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Salary Survey: The Age of COVID

Medable has announced that its DCT platform was selected by the Nova Scotia Health Innovation Hub to increase the accessibility of oncology care for remote patients in rural Nova Scotia, with the long-term aim to improve patient access and trial diversity across Canada.

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Medable's DCT platform selected by Nova Scotia Health to increase the accessibility of oncology care for remote patients in rural Nova Scotia.

Nova Scotia Health Partners with Medable

 Decentralized Trials Solutions Manger, Q² Solutions

Director, Decentralized Trial Solutions, Q² Solutions

Principal Scientist Regulatory Operations, Q² Solutions

In February 2021 we published an article in 

 entitled, “Self-collection of Blood Specimens in Clinical Trials."

 The article described how the pandemic accelerated interest in decentralized clinical trial (DCT) approaches, including the use of blood self-collection devices to enable a clinical trial participant to collect their own blood without having to visit an investigator site or have a healthcare worker visit them at home. We went on to describe innovative self-collection devices and the operational and patient burden considerations associated with such an approach.

From an operational perspective, we reviewed the various collection approaches, the need for assay development (since the devices collect capillary blood vs. venous blood, which is typically used for laboratory safety testing), the device regulatory framework, kit building, centrifugation, and direct to and from participant processes. As for patient burden, we discussed considerations around study design, tests required, pain tolerance, collection time and complexity requirements, participant use of collection devices and centrifuges, participant logistics considerations, and participant support needs. Finally, we described a correlation feasibility study we conducted, which demonstrated good correlation between venous and capillary blood specimens for a 12-analyte chemistry panel using a Tasso-SST (serum separator tube) self-collection device and a Sandstone Diagnostics portable centrifuge.

Since then, we have continued to perform scientific and operational feasibility studies to determine how we could make a safety testing panel available in clinical trials via at-home self-collection of blood specimens. While a finger prick via a lancet and dripping blood into a tube may be technically possible for at home collection, participant feedback indicated that this approach was less preferred and more painful than venous phlebotomy and the shoulder based innovative blood collection devices, like those produced by Tasso, therefore we focused our research on the Tasso+ device.

Most safety lab tests require venous blood specimens to be centrifuged within one hour after specimen collection and prior to shipment to the laboratory for testing. Fortunately, there are small portable centrifuges on the market and others under development, which are designed for at-home use. Clinical trial laboratories can develop robust processes to enable shipment of centrifuges to participants, clear participant instructions, and shipment of centrifuges back to labs. And labs can develop centrifuge reutilization programs, so that the right number of centrifuges are available at the right time for a study, to optimize cost and simplify logistics.

With the intention of reducing patient burden and operational complexity regarding centrifugation, we wondered if it would be possible to generate test results that correlate, if participants ship specimens to the lab without centrifugation, and have the lab staff perform the centrifugation, versus the standard process of investigator site staff performing centrifugation prior to specimen shipment to the lab. While we assumed this would not work for all analytes, the team felt it would be worthwhile to determine feasibility.

As such, we embarked upon a feasibility study to compare the results from three specimen collection approaches to help determine if lab centrifugation of specimens for safety (chemistry) testing is feasible. Approach 1 utilized venous blood centrifuged immediately, approach 2 utilized capillary blood, obtained via the Tasso+ SST device centrifuged within one hour of collection, and approach 3 also utilized capillary blood, via the Tasso+ SST device, but it was not centrifuged and instead shipped to the Q2 Solutions laboratory, where the specimens were centrifuged. The specimen sets were tested on the Roche Cobas 8000/c702 for a 15-analyte chemistry panel, including: Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Total bilirubin, Direct bilirubin, Total protein, Albumin, Glucose, Sodium, Potassium, Chloride, Magnesium, Calcium, Phosphorus, Enzymatic Creatinine.

Process optimization—refrigerated shipments

We observed good correlation between the venous and Tasso SST capillary specimens that were centrifuged immediately at the investigator site. However, some capillary specimens that were not centrifuged at the investigator site arrived at the laboratory hemolyzed, which for some analytes (e.g. AST and ALT) would result in result cancellation. Through experimentation, we found that refrigerated shipment of specimens enabled the non-centrifuged specimens to arrive in an acceptable condition for testing. Upon testing the specimens, the results also showed acceptable correlation with results from the other two approaches (routine venipuncture and centrifuging Tasso SST samples at site) for most analytes studied.

