How to speed up the regulation of gene therapy?

Source: Yao mingkant, May 28, 2018 editor's note: on May 22, 2018, Dr Scott Gottlieb, director of FDA of the United States, delivered a speech on gene therapy at the annual conference of regenerative medicine held in Washington He reviewed the FDA's policy on cell-based regenerative medicine, as well as the planned release of the policy on gene therapy, with special reference to the advanced treatment identification of regenerative medicine (rmat) Dr Gottlieb says gene therapy, which produces lasting effects, is part of a larger regenerative medicine product In the traditional drug review, 80% of the reviews are focused on the clinical part, and 20% will focus on the problems of the product itself This general principle is almost reversed in terms of cell and gene therapy In terms of gene therapy regulation, FDA intends to issue a set of draft guidance documents to clarify the manufacturing and clinical development framework of gene therapy products Here is Dr Gottlieb's full speech Dr Scott Gottlieb, director of FDA, recently delivered a speech on regenerative medicine products and gene therapy (picture source: FDA website) We are at a critical moment of cell and gene therapy These therapies are expected to treat hundreds of rare and common diseases For a long time, gene therapy mainly existed in theory Now, they become reality I expect that gene therapy will soon become the main way to treat various diseases We have reached the turning point of science, opening the door for these application opportunities One of them is the emergence of effective vectors of genes The significance of this breakthrough can be referred to the history of technological progress in the field of monoclonal antibodies The ability to develop fully humanized antibody is a scientific turning point, which promotes antibody to become the main means of drug treatment In this case, product innovation has completely changed the treatment opportunities The same concept applies to gene therapy The emergence of reliable vectors is a turning point in the development of gene therapy and car-t cell therapy But gene therapy also brings new challenges In order to embrace this technological progress and meet these challenges, FDA is conducting applied scientific research on new clinical trial design of cell and gene therapy We are also trying to develop a drug accelerated development plan through the use of all regulatory avenues This includes the use of "breakthrough therapy" identification, as well as the recent identification of advanced therapy in regenerative medicine, also known as rmat (regenerative medicine advanced therapy design) identification As part of the regenerative medicine framework released in November 2017, FDA proposed draft guidance on how to apply rmat certification and other new initiatives to accelerate new product development We will soon release a similar framework to discuss how to address the manufacturing and development of gene therapy products ▲ in the draft framework of Regenerative Medicine released in November 2017, FDA mentioned that it would take five ways to speed up the approval of regenerative medicine products (picture source: FDA website) I want to talk about two things today First of all, I would like to review the policy of cell-based regenerative medicine promoted by FDA last year, which involves the second topic I want to talk about - we plan to release the policy on gene therapy Our regenerative medicine framework, released in November 2017, sets out existing organizational regulations and describes our compliance and oversight policies for these products Our goal is to promote the development and supply of safe and effective regenerative medical products And where necessary, a framework for centralized law enforcement action to ensure that unsafe products are not illegally sold to patients This framework provides impetus and pulling force to achieve these goals It sorts out the conditions to meet the pre market licensing provisions of FDA, and describes the effective ways to develop these products and seek FDA approval According to the FDA, small developers can aggregate their data as long as they follow a common manufacturing protocol This will enable small institutions to more effectively meet the evidentiary requirements of the approval process and provide a way for them to obtain individual product licenses The framework also describes how FDA intends to enforce laws if pre market licensed products are sold illegally and put patients at risk Recently, the FDA sought a permanent injunction from two stem cell clinics to prevent the sale of stem cell products without FDA approval The production of these two stem cell clinics is far from the current GMP requirements The field of regenerative medicine continues to expand, and we are committed to adjusting policies as needed to ensure the changing risks and benefits of the products we are evaluating Since the implementation of the plan in December 2016, as of the end of April this year, a total of 62 rmat certification materials have been submitted, and FDA has issued 19 certification Of the 19 products, 14 were also identified as orphan drugs It shows how the program promotes the development of drugs for rare diseases When it comes to gene therapy, it reminds me of what we are doing Some gene therapies may be in line with rmat's findings Gene therapy, which produces lasting effects, may be part of a larger regenerative medicine product The development of gene therapy is amazing According to a paper published by MIT, based on 930 product lines under development in 2017, about 40 gene therapy products will be approved by FDA by the end of 2022 MIT also predicts that 45% of these approved gene therapies will be used to treat cancer I don't know if their forecast is accurate But I