Institutional Considerations for Human Gene Transfer Research and Institutional Biosafety Committees (IBCs): An Introduction

Transcription

1 Institutional Considerations for Human Gene Transfer Research and Institutional Biosafety Committees (IBCs): An Introduction Daniel Eisenman, PhD, RBP, SM(NRCM), CBSP Director of Biosafety Service, Advarra

2 Conflict of Interest Disclosure The presenter is employed by a for-profit company. Daniel Eisenman, PhD, RBP, SM(NRCM), CBSP Director of Biosafety Services, Advarra

3 About the Presenter Daniel Eisenman, PhD, RBP, SM(NRCM), CBSP Director of Biosafety Services, ADVARRA PhD in molecular biology and immunology Certified Biological Safety Professional, American Biological Safety Association Specialist Microbiologist in Biological Safety, National Registry of Certified Microbiologists, American Society for Microbiology Over a decade of experience in biosafety program management Experienced educator and presenter in the fields of biological safety, genetic engineering, immunology and infectious diseases Previously ran the Institutional Biosafety Committee program at UNC Chapel Hill Also served as Alternate Responsible Official for select agents and Institutional Contact for Dual Use Research

4 Agenda I. Introduction to Genetic Engineering, Gene Therapy Research and IBCs 1. What is an Institutional Biosafety Committee (IBC)? 2. What is Human Gene Transfer (HGT)? Why Should I Care? 3. Introduction to Recombinant DNA 4. Recombinant DNA in Clinical Trials II. Regulatory Oversight of Gene Therapy Research 5. Oversight of Recombinant DNA Research 6. Overlap & Communication Between the IBC & IRB 7. Guidance for Preparing for IBC Review 8. The Evolving Regulatory Environment in the U.S.

5 1. What Is an Institutional Biosafety Committee (IBC)?

6 Institutional Biosafety Committee (IBC) VS. Institutional Review Board (IRB) Both Committees focus on risk. While IRBs focus on risks to human research subjects, IBCs focus on risks posed by genetically modified materials to study personnel, the community and the environment. IBCs MUST: Ensure compliance with NIH Guidelines Be comprised of at least 5 members who collectively possess the expertise to assess the risks for the proposed research Local component: membership must include two community members for each site who are not associated with the site or the study.

7 NIH Guidelines: Mandating Risk Assessment Ensure adequate risk assessment for the proposed research Containment levels specified in NIH Guidelines, elaborated on in Biosafety in Microbiological and Biomedical Laboratories (BMBL) Adequacy of: Facilities, Safety equipment Personal protective equipment (PPE) SOPs Training Waste Disposal Practices Inspection Post approval monitoring Annual Safety reports Incident reports

8 What is The Connection Between Recombinant DNA and IBCs? Recombinant DNA: Engineered genetic material. The product of genetic engineering. The National Institutes of Health (NIH) provides oversight of federally funded research involving recombinant DNA under NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). Research involving recombinant DNA that is performed with *federal funds or at sites that receive NIH funding must be reviewed by an Institutional Biosafety Committee (IBC). *Includes the development of the IP Even if the NIH does not fund the study: IBC review is required at sites / institutions that have received any NIH funds. If no NIH funding is involved, IBC review is recommended by the NIH (NIH Guidelines Section IV-D-1) and considered a best practice

9 2. What Is Human Gene Transfer? Why Should I Care?

10 What Is Human Gene Transfer? Human gene transfer involves delivering genetic material to humans with the goal of compensating for genetic mutations, conferring the capability to produce potentially therapeutic substances, or eliciting immune responses to fight disease Oftentimes this research utilizes viral vector based gene delivery to create genetically modified investigational products The investigational products may be infectious

