Feeds:
Posts
Comments

Posts Tagged ‘FDA guidance’

FDA Moves Forward With Its Guidance Framework for Rare Disease Trials: 2026

Posted in Artificial Intelligence in Medicine - Applications in Therapeutics, children, Clinical & Translational, Drug Development Process, FDA, FDA Regulatory Affairs, New Drug Approval, tagged , , , , , , , , on August 3, 2026| Leave a Comment »

FDA Moves Forward With Its Guidance Framework for Rare Disease Trials: 2026

Reporter: Stephen J. Williams, Ph,D.

In 2025, the Trump Administration had determined it wants to streamline the FDA and clinical trials in order to expedite much needed drugs for various terminal diseases such as cancer and rare childhood diseases.  In 2026, under the guidance of the new FDA commissioner, Dr. Makary, the FDA initiated guidance for the proposed changes in February and available for comments at that time.  This has been a growing discussion aver the years and the FDA wanted, for many years, to figure out they could speed bringing new therapies to market, especially for terminally  ill patients. Given the progress of biomarkers development early in the drug discovery process and new computational technologies, the time seems to be ready for such changes in trial design and even for the long drug development process.  In addition the FDA up to this point was focused on other matters so it wasn’t really at the forefront of their to do list.

From: https://www.fda.gov/news-events/press-announcements/fda-launches-framework-accelerating-development-individualized-therapies-ultra-rare-diseases

FDA Launches Framework for Accelerating Development of Individualized Therapies for Ultra-Rare Diseases

For Immediate Release:

The U.S. Food and Drug Administration today issued draft guidance for sponsors seeking approval for targeted individualized therapies by generating substantial evidence of effectiveness and safety when randomized controlled trials are not feasible due to small patient populations.

The draft guidance, issued by the Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research, specifically discusses genome editing and RNA-based therapies such as antisense oligonucleotides but leaves open the potential that this framework may apply to additional tailored therapeutics provided they directly address the underlying specific cause of the disease.

“President Trump promised to accelerate cures for American families — and we are delivering, especially for children with ultra-rare diseases who cannot afford to wait,” said Health and Human Services Secretary Robert F. Kennedy, Jr. “We are cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most.”

“This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions,” said FDA Commissioner Marty Makary, MD, MPH. “It is our priority to remove barriers and exercise regulatory flexibility to encourage scientific advances and deliver more cures and meaningful treatments for patients suffering from rare diseases.”

The draft guidance focuses on therapies that target a specific genetic, cellular or molecular abnormality and are designed to correct or modify the underlying cause of disease. Key criteria include:

  • Identifying the disease-causing abnormality.
  • Demonstrating the therapy targets the root cause or proximate biological pathway.
  • Relying on well-characterized natural history data in untreated patients.
  • Confirming successful target drugging or editing.
  • For traditional approval, therapies should demonstrate improvement in clinical outcomes, disease course, or biomarkers if they are established to predict clinical benefit.

“Designing treatments unique to individual patients has always been the promised goal of personalized medicine,” said Chief Medical and Scientific Officer and Center for Biologics Evaluation and Research Director Vinay Prasad, MD, MPH. “After 25 years the FDA has, for the first time, outlined a framework to facilitate these approvals. The Plausible Mechanism Framework is a revolutionary advance in regulatory science.”

“The Plausible Mechanism draft guidance creates a novel framework through which cutting-edge treatments tailor-made for patients with ultra-rare diseases can be used as a basis for FDA approval,” said Center for Drug Evaluation and Research Acting Director Tracy Beth Høeg, MD, Ph.D. “We anticipate our Plausible Mechanism draft guidance will inspire industry to place increased focus on individualized therapies, thereby driving innovation, improving safety, lowering costs and offering more patients with ultra-rare diseases a unique shot at a life-saving treatment.”

Because genome editing technologies are designed to be highly specific to unique DNA sequences, a product targeting different mutations in a single gene could be included in a single product application and potentially evaluated through the use of master protocols that evaluate these product variations in a single trial. A highly supported “plausible” mechanism of action may then be used to support the addition of other such genome editing product variants, intended to treat patients with mutations that were not included in the clinical trial used to support the original approval.

The FDA recognizes that an adequate and well-controlled clinical investigation in this context will include a small sample size, therefore, investigation results should be sufficiently robust to exclude chance findings. When determining effectiveness, the FDA considers the specific disease, the strength of the evidence and the challenges of conducting clinical investigations for individualized therapies.

 

In June of 2026, the FDA formalized their discussion into guidelines for discussion so it appears the following are not set into register of regulations as of yet.

From https://www.fda.gov/drugs/guidances-drugs/guidance-documents-rare-disease-drug-development

Guidance Documents for Rare Disease Drug Development

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in agency guidances means that something is suggested or recommended, but not required.

Below are selected guidances that are relevant to rare disease drug development, organized by topic. This list does not include all FDA guidances on or relevant to rare disease drug development but represents our most commonly used guidances. This list may be updated periodically.

