EMA new FINAL Guideline: Guideline on computerised systems and electronic data in clinical trials

Approved by the Expert Working Group on 7Mar2023, this final guidance was recently released. After the TOC, it starts with a glossary whose first entry is artificial intelligence.  With the recent explosion of AI systems and the discussions on their use, that is certainly fitting (recognizing that, yes, the glossary is alphabetical).  It includes an Executive Summary which nicely captures the content, including a focus on the patients and their rights. This guideline is also important as more and more trials are being decentralized with increased use of apps and devices for remote and in-home data collection.

Executive summary
Computerised systems are being increasingly used in clinical research. The complexity of such systems has evolved rapidly in the last few years from electronic case report forms (eCRF), electronic patient reported outcomes (ePROs) to various wearable devices used to continuously monitor trial participants for clinically relevant parameters and ultimately to the use of artificial intelligence (AI). Hence, there is a need to provide guidance to all stakeholders involved in clinical trials reflective of these changes in data types and trial types on the use of computerised systems and on the collection of electronic data, as this is important to ensure the quality and reliability of trial data, as well as the rights, dignity, safety and wellbeing of the trial participants.

This would ultimately contribute to a robust decision-making process based on such clinical data. This guideline will describe some generally applicable principles and definition of key concepts. It also covers requirements and expectations for computerised systems, including validation, user management, security, and electronic data for the data life cycle. Requirements and expectations are also covered related to specific types of systems, processes, and data.

I'll be reading this in detail today, since the implications are extensive for anyone working in clinical drug development.

FDA Webinar: Methods and Approaches for Capturing Post-Approval Safety and Efficacy Data on Cell and Gene Therapy Products

 From the announcement:

The FDA is seeking input on methods, approaches, logistics, privacy concerns, and other aspects related to efficacy and safety data collection in the post-approval setting for cell and gene therapies. 

Meeting Logistics and Registration

• Date: Thursday, April 27, 2023
• Time: 12:00 p.m.–4:30 p.m. ET
• Location: This is a virtual public listening meeting and will be held via Zoom.
• Registration: This meeting is free and open to the public; however, registration is required. Early registration is recommended. Please register for the event nowExternal Link Disclaimer.

Registration will close on Wednesday, April 26, 2023 at 11:59 p.m. ET. A recording and other relevant meeting materials will be posted online following the event. 

If you would like to speak, the registration site has the information, but you must requests to make oral presentations by 11:59 p.m. ET on March 30, 2023 ET.

Written or electronic comments are also invited and directions are at the website.

FDA Diagnostic Data Program new webpage announced

Aimed at the diagnostics market, solutions with Diagnostic Data interoperability will help in patient care, but also aid in clinical trial operations and improve data for filings and regulatory review.  Real challenges exist, however, since some instrumentation used in clinical diagnostic labs is also used in other industries (e.g., immuno-assay plate readers, mass spectrometers).  There have been a number of industry led consortia over the past 2 decades that have made strides in laboratory data interoperability, but broad acceptance has not been achieved.

A new webpage was recently announced for the Diagnostic Data Program.  The program is aimed at improving portability and usability of diagnostic data.  The FDA notes 4 barriers to be eliminated to help achieve high-quality safe patient care:

• Difficulty in the collection of valuable data from tests conducted in laboratories, clinics, and nontraditional testing locations (for example, at-home or point-of-care).   
• Consistent erosion of accuracy as the data is transformed between systems.   
• Insufficient data infrastructure to support the transmission, aggregation, and analytics of high-volume data.  
• Challenges in data transparency, communication, security, and utility amongst diverse public and private stakeholders.  

Two specific activities are also planned for actions:

• Systemic Harmonization and Interoperability Enhancement for Laboratory Data (SHIELD)  (webpage link)
• Digital Diagnostics: Over-the-Counter (OTC) and Point-of-Care (POC) (webpage link)

With more than 70 organizations participating, SHEILD addresses the challenges with lab data sharing (standards, IVD devices, lab workstations and electronic health records. Harmonization of data standards and taxonomy are essential to the process SNOMED-CT and LOINC are two examples. Many more details are available at the webpage.

 

The recent growth and expected increased use in coming years of point-of-care (POC) and over-the-counter (OTC) tests used in homes has resulted in some data not being available for physicians and public health authorities to make evidence-based decisions. Many more details are available at the webpage.

 

Additionally, funding is under the FDA Extramural Research program.