11 What Is Human Gene Transfer? NIH Guidelines: Section III-C-1. Experiments Involving the Deliberate Transfer of Recombinant or Synthetic Nucleic Acid Molecules, or DNA or RNA derived from Recombinant or Synthetic Nucleic Acid Molecules, into one or more Human Research Participants Human gene transfer is the deliberate transfer into human research participants of either: 1. Recombinant nucleic acid molecules, or DNA or RNA derived from recombinant nucleic acid molecules, or 2. Synthetic nucleic acid molecules, or DNA or RNA derived from synthetic nucleic acid molecules, that meet any one of the following criteria: a. Contain more than 100 nucleotides b. Possess biological properties that enable integration into the genome (e.g., cis elements involved in integration) c. Have the potential to replicate in a cell d. Can be translated or transcribed

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13 Use of Recombinant & Synthetic Nucleic Acid Molecules in Clinical Trials To date, over 2,400* clinical trials have been initiated involving human gene transfer (HGT). HGT studies typically require IRB and IBC approval as well as registration with the NIH (based on NIH funding to study, site or institution). According to clinicaltrials.gov, there are 186 gene therapy trials currently enrolling participants. Recombinant DNA has been utilized in clinical trials for various disease indications. Approximately 2/3 of HGT studies involve oncology research*. Indications Addressed by Gene Therapy Clinical Trials Cancer diseases 64.6% (n=1590) Monogenic diseases 10.5% (n=259) Infectious diseases 7.4% (n=182) Cardiovascular disesases 7.4% (n=178) Neurological diseases 1.8% (n=45) Ocular diseases 1.4% (n=34) Inflammatory diseases 0.6% (n=14) Other diseases 2.3% (n=56) Gene marking 2% (n=50) Healthy volunteers 2.2% (n=54) *The Journal of Gene Medicine: Gene Therapy Clinical Trials Worldwide (accessed 7/16/17)

14 Use of Recombinant & Synthetic Nucleic Acid Molecules in Clinical Trials Most HGT trials take place in the U.S. and Europe Marketing approval issued for gene therapy products in China, Europe, the U.S. and S. Korea Advances in various technologies are making such studies more common: Human genome project/genomics Genetic engineering Synthetic biology Increased trend for tech transfer and startups originating from Academia Geographical Distribution of Gene Therapy Clinical Trials (by Continent) Multi-country 4.1% (n=102) America 64.4% (n=1587) Europe 23.7% (n=584) Asia 6.1% (n=150) Australasia 1.4% (n=34) Africa 0.2% (n=6) *The Journal of Gene Medicine: Gene Therapy Clinical Trials Worldwide (accessed 7/16/17)

15 Recent FDA Approvals: Gene Therapy Is No Longer Science Fiction FDA approval of gene therapies are a recent phenomenon: Name Manufacturer Indication Recombinant DNA Approval Date IMLYGIC Amgen Melanoma Herpes simplex virus 1 based Oncolytic Therapy VAXCHORA PaxVax Cholera vaccine (serogroup O1) KYMRIAH Novartis B Cell Acute Lymphoblastic Leukemia YESCARTA Kite (Gilead) Non Hodgkins Lymphoma LUXTURNA Spark Therapeutics Retinitis Pigmentosa Live, attenuated, orally administered V. cholerae bacteria, cholera toxin A gene (ctxa) deleted Chimeric Antigen Receptor (CAR) T Cells Chimeric Antigen Receptor (CAR) T Cells October 2015 June 2016 August 2017 October 2017 AAV vector delivering RPE65 December 2017

16 The RMAT Designation for Expedited Review The 21 st Century Cures Act created a Regenerative Medicine and Advanced Therapies (RMAT) designation to facilitate expedited review by the FDA. a. The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations; b. The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and c. Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition Source: U.S. FDA, Vaccines, Blood and Biologics Regenerative Medicine Advanced Therapy Designation

17 3. Introduction to Recombinant DNA

18 Humans are made of cells. Brain cells Liver cells Heart muscle cell Intestinal cells Blood cells Sources: istock.com/katrinaelena; istock.com/ttsz When cells malfunction, disease can result.

