FDA launches drug app Drugs@FDA

FDA has released an app - "Drugs@FDA includes most of the drug products approved since 1939. The majority of patient information, labels, approval letters, reviews, and other information are available for drug products approved since 1998."

More info is available @ https://www.fda.gov/drugs/drug-approvals-and-databases/about-drugsfda

It can be downloaded for Apple and Android devices.

This could be a great app for patients, medical staff and those in drug development looking for information from an easy to access source.

FDA publishes ICH Q9(R1) Quality Risk Management as final Guidance

FDA published ICH Q9(R1) Quality Risk Management as final Guidance.  It updates the original Q9 from 2006. As with all FDA implementations of ICH guidelines, there will be minor changes in language to accommodate US law on Guidance (e.g., use of ‘will’ or ‘shall’ is normally changed to ‘should’ since FDA Guidance are always recommendations).

Having sat through numerous risk discussion on drug development teams, as well as CAPA assessments, I find this text in the Introduction most appropriate with regard to the differences in individual perspective influence on risk assessment.

It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm. In addition, subjectivity can directly impact the effectiveness of risk management activities and the decisions made. Therefore, it is important that subjectivity is managed and minimized. In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, the protection of the patient is of prime importance when managing the risk to product quality and availability, when availability risks arise from quality/manufacturing issues.

In addition to defining key elements of the process early in the Guidance, 8 example Quality Risk Management methods and a number of statistical software tools are discussed in the first Annex. The second Annex discusses potential applications for Quality Risk Management.

MHRA Blog on the ICH draft E6(R3) Good Clinical Practices - Differences vs both E6(R2) and UK regulations

Andrew Fisher, Lead Senior GCP Inspector at the UK Medicines and Healthcare products Regulatory Agency (MHRA), has published a blog comparing ICH E6(R3) (i.e., Revision 3) Good Clinical Practice (GCP) guideline with the currently approved and globally implemented E6(R2). Andrew, a member of the ICH Expert Working Group, provides a perspective on what is in this very long blog (it prints as 41 pages):

 

I have reviewed ICH E6(R2) and ICH E6(R3) and examined what changes have been by EWG which was a quite a time-consuming task! The following information is a personal summary of the changes that I have identified and I am not representing the EWG. A presentation is available from the EWG that provides their high-level summary of key changes made to the ICH GCP guideline. This blog is not intended to include every detailed change made or cover all text retained but should give you a flavour of the amendments made by the EWG. I anticipate that there could be publications that set out to discuss the changes in full detail during the consultation period, but this blog should start your understanding of what’s changed.

 

Personally, I’m in the process of reading E6(R3) and will follow up with this blog to better understand the changes as I consider what the impacts will be to organizations and people operating under the GCPs. But as I read both documents, I will keep in mind that E6(R3) is a draft and will change prior to finalization, so I won’t be recommending any changes to current practice at this time.

Draft ICH E6(R3) Good Clinical Practice released for Consultation

The draft E6(R3), that is revision 3, of the Good Clinical Practice guideline was released as draft for Consultation on 19 May by the ICH Assembly after completion by the Expert Working Group.  Expect countries globally to release it for comment also - but that will take time. Those involved in any aspect of clinical trials should assess the revision to the GCPs to assess what has changed, but not act yet to change their practices as the final guidance will surely contain some differences. The volume of comments will be high given the topic and content; which runs to 73 pages with Appendices.

Do you know what GASK is? New FDA draft guidance

 GASK: Generally Accepted Scientific Knowledge is topic of a recently released (and short) FDA draft guidance (Generally Accepted Scientific Knowledge in Applications for Drug and Biological Products: Nonclinical Information).  The Introduction notes “FDA has received an increasing number of questions regarding the extent to which generally accepted scientific knowledge (GASK) may be relied on for drug or biological product approval”; which has spurred the need for the draft guidance. 

 

I like this clarifying statement on what GASK is “Generally, GASK is based on widely accepted scientific principles that are typically long-standing.”, as it ensures that knowledge has been widely tested and known, and not a recent breakthrough that has not undergone rigorous evaluation.