New FDA Draft Guidance: Considerations to Support Accelerated Approval of Oncology Therapeutics

 This draft guidance covers both drugs and biologics and provides recommendations for designing clinical trials that support approval. It notes that single-arm trial desings and response endpoint are most common for oncology accelerated approvals, and then list 5 limitations of single-arm trials.  It goes on to suggest that "properly designed and executed, a randomized controlled trial can address the limitations of single-arm trials, including but not limited to, the following way" and then lists the 5 ways. A sixth value for a randomized trial is then discussed:

Another potential advantage to conducting a randomized controlled trial to support accelerated approval is that, in appropriate cases, longer term follow-up in the same trial could fulfill a postmarketing requirement to verify clinical benefit. This “one-trial” approach maintains efficiency in drug development and can provide early access to a drug using the accelerated approval pathway, while ensuring that a postmarketing trial is fully accrued and well underway to verify longer term benefit in a timely fashion.

 The draft guidance then goes onto to provide recommendations for both randomized and single-arm trials before concluding with a section on a 'Confirmatory Trial Following Accelerated Approval".

FDA releases "Framework for the Use of Digital Health Technologies in Drug and Biological Product Development"

The document "Framework for the Use of Digital Health Technologies in Drug and Biological Product Development" has been released by the FDA.  The PDUFA VII commitment letter includes the Congressional mandates for the FDA and it includes "the use of digital health technologies (DHTs) to support drug development and review". This document is notes as a guide and not guidance. The definition section defines what the Agency considers falling under the umbrella of DHTs, but they can be hardware AND/OR software.

From the section "Current Landscape of DHTs"

DHTs include technologies such as wearable, implantable, ingestible, and environ- mental sensors and software applications on mobile phones, among others. Advances in sensor technology, general-purpose computing platforms, and methods for data capture, transmission, and storage have revolutionized the ability to remotely obtain and analyze clinically relevant information from individuals. DHTs used for remote data acquisition are playing a growing role in health care and offer important opportunities in clinical research. DHTs can support traditional site-based clinical trials and enable the conduct of DCTs, which are clinical investigations where some or all trial-related activities occur at locations other than traditional clinical trial sites. DHT software can also be disseminated for use with a prescription drug. 

The Agency expects to develop its technical expertise and train staff on 5 topics:

a. Verification and Validation

b. Use of a Participant’s Own DHT or General-Purpose Computing Platform

c. Upgrades and Updates of DHTs in Drug Development

d. Artificial Intelligence and Machine Learning

e. Technical Consultation of Experts and Staff Training 

This will not be a completely internal process and will include interactions with :

a.      FDA Meetings With Sponsors

b.     Drug Development Tool Qualification Program

c.      Developing and promulgating Guidance

d.     Public Meetings

e.      Demonstration Projects

f.      External Organizations 

 

If you are in drug development, you may want to read this to see what the Agency plans are that will enable or cause you to plan differently to ensure the data resulting from DHTs is acceptable within your filing.  

Press Release; MHRA to streamline clinical trial approvals in biggest overhaul of trial regulation in 20 years

 From the Press Release:

A series of new measures will be introduced by the Medicines and Healthcare products Regulatory Agency (MHRA) with support from partners to make it faster and easier to gain approval and to run clinical trials in the UK. These changes represent the biggest overhaul in UK clinical trials regulation in over 20 years and will help to make the UK one of the best countries in the world to conduct clinical research for patients and researchers.

Under the new framework, clinical trials application processes in the UK will be more proportionate, streamlined and flexible without compromising on safety, helping to cement the UK as an attractive destination for trials, including global “multi-site” trials. For example, the integration of the regulatory and ethics reviews of clinical trial applications, which in pilot phase halved the approval times for studies and cut the time from application to recruiting a first patient by 40 days, will be embedded into the new regulation.

The MHRA will also implement a timeline for completion of an application review within a maximum 30 days in general, with a maximum 10 calendar days for a decision to be granted once the regulator has received any final information. The legislative changes will result in a regulatory framework that is as future-proof as possible, responsive to different types of trials and innovative designs, and supportive of new ways of carrying out trials such as decentralised trials.

The press release also notes that among the changes will be a greater collaboration with patient groups. 

A PDF document that summarizes, as well as reviews details on the planned changes can be found here.