19 If a cell is a factory. Source: istock.com/microolga Source: istock.com/maksymka Source: istock.com/bugphai DNA Blueprints to all proteins made by the cell Proteins Perform cellular functions or work

20 Gene: a piece of DNA that contains the information necessary to create a protein product with a particular function

21 Manipulating DNA allows us to create useful drugs and potential therapies. Before the development of modern recombinant DNA technology: Not human Not pure Potentially contaminated with animal pathogens Source: Smithsonian Institute

22 Paraphrasing NIH s Definition of Recombinant DNA Molecules that are constructed outside living cells by joining natural or synthetic genetic material that can replicate in a living cell. Insert: Piece of DNA that codes for the desired protein product Vector Vehicle for delivering DNA to cells Recombinant DNA

23 Recombinant DNA Replicates Once Inside Living Organisms Bacterial Cell Daughter Cells New copies of the Recombinant DNA from the Parent Cell are inherited by the Bacterial Clones Daughter Cells Each cell containing rdna can make the protein coded by the insert

24 Manipulating DNA Allows Us To Create Therapeutic Substances Insulin Producing Bacteria Recombinant DNA Source: Smithsonian Institute Source: By Gardasil_vaccine_and_box.jpg: Jan derivative work: Photohound (talk) - Gardasil_vaccine_and_box.jpg, CC BY-SA 2.0,

25 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules What Are Synthetic Nucleic Acids? ATCGAATT Chemically Synthesized Common uses include genome editing technology in viral vectors (e.g., TALEN, ZFN, CRISPR) Bind to genetic material or reproduce Disease Causing Mutation

26 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules What Are Synthetic Nucleic Acids? ATCGAATT Chemically Synthesized Bind to genetic material or reproduce Common uses include genome editing technology in viral vectors (e.g., TALEN, ZFN, CRISPR) Source: istock.com/lvcandy Disease Causing Gene removed or replaced

27 4. Recombinant DNA in Clinical Trials

28 Commonly utilized strategies in oncology research require delivery of recombinant DNA to study subjects. Reprogrammed immune cells Cancer vaccines Oncolytics: Reprogramming viruses to kill cancer Sources: istock.com/somersault18:24; istock.com/rtimages; istock.com/rost-9d; istock.com/ttsz

29 Reprogrammed Immune Cells Blood has a mixed population of immune cells called T cells, with the ability to kill cells that may be infected, foreign transplants or cancer Genetic reprogramming allows the T cells to pursue the same target Each color represents a T cell with a different target to kill Returned to Donor Sources: istock.com/somersault18:24; istock.com/jull1491

30 Chimeric Antigen Receptor T cells Killing Cancer Cells Green cells: Live cancer cells Red cells: Dead cancer cells Name Manufacturer Indication Recombinant DNA FDA Approval Date KYMRIAH Novartis B Cell Acute Lymphoblastic Leukemia Chimeric Antigen Receptor (CAR) T Cells August 2017 YESCARTA Kite (Gilead) Non Hodgkins Lymphoma Chimeric Antigen Receptor (CAR) T Cells October 2017

31 Cancer Vaccines Cell-Based Cancer Vaccine Viral Cancer Vaccines

32 Oncolytics: Reprogrammed Viruses to Kill Cancer

33 Oncolytics: Reprogrammed Viruses to Kill Cancer Herpes Virus! Imlygic, Amgen FDA Approval October 2015 Melanoma Sources: istock.com/ttsz; istock.com/somersault18:24

34 Looking to Nature for Better DNA Delivery Vehicles Recombinant DNA

35 Viral Life Cycle Attachment Release of Viral Particles (cell death) Infection (transmission of genetic material) Assembly of Viral Particles Production of Viral Components Sources: istock.com/rtimages; istock.com/rost-9d

36 Viral Life Cycle Attachment Release of Viral Particles (Cell Death) DNA loaded syringe Infection (transmission of genetic material) Assembly of Viral Particles Production of Viral Components Sources: istock.com/rtimages; istock.com/rost-9d