I have kept the original text in order for reference and to provide the background for these changes “in their words”.

However there are a few themes in these guideline changes and discussions including:

  • definitions of rare diseases
  • reduction of complexities and simplification of trial design and requirements (the FDA wants to go to a more ONE trial with very well designed controls than the two trial design for INDs (I will discuss this further in a near future post)
  • accelerated approval which will entail streamlining both the submission and approval process for rare conditions
  • heavy reliance on biomarkers during drug development and clinical trials (which is already in frequent use in pharma)
  • early communication with the FDA
  • more reliance on plausible mechanism of action to reduce number of studies needed

Rare Disease

Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause
The purpose of this guidance is to describe considerations for generating substantial evidence of effectiveness and evidence of safety for individualized therapies based on a plausible mechanism framework.

Rare Diseases: Considerations for the Development of Drugs and Biological Products
This guidance clarifies FDA’s thinking on important considerations in rare disease drug development to ultimately assist rare disease drug and biologic product developers in conducting successful drug development programs.

Rare Diseases: Natural History Studies for Drug Development: Draft Guidance for Industry
FDA is publishing this draft guidance to help inform the design and implementation of natural history studies that can be used to support the development of safe and effective drugs and biological products for rare diseases. A natural history study collects information about the natural history of a disease in the absence of an intervention, from the disease’s onset until either its resolution or the individual’s death. Although knowledge of a disease’s natural history can benefit drug development for many disorders and conditions, natural history information is usually not available or is incomplete for most rare diseases; therefore, natural history information is particularly needed for these diseases.

Rare Pediatric Disease Priority Review Vouchers
This guidance provides information on the implementation of section 908 of the Food and Drug Administration Safety and Innovation Act (FDASIA), which added section 529 to the Federal Food, Drug, and Cosmetic Act (the FD&C Act). Under section 529, FDA will award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in that section.

Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings : Draft Guidance for Industry
The purpose of this draft guidance is to assist sponsors of drug and biological products for the treatment of rare diseases in planning and conducting more efficient and productive pre-investigational new drug application (pre-IND) meetings. Drug development for rare diseases has many challenges related to the nature of these diseases. This draft guidance is intended to advance and facilitate the development of drugs and biological products for the treatment of rare diseases.

Slowly Progressive, Low-Prevalence Rare Diseases with Substrate Deposition That Results from Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies : Guidance for Industry
This document provides guidance to sponsors on the evidence necessary to demonstrate the effectiveness of investigational new drugs or new drug uses intended for slowly progressive, low-prevalence rare diseases that are associated with substrate deposition and are caused by single enzyme defects. This guidance applies only to those low-prevalence rare diseases with well-characterized pathophysiology, and in which changes in substrate deposition can be readily measured in relevant tissue or tissues.

Pediatric Rare Diseases–A Collaborative Approach for Drug Development Using Gaucher Disease as a Model : Draft Guidance for Industry
The purpose of this guidance is to facilitate drug development in pediatric rare diseases. In particular, it discusses a new possible approach to enhance the efficiency of drug development in pediatric rare diseases using Gaucher disease as an example.

Inborn Errors of Metabolism That Use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development: Guidance for Industry
This guidance describes the Food and Drug Administration’s (FDA’s) current recommendations regarding how to optimize and standardize dietary management in clinical trials for the development of drugs that treat inborn errors of metabolism (IEM) for which dietary management is a key component of patients’ metabolic control. Optimizing dietary management in these patients before entry into and during clinical trials is essential to providing an accurate evaluation of the efficacy of new drug products.

Accelerated Approval

Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway
For drugs granted accelerated approval, sponsors have been required to conduct confirmatory studies postapproval to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. In the Consolidated Appropriations Act, 2023 (CAA), Congress amended section 506(c) of the FD&C Act (21 U.S.C. 356(c)), to provide additional authorities to help ensure timely completion of such trials, including that FDA “may require, as appropriate, a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.” This draft guidance, when finalized, will describe FDA’s interpretation of the term “underway” and policies for implementing this requirement, including factors FDA intends to consider when determining whether a confirmatory trial is underway prior to an accelerated approval action.

Accelerated Approval – Expedited Program for Serious Conditions
Accelerated approval is one of FDA’s expedited programs intended to facilitate and expedite development and review of new drugs to address an unmet medical need in the treatment of a serious or life-threatening condition. The purpose of this guidance is to provide information on FDA’s policies and procedures for accelerated approval as well as threshold criteria generally applicable to concluding that a drug is a candidate for accelerated approval. This guidance also describes the procedures for expedited withdrawal of approval of a product approved under accelerated approval and the revisions Congress made through the Consolidated Appropriations Act, 2023 (Public Law 117-328). Additional programs to expedite product development and review are covered in other guidances.