With the success of the feasibility study, we conducted a validation study with a similar design around the three specimen types, but this time with 25 different analytes. At the time of publication, we have successfully completed the validation report for a 7-analyte liver safety panel, including Total Protein, Albumin, Alkaline phosphatase (ALP), Alanine transaminase (ALT), Aspartate transaminase (AST), Direct Bilirubin, and Total Bilirubin. The results for the 7-analyte liver safety panel showed good correlation and good sample stability to provide enough time to ship samples from a participant’s home to the laboratory. Details are available upon request. The report for the other 18-analytes is under development. It is important to note that the validation report is based on an alternate sample type validation performed according to industry guidelines such as Clinical and Laboratory Standards Institute (CLSI) EP35 (Assessment of Equivalence or Suitability of Specimen Types for Medical Laboratory Measurement Procedures). We encourage clinical trial sponsors to discuss the approach, and share the validation report, with regulators prior to using for diagnostic and patient care purposes.

The term “Liver function tests,” is a historical misnomer to describe Liver Chemistry Testing, as the assays performed not only access the function of the liver (synthetic function) but also hepatocellular injury and the hepatobiliary tract conditions. Testing and monitoring of the various proteins made by the liver is important for determining hepatic health, especially in subjects enrolled in clinical trials.

 Most drugs are metabolized by the liver and monitoring early damage is essential in preventing Drug Induced Liver Injury which may lead to liver transplant or even death.

 Levels that are higher or lower than normal can indicate liver problems. Some common liver chemistry tests include:

Alanine transaminase (ALT). ALT is an enzyme found in the liver cells and convert alanine into pyruvate to provide energy for the liver cells. When the liver is damaged, ALT is released into the bloodstream and levels increase.

Aspartate transaminase (AST). AST is an enzyme that is involved in gluconeogenesis in the liver Like ALT, AST is normally present in blood at low levels. An increase in AST levels may indicate liver damage, disease, or muscle damage.

Alkaline phosphatase (ALP). ALP is an enzyme found in the liver and bone and is important for breaking down proteins. ALP made in the liver, bone, kidney, small intestine, and other organs of the body and thus is non-specific; however elevated levels may indicate liver damage or cholestasis or certain bone diseases.

Albumin and total protein are proteins used to measure function of the liver. These are produced in the liver to be secreted into the plasma. Albumin is the major protein in the blood and helps transport many important molecules the body needs to regulate metabolic processes. Lower-than-normal levels of albumin and total protein may indicate the failure of the liver to produce these important proteins, thus liver damage or disease.

Bilirubin, is a byproduct of the normal breakdown of red blood cells. Bilirubin normally is processed in the liver and is excreted in stool. Elevated levels of bilirubin (jaundice) indicate liver damage of the hepatobiliary tract or disease or certain types of anemia.

Measuring the transaminases (ALT/AST) and bilirubin are critically important in determining if a drug is responsible for causing Drug Induced Liver Injury (DILI). DILI is responsible for the majority of liver transplants, thus being able to assess liver chemistries before DILI occurs is critical in pharmaceutical trials.

Operational and patient-burden oriented processes

At the same time as investigating analyte correlation feasibility and validation, we examined operational and patient burden-oriented processes. As with the scientific work, our operational work began with a feasibility study to work through how a self-collection visit would impact clinical trial laboratory processes, investigator site processes, and most importantly patient burden. After the feasibility work, we formalized the processes as described below.

: Based on information in the validation report and the specimen collection instructions a test code was created to enable the laboratory systems to generate lab reports and reference range alerts.

The Tasso direct to participant (DtP) investigator kit ordering portal

: The Tasso kit ordering portal was enhanced to enable a clinical trial investigator to order a kit and send it directly to a study participant, while capturing the necessary details for a clinical trial laboratory to accession samples. The portal is required to be compliant with regulations and assure that the laboratory and many study team personnel do not have access to personally identifiable information (PII).

: Information from the portal is printed onto paper requisitions which are included in the kits that are sent to study participants. In addition, unique bar codes are printed onto tube labels. These steps enable the laboratory to accession samples according to standard procedures. Electronic approaches to this process are also under consideration.

: Participants are provided with written and video instructions for use regarding the proper way to prepare for the specimen collection, the use of the Tasso+ device, packaging, and shipping instructions. Some study teams may require that investigator site personnel provide training on site or via video call to assure proper collection, packaging, and shipment and to help participants become confident with the process.

: Two options are available to mitigate the risk of participants not being able to collect a specimen via a potential device failure. First, it is possible to ship out a new device within 24 hours of receipt of an order for a replacement from an investigator site. Second, it is possible to include two devices in the original kit order.

: To minimize patient burden, we chose not to require participants to register devices via a web portal, but instead they are provided with pre-printed patient-specific requisitions and tubes. Beyond self-specimen collection and shipment, the only other requirement is for the participant to enter the time and date of collection on the requisition form.

: Shipping specimens in a cool refrigerated state, via a commercially available packaging solution, reduces patient burden by eliminating the need for at home centrifugation for the liver panel analytes above.