 

It is in the Discussion section where the best description exists for the value of GASK: the ability to not perform some nonclinical studies:

“As discussed above, in most cases, nonclinical studies provide necessary information relevant to the determination of the safety and effectiveness of a drug, or the safety, purity, and potency of a biological product, to support approval of a marketing application. In some cases, however, what is already known, for example, about a drug, the patient’s condition, or a relevant biological process (i.e., the biological context in which a drug is expected to act) in a given patient population is sufficient to confidently predict the outcome of a given nonclinical study. If there is GASK relevant to the application, it may be unnecessary for a sponsor to conduct certain nonclinical studies. This may result in streamlined product development that avoids unnecessary animal testing, decreases a drug’s development costs, and quickens the drug’s time to approval and marketing — and thus, its availability to patients.”

Two examples are given of GASK where testing would not be needed:

            -- Substances Typically Present in a Healthy Human Body (endogenous or dietary)

            -- GASK Regarding an Altered Biological Mechanism or Pathway

The draft guidance notes that these are just examples and specifies that GASK is situational and related to its use within a particular application: “Notably, while the examples provided here are for illustrative purposes, determinations regarding the appropriateness of data submitted for any application, including GASK, are fact-specific, and the question of whether certain information can be considered GASK and the purpose such information would serve in an application will be considered in the context of a particular application.”

 

As with all FDA draft guidance, there is an open comment period for those who would like to request clarifications or corrections to the document.

FDA Free Webinar on Decentralized Clinical Trials (DCT) Draft Guidance

FDA’s CDER Small Business and Industry Assistance (SBIA) group is hosting a webinar on June 20, 2023 @ 3:00 PM - 4:00 PM ET.  The webinar is FREE and more info and link to the registration is here.

ABOUT THIS WEBINAR

The FDA sees important potential benefits and value in DCTs. Advances in clinical care using electronic communications and information technology to interact with trial participants in different locations (i.e., telehealth) allow for fewer in-person visits to clinical trial sites and facilitate decentralization. In addition, digital health technologies have expanded the types of trial-related data that can be obtained remotely from trial participants. By enabling remote participation, DCTs may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more diverse patient populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility. As part of the FDA’s efforts to be responsive to the rapidly evolving clinical trial landscape and clarify the Agency’s recommendations on the conduct of DCTs, the FDA will provide an overview of the draft guidance titled Decentralized Clinical Trials for Drugs, Biological Products, and Devices.

TOPICS COVERED

• Design of a DCT
• Conduct of remote clinical trial visits and clinical trial-related activities in a DCT
• Use of digital health technologies to remotely acquire data in a DCT
• Roles and responsibilities of the sponsor and investigators in a DCT
• Obtaining informed consent and institutional review board oversight of the informed consent process in a DCT
• Determination of the appropriateness of investigational products for use in a DCT
• Packaging and shipping of investigational products in a DCT
• Safety monitoring of trial participants in a DCT
• Software used to support the conduct of a DCT

FDA SPEAKERS

Leonard Sacks, MBBCh
Associate Director
Clinical Methodologies | Office of Medical Policy (OMP) | CDER | FDA

Ryan Robinson, MD
Medical Officer
Clinical Methodologies | OMP | CDER | FDA

Aptamer use in pre-natal cellular isolation for genetic testing

As part of the Eurostar-3 program Aptamer Group, Bioliquid Innovative Genetics and Anima Design of Spain were awarded 1.125 million Euro grant for their project proposal MIRACLE (Medical device to dIagnose  pRenatal and plACentaL disEases).  Using aptamers selected through Aptamer Group's optimization process, the devices will the aptamers to capture and isolate specific cell types to be isolated and analysed for diagnostic biomarkers from samples of the pregnant mother’s blood.  Non-target cell types will not be captured. 

This use of aptamers is interesting in that it suggests their use for any other time cells with specific, surface biomarkers need to be isolated, custom antibody generation can be side-stepped in favor of aptamers which eliminate batch to batch reproducibility issues. This then opens the door for a wide range of diagnostic tests, including lateral flow devices.