Benefit-Risk

Benefit-Risk Assessment for New Drug and Biological Products
The intent of this guidance is to clarify for drug sponsors and other stakeholders how considerations about a drug’s benefits, risks, and risk management options factor into certain premarket and postmarket regulatory decisions that the Food and Drug Administration (FDA or Agency) makes about new drug applications (NDAs) submitted under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as well as biologics license applications (BLAs) submitted under section 351(a) of the Public Health Service Act (PHS Act).

Biomarkers

For general information on Biomarkers, please see About Biomarkers and Qualification

Biomarker Qualification: Evidentiary Framework
This draft guidance provides recommendations on general considerations to address when developing a biomarker for qualification under the 21st Century Cures Act (Cures Act), enacted on December 13, 2016, that added a new section to the Federal Food, Drug, and Cosmetic Act (FD&C Act). Qualification of a biomarker is a determination that within the stated context of use, the biomarker can be relied on to have a specific interpretation and application in drug development and regulatory review.

Qualification Process for Drug Development Tools
This guidance describes the qualification process for drug development tools (DDTs) intended for potential use, over time, in multiple drug development programs.

Clinical Outcome Assessments (COAs) and Endpoints

For information on the COA Qualification Program, please see Clinical Outcome Assessment (COA) Qualification Program

Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments
This guidance (Guidance 3) is the third in a series of four methodological patient-focused drug development (PFDD) guidance documents that describe how stakeholders (patients, caregivers, researchers, medical product developers, and others) can collect and submit patient experience data and other relevant information from patients and caregivers to be used for medical product development and regulatory decision-making.

Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making
This guidance (Guidance 4) is the fourth in a series of four methodological patient-focused drug development (PFDD) guidance documents that describe how stakeholders (patients, caregivers, researchers, medical product developers, and others) can collect and submit patient experience data and other relevant information from patients and caregivers to be used for medical product development and regulatory decision-making.

Multiple Endpoints in Clinical Trials Guidance for Industry
This guidance provides sponsors and review staff with the Agency’s thinking about the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for human drugs, including drugs subject to licensing as biological products.

Clinical Pharmacology

Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications 
This document provides recommendations for sponsors of investigational new drugs (INDs) and applicants submitting new drug applications (NDAs) or biologics license applications (BLAs) on the use of exposure-response information in the development of drugs, including therapeutic biologics. It can be considered along with the International Conference on Harmonisation (ICH) E4 guidance on Dose-Response Information to Support Drug Registration and other pertinent guidances (see Appendix A).

Bioavailability Studies Submitted in NDAs or INDs – General Considerations
This guidance provides recommendations to sponsors and applicants submitting bioavailability (BA) information for drug products in investigational new drug applications (INDs), new drug applications (NDAs), and NDA supplements. This guidance contains recommendations on how to meet the BA requirements set forth in 21 CFR part 320 as they apply to dosage forms intended for oral administration.

General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products
This guidance assists sponsors of investigational new drug applications (INDs) and applicants of new drug applications (NDAs) under section 505 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), biologics license applications (BLAs) under section 351(a) of the Public Health Service Act (PHS Act), and supplements to such applications who are planning to conduct clinical studies in pediatric populations.

General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products Guidance for Industry
This guidance is intended to assist sponsors of investigational new drug applications (INDs) and applicants of new drug applications (NDAs), biologics license applications (BLAs), and supplements to such applications who are planning to conduct clinical studies in neonatal populations. This guidance provides recommendations for neonatal clinical pharmacology studies, whether the studies are conducted pursuant to section 505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), section 505B of the FD&C Act, or neither.

Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations
This guidance provides recommendations to sponsors planning to conduct food-effect (FE) studies for orally administered drug products under investigational new drug applications (INDs) to support new drug applications (NDAs) and supplements to these applications for drugs being developed under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355).

Population Pharmacokinetics
This guidance is intended to assist sponsors and applicants of new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), and investigational new drugs (IND) applications in the application of population pharmacokinetic (PK) analysis.

Clinical Pharmacology Considerations for Antibody-Drug Conjugates Guidance for Industry
This guidance provides recommendations to assist industry and other parties involved in the development of antibody-drug conjugates (ADCs) with a cytotoxic small molecule drug or payload. Specifically, this guidance addresses the FDA’s current thinking regarding clinical pharmacology considerations and recommendations for ADC development programs, including bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic factors, QTc assessments, immunogenicity, and drug-drug interactions (DDIs).

Drug-Drug Interaction Assessment for Therapeutic Proteins Guidance for Industry
The purpose of this guidance is to help sponsors of investigational new drug applications (INDs) and applicants of biologic license applications (BLAs) determine the need for drug-drug interaction (DDI) studies for a therapeutic protein (TP) by providing a systematic, risk-based approach.

Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease
The pharmacological effect of a targeted therapy is often related to a particular molecular alteration, and many diseases are caused by a range of different molecular alterations (some of which may be rare). Therefore, a targeted therapy may have differential effects among patients with the same disease who have different molecular alterations. The purpose of this guidance is to describe general approaches to evaluating the benefits and risks of targeted therapeutics within a clinically defined disease where some molecular alterations may occur at low frequencies.

Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling
This guidance is intended to assist the pharmaceutical industry and other investigators engaged in new drug development in evaluating how variations in the human genome, specifically DNA sequence variants, could affect a drug’s pharmacokinetics (PK), pharmacodynamics (PD), efficacy, or safety. The guidance provides recommendations on when and how genomic information should be considered to address questions arising during drug development and regulatory review.

Clinical Trials

All clinical trials guidances are listed here.

Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs
This guidance recommends approaches that sponsors of clinical trials intended to support a new drug application or a biologics license application can take to increase enrollment of a representative population in their clinical trials. This guidance considers both demographic characteristics of study populations (e.g., sex, race, ethnicity, age, location of residency) and non-demographic characteristics of populations (e.g., patients with organ dysfunction, comorbid conditions, disabilities, those at the extremes of the weight range, and populations with diseases or conditions with low prevalence). Enrolling participants with a wide range of baseline characteristics may create a study population that more accurately reflects the patients likely to take the drug if it is approved and allow assessment of the impact of those characteristics on the safety and effectiveness of the study drug.

E8(R1) General Considerations for Clinical Studies
This guidance describes internationally accepted principles and practices in the design and conduct of clinical studies of drug and biological products. The guidance is intended to assist sponsors and other parties that design clinical studies, and to promote the quality of the studies submitted to regulatory authorities, while allowing for flexibility.

Multiple Endpoints in Clinical Trials Guidance for Industry
The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity within a study in order to control the chance of making erroneous conclusions about a drug’s effects. Basing a conclusion on an analysis where the risk of false conclusions has not been appropriately controlled can lead to false or misleading representations regarding a drug’s effects.

E17 General Principles for Planning and Design of Multi-Regional Clinical Trial
With the increasing globalization of drug development, it has become important that data from multiregional clinical trials (MRCTs) can be accepted by regulatory authorities across regions and countries as the primary source of evidence to support marketing approval of drugs (medicinal products). The purpose of this guidance is to describe general principles for the planning and design of MRCTs with the aim of increasing the acceptability of MRCTs in global regulatory submissions.

Decentralized Clinical Trials for Drugs, Biological Products, and Devices
This draft guidance provides recommendations for sponsors, investigators, and other stakeholders regarding the implementation of decentralized clinical trials (DCTs) for drugs, biological products, and devices. In this guidance, a DCT refers to a clinical trial where some or all of the trial-related activities occur at locations other than traditional clinical trial sites.

Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products: Guidance for Industry
The purpose of this guidance is to assist industry in developing enrichment strategies that can be used in clinical investigations intended to demonstrate effectiveness (and in some cases safety) of human drugs and biological products. This guidance defines several types of enrichment strategies, provides examples of potential clinical trial designs, and discusses potential regulatory considerations when using enrichment strategies in clinical trials.

Ethical Considerations for Clinical Investigations of Medical Products Involving Children
Clinical investigations in children are essential for obtaining data on the safety and effectiveness of drugs, biological products, and medical devices in children and to protect children from the risks associated with exposure to medical products that may be unsafe or ineffective. Children are a vulnerable population who cannot consent for themselves and who therefore are afforded additional safeguards when participating in a clinical investigation. Such safeguards are an essential requirement for the initiation and conduct of pediatric investigations as part of a medical product development program.

Master Protocols for Drug and Biological Product Development
This guidance document provides recommendations on the design and analysis of trials conducted under a master protocol as well as guidance on the submission of documentation to support regulatory review.

There are some other Guidances which were issued and I will discuss them in another post.  These include Guidances on minimizing use of animals for preclinical toxicology, Innovative clinical trial design especially for gene and cell therapies, and use of AI in designing of clinical trials.

For more information go to the FDA website at : https://www.fda.gov/drugs/guidances-drugs/guidance-documents-rare-disease-drug-development

Other Articles on FDA Guidances on this Open Access Scientific Journal Include:

FDA Guidance on Use of Xenotransplanted Products in Human: Implications in 3D Printing

FDA Guidance Documents Update Nov. 2015 on Devices, Animal Studies, Gene Therapy, Liposomes

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials 

New FDA Draft Guidance On Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products – Implications for 3D BioPrinting of Regenerative Tissue

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

 

Read Full Post »

NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

Posted in Cancer - General, Cancer and Current Therapeutics, Cancer Informatics, Childhood cancer, Clinical & Translational, Curation, Global Medical Publishers by Country, Health Care System by Country, LPBI Management, Personal Health Applications: Tech Innovations serves HealhCare, Pharmaceutical Industry Competitive Intelligence, Pharmacovigilance, Population Health Management, Prostate Cancer: Monitoring vs Treatment, Scientific Publishing, tagged , , , , , , , , , , , , , , , , , , , , on September 14, 2021| Leave a Comment »

NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

Reporter: Stephen J. Williams, Ph.D.