37 Viral Vectors: A Genetic Syringe Virus vectors easily introduce genetic material into target cells during infection. Disease-causing genes are removed and replaced with genes of interest. DNA loaded syringe Sources: istock.com/rtimages; istock.com/rost-9d

38 Viruses Are Diverse! Several animal virus families possessing varying properties, uses and risks Diverse risks lead to diverse possibilities for toxicities

39 Retrovirus Retrovirus Retrovirus Genes Host Cell Integration into host genome Host DNA

40 Severe Combined Immunodeficiency (SCID): The Boy in the Bubble David Vetter required an isolator to prevent exposure to microorganisms until a bone marrow transplant could be performed. Source: Baylor College of Medicine Archives Bone Marrow White Blood (Immune) Cell Mutated Gene Immune Response Against Infection

41 Serious Adverse Events and Lessons Learned SCID patient bone marrow was harvested and normal copies of the mutated gene were delivered via a retrovirus. Donors received autologous grafts. (9 of 11) Participants developed fully functional immune systems. Source: Michael Stephens/PA Archive/PA Images Rhys Evans became the first SCID patient to receive genetically modified bone marrow. Strimvelis (GSK) approved for use in Europe to treat ADA-SCID. Only the second gene therapy approved in Europe. Unintended Consequences? 3 children developed leukemia Trial suspended Other trials found similar SAE Corrective Action Vectors redesigned for safety Interventionary contingencies Informed consent modified Long term follow up for delayed adverse events Nat Biotechnol Mar;21(3):217.

42 Serious Adverse Events and Lessons Learned Gene Therapy Death Prompts Review of Adenovirus Vector Source: istock.com/ttsz Jesse Gelsinger ( ) Was not fully informed of potential hazards Died as a direct result of an acute immune response to high dose adenovirus based viral vector injected into the liver Investigator did not disclose conflict of interest Halted clinical trials at the University of Pennsylvania Altered guidance for consent language and safety monitoring Science 17 December 1999: Vol. 286 no pp

43 Pox Viruses: The Higher End of Risk for Viral Vectors in Clinical Trials Pox viruses: related to smallpox Source: By Dr Graham Beards at en.wikipedia, CC BY-SA 4.0, NOT related to chicken pox, which is a herpes virus Several species and strains with various degrees of risk Vaccinia (smallpox vaccine) Potent stimulators of immune responses Used in vaccination studies Usually replication competent (capable of spread) Transmitted by needle sticks, contact with broken skin or mucus membranes

44 Pox Viruses: The Higher End of Risk for Viral Vectors in Clinical Trials Shed from Inoculation Site Protect with bandage Dispose of properly Avoid contact with others At increased risk: Immune compromised individuals, children, elderly, pregnant women and people with conditions affecting the integrity of the skin. Based on the type of pox virus and procedures, vaccination of study personnel may be recommended. Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP)

45 Post Vaccination Transmission of Vaccinia CDC. Secondary and tertiary transfer of vaccinia virus among U.S. military personnel United States and worldwide, MMWR 2004;53: CDC. Vulvar vaccinia infection after sexual contact with a military smallpox vaccinee Alaska, MMWR 2007;56: CDC. Vaccinia virus infection after sexual contact with a military smallpox vaccinee Washington, MMWR 2010;59: Hughes CM, Blythe D, Reddy R, et al. Vaccinia virus infections in martial arts gym, Maryland, USA, Emerg Infect Dis 2011;17: Young GE, Hidalgo DM, Sullivan-Frohm A, et al. Secondary and tertiary transmission of vaccinia virus from US military service member. Emerg Infect Dis 2011;17:

46 5. Oversight of Recombinant DNA Research

47 Structure of Oversight for Recombinant DNA Research NIH OSP NIH Guidelines RAC National perspective IBC Local oversight

48 Recombinant DNA Advisory Committee (RAC) Provides advice to the NIH Director on the conduct and oversight of research involving recombinant DNA Comprised of up to 21 voting members with expertise in: Recombinant DNA and human gene transfer Public health Laboratory safety Occupational safety and health Protection of human subjects Environmental protection Etc. Meets quarterly Materials must be submitted 8 weeks in advance PI must present study to the RAC