EFPIA News release: New EU in vitro regulations delaying clinical trials

In a 20Mar2023 news release, the European Federation of Pharmaceutical Industries and Associations (EFPIA) that notes a large number of clinical trials in the EU are being delayed because of problems related to the implementation of the In Vitro Diagnostic Regulation (IVDR) came into effect in May 2022.  EFPIA claims, the implementation of the regulation has been challenged by a lack of infrastructure, guidance, and coordination, triggering a series of unintended consequences. The release notes:

The number of clinical trials delayed is expected to run into the hundreds, affecting up to 42,200 patients over the next three years, according to a survey run by EFPIA. The legislation is also likely to result in delays to therapies reaching patients in Europe. 

 From the article:

The EFPIA member survey showed:

• Between 82 and 160 trials are currently being delayed in Europe, with an expected 238 to 420 trials to be delayed over the next three years.
• These delays mean that between 33,815 to 42,200 patients in Europe are expected to have delayed access to clinical trials over the next three years, around half of them (up to 27,400) being cancer patients.
• The launch of 89 therapies could be delayed because of this legislation, in innovative therapeutic areas such as oncology and rare diseases.
• Up to 400 trials are expected to enrol fewer patients, meaning some people missing out on innovative new treatments. These include trials for cancer, rare disease, neuroscience, inflammation, cell and gene therapies, paediatrics and cardiovascular diseases.
• 43% of companies surveyed said they expect delays of six to12 months to current clinical trials, with 48% expecting six to 12 month delays over the next three years.
• 67% of companies would consider reducing the number of EU trial sites if IVDR requirements remain the same, noting these trials would move to the US, Canada, UK, and Asia, among other locations.
• Compliance with the IVDR means IVDs used in clinical trials go through an assessment process when the diagnostic test result influences patient medical management. However, this process is currently complex and uncoordinated. It results in patients waiting longer to participate in clinical trials, or even not participating at all.

A number of recommendation were proposed by EFPIA to reduce the current barriers implemented by the IVDR.

New FDA Draft Guidance: Pharmacogenomic Data Submissions

When finalized, this draft guidance will replace a 2005 final guidance of the same name. 

The guidance can be downloaded here.

From the introduction:

This guidance is intended to facilitate progress in the field of pharmacogenomics and the use of pharmacogenomic data in drug2 development. This document is intended to clarify the contexts in which pharmacogenomic study findings and data must be included in submissions related to investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) based on the FDA’s regulations. In addition, this document provides recommendations to sponsors and applicants on the format and content of the pharmacogenomic data submissions.

 

For the purposes of this guidance, the term pharmacogenomics is defined as the study of variations of DNA and RNA characteristics as related to drug response;3 DNA or RNA variations can be germline, somatic, or microbial. Pharmacogenomics does not refer to data resulting from proteomic, metabolomic, or other -omic studies, although similar considerations in this guidance could be applicable for determining whether to submit findings and data from such studies.

 

This draft guidance is not intended to cover pharmacogenomic data associated with an investigational device exemption (IDE) application.

 

A table is provided that defines whether a synopsis or full report is needed for an IND vs NDA/BLA.  However, in reading the text, there are exceptions for when the Agency would require a full report and not a synopsis (e.g., “… genomic biomarker studies that are related to pharmacokinetics (e.g., drug metabolizing enzyme gene variants) are recommended to be submitted as a synopsis. However, if those same genomic data are also the basis for patient dosing, subject-level data, and a full report rather than only a synopsis should be submitted.”).  Two sections discuss reports for IND and NDA/BLAs. Details are also provided on the format and sections for reports. Actual data formatting is referenced to two other guide documents. Lastly, the draft guidance notes where in an NDA/BLA the reports should be located.  

FDA new Draft Guidance: Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations Questions and Answers

For everyone working in or supporting clinical studies this is a worthwhile read.

This draft guidance revises a prior version (Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 — Questions and Answers (June 2017) and also expands on others and will supersede one when finalized.

From the Introduction:

This document provides guidance to sponsors, clinical investigators, institutional review boards (IRBs), contract research organizations (CROs), and other interested parties on the use of electronic systems, electronic records, and electronic signatures in clinical investigations of medical products, foods, tobacco products, and new animal drugs. The guidance provides recommendations regarding the requirements, including the requirements under 21 CFR part 11 (part 11), under which FDA considers electronic systems, electronic records, and electronic signatures to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.

This guidance expands upon recommendations in the guidance for industry Part 11, Electronic Records; Electronic Signatures — Scope and Application (August 2003) (2003 part 11 guidance) that pertain to clinical investigations conducted under 21 CFR parts 312 and 812.