Currently many biomedical texts and US government agency guidelines are only offered in English or only offered in different languages upon request. However Spanish is spoken in a majority of countries worldwide and medical text in that language would serve as an under-served need. In addition, Portuguese is the main language in the largest country in South America, Brazil.

The LPBI Group and others have noticed this need for medical translation to other languages. Currently LPBI Group is translating their medical e-book offerings into Spanish (for more details see https://pharmaceuticalintelligence.com/vision/)

Below is an article on The National Comprehensive Cancer Network’s decision to offer their cancer treatment guidelines in Spanish and Portuguese.

Source: https://www.nccn.org/home/news/newsdetails?NewsId=2871

PLYMOUTH MEETING, PA [8 September, 2021] — The National Comprehensive Cancer Network® (NCCN®)—a nonprofit alliance of leading cancer centers in the United States—announces recently-updated versions of evidence- and expert consensus-based guidelines for treating prostate cancer, translated into Spanish and Portuguese. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) feature frequently updated cancer treatment recommendations from multidisciplinary panels of experts across NCCN Member Institutions. Independent studies have repeatedly found that following these recommendations correlates with better outcomes and longer survival.

“Everyone with prostate cancer should have access to care that is based on current and reliable evidence,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. “These updated translations—along with all of our other translated and adapted resources—help us to define and advance high-quality, high-value, patient-centered cancer care globally, so patients everywhere can live better lives.”

Prostate cancer is the second most commonly occurring cancer in men, impacting more than a million people worldwide every year.[1] In 2020, the NCCN Guidelines® for Prostate Cancer were downloaded more than 200,000 times by people outside of the United States. Approximately 47 percent of registered users for NCCN.org are located outside the U.S., with Brazil, Spain, and Mexico among the top ten countries represented.

“NCCN Guidelines are incredibly helpful resources in the work we do to ensure cancer care across Latin America meets the highest standards,” said Diogo Bastos, MD, and Andrey Soares, MD, Chair and Scientific Director of the Genitourinary Group of The Latin American Cooperative Oncology Group (LACOG). The organization has worked with NCCN in the past to develop Latin American editions of the NCCN Guidelines for Breast Cancer, Colon Cancer, Non-Small Cell Lung Cancer, Prostate Cancer, Multiple Myeloma, and Rectal Cancer, and co-hosted a webinar on “Management of Prostate Cancer for Latin America” earlier this year. “We appreciate all of NCCN’s efforts to make sure these gold-standard recommendations are accessible to non-English speakers and applicable for varying circumstances.”

NCCN also publishes NCCN Guidelines for Patients®, containing the same treatment information in non-medical terms, intended for patients and caregivers. The NCCN Guidelines for Patients: Prostate Cancer were found to be among the most trustworthy sources of information online according to a recent international study. These patient guidelines have been divided into two books, covering early and advanced prostate cancer; both have been translated into Spanish and Portuguese as well.

NCCN collaborates with organizations across the globe on resources based on the NCCN Guidelines that account for local accessibility, consideration of metabolic differences in populations, and regional regulatory variation. They can be downloaded free-of-charge for non-commercial use at NCCN.org/global or via the Virtual Library of NCCN Guidelines App. Learn more and join the conversation with the hashtag #NCCNGlobal.

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, in press. The online GLOBOCAN 2018 database is accessible at http://gco.iarc.fr/, as part of IARC’s Global Cancer Observatory.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing education, global initiatives, policy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

Please see LPBI Group’s efforts in medical text translation and Natural Language Processing of Medical Text at

2.0 LPBI – 2021-2025 VISION
2021-2025 Medical Text Analysis (NLP)

Read Full Post »

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

Posted in 3D Printing for Medical Application, CRISPR/Cas9 & Gene Editing, FDA, FDA Regulatory Affairs, Tissue Engineering, tagged , , , , , , , , , , on November 10, 2015| Leave a Comment »

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

Reporter: Stephen J. Williams, PhD

The recent announcement by Editas CEO Katrine Bosley to pursue a CRSPR/Cas9 gene therapy trial to correct defects in an yet to be disclosed gene to treat one form of a rare eye disease called Leber congenital amaurosis (multiple mutant genes have been linked to the disease) have put an interesting emphasis on the need for a regulatory framework to initiate these trials. Indeed at the 2015 EmTechMIT Conference Editas CEO Katrine Bosley had mentioned this particular issue: the need for discourse with FDA and regulatory bodies to establish guidelines for design of clinical trials using the CRSPR gene editing tool.

See the LIVE NOTES from Editas CEO Katrine Bosley on using CRSPR as a gene therapy from the 2015 EmTechMIT Conference at http://pharmaceuticalintelligence.com/2015/11/03/live-1132015-130pm-the-15th-annual-emtech-mit-mit-media-lab-top-10-breakthrough-technologies-2015-innovators-under-35/

To this effect, I have listed below, the multiple FDA Guidance Documents surrounding gene therapy to show that, in the past year, the FDA has shown great commitment to devise a regulatory framework for this therapeutic area.

