CHAPTER 9 Applications of Recombinant DNA Technology
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Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. In any area of biomedical research, many scientific and regulatory challenges stand between promising ideas generated from basic research and the approval of a therapeutic product. Among these emerging technologies, gene transfer research, in particular, stands out as a highly regulated area of scientific investigation.
The late s and early s saw the rapid progression of the concepts and technology that led to the first intentional creation of rDNA molecules Berg and Mertz, The RAC was established by then—NIH Director Donald Frederickson in in response to scientific, public, and political concerns about the potential use and misuse of rDNA technologies, as well as the associated and unknown risks described later in this chapter.
In the original formulation of the RAC. These nonscientists, among whom were ethicists, theologians, and university presidents, were to offer a broader public perspective on the emerging technology. Recombinant dna technology ppt 2010 time, RAC membership and responsibilities have evolved in response to scientific developments and public concerns.
Early actions by the RAC included defining certain conditions for recombinant dna technology ppt 2010 awarding of grants for rDNA research pending adoption of more comprehensive guidelines.
The RAC was guided in considerable measure by the conclusions from a second conference at Asilomar in February Berg et al. Those conclusions provided a framework for. The guidelines, first published in Recombinant DNA Research Guidelines, and amended through the years, have provided a comprehensive description of facilities and practices to prevent unintended release of or human exposure to genetically modified organisms and material. Although some officials within what was then recombinant dna technology ppt 2010 Department of Health, Education, and Welfare argued that the guidelines should be issued as formal regulations, in the end they were not.
The guidelines are applicable to all rDNA recombinant dna technology ppt 2010 that is conducted by or sponsored by a public or private institution that receives NIH funding for any such research NIH, a. In addition, many other U.
In the s, after a brush with termination, the RAC shifted into an advisory capacity and initiated the first of many revisions to the NIH Guidelines to ease constraints on rDNA research, including the implementation of an accelerated review process in Rainsbury, During the s, however, as scientists were convening to establish the RAC, public interest and concern, even alarm, about rDNA research.
Both the Senate and the House recombinant dna technology ppt 2010 Representative held hearings in the s and early s. Members of Congress proposed various pieces of legislation that would have replaced the guidelines with regulations, extended the NIH Guidelines to include privately funded research, and created a national commission that would have diminished the role of NIH and scientific experts in overseeing rDNA investigations.
Ultimately, no legislation along these lines emerged. The controversy surrounding rDNA research recombinant dna technology ppt 2010 not eased in by the discovery that an U. The investigator was later censured for misleading foreign regulators and barred from NIH funding Rainsbury, Parties outside Congress also called for modifications in the public oversight of rDNA research. The report reviewed public concerns and moral issues in genetic engineering and made recommendations for greater oversight related recombinant dna technology ppt 2010 ethical issues in gene therapy.
Two years later, the congressional Office of Technology Assessment concluded that existing oversight procedures were adequate for cell therapy that does not create changes that can be inherited OTA, The guidance, which was revised after public comment and later integrated into the NIH Guidelines, identified more than questions that covered both scientific and ethical aspects of protocols.
This oversight framework was in place well before the first protocols for human trials were submitted. The first protocol approved by recombinant dna technology ppt 2010 RAC in involved a gene marker study. The second approved protocol involved a test of gene transfer for severe combined immunodeficiency SCID Wolf et al.
Initially, the RAC through a subcommittee reviewed all gene transfer research protocols. As the amount of research accelerated in the early s, however, and a large number of similar protocols came under review, the review process became strained, which, in turn, increased criticism of the process.
Among other responses including attempts to expedite the review processNIH and FDA agreed in that NIH would limit its public reviews to novel protocols, while FDA would assume primary responsibility recombinant dna technology ppt 2010 reviewing gene therapy protocols Rainsbury, ; Wolf et al.
FDA first asserted a role in the oversight of gene therapy products—and therefore the research undertaken to develop such products—in Wolf recombinant dna technology ppt 2010 al. The agency began to assert a greater role in regulation of gene therapy products in Statement of policy for regulating biotechnology products,and inNIH and FDA agreed that primary regulatory responsibility for review of gene therapy protocols would rest with FDA Rainsbury, ; Wolf et al.