: Prior to specimen collection participants are asked to schedule their specimen pick up with the courier to occur on the same day as specimen collection. It is recommended that pickups be scheduled between Monday and Thursday only when the participant is available to give the sample directly to the courier.

: The blood specimens arrive at the laboratory in a 0.6 mL SST Tube where they are accessioned into the laboratory information system and sent to the lab for centrifugation and then testing. Lab reports, alerts, queries, and data transfers are managed via standard processes.

: The role of the clinical trial investigator remains unchanged. The investigator remains accountable for specimen collection, as well as patient care and support, including questions about how to utilize the device or ship the samples. Lab reports and alerts are provided to investigators just like any other lab test and investigators remain accountable for queries.

: Currently the offering is only available in the United States of America, but plans are in place to expand geographically.

: The table below compares the fee structure of an investigator site specimen collection, home healthcare specimen collection, and self-collection. The table assumes a single specimen collection visit for a liver panel. The fees for the self-collection liver panel process are far less, at least an order of magnitude less, than a nurse visit to a participant’s home. In the US there are some phlebotomist networks, and the fee for a phlebotomist visit with courier fees and testing are similar to the overall fees for the self-collection liver panel.

: Identity verification is available by having investigator site staff observe a patient via video conference. In addition, digital identity verification solutions, some of which have grown out of a need to manage COVID-19 testing, have become available. Finally, colleagues have opined about the concept of genetic identity verification as well as advanced analytics.

: Since the Tasso system can capture a participant’s email address or mobile phone number, it is possible for the system to send reminders to participants. Alternatively, Decentralized Clinical Trial (DCT) suppliers may manage patient reminders.

Laboratory scientists and operations teams around the world continue to collaborate to find ways to drive increased utilization of the self-collection of blood specimens for laboratory testing in clinical trials and diagnostics. Further innovation, including in the areas below, may help to drive adoption.

: Clinical trial protocols may require many tubes of blood and a dozen or more panels and tests per visit. How could this be accomplished via self-collection devices, which collect relatively small volumes of blood? Would a participant have to use a dozen or more devices and manage a convoluted specimen processing and shipping process?This doesn’t seem practical. A significant reason why the self-collection liver panel has become a reality relates to the work that Roche Diagnostics has done to minimize the sample volume requirements for their automated chemistry analyzers. It’s also why we were able to test 25 analytes using as little as about 600 µL of whole blood (200-300 µL serum). If Roche Diagnostics and other instrument manufacturers can continue to innovate by reducing sample volume requirements while maintaining automated approaches, the chances of expanding the self-collection test menu, to meet the needs of clinical trial protocols, will be improved.

: Some tests that require immediate centrifugation may not correlate to centrifugation at the laboratory, so the operational and patient burden considerations around the distribution of small portable centrifuges to trial participants, use, and return of centrifuges to the laboratory will have to be addressed.

 Some sample types have very limited stability and require freezing soon after specimen collection. Today, in many jurisdictions, it is possible for a courier to bring dry ice to a participant’s home to pick up specimens, however, to date the authors are unaware of instances in which this has been attempted in a self-collection process utilized for data reported in a clinical trial.

: Tasso, along with other innovative device suppliers like Neoteryx and Drawbridge Health, offer solutions that collect blood onto porous material, and others provide participant oriented dried blood cards and lancets. These dried blood approaches enable improved sample stability. There has been some success with this approach regarding Pharmacokinetics (PK),

Can self-collection of blood in clinical trials improve patient recruitment and retention?

 That’s exactly what the non-profit Patient Centric Sampling Interest Group (PCSIG) is trying to determine via a carefully constructed clinical trial.

While the creation of the first ever self-collection 7-analyte liver safety panel for clinical trials via the Tasso+ device is a considerable achievement, it is recognized that for the use of self-collection of blood in clinical trials to gain further acceptance a much broader test menu is required. Many clinical trial testing and commercial diagnostic testing colleagues are performing feasibility studies related to many kinds of tests with the aim of making additional tests available via self-collection approaches in clinical trials and healthcare.

, Vice President, Strategy & Corporate Development, 

, Global Director, Scientific Harmonization, 

, PhD, Decentralized Trials Solutions Manger, 

, Director, Decentralized Trial Solutions, 

, PhD, D-ABMLI, MBA, FACB, Senior Laboratory Director, 

, PhD, Principal Scientist Regulatory Operations; all with Q² Solutions

Drucker, Chuck, et al. “Self-Collection of Blood Specimens in Clinical Trials.” Applied Clinical Trials Online, 

https://www.appliedclinicaltrialsonline.com/view/self-collection-of-blood-specimens-in-clinical-trials

Wickremsinhe, Enaksha. “Standard Venipuncture vs a Capillary Blood Collection Device for the Prospective Determination of Abnormal Liver Chemistry.” Academic.oup.com, T

he Journal of Applied Laboratory Medicine

https://academic.oup.com/jalm/advance-article/doi/10.1093/jalm/jfac127/6931879

M Ammar Kalas, Luis Chavez, Monica Leon, Pahnwat Tonya Taweesedt, Salim Surani. World Journal of Hepatology (2021) 13:1688-1698

Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). July 2009

Williams, Kathi J, et al. “Assessment of Low Volume Sampling Technologies: Utility in Nonclinical and Clinical Studies.” 