Cellular & Gene Therapy Guidance Documents

Withdrawn Guidance Documents

Three other posts on this site goes into detail into three of the above-mentioned Guidance Documents

FDA Guidance on Use of Xenotransplanted Products in Human: Implications in 3D Printing

New FDA Draft Guidance On Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products – Implications for 3D BioPrinting of Regenerative Tissue

FDA Guidance Documents Update Nov. 2015 on Devices, Animal Studies, Gene Therapy, Liposomes

 

Read Full Post »

FDA Guidance on Use of Xenotransplanted Products in Human: Implications in 3D Printing

Posted in 3D Plotting Scaffolds, 3D Printing for Medical Application, BioInks, Biopolymer Blend Open Porous, BioPrinting in Regenerative Medicine, Cell Level, FDA, FDA Regulatory Affairs, MicroEngineering Cell-Tissue & Systems, tagged , , , , , , , , , , , , , on November 9, 2015| Leave a Comment »

FDA Guidance On Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotranspantation Products in Humans – Implications for 3D BioPrinting of Regenerative Tissue

Curator: Stephen J. Williams, Ph.D.

UPDATE: 07/09/2026

This update concern use of porcine xenotransplated tissue in human patients and examines the biochemical and genetic changes occurring both in host and transplanted material. With advances in pig genetic engineering (see post at bottom on the SCID Pig), this has allowed the feasability of improving the outcomes of several porcine to human xenotransplations, including pig to human heart, kidney, lung and even bain xenotransplantation. Studies had demonstrated that gene-edited porcine
livers can function in human recipients with intact native livers under intensive immunosuppression.   Guo et al. had perfomed longitudinal multiomics studies (1) after genetically-modified porcine liver to human xenotransplation suggest future strategies and important biomarkers which can improve the biocompatibility of porcine-human xenotransplatation from short to long term outcomes.

The genetic modification to livers of Yucatan minipigs  EGEN-5784, were supplied by  the company eGenesis  (Cambridge, MA).  EGEN-5784 livers were from ESUS-1784 Yucatan minipigs have the following gene edits: (1) knock out of three porcine genes (GGTA1, CMAH and B4GALNT2) to eliminate three glycan antigensresponsible for hyperacute rejection in humans and old world mon-keys; (2) insertion of seven human transgenes (CD46, CD55, THBD, PROCR, CD47, TNFAIP3 and HMOX1) to improve compatibility with
inflammatory, coagulation and complement pathways in humans; (3) inactivation of the porcine endogenous retroviruses in the genome.

 

(1) Guo, Q., Wang, C., Mauduit, V. et al. Longitudinal multiomics profiling of extracorporeal cross-circulation with pig liver xenografts in human decedents. Nat Med (2026). https://doi.org/10.1038/s41591-026-04511-6

(2) Anand, R. P. et al. Design and testing of a humanized porcine
donor for xenotransplantation. Nature 622, 393–401 (2023) https://doi.org/10.1038/s41586-023-06594-4

Human-Pig Interactions in Liver Xenotransplant Recipients: A Multi-Omics Study

Source: https://www.insideprecisionmedicine.com/topics/translational-research/human-pig-interactions-in-liver-xenotransplant-recipients-a-multi-omics-study/?_hsenc=p2ANqtz-9h_Iwa3u-JgsZr3-j7hT69VLt4Cv1Vksaa70tJpCjUNFjcDfT10eR0qgcM_D9aeTiR6fQnOi0ptB0coHEi_vsB5JlOqQ&_hsmi=427683749 

A comprehensive multi-omics analysis published in Nature Medicine provides new mechanistic insights into extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts, advancing understanding of the molecular and cellular interactions that will shape the clinical translation of xenogeneic liver support.The study builds on a previously reported first-in-human decedent model in which blood from four brain-dead human recipients was circulated through ten-gene-edited porcine livers for up to 84 hours. While the initial work demonstrated that ELC could provide meaningful metabolic support, significant thrombocytopenia and evidence of host immune activation remained major barriers. The new study applies longitudinal, species-resolved multi-omics to dissect these biological responses at unprecedented resolution.