CVS Steps out of clinical trial support

 After 2 years, CVS has decided that clinical trial support was no longer a part of its business mission.  That leaves Walgreen's and Walmart as pharmacy providers still in the game.  Nothing specific in the announcement provides what problems may have been encountered that led to the decision.  These problems may have already been solved by the remaining players, but if not, they would be valuable lessons for those still in the game.  With the continued need for patient support outside of physician offices and clinics, I am wondering how the industry will respond to keep decentralized trials available to the most patients, especially those in under served urban and rural areas.

New FDA Draft guidance: Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act

 The US government passed the Pediatric Research Equity Act (PREA) in 2003. A number of prior regulations and FDA reauthorizations supported that law.  This new draft guidance is specifically focused on:

37. The scientific aspects of a pediatric program (e.g., considerations regarding data in pediatric Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations (May 2023).  

    This guidance, along with the draft guidance for industry Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations, revises and replaces the draft guidance for industry How to Comply With the Pediatric Research Equity Act.  In addition to addressing the PREA topics covered in the earlier draft guidance (i.e., the pediatric assessment, pediatric plan, waivers and deferrals, compliance issues, and pediatric exclusivity provisions), this guidance addresses statutory changes relating to adverse event reporting, pediatric study plans (PSPs), deferral extensions, and noncompliance.

UPDATE on 18May23 - Note that there was a second draft guidance released that covers Scientific Considerations including: 1) Formulation Development, 2) Nonclinical Information, 3) Clinical Pharmacology, 4) Safety Information, and a major section on Pediatric Extrapolation.

This guidance goes into when a pediatric version of a drug is required to be developed and when it is not (e.g., adult only diseases, orphan products).  For testing of oncology drugs in pediatric populations, upon sponsor request, the FDA may waive the requirement to submit pediatric assessments or reports if certain criteria are met 1)extremely small patient group, 2) likelihood of the drug being unsafe or ineffective or 3) the drug is unlikely to have benefit greater than existing therapies and is unlikely to be used in a substantial number of pediatric patients. 

The FDA may also issue Written Requests (WR) to sponsors "requesting submission of a study or studies intended to provide meaningful health benefits in the pediatric population".  Interestingly, "Completion of studies described in a WR is voluntary." Other details around content of the WR and its implications e.g., potential 6-month extension of exclusivity, are also included in the draft. 

While there is not much here for my bioanalytical colleagues, those working on drug development strategy will find this interesting

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FDA Webinar: Overview: Clinical Pharmacology Considerations for Food Effect Studies

For those who participate in or support food effect studies a good opportunity to hear FDA perspectives on the guidance

Date:  June 15, 2023

Time:1:00 PM - 2:00 PM ET

Registration link 

In this webinar, FDA will discuss:

• Importance of assessing the effect of food on drugs and reasons for issuing the final guidance
• Timing of conducting food effect studies during drug development
• General considerations for designing food effect studies
• Other considerations related to assessing the effect of food on a drug

TOPICS COVERED

• Timing of conducting food effect studies during drug development
• Type of meals to be evaluated
• General considerations for designing food effect studies

LEARNING OBJECTIVES

• Understand the importance of assessing the effect of food on drugs
• Comprehend general considerations for designing food effect studies
• Discuss data analysis considerations related to food effect assessment

FDA SPEAKERS

Vikram Arya, Ph.D., FCP
Associate Director for Therapeutic Review, Division of Infectious Disease Pharmacology | Office of Clinical Pharmacology| CDER | FDA

Panelists

Vikram Arya, Ph.D., FCP
Associate Director for Therapeutic Review, Division of Infectious Disease Pharmacology | Office of Clinical Pharmacology| CDER | FDA

Brian Booth, Ph.D.
Director; Division of Cancer Pharmacology I | Office of Clinical Pharmacology | CDER | FDA

Ethan Stier, Ph.D.
Associate Director for Lifecycle Management, Immediate Office | Office of Clinical Pharmacology | CDER | FDA

 

FDA Breifing on its activities related to "Artificial Intelligence and Machine Learning (AI/ML) for Drug Development"

The FDA posted a brief update on its activities related to AI and ML on 10May23.

In it it notes that there were 100 submission in 2021 that included some form of AI or ML, and covered a broad range " of drug development — from drug discovery and clinical research to postmarket safety surveillance and advanced pharmaceutical manufacturing."