, vol. 13, no. 9, 2021, pp. 679–691., https://doi.org/10.4155/bio-2021-0027.

Hendelman, Tess, et al. “Self-Collection of Capillary Blood Using Tasso-SST Devices for Anti-SARS-Cov-2 IGG Antibody Testing.” PLOS ONE, Public Library of Science, 21 Sept. 2021, 

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0255841

Laboratory services organization focuses on easing patient and site burden with improved collection device.

At-home Self-collection of Blood Specimens for Safety Lab Testing in Clinical Trials via the Tasso+ Device

Mural Health and Ledger Run have announced a strategic partnership. Through this partnership, Mural Health's Mural Link™ platform and Ledger Run's ClinRun™ platform work together to improve clinical operations and materially improve the efficiency, and outcomes, of global clinical trials.

Life science technology companies will create an integrated software solution to simplify clinical research activities and improve operational processes.

Mural Health and Ledger Run Form Partnership

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

There are probably very few readers of this site who are not by now aware that, as from today, arguably the biggest change ever in European rules on clinical trials has come into effect. The EU’s Clinical Trials Regulation (CTR) has been the subject of extensive comment over the last eight years, since the underlying legislation was adopted. Its aim of simplifying and easing clinical trial approvals across Europe is widely seen as valuable, and in official circles is being celebrated today. But it is perhaps worth noting that not everything is going to get easier, and not right away.

For a start, the opportunities for streamlining applications and procedures are accompanied by plenty of new obligations that sponsors must comply with. Many relate to tight and strict deadlines for reporting and for providing the authorities with notifications or replies to questions—and in many cases the penalty for non-compliance is that the application will lapse. The details of all these provisions have been neatly—and more comprehensibly—summarized in a note compiled by the European Commission and published to coincide with this momentous occasion.

The tightness of the deadlines is easily judged: for instance, once a clinical trial approval has been granted and the study has started (defined as the start of recruitment), sponsors have just 15 days to notify this. The same deadline for notification applies to the first visit of the first subject, the end of recruitment, any restart of recruitment, and the end of the trial (defined as the last visit of the last subject in any of the participating member states). Any temporary halt of the trial, its resumption, or its early termination fall under the same obligation. Any breach of the protocol likely to affect safety rights of the subject or the reliability of the data must be reported within seven days, and the seven-day limit also applies to unexpected events—except for serious adverse events, which must be reported within 24 hours

Still more constraining, a new deadline of one year from the end of the trial applies to the filing of a summary of results, accompanied by the novel concept of a laypersons summary. And once a marketing authorization has been granted on the product, a clinical study report must be submitted.

It may be of interest to sponsors beyond Europe that where the provisions of the regulation on good clinical practice differ from those of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, the rules in the EU regulation prevail.

Naturally, there is satisfaction in the emergence at last of a system allowing for a single EU application to be made for a clinical trial that can lead to an approval valid across all the member states. Similarly, many sponsors see as helpful the obligations that are also placed on the authorities. In contrast to the weeks, months, and even years that it has often taken to obtain a decision on an application in just one country, a tacit approval now underlies the system. Broadly speaking, once the EU level procedure has been completed, each member state has to inform the applicant of the result within just five days. Where any of these new deadlines are missed by a member state, the application is deemed to be accepted.

The perennial European Union problem of its very diversity still, of course, tends to dampen hopes for speedy compliance by the authorities. Cristian Busoi, a Romanian physician who heads one of the most influential committees in the European Parliament, today lamented the continuing tendency of different countries to interpret common rules in their own way—which he sees as an obstacle to clear implementation of the CTR. The main drug industry lobby group in Europe, the European Federation of Pharmaceutical Industries and Associations (EFPIA), also greeted the general jubilation with some admonitory comments on “initial problems,” some requiring “extensive work to achieve a resolution.” It urged a focus on “further developing and enhancing the usability and functionality of the system,” which it says “is necessary for the effective conduct of clinical trials and for the EU to remain attractive for clinical research.” In particular it highlighted a lack of alignment of member state requirements, and situations where member states take different approaches to reviewing trials that need to be transitioned to the new system.

https://health.ec.europa.eu/system/files/2023-01/mp_ctr-536-2014_guide_en.pdf#page14

Formal compliance with EU’s Clinical Trials Regulation takes effect, designed to speed up the application and approval of studies.