Researchers from NYU Langone Health, NYU Grossman School of Medicine, and the Perelman School of Medicine at the University of Pennsylvania profiled 64 serial blood samples using proteomics, metabolomics, and lipidomics alongside spatial transcriptomic analysis of 25 porcine liver biopsies and three native human liver samples. This integrated approach enabled simultaneous tracking of human and porcine molecular signatures throughout the xenoperfusion procedures. Spatial transcriptomics revealed progressive infiltration of human innate immune cells into the porcine xenografts, dominated by inflammatory macrophages and neutrophils. These infiltrating cells expressed pro-inflammatory cytokines including IL1B, TNF, and IL6, while resident porcine Kupffer-like macrophages and T cells declined over time. Adaptive immune cell infiltration remained comparatively limited, suggesting that the extensive genetic engineering of the donor pigs may mitigate early adaptive rejection during short-term support. One of the study’s most important findings was the distinct behavior of the human and porcine complement systems. While human complement proteins declined during ELC, the pig liver continued producing high levels of complement components C3 and C5 alongside acute-phase proteins and coagulation factors. The findings suggest that the xenograft actively drives innate immune and inflammatory responses rather than simply replacing liver function. Because currently available complement inhibitors are designed to target human proteins, they may not adequately suppress pig-derived complement activity, highlighting a potential need for species-specific therapeutics and additional genetic engineering to improve xenograft compatibility.

Original Article

The FDA has submitted Final Guidance on use xeno-transplanted animal tissue, products, and cells into human and their use in medical procedures. Although the draft guidance was to expand on previous guidelines to prevent the introduction, transmission, and spread of communicable diseases, this updated draft may have implications for use of such tissue in the emerging medical 3D printing field. This document is to provide guidance on the production, testing and evaluation of products intended for use in xenotransplantation. The guidance includes scientific questions that should be addressed by sponsors during protocol development and during the preparation of submissions to the Food and Drug Administration (FDA), e.g., Investigational New Drug Application (IND) and Biologics License Application (BLA). This guidance document finalizes the draft guidance of the same title dated February 2001.

For the purpose of this document, xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. For the purpose of this document, xenotransplantation products include live cells, tissues or organs used in xenotransplantation. (See Definitions in section I.C.)This document presents issues that should be considered in addressing the safety of viable materials obtained from animal sources and intended for clinical use in humans. The potential threat to both human and animal welfare from zoonotic or other infectious agents warrants careful characterization of animal sources of cells, tissues, and organs. This document addresses issues such as the characterization of source animals, source animal husbandry practices, characterization of xenotransplantation products, considerations for the xenotransplantation product manufacturing facility, appropriate preclinical models for xenotransplantation protocols, and monitoring of recipients of xenotransplantation products. This document recommends specific practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population. FDA expects that new methods proposed by sponsors to address specific issues will be scientifically rigorous and that sufficient data will be presented to justify their use.

Examples of procedures involving xenotransplantation products include:

  • transplantation of xenogeneic hearts, kidneys, or pancreatic tissue to treat organ failure,
  • implantation of neural cells to ameliorate neurological degenerative diseases,
  • administration of human cells previously cultured ex vivo with live nonhuman animal antigen-presenting or feeder cells, and
  • extracorporeal perfusion of a patient’s blood or blood component perfused through an intact animal organ or isolated cells contained in a device to treat liver failure.

The guidance addresses issues such as:

  1. Clinical Protocol Review
  2. Xenotransplantation Site
  3. Criteria for Patient Selection
  4. Risk/Benefit Assessment
  5. Screening for Infectious Agents
  6. Patient Follow-up
  7. Archiving of Patient Plasma and Tissue Specimens
  8. Health Records and Data Management
  9. Informed Consent
  10. Responsibility of the Sponsor in Informing the Patient of New Scientific Information

A full copy of the PDF can be found below for reference:

fdaguidanceanimalsourcesxenotransplatntation

An example of the need for this guidance in conjunction with 3D printing technology can be understood from the below article (source http://www.geneticliteracyproject.org/2015/09/03/pig-us-xenotransplantation-new-age-chimeric-organs/)

Pig in us: Xenotransplantation and new age of chimeric organs

David Warmflash | September 3, 2015 | Genetic Literacy Project

Imagine stripping out the failing components of an old car — the engine, transmission, exhaust system and all of those parts — leaving just the old body and other structural elements. Replace those old mechanical parts with a brand new electric, hydrogen powered, biofuel, nuclear or whatever kind of engine you want and now you have a brand new car. It has an old frame, but that’s okay. The frame wasn’t causing the problem, and it can live on for years, undamaged.

When challenged to design internal organs, tissue engineers are taking a similar approach, particularly with the most complex organs, like the heart, liver and kidneys. These organs have three dimensional structures that are elaborate, not just at the gross anatomic level, but in microscopic anatomy too. Some day, their complex connective tissue scaffolding, the stroma, might be synthesized from the needed collagen proteins with advanced 3-D printing. But biomedical engineering is not there yet, so right now the best candidate for organ scaffolding comes from one of humanity’s favorite farm animals: the pig.

Chimera alarmists connecting with anti-biotechnology movements might cringe at the thought of building new human organs starting with pig tissue, but if you’re using only the organ scaffolding and building a working organ from there, pig organs may actually be more desirable than those donated by humans.

How big is the anti-chimerite movement?