49 Overlap & Communication Between IBC & IRB: NIH RAC Determinations The April 2016 version of NIH Guidelines require the IBC and IRB to determine whether HGT studies at the initial site should undergo review by the NIH Recombinant DNA Advisory Committee (RAC) RAC Meets quarterly Materials must be submitted 8 weeks in advance PI must present study to the RAC

50 Overlap & Communication Between IBC & IRB Criteria for determining whether to recommend RAC review i. The protocol uses a new vector, genetic material, or delivery methodology that represents a first-inhuman experience, thus presenting an unknown risk OR ii. The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value OR iii. The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies involved in the review at an initial site(s) to evaluate the protocol rigorously OR iv. The protocol otherwise raises significant scientific, societal, or ethical concerns

51 Institutional Biosafety Committee (IBC) VS. Institutional Review Board (IRB) Both Committees focus on risk. While IRBs focus on risks to human research subjects, IBCs focus on risks posed by genetically modified materials to study personnel, the community and the environment. IBCs MUST: Ensure compliance with NIH Guidelines Be comprised of at least 5 members who collectively possess the expertise to assess the risks for the proposed research Local component: membership must include two community members for each site who are not associated with the site or the study.

52 NIH Guidelines: Mandating Risk Assessment Ensure adequate risk assessment for the proposed research Containment levels specified in NIH Guidelines, elaborated on in Biosafety in Microbiological and Biomedical Laboratories (BMBL) Adequacy of: Facilities, Safety equipment Personal protective equipment (PPE) SOPs Training Waste Disposal Practices Inspection Post approval monitoring Annual Safety reports Incident reports

53 How to Conduct a Risk Assessment for HGT Predictable Adverse Events Mutagenicity Carcinogenicity Teratogenicity Toxicity Risk to Public Health/Environment Biodistribution, Route of transmission Environmental stability, waste disposal Risk Assessment Exposure to Health Care Workers Horizontal Transmission Transmission from person to person Biodistribution Route of transmission (entry/exit) Participant training/safety precautions Vertical Transmission Infection of germline cells (sperm/ovaries) Transmission to offspring

54 6. Overlap & Communication Between the IBC & IRB

55 IBC Expertise & Membership When Conducting an HGT Clinical Trial Appropriate IBC expertise NIH Guidelines specify the committee must possess adequate expertise and training to review the proposed research Committees focused on laboratory, animal or plant research may lack adequate expertise to review HGT Beyond HGT experts on the IBC, input may be elicited from: - Occupational Health - Pharmacy - Nursing - Infection Control - Research Compliance

56 Overlap & Communication Between IBC & IRB: NIH RAC Determinations The April 2016 version of NIH Guidelines require the IBC and IRB to determine whether HGT studies at the initial site should undergo review by the NIH Recombinant DNA Advisory Committee (RAC) RAC Meets quarterly Materials must be submitted 8 weeks in advance PI must present study to the RAC

57 Overlap & Communication Between IBC & IRB: Which Review Goes First? Order of Review Pros Cons IBC before IRB IBC can serve as gatekeeper for RAC review determinations for HGT studies at the initial site The IRB can also elect to defer RAC determinations to the IBC The IBC can provide comments on the Informed Consent and other documents before the IRB review Potential delay to initiating the IRB review IRB before IBC IRB review initiated without delay Potentially lengthiest delays to study initiation due to: IBC review may require protocol or ICFlevel changes requiring IRB re-review IRB may miss RAC determinations Parallel Most efficient if IBC can keep up with the IRB HGT review procedures and reviewers should already be in place Requires communication and collaboration in real time IBC must be ready to minimize delays

58 Overlap & Communication Between IBC & IRB: Informed Consent The IBC may request changes to the informed consent The informed consent should reference: The investigational product contains engineered genetic material, may be a GMO Risks pertaining to the recombinant/synthetic nucleic acids (insert, vector, etc.) Biodistribution, caring for the inoculation site and risks to others - Casual contacts - Sexual partners - Immune compromised individuals - Children