Eight Years Later, Europe’s ‘New’ Clinical Trial Rules Finally Come into Force

Jill Wechsler is ACT's Washington Correspondent

FDA just announced that it will restart in-person, face-to-face meetings with industry sponsors of drugs and biologics, beginning Feb. 13, after a shift to all-virtual meetings during the COVID-19 health emergency for nearly three years. However, the agency also clarified that it has revised its definition of such formal meetings to include both in-person and virtual components utilizing IT platforms that allow for both audio and visual communication.

 The agency explains that a face-to-face (FTF) meeting between FDA and industry will be a hybrid session, with both in-person and virtual components using cameras.

This redefinition of “in-person” meetings was agreed on in the recently updated user fee agreements for drugs (PDUFA VII) and biosimilars (BsUFA III). FDA also plans to apply this process to formal meetings involving over-the-counter medicines, even though that new user-fee agreement does not specify this policy. For now, the agency will limit face-to-face hybrid sessions to requests for Type A meetings, Biosimilar Product Development Type 1 sessions, and Type X meetings, with other meeting types continuing to be fully virtual, without an in-person component.

FDA says it is in the process of updating guidance documents for formal meetings to include this revised definition, and is highlighting the new meeting policy on its website to “help reduce uncertainties” for all parties. This dual approach for in-person meetings reflects a hybrid workplace format at the Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER), where many staffers still work only a portion of the time at FDA’s White Oak, Md., facility. The agency is upgrading its conference rooms there in phases to better handle hybrid meetings, a process that limits the number of in-person sessions that can be accommodated at this time.

To better manage the in-person component of these hybrid sessions, FDA plans to limit the number of people in the room to “core participants”—i.e., those with “primary speaking roles”—and encourages industry to do the same. Other staffers from both parties will join the session virtually. As FDA gains more upgraded conference rooms, it will consider phasing in additional types of meetings for in-person scheduling, such as Type A and Type B (milestone meetings), BPD Type 1 and Type 2, and Type X and Type Y. Eventually, all FTF formal meetings may be eligible for the in-person format.

https://www.fda.gov/industry/prescription-drug-user-fee-amendments/update-person-face-face-formal-meetings-fda?utm_medium=email&utm_source=govdelivery

Face-to-face meetings will now include in-person and virtual components.

FDA Resumes In-Person Meetings with Industry…Sort Of

AiCure, an AI and advanced data analytics provider, is working with the Defense Health Agency’s (DHA) PTSD Drug Treatment (PTSD-DT) program to deploy its medication adherence platform to guide patients in their compliance to complex treatment regimens, as well as its digital biomarker solution to capture the subtleties of a patient’s response. As PTSD has a wide range of symptoms, 

 aims to develop a precision medicine approach to prescribing the most effective therapy based on a patient’s unique biological and clinical characteristics. Rich Christie, MD, PhD, Chief Medical Officer at AiCure, spoke to our sister publication 

Rich Christie, MD, PhD, Chief Medical Officer at AiCure

 Can you provide the background on AiCure’s digital biomarker solution as a whole?

: During a clinical trial, a precise and accurate understanding of a patient’s response to treatment is critical to measure the state of their disease and a drug’s impact. Traditional means of measuring a patient’s well-being, including sporadic in-person assessments or a patient’s self-reported outcomes, only tell clinicians how a patient is feeling at that moment in time. The stretches between these check-ins can tell an entirely different story, filled with critical, subtle cues about their condition.

AiCure’s AI-powered digital biomarker solution enables remote detection of subtle changes in a patient’s health status and response to treatment by capturing audio and visual data between clinic visits. Accessed through AiCure’s Patient Connect application, patients use their smartphone’s front-facing camera to complete brief assessments. AiCure’s algorithm then analyzes behavior, such as emotional expressivity, physical movement and speech patterns. By frequently aggregating these sensitive, objective insights, AiCure empowers pharmaceutical companies to improve their understanding of the disease and treatment side effects, elevating the integrity of their trial data, and optimizing patient outcomes.

 How does the technology work in the context of the DHA partnership?

 The DHA PTSD Drug Treatment Program is conducting an adaptive platform trial designed for the efficient and cost-effective testing of multiple PTSD treatments in both active service members and veterans. AiCure's medication adherence platform guides patients in their compliance to complex treatment regimens. The biomarker solution is described above, and the application features integrated built-in reminders and a communication system, allowing sites to contact the participant if they’ve missed a dose or check-in.

: Can you describe the challenges of PTSD treatment?

