent-Template-HRP-500.doc?v=1701459189
6. https://www.fda.gov/media/176663/download
7. https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research

The post How WCG Is Preparing for FDA Harmonization with the Common Rule appeared first on WCG.

About this episode:

In this episode of WCG Talks Trials, our expert panel discusses various ethical, safety, and logistical challenges in accelerating clinical trials for gene and cell therapies in oncology. The conversation explores the role of Institutional Review Boards (IRBs), Institutional Biosafety Committees (IBCs), Endpoint Adjudication Committees (EACs), and Data Monitoring Committees (DMCs) in overseeing these trials, addressing issues such as patient safety, complex trial designs, and emerging biosafety concerns. Our panelists emphasize the importance of transparent communication and collaboration between IRBs and IBCs, highlighting the need to balance the urgency of advancing research with ethical considerations. Additionally, the podcast explores unrealized ethical and safety issues, such as the pace of technological advancements and potential risks associated with gene editing. The speakers also touch upon future opportunities in oncology research, including precision medicine, artificial intelligence, wearable devices, and accelerated regulatory pathways.

The post The Ethical and Safety Considerations of Accelerating Oncology Trials appeared first on WCG.