When finalized, this guidance will supersede the guidance for industry Computerized Systems Used in Clinical Investigations (May 2007).

This draft guidance covers many divisions of the FDA: CDER, CBER, CDRH, CFSAN, CTP, CVM, ORA and OCLiP.

#FDA #21CFRPart11 #DraftGuidanceQ&A #electronicsystems# electronicrecords #electronicsignatures #clinicalstudies

The draft guidance is available here: https://www.fda.gov/media/166215/download

FDA Webinar: Navigating the First ICH Generic Drug Draft Guideline “M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms”

 The FDA is holding a webinar on this DRAFT guideline on May 2, 2023 from 1:00 PM - 3:00 PM ET.

Registration is available here.

From the announcement:

In December 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Assembly endorsed the draft ICH M13A guideline titled “M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms” which provides recommendations for conducting bioequivalence (BE) studies during development and post-approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.

On January 31, 2023, FDA issued a draft guidance for industry titled M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms, and a Federal Register (FR) notice to solicit public comments on M13A on the FDA website. This draft guidance was developed by the ICH M13 Expert Working Group (EWG) and is intended to provide harmonized, global, scientific recommendations for conducting BE studies during both development and post-approval phases that can increase the efficiency of drug development and accelerate the availability of safe and effective orally administered IR solid oral dosage forms.

The comment period will close on April 3, 2023. Please submit comments before April 3 to ensure that the FDA and ICH M13 EWG consider your comments on this draft guidance before they begin work on the final version of the guidance.

This webinar will take an in-depth look into the draft guidance and explain the ICH EWG’s current scientific thinking, and provide clarification on FDA’s planning on the implementation of M13A.

Two things stand out from this announcement: 

1) The FDA is holding a webinar on a draft guideline (Which makes me wonder if they are looking to obtain compliance in advance of the final version)

2) The webinar will be AFTER the comment period closes.  (Does this indicate that they are interested in comments outside the comment period?)

Publication: Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS-CoV-2 Antibodies, and Protein Profiling

Federico Ribet, et al., published this article in Advanced Healthcare Materials that presents a "cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes".  Just in that sentence there are a lot of things to consider:

1. single microneedle
2. painless
3. 1.1 µL 
4. interstitial fluid

The single microneedle drives the latter three - i.e., the microneedle is unlikely to hit a nerve, therefore painless, the microneedle cannot draw large volumes, hence 1.1 µL, and lastly the microneedle is unlikely to penetrate a capillary to draw blood, thus interstitial fluid is obtained. The use of interstitial fluid is interesting as any drug or biomarker molecules measured would be those which were able to cross the capillary boundaries and most likely represent free drug.  For those who have dealt with the whole free vs bound drug discussion and which is more appropriate to pharmacological models, I'll leave it to you to comment on the value of interstitial fluid concentrations. 

Regarding the volume, so many technologies are able to measure picomolar and femtomolar amounts, that this device has some potential for clinical study use, post-marketing therapeutic drug monitoring, as well as some clinical lab applications. 

Not noted is that the sample is absorbed into a paper storage component and stored dry.  A blue powder is used within the paper to identify when the volume hits the demarcated visualization volume window so that the device can be removed from the skin. The accuracy of the volume may be a hindrance when considering use by "free-range" humans, but there will be situations where the overall simplicity and cost would override any analytical variability.

The article includes a number of good graphics and pictures of the device, as well as skin penetration.  Using caffeine as a test compound, 5 dosed and one placebo subject had samples drawn using the device and concurrent 10uL capillary blood DBS samples drawn.  Reasonably good relationship exists between the two measures by LC-MS/MS.  They also presented data on a number of proteins, as well as antibodies to SARS Cov-2 spike protein. 

If interested, please read the article and come back and comment here.

Publication: Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease

I first saw a summary of this at the Broad Institute websites ("Researchers map brain cell changes in Alzheimer’s disease" https://www.broadinstitute.org/news/researchers-map-brain-cell-changes-alzheimers-disease) which provided a nice summary of the article and a few statements from the researchers. The original article was published in February in Nature Neuroscience:

Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease

• Hu Zeng, et al., Nature Neuroscience volume 26, pages 430–446 (2023)

 

Using a technique called STARmap PLUS, the researchers used high-resolution spatial transcriptomics and specific protein detection in tissue sections from a mouse model of Alzheimer's. From the abstract:

It reveals a core–shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like (DAA-like) cells and oligodendrocyte precursor cells (OPCs) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerges mainly in excitatory neurons in the CA1 region and correlates with the local enrichment of oligodendrocyte subtypes. The STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing a tool to pinpoint the molecular and cellular changes underlying pathology.