Unlike anti-GMO and anti-vaccination activists, there really aren’t too many anti-chemerites around. Nevertheless, there is a presence on the web of people who express concern about mixing of humans and non-human animals. Presently, much of their concern is focussed on the growing of human organs inside non-human animals, pigs included. One anti-chemerite has written that it could be a problem for the following reason:

Once a human organ is grown inside a pig, that pig is no longer fully a pig. And without a doubt, that organ will no longer be a fully human organ after it is grown inside the pig. Those receiving those organs will be allowing human-animal hybrid organs to be implanted into them. Most people would be absolutely shocked to learn some of the things that are currently being done in the name of science.

The blog goes on to express alarm about the use of human genes in rice and from there morphs into an off the shelf garden variety anti-GMO tirade, though with an an anti-chemeric current running through it. The concern about making pigs a little bit human and humans a little bit pig becomes a concern about making rice a little bit human. But the concern about fusing tissues and genes of humans and other species does not fit with the trend in modern medicine.

Utilization of pig tissue enters a new age 

pigsinus

A porcine human ear for xenotransplantation. source: The Scientist

For decades, pig, bovine and other non-human tissues have been used in medicine. People are walking around with pig and cow heart valves. Diabetics used to get a lot of insulin from pigs and cows, although today, thanks to genetic engineering, they’re getting human insulin produced by microorganisms modified genetically to make human insulin, which is safer and more effective.

When it comes to building new organs from old ones, however, pig organs could actually be superior for a couple of reasons. For one thing, there’s no availability problem with pigs. Their hearts and other organs also have all of the crucial components of the extracellular matrix that makes up an organ’s scaffolding. But unlike human organs, the pig organs don’t tend to carry or transfer human diseases. That is a major advantage that makes them ideal starting material. Plus there is another advantage: typically, the hearts of human cadavers are damaged, either because heart disease is what killed the human owner or because resuscitation efforts aimed at restarting the heart of a dying person using electrical jolts and powerful drugs.

Rebuilding an old organ into a new one

How then does the process work? Whether starting with a donated human or pig organ, there are several possible methods. But what they all have in common is that only the scaffolding of the original organ is retained. Just like the engine and transmission of the old car, the working tissue is removed, usually using detergents. One promising technique that has been applied to engineer new hearts is being tested by researchers at the University of Pittsburgh. Detergents pumped into the aorta attached to a donated heart (donated by a human cadaver, or pig or cow). The pressure keeps the aortic valve closed, so the detergents to into the coronary arteries and through the myocardial (heart muscle) and endocardial (lining over the muscle inside the heart chambers) tissue, which thus gets dissolved over the course of days. What’s left is just the stroma tissue, forming a scaffold. But that scaffold has signaling factors that enable embryonic stem cells, or specially programed adult pleuripotent cells to become all of the needed cells for a new heart.

Eventually, 3-D printing technology may reach the point when no donated scaffolding is needed, but that’s not the case quite yet, plus with a pig scaffolding all of the needed signaling factors are there and they work just as well as those in a human heart scaffold. All of this can lead to a scenario, possibly very soon, in which organs are made using off-the-self scaffolding from pig organs, ready to produce a custom-made heart using stem or other cells donated by new organ’s recipient.

David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

And a Great Article in The Scientist by Dr. Ed Yong Entitled

Replacement Parts

To cope with a growing shortage of hearts, livers, and lungs suitable for transplant, some scientists are genetically engineering pigs, while others are growing organs in the lab.

By Ed Yong | August 1, 2012

Source: http://www.the-scientist.com/?articles.view/articleNo/32409/title/Replacement-Parts/

.. where Joseph Vacanti and David Cooper figured that using

“engineered pigs without the a-1,3-galactosyltransferase gene that produces the a-gal residues. In addition, the pigs carry human cell-membrane proteins such as CD55 and CD46 that prevent the host’s complement system from assembling and attacking the foreign cells”

… thereby limiting rejection of the xenotransplated tissue.

In addition to issues related to animal virus transmission the issue of optimal scaffolds for organs as well as the advantages which 3D Printing would have in mass production of organs is discussed:

To Vacanti, artificial scaffolds are the future of organ engineering, and the only way in which organs for transplantation could be mass-produced. “You should be able to make them on demand, with low-cost materials and manufacturing technologies,” he says. That is relatively simple for organs like tracheas or bladders, which are just hollow tubes or sacs. Even though it is far more difficult for the lung or liver, which have complicated structures, Vacanti thinks it will be possible to simulate their architecture with computer models, and fabricate them with modern printing technology. (See “3-D Printing,” The Scientist, July 2012.) “They obey very ordered rules, so you can reduce it down to a series of algorithms, which can help you design them,” he says. But Taylor says that even if the architecture is correct, the scaffold would still need to contain the right surface molecules to guide the growth of any added cells. “It seems a bit of an overkill when nature has already done the work for us,” she says.

Other articles of FDA Guidance and 3D Bio Printing on this Open Access Journal Include:

Read Full Post »