FDA new Draft Guidance: Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations Questions and Answers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This draft guidance revises a prior version (Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 — Questions and Answers (June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This draft guidance covers many divisions of the FDA: CDER, CBER, CDRH, CFSAN, CTP, CVM, ORA and OCLiP.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The draft guidance is available here: https://www.fda.gov/media/166215/download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.