 PTSD has a wide range of symptoms and has significant variation in how it presents across patients. Eighty percent of PTSD patients have at least one additional comorbidity such as depression, anxiety or substance abuse disorder, further complicating diagnosis and treatment. Despite the societal, financial, and emotional strain that PTSD exerts upon patients, there are only two FDA-approved therapies on the market.

The PTSD-DT Program's adaptive platform trial will evaluate the effect of therapeutics on a patient's PTSD symptoms over 12 weeks. Because medication compliance has historically been a significant methodological problem in PTSD clinical trials, AiCure's adherence platform will offer patients the necessary support to ensure correct dosing. The digital biomarker solution can be used to capture the subtle changes we discussed earlier, and may help investigators identify the right drug for the right patient, or allow clinicians to intervene in a patient's treatment plan in a timely manner if the drug is not likely to be effective.

 What does it involve in terms of patient interactions?

 Each time a patient doses in the trial, they will use the AiCure application. The smartphone-based application leverages computer vision and AI to remotely assess patient dosing behavior, ensuring the right patient ingested the right drug at the right time. This allows sites to monitor adherence and follow up with participants in instances of non-adherence. For the biomarker assessments, participants will be asked to perform simple tasks, such as describing images presented through the AiCure app in a few sentences to the camera of the smartphone, in order to record and analyze their responses.

 How many patients will participate in the PTSD clinical trial?

Rich Christie, MD, PhD, Chief Medical Officer at AiCure discusses the use of the company's technology in a clinical trial for PTSD.


PTSD Study Uses Precision Medicine Tech from AiCure

COTA has announced its membership in the Clinical Research Data Sharing Alliance (CRDSA), a nonprofit, cross-industry alliance of biopharma companies, data sharing platforms, academic institutions, and service and technology partners.

COTA joins consortium of biopharma companies, data sharing platforms, academic institutions, and service and technology partners.

COTA Announces Membership in Clinical Research Data Sharing Alliance 

A more harmonized formula and schedule for administering anti-COVID-19 vaccines gained strong support from FDA’s expert advisory panel last week, with agreement on the need to reduce confusion over which shot to take and when in order to increase vaccination rates among both adults and children in the US. The 21 members of FDA’s Vaccine and Related Biological Products Advisory Committee (VRBAC) voted unanimously for a more simplified approach, setting the stage for the agency to authorize a common bivalent shot for all patients that targets the original COVID strain and the Omicron subvariants. The new program would end use of Pfizer and Moderna monovalent vaccines that only target the original COVID strain.

FDA received less support for setting a schedule for annual vaccination against COVID, as the advisors expressed uncertainty about the effectiveness of the current shots and questioned what time during the year would be best for a national COVID vaccination campaign. Several panel members urged additional research on the effectiveness of the new formulations on frequently changing variants and the possible need for different vaccination schedules for both children and older adults with health impairments. The experts called on FDA to provide additional data on vaccine effectiveness and timing to better determine whether all patients would need an annual shot.

The strategy to set a common formula for anti-COVID vaccines across the country aims to increase vaccination rates overall. New data from the Centers for Disease Control and Prevention (CDC) indicates that less than half of all older Americans (over age 65) have received the updated booster, and that vaccination rates are a meager 10% for children under age 4. The hope is that a shift away from differing vaccine compositions and varying immunization schedules, along with clearer alignment between US and European vaccination recommendations, will encourage more people to get such protection.

Pfizer, Moderna, and Novavax reported to VERBAC on efforts underway to produce reformulated bivalent vaccines and supported the plan to establish a common formulation for all manufacturers of the adopted shot to simplify vaccination recommendations and reduce patient uncertainty over effectiveness and safety of vaccines from different companies. The manufacturers emphasized the need for specifics from FDA on the process for updating vaccine strains, including the timing, process, and methodology for producing a data package for new licensure. While such filings are expected to include new preclinical and manufacturing data, sponsors opposed requirements for additional clinical trials, indicating that it will be more productive to assess post-authorization real-world data to confirm effectiveness.

FDA officials proposed to meet with the advisory panel in May or June to decide on which COVID strain to target in vaccines for later this year, anticipating a fast reformulation by manufacturers of mRNA vaccines. But Novavax officials indicated that it might need to identify the strain earlier, probably in March, to produce a new vaccine by fall with its more traditional vaccine production process. All three shot manufacturers reported that they were already shifting to use prefilled syringes and single-dose vials, which are important for physicians, clinics, and pharmacies planning to administer the new vaccines more widely in the wake of reduced federal government involvement in the program.

A related question is whether FDA will ask manufacturers to produce combination influenza/COVID vaccines to further simplify annual vaccination programs. The three firms reported that they are already studying such combination shots, but any shift toward such products will involve much further assessment of the need for and effectiveness of annual COVID vaccines or combination products.