The three divisions involved in ensuring the safety of drugs and biological products, CDER, CBER and CDRH, were all involved with the issuance of an initial discussion paper (references below).

Related Publications

• FDA Releases Two Discussion Papers to Spur Conversation about Artificial Intelligence and Machine Learning in Drug Development and Manufacturing
• AI/ML for Drug Development Discussion Paper (PDF - 1 MB)
• CDER Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative, including discussion papers:
  • Artificial Intelligence in Drug Manufacturing (PDF - 2 MB)
  • Distributed Manufacturing and Point-of-Care Manufacturing of Drugs (PDF - 1 MB)
• For specific AI/ML publications related to devices, please visit CDRH’s Digital Health Center of Excellence webpage

 

Regulatory Developments in Genetic Testing in the United States

 I found information that summarizes the various US regulatory bodies involvement in Genetic Testing at the OECD site (https://www.oecd.org/health/emerging-tech/regulatorydevelopmentsingenetictestingintheunitedstates.htm).  Based on the content, either a US representative to the OECD supplied the content or someone very familiar with the interconnected Agencies and committees provided the details. 

The introduction provides the framework that is then delved into with greater detail in subsequent paragraphs:

Currently in the United States, genetic and non-genetic tests receive the same level of oversight from governmental agencies. Genetic tests are regulated at the federal level through three mechanisms:

1) the Clinical Laboratory Improvement Amendments (CLIA); 2) the Federal Food, Drug, and Cosmetic Act; and 3) during investigational phases, regulations for the Protection of Human Subjects (45 CFR 46, 21 CFR 50, and 21 CFR 56). In addition to the Federal role, oversight of genetic tests is provided by states and private sector organisations. A summary is provided below of the roles of five organisations of the Department of Health and Human Services (DHHS) in oversight of genetic tests: the Centres for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), Health Care Financing Administration (HCFA), Office for Protection from Research Risks (OPRR), and National Institutes of Health (NIH). Although it does not have a regulatory function, the NIH supports research activities that generate knowledge about genetics and genetic testing. The roles of the states and the private sector in oversight also are described.

The general framework discussed here (i.e. multiple Agency and Committee involvement) is representative of all US patient testing where the medical results are used in assessing patient health and administering appropriate care.  

New FDA Draft Guidance: Decentralized Clinical Trials for Drugs, Biological Products, and Devices

Today, the FDA released its draft guidance on "Decentralized Clinical Trials for Drugs, Biological Products, and Devices". As the name implies it is aimed to provide guidance on developing new drug and biologic therapies, as well as digital health technologies (devices) within decentralized clinical trials (DCTs).  The background section notes that these trials "may enhance convenience for trial participants, reduce the burden on caregivers, and facilitate research on rare diseases and diseases affecting populations with limited mobility or access to traditional trial sites. This may help improve trial participant engagement, recruitment, enrollment, and retention of a meaningfully diverse clinical population."

Since there are no sites related to DCT, the draft guidance still recommends a physical location for record keeping, which can also serve as the location for review during regulatory inspections. Another section discusses the use of digital health technologies, their inclusion, use and data management. The guidance includes sections on sponsor, investigator and IRBs.  It also discusses dosing of drug and biologic therapies that ensure patient safety as a principle consideration.  Many more detail are in the guidance for anyone working in this space.

 

As with all draft guidance, the FDA has opened a public comment period (info at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/decentralized-clinical-trials-drugs-biological-products-and-devices)

MHRA Blog on ICH E6(R3) Good Clinical Practice guidance - Step 2 Public Consultation

Post-BREXIT, the UKs MHRA joined ICH as an independent body in May 2022.  This notification on the Agency's Blog provides an overview of the ICH plans for revision to the existing E6(R2) Good Clinical Practice Guidance.  It notes the MHRA's intent to "consult directly with UK stakeholders to compile and co-ordinate their comments to the EWG".

 Plans are in development for "a MHRA GCP Stakeholder Engagement Meeting ... to be held concerning this document during the consultation period"; providing a second pathway for comments to be provided to the Agency.