As a result, the RAC became an advisory body. ByFDA had reviewed hundreds of clinical research proposals involving somatic cell and gene transfer technologies Kessler et al. Sincetables of adverse event reports from gene transfer trials have been posted with the RAC meeting minutes. The summary descriptions vary significantly in the extent to which they include specific statements about the likelihood that a reported event can be linked to the gene transfer procedure.
Inrecombinant dna technology ppt 2010 ad hoc committee appointed by the director of NIH to advise on the future role of the RAC concluded that gene transfer research was different enough from other research to deserve continued public scrutiny. The committee concluded that the RAC should, however, no longer review every protocol; rather, its reviews should focus on protocols raising special concerns e. Although the RAC thus became an advisory body, NIH still required and continues to require that NIH-supported investigators submit gene transfer protocols for advisory review.
Concern about the conduct of gene transfer trials reached a new level of intensity after the death of Jesse Gelsinger in Congress again held hearings on rDNA oversight but did not act further Rainsbury, InNIH shifted the timing of the public reviews undertaken by the RAC so that they would occur before, rather than after, protocol re. Today, the RAC has responsibilities in addition to its advisory role in reviewing gene transfer protocols. In recent years, OBA has sponsored or cosponsored meetings on gene transfer and rare diseases, vector and trial design challenges in studying retroviral and lentiviral vectors for long-term gene correction, challenges in trial design in research with gene-modified T cells, and future directions for gene therapy NIH, Within the entire gene transfer research oversight system, the RAC is the only oversight or regulatory body that provides a public venue for the review of a protocol.
Therefore, gene transfer protocols are one of very few areas of emerging human subjects research that receive additional oversight, and the only area for which that review occurs through an additional oversight body—even though, as previously discussed, its risk portfolio.
In order to comply with FACA regulations, the RAC must have open meetings with advance notice of the time and place, provide detailed transcripts, and allow public participation at meetings Steinbrook, Thus, the RAC is an advisory body with oversight defined in NIH guidelines that require NIH-supported researchers and institutions to submit gene transfer protocols for advisory review.
A majority of the 21 voting members must have expertise in relevant scientific fields, such as molecular genetics, molecular biology, and rDNA research, including clinical gene transfer research. Further, at least four voting members must have expert knowledge in fields dealing with public health and safety, such as human subjects protection, environmental safety, ethics, and law.
Terms for the chair and committee members, who are appointed by the director of NIH, are 4 years. The RAC meets in person quarterly in an open forum, with a webcast of the full meeting and the meeting transcript later posted online. The RAC also may form ad hoc working groups, and recombinant dna technology ppt 2010 it has several. For example, the Gene Transfer Safety Assessment Board consists of clinical members of the RAC who meet quarterly to review all serious adverse events that may possibly be trial-related as well as summaries of more than amendments and annual reports filed on active protocols Corrigan-Curay, The safety board reviews safety information from gene transfer trials for the purpose of assessing toxicity and safety data across trials and identifying significant trends or single events, and it reports such findings and aggregated trend data to the full RAC Corrigan-Curay, ; NIH, c.
The RAC also continues to sponsor public symposia on important scientific and policy questions related to rDNA research Friedmann et al. In this way, the RAC serves as an important mechanism for scientific debate, informing institution-level oversight, increasing transparency, and promoting public trust and confidence in the field of gene transfer.
One criticism of RAC oversight is that it does not apply to privately funded research. Private institutions, however, often voluntarily submit protocols and comply with NIH guidelines Corrigan-Curay,in part because any NIH-funded institution involved in gene therapy clinical trials needs RAC approval. Public review of protocols is intended to achieve two purposes: The guidelines stipulate that the RAC will not accept either clinical research protocols involving germ-line modification or procedures involving in utero gene transfer.
This means, in practice, that NIH does not fund these lines of clinical research. After an investigator submits a protocol, including responses to the recombinant dna technology ppt 2010 listed in Appendix M, OBA sends a summary to the RAC members for an initial review.