While advisory committee experts and officials from FDA and other health agencies acknowledged the value of utilizing mRNA platforms to produce anti-COVID vaccines so quickly and effectively at the start of the pandemic, some panel members called for further research on how well the new formulations provide long-term protection and avoid safety issues, urging continued examination of whether more traditional vaccine production methods may have broader benefits moving forward. In its presentation, Novavax presented data indicating a “robust breadth of immunity” and strong manufacturing consistency for its more recently approved preventive.

In concluding the meeting, Peter Marks, director of the Center forBiologics Evaluation and Research (CBER), reiterated the need for a “data-driven approach” to achieve a vaccine regimen that is as simple as possible. But he also noted the importance of monitoring vaccine safety and assessing product effectiveness in shifting to a next generation of COVID vaccines able to provide “greater depth of protection.”

Agency panel backs the use of a common bivalent shot for all patients.

FDA Seeks to Simplify COVID Vaccination Program

The Pistoia Alliance launched its freely accessible FAIR4Clin guide. The guide will help clinical regulators, biopharmaceutical and healthcare organizations to implement the FAIR principles (Findable, Accessible, Interoperable, Reusable) in clinical datasets. 

FAIR4Clin was co-authored by the Pistoia Alliance and experts in the field, including from AstraZeneca, Bayer, Roche, Genentech, Galapagos, The Hyve, Elixir, The University of Manchester, and Oxford University.

Read more about the guide and how to access it 

Guide will help clinical regulators, biopharma, and healthcare organizations to implement the FAIR principles.

Pistoia Alliance Publishes Freely Accessible FAIR4Clin Guide

In order to comply with the 21st Century Cures Act,

 FDA has released two notices of proposed rulemaking intended to harmonize the FDA institutional review board (IRB) and informed consent regulations with the Federal Policy for the Protection of Human Subjects (the “Common Rule”) to the extent possible.

 The Common Rule was revised in 2018 and the FDA notices of proposed rulemaking will harmonize the FDA regulations with the majority of those 2018 revisions. The Common Rule has been adopted by 20 federal agencies and applies to research that is conducted or supported by those agencies.

The first FDA notice of proposed rulemaking on Cooperative Research2 focuses on harmonization with the Common Rule requirement at 45 CFR 46.114(b)(1) that “Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States.” The FDA proposed language is virtually identical.

However, FDA has proposed differences in the exceptions to the rule. The Common Rule provides two exceptions:

The following research is not subject to this provision:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or

(ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.

While the FDA has proposed acceptance of the first exemption, it has not proposed adoption of the second and is proposing additional exceptions (items ii through iv):

Research is not subject to paragraph (b)(1) of this section if at least one of the following criteria is met:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe);

(ii) Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required;

(iii) Cooperative research on drugs that meets the exemptions from an investigational new drug application under § 312.2(b) of this chapter; or

(iv) Cooperative research on medical devices that meets the abbreviated requirements under § 812.2(b) of this chapter, or that meets the requirements for exempted investigations under § 812.2(c) of this chapter.

These different exemptions have the potential to create regulatory conflicts for research that is federally funded and thus subject to the Common Rule and FDA regulated. For instance, if an NIH-funded study qualified for the exceptions at 21 CFR 56.114(b)(2)(ii), (b)(iii), or b(iv), there would be conflicting regulatory requirements. Because the Common Rule does not include these provisions, the Common Rule would still require single IRB review unless the NIH took action under 45 CFR 46.114(b)(2)(ii) to determined that “Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.” While these regulatory conflicts create some additional regulatory burden, it will not be unmanageable for the regulated community.

If FDA adopts this requirement, sponsors will be required to use a single IRB for their US sites, whereas in the past that had been allowed but not required. Many industry sponsors have voluntarily taken this approach for some time, so disruption at the sponsor level will be minimal. For institutions and investigators, the imposition of the single IRB requirement would likely require some modifications to standard operating procedures and resources to comply, but many have already taken these steps due to the previous adoption of this requirement in the Common Rule.

In the FDA notice of proposed rulemaking on Protection of Human Subjects and IRBs,3 it is the proposed harmonization with the Common Rule requirements for informed consent documents that will most likely affect sponsors. Like the Common Rule, the FDA proposed rule would require:

(e)(1) Informed consent must 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. This part of the informed consent must be organized and presented in a way that facilitates comprehension.

(2) Informed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.(21 CFR 50.20(e)).

FDA is proposing to include three additional elements of informed consent, which have already been included in the revised Common Rule, at sections 21 CFR 50.25(b)(7), (8), and (9). Section 50.25(b)(7) would require a statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit. Section 50.25(b)(8) would require a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions. Finally, section 50.25(b)(9) pertains to research involving biospecimens and would require that subjects be informed whether the research will (if known), or might, include whole genome sequencing (WGS).