The mapping was able to identify the location of protein expression of 2,700 genes and with antibodies to tag specific proteins their location - all done with 3-D positioning within tissue slices. Based on their observations, the researchers felt the microglia were activated near the plaques to form protective shells as part of an inflammatory response rather than being activated elsewhere and recruited to the plaques. However, they have not yet fully determined the role of the microglia cells within the overall disease.

AAPS Webinar: Development and Regulatory Landscape of Cell-based and CAR-T Therapies

 Tuesday May 9, 2023 @ 12:30 PM EDT

Register here.

Description

The webinar on CAR-T and cell-based therapies will touch on emerging concepts in the R&D, manufacturing and regulatory landscape of these immunotherapies. As living drugs, CAR-T and other cell-based therapies present particular challenges in terms of development and clinical and commercial deployment. Despite multiple FDA approvals, challenges in global access, manufacturing and targeting complex diseases such as solid tumors remains challenging. This webinar will present a history of CAR-T therapy and outline recent and emerging innovations of these therapies in terms of disease targeting, CAR design and architecture, and manufacturing advancements.

 

Speaker:

Sandro Matosevic, Ph.D.

Dr. Sandro Matosevic is an assistant professor in the College of Pharmacy at Purdue University, and is a member of the Purdue Center for Cancer Research. Dr. Matosevic runs an NIH-funded research program focused on the development and use of cell-based therapies with natural killer cells and CAR-engineered immune cells in the treatment of cancer and holds a number of patents on the engineering and utilization of NK cells and stem cell-derived NK cells in cancer immunotherapy.

Dr. Matosevic is on the editorial board of several journals, acts on pharmaceutical advisory boards, and has been on committees for several organizations advancing the development and standardization of cell-based therapies, and is current chair of the BIO Focus group of the National Institute for Pharmaceutical Technology and Education. Dr. Matosevic obtained his graduate degree from University College London and completed his postdoctoral training at the Scripps Research Institute.

EU drug therapy approval process changes: Dynamic Regulatory Assessment will support more efficient treatment development for patients

 An article from EFPIA reviews the current situation with Dynamic Regulatory Assessment (DRA).  Not used for most routine MAA submissions, but rather for situations of promising treatments or emergency situations (e.g., pandemic).  A DRA model proposed by EFPIA would use greater regulatory interactions, continuous knowledge building, data submissions at predetermined timepoints to achieve a faster approval - and doing so without compromising the level of evidence.  Current IT technologies could support the approach but are not sufficiently robust to and may need to be specifically developed to make the use of DRA more routine.  The EFPIA proposal for DRA is in line with EMA activities and proposed fee structures and is based on lessons learned from the development and approval of Covid-19 therapies.

Other considerations are in the brief article, as well as links to related information.

FDA Final Guidance: ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products

 For my CMC colleagues, if you follow ICH releasing new guidance, you may have already seen and are preparing for this guidance. With the FDA publishing it, compliance with its content is now expected in the US. 

The Objective and Scope provide clarity on what is being covered:

A. Objective (1.1)

This guidance describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). Building on existing International Council for Harmonization (ICH) Quality guidances, this guidance provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products. 

Pretty straight forward as to which phases (all) of continuous manufacturing are covered.

B. Scope (1.2)

This guidance applies to CM of drug substances and drug products for chemical entities and therapeutic proteins. It is applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products. The principles described in this guidance may also apply to other biological/biotechnological entities. 

Interesting here are several things:

1. Coverage of chemical drugs and therapeutic proteins, including generics and biosimilars

2. New processes or conversion of batch processes to continuous manufacturing

and perhaps the most impactful

3. "The principles described in this guidance may also apply to other biological/biotechnological entities."

This last item indicates that the ICH working group was forward looking to other therapeutic modalities (oligonucleotides, vaccines, gene therapy and perhaps cell therapies).  However, without specifically stating coverage, some confusion may arise if the guidance is to be applied or not. If you have questions, the FDA and other global regulatory groups are typically available to answer questions.

The guidance itself is only 18 pages, but several Annexes with examples follow to provide further interpretation of the guidance into real world situations. 

If you are in the CMC space, a recommended read.