59 Overlap & Communication Between IBC & IRB: Post-Approval Reporting Requirements Incident report: NIH Guidelines Appendix G-II-B-2-k Spills and accidents which result in overt exposures to organisms containing recombinant or synthetic nucleic acid molecules Annual report: Safety report: NIH Guidelines Appendix M-I-C-3 (a) Clinical trial information (b) Progress report and data analysis (c) Updated protocol and technical abstract NIH Guidelines Appendix M-I-C-4 (1) Any serious adverse event that is both unexpected and associated with the use of the gene transfer product (2) Any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity

60 6. Guidance for Preparing for IBC Review

61 Guidance for Submitting Applications for IBC Review Be proactive in contacting the site s IBC / Biosafety office. Consider utilizing a central IRB with an associated IBC service if your site lacks an IBC or the requisite expertise. Become familiar with the site s existing policies / procedures for: IBC review Handling infectious agents Biohazardous waste disposal The site s PI will be ultimately responsible for all research activities. Can delegate tasks (NOT responsibility) to a study coordinator / Sub Investigator

62 Guidance for Preparing Site Personnel Identify key study personnel at the site and prepare them for their duties. Roles involving the recombinant DNA: Shipping / receiving Storage Dispensing Transport Agent administration Waste disposal Review / prepare training and SOPs Review the Exposure Control Plan and infectious waste disposal procedures Walk through the steps in using the agent to ensure potential safety issues are identified and addressed. Consider facility issues and personnel training.

63 Guidance for Preparing Site Personnel Potential Issues to Identify During Walkthroughs: Limiting access: How many people have access to the areas where the recombinant DNA is stored or utilized? When the agent is manipulated, access should be restricted to minimize the number of people that could be exposed. Transport: Will the recombinant material need to be transported from the areas of storage, dispensing, use and disposal? Utilize sealed, leakproof and labeled secondary transport containers. Spills and work surface decontamination: Biologicals require disinfection with a specified contact time rather than a rinse with soap and water. Review spill response procedures. Limiting access #2: How do you mitigate the risk of exposure from spills to other patients or family in shared infusion suites? When the agent is manipulated, access should be restricted to minimize the number of people that could be exposed.

64 7. The Evolving Regulatory Environment in the US

65 NIH Single IRB Policy & Change to Common Rule Require Single IRB Review NIH Single IRB Policy for Multi-Site Research Applicable to: Domestic sites Funded by the NIH Conducting the same protocol involving non-exempt human subjects Applicants expected to include a plan for the use of a single IRB in their grant applications and contract proposals submitted to the NIH for due dates on or after January 25, 2018 Revision to the Common Rule: Single IRB-of-Record (sirb) IRB oversight for most federally funded collaborative research projects located in the US will be required to use a single IRB starting January 20, 2020

66 Strategies for Handling Federally Funded Multi-Site HGT Studies How do we accommodate? NIH Single IRB policy and the upcoming changes to the Common Rule requiring multi-site studies to utilize single IRBs? NIH Guidelines focus on local IBC oversight? Added burden of RAC determinations placed on IBCs and IRBs at initial study sites for HGT studies?

67 Strategies for Handling Federally Funded Multi-Site HGT Studies 1. Utilize a single IRB from an institution with the bandwidth to service additional sites Select an institution with an IBC and IRB capable of handling RAC reviews Creation of a consortium of IRBs This approach minimizes or eliminates crosstalk between the additional sites IBCs and the single IRB Some sites may lack IBCs or the expertise to review HGT studies 2. Utilize a commercial IRB with an associated IBC service Standardization of IBC forms, policies and procedures across sites/institutions to minimize turnaround times HGT expertise readily available for all sites Maintains crosstalk between the single IRB and all sites utilizing the IBC service

68 Questions? Daniel Eisenman, PhD, RBP, SM(NRCM), CBSP Director of Biosafety Service, Advarra