FDA has also proposed to clarify in 21 CFR 50.27 that electronic informed consent is acceptable by adding a parenthetical statement to that effect, so that it would state, “informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated (including in an electronic format) by the subject or the subject’s legally authorized representative at the time of consent.”

FDA has also proposed not harmonizing with two elements of informed consent that were added to the Common Rule in the 2018 revisions. The first of these involves the Common Rule requirement to provide subjects with information regarding the future use of data for additional research purposes.

FDA requested public comment on whether its proposed new element of informed consent at § 50.25(a)(9) would provide adequate notice to potential subjects regarding the possible future research use of their information and biospecimens or if the Common Rule’s provision at 45 CFR 46.116(b)(9) is more informative. It also inquired whether the research community anticipated challenges in implementing the proposed new element and if an alternative approach could lessen those challenges.

in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … (9) One of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

(i) A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility; or

(ii) A statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.

FDA’s proposed new regulatory language at 21 CFR 50.25(a)(9) reads as follows:

in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … A description of how information or biospecimens may be used for future research or distributed to another investigator for future research.

FDA’s proposed language at 21 CFR 50.25(a)(9) is more open ended and will in many cases be difficult for the sponsor or investigator drafting the consent form to complete. Future research with information or biospecimens is often not contemplated when writing the protocol and informed consent form, so there would be no information to provide to the subject. The goal of this new element in the Common Rule was to let subjects know whether their information and specimens might be used for further research without their consent. FDA has attempted to improve the language by making it more open ended, but it could lead to several unintended consequences. FDA’s proposed language could result in IRBs and other parties interpreting the failure to describe future secondary research in the consent form as a prohibition on secondary research without consent, which would restrict the ability to perform that research under the current HHS regulations. Parties in research may also be concerned that the conduct of secondary research without consent could be a finding in an FDA inspection if it was not described in the consent form. Thus, reducing their ability or willingness to conduct such research.

The second element which FDA is proposing not to harmonize involves activities preparatory to research. FDA requested comment on whether its current policy adequately addresses screening, recruiting, or determining eligibility for an FDA-regulated clinical investigation, or if including the revised Common Rule provision at 45 CFR 46.116(g) would be useful for FDA-regulated clinical investigations.

The Common Rule, 45 CFR 46.116(g), includes the following requirement:

(g) Screening, recruiting, or determining eligibility. An IRB may approve a research proposal in which an investigator will obtain information or biospecimens for the purpose of screening, recruiting, or determining the eligibility of prospective subjects without the informed consent of the prospective subject or the subject’s legally authorized representative, if either of the following conditions are met:

(1) The investigator will obtain information through oral or written communication with the prospective subject or legally authorized representative, or

(2) The investigator will obtain identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens.

In essence, this new Common Rule requirement harmonized with the 1998 FDA Information Sheet entitled “

Screening Tests Prior to Study Enrollment

Guidance for IRBs and Clinical Investigators

FDA notes that because its definition of a “clinical investigation” is distinct from the HHS definition of “research,” it is unnecessary for it to adopt the new HHS regulatory language. However, it might not be clear to all parties involved in the conduct of research that FDA has already adopted this position through guidance. This could lead to confusion in the future for individuals trying to understand FDA’s position regarding activities preparatory to research.

Commercial sponsors and investigators who do not participate in federally-funded research will be more heavily affected by these FDA proposed regulations as they will be novel to them. Those parties should be prepared to address these new requirements if and when these revisions are implemented. IRBs, institutions, and investigators involved in the review and conduct of federally-funded research have already adopted many of these provisions in 2018 in the Common Rule, and thus will not be as affected.That said, the timeline for adoption of these proposed changes to the FDA regulations is unclear, and could take several months, or even several years.

, JD, MA, CIP is Chief Compliance Officer at WCG

21st Century Cures Act, Section 1002, Public Law 114-255. 

https://www.govinfo.gov/app/details/PLAW-114publ255

Notice of Proposed Rulemaking: Institutional Review Boards; Cooperative Research (87 FR 58752) 

https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research

Notice of Proposed Rulemaking: Protection of Human Subjects and Institutional Review Boards (87 FR 58733) 

https://www.federalregister.gov/documents/2022/11/14/2022-24689/protection-of-human-subjects-and-institutional-review-boards-and-institutional-review-boards

Code of Federal regulations Title 45 46.114 

https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46/subpart-A/section-46.114

Code of Federal Regulations Title 21 56.114(b) 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=56.114

21st Century Cures Act prompts FDA to harmonize regulations.

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