know the trend is right Just last year, we saw approval for the first three gene therapies: two cell-based gene therapies for blood cancer, and a direct gene therapy for hereditary retinal atrophy Gene therapy is moving from promise to reality These recently approved products are just the tip of the iceberg ▲ three kinds of gene therapy approved by FDA (information source: FDA website) FDA has received more than 500 new drug applications (NDA) involving gene therapy products Last year alone, we received more than 100 such applications It fully shows the heat of this research field These are extraordinary developments These products have the potential to cure some of the most difficult genetic diseases These advances bring hope to the general population, such as parents of children with rare metabolic diseases, and people with more common diseases, such as diabetes and heart failure In terms of regulation, in order to make progress in the development of gene therapy, as I mentioned earlier, FDA intends to issue a set of draft guidance documents to clarify the manufacturing and clinical development framework of gene therapy products Many new guidelines will focus on product related issues, but they will also provide recommendations for clinical development in other areas In the traditional drug review, 80% of the approval is focused on the clinical part, and 20% will focus on the problems of the product itself I think this general principle is almost reversed in terms of cell and gene therapy The initial clinical efficacy is often established early, sometimes in a small number of patients The more challenging problem is the product manufacturing and quality control, as well as the problem of change or amplification Before gene insertion, it needs to be placed on a carrier, which will change the conformation of the carrier, thus fundamentally changing the safety or effect of the whole product Another problem is the durability of the response Any pre IPO trial with a reasonable scale often fails to fully answer this question For some products, there will be some uncertainty even at the time of approval But the initial goal of these products is to treat serious diseases, many of which are fatal diseases without treatment Under these circumstances, FDA has been willing to accept more uncertainties to facilitate timely access to promising therapies Through accelerated approval, breakthrough therapy certification or rmat certification, this is the direction given by the U.S Congress to FDA When we adopt these methods to accelerate the development and approval of treatment methods with high potential but uncertain safety or efficacy to achieve unmet clinical needs, we usually follow strict evaluation criteria These therapies require follow-up studies after marketing to answer questions about possible product risks or long-term effectiveness Accelerating approvals helps to achieve this careful balance This gives FDA the opportunity to approve very promising products early in the drug development process, based on alternative indicators that can reasonably predict clinical benefits At the same time, it gives FDA strong authority to conduct post market studies to confirm these effects Therefore, as part of our comprehensive policy framework, we will launch guidance documents that will design potential accelerated approval endpoints for certain gene therapy products Our first area of interest is hemophilia Gene therapy can normalize the production of clotting factors In some cases, the production of clotting factors may be sufficient as an alternative indicator of the benefits of gene therapy In these cases, evidence of reduced bleeding rates can be confirmed after approval as we continue to study the long-term safety and durability of the product We will issue additional guidance documents on specific manufacturing and clinical issues related to gene therapy products By providing developers with manufacturing parameters, safety measures and clinical development path, FDA hopes to promote greater innovation and development in the field of gene therapy Once these draft guidance documents are released, we look forward to your participation in the discussion We value the inclusion of informed stakeholders, such as the Alliance for regenerative medicine The challenges we see related to gene therapy products are problems we can solve through cooperation Although it is possible for gene therapy to treat both common and rare diseases at the same time, it is now more promising for patients with more than 7000 rare diseases Developing products for each of these rare diseases, from less than 100 to more than 10000 patients, is challenging for all of us Obviously, we will use all the existing innovative methods for clinical development, including the use of novel patient-centered endpoints and trial designs In addition, we will use all existing tools as part of the FDA's accelerated development program to facilitate the timely development of safe and effective products, including the use of expanded regulations to obtain confirmation evidence, so as to accelerate the approval of treatment methods through the regenerative medicine provisions of the 21st century cure act ▲ in this regard, the use of registration authorities and real world evidence may play an increasingly important role Therefore, as part of our budget application for fy2019, we are looking for new resources to expand our ability to collect data after the launch of new drugs One of our goals is to establish a system that can monitor the safety of new products in real time after approval ▲ the source of real world evidence published by FDA (picture source: FDA website) although the clinical development of drugs for small population is obviously challenging, there seems to be another greater challenge at present, which is slowing down gene therapy