During this preliminary review, the individual RAC members may request additional information or clarification or make specific comments or suggestions about the protocol design, recombinant dna technology ppt 2010 informed-consent document, or other matters. Based on the materials submitted by the investigator, including responses to Recombinant dna technology ppt 2010 M, only a subset of submitted protocols recombinant dna technology ppt 2010 selected for additional review by the RAC in its public forum see Figure Currently, the guidelines state that the RAC reviewers should.
Other factors recombinant dna technology ppt 2010 may warrant public review and discussion of a human gene. All comments by the RAC members are conveyed to the investigator NIH, aand within 15 days of submission of the protocol, the investigator is notified as to whether the protocol has been selected for public review and discussion by the RAC. The in-depth, public review of a protocol may occur when either 1 the OBA director initiates a review following recommendations from at least three RAC members current practice is at least five votes personal communication, J.
Prior to a scheduled public review, RAC members and sometimes ad hoc members chosen for their expertise in the field pose a series of questions in writing to the investigator about the gene transfer protocol. At the meeting, the investigator responsible for the design and conduct of the trial makes a to minute presentation about the gene transfer protocol.
The investigator will often bring colleagues to the meeting to help answer questions from recombinant dna technology ppt 2010 RAC members.
The current process is highly transparent. The OBA website posts protocols that are to undergo public review, and the recombinant dna technology ppt 2010 themselves are made available to members of the public upon request OBA, However, according to OBA, in the past decade, there has been a decreasing emphasis on individual protocol review by the RAC; the percentage of protocols selected for public review dropped from percent in to 37 percent in to 20 percent in Corrigan-Curay, There are policy exemptions in place for certain types of human gene transfer protocols that are exempt from the RAC review.
Appendix M Section VI-A of the NIH Guidelines details exemption for protocols for certain gene transfer vaccines against infectious diseases, specifically, those using plasmids and other vectors that usually do not persist e. The RAC does, however, review vaccine protocols that include a recombinant or synthetic construct that is not a microbial antigen, such as a gene to express a cytokine. It also reviews cancer vaccines for which the goal is not an immune response to a microbial antigen NIH, a.
The RAC process of public review is defined as complete when, after the public review, the investigator receives a letter summarizing the RAC findings. Minutes of the RAC meetings and webcasts of the meetings are made available on the public website. A protocol must be approved by the relevant IBC s and IRB s before research participants can be enrolled in a clinical trial.
FDA, the agency responsible for regulatory approval, considers the RAC recommendations as a basis for review decisions in its investigational new drug IND application process described later in this chapter Takefman, In addition to the RAC oversight, gene transfer research faces several layers of federal and local oversight and regulations, which are required to initiate clinical gene transfer research protocols. This section also describes the relationship of each oversight body to the RAC and the timing of the work of each in cases where this is dictated —relationships that are important for assessing continuing need for the level and type of oversight currently provided by the RAC.
Although NIH provides funding for gene transfer research and has broad authority to oversee research involving rDNA and therefore gene. An unapproved drug or, in this case, an unapproved gene therapy product, must undergo FDA review as an IND prior to human use. A key purpose of IND review is to ensure the safety and rights of subjects. The purpose of reviews of phase II and III clinical trials specifically is to help ensure that the quality of the scientific evaluation is adequate to permit determination of drug efficacy and safety.
To date, none of the INDs has progressed to approval for marketing. CBER regulates cellular transfer products, human gene therapy products, and certain devices related to cell and gene transfer. The general types of gene therapy products that Recombinant dna technology ppt 2010 has reviewed to date are non-viral vectors plasmidsreplication-deficient viral vectors e.
According to a statement by Jay Siegel to the U. FDA recombinant dna technology ppt 2010 maintains a federal advisory committee, the Cellular, Tissue and Gene Therapies Advisory Committee, which reviews and evaluates available data related to the safety, effectiveness, and appropriate use of human cells, human tissues, gene transfer therapies, and xenotransplantation products that are intended for transplantation, implantation, infusion, and transfer in the prevention and treatment of a broad spectrum of human diseases and in the reconstruction, repair, or replacement of tissues for various conditions Statement of policy for regulating biotechnology products, Although several gene transfer products have progressed to late-stage trials, FDA has not yet approved any gene transfer product for marketing.
When it does, the agency will post on its website key documents summarizing the findings of its assessments of the recombinant dna technology ppt 2010 submitted by sponsors.
