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Regulatory Focus™ > News Articles > 2020 > 5 > Bespoke therapies – opportunities, challenges, and hope

Bespoke therapies – opportunities, challenges, and hope

Posted 29 May 2020 | By Shawn Roach, PhD, RAC 

Bespoke therapies – opportunities, challenges, and hope

This article discusses the advent of bespoke therapies, defined as the tailoring of medical treatment to the individual characteristics or symptoms and responses of a patient during all stages of care and as a new frontier beyond personalized medicine. The author covers the revolutionary genetic tools implementing such therapies and the clinical and nonclinical safety perspectives for bespoke therapies. The author concludes that with bespoke therapies we are entering a new era of highly individualized therapies where traditional paradigms of drug development are being significantly challenged.
Beginning in the mid-1980s and through the last decade, several scientific discoveries have paved the way for ultra-personalized therapeutics. Among these discoveries were the chemical synthesis of oligonucleotides (short bits of DNA and/or RNA), the mapping of the human genome, and the mechanisms of RNA interference (RNAi) and CRISPR (clustered regularly interspace short palindromic repeats) technologies.
Having access to the map of the human genome and powerful genetic tools, such as RNAi and CRISPR, has allowed scientists and healthcare and regulatory professionals to forge a new therapeutic frontier. The first step toward this frontier came with the development of personalized medicines, more commonly referred to as gene therapies. In personalized medicines, a gene known to be the cause of a disease state for a significant population of individuals is targeted for therapeutic intervention. The second step pertained to the development of bespoke therapies, often referred to as the “next chapter” in personalized medicine.
A bespoke therapy is a medical treatment that has been tailored to the specific individual characteristics, symptoms, and responses of a patient during all stages of care. The genetic tools developed in recent years have made these individualized therapies a reality. This approach translates into the treatment of a small patient population suffering from rare or ultra-rare genetic diseases for which the therapeutic agent is designed specifically for an individual.
In March 2020, the FDA held a workshop on the development of individualized therapeutics to connect with the scientific and regulatory communities to better understand the needs, challenges, and opportunities in the bespoke therapies landscape.1 Based on its insights from the workshop, the agency plans to develop guidance to foster progress in the nascent field while recognizing and protecting the rights of the individual patients who will benefit from these therapies.
Traditional models of regulation, clinical trial design, and business development are no longer valid for ultra-personalized therapies. Several questions arise:
  • How does one design a clinical trial around a patient population that is too small for the traditional statistical metrics?
  • How must the traditional model of process validation be adapted when the demand for the therapeutic agent is such a small population?
  • Are there common, nonproprietary bases of knowledge that can be shared to reduce the development costs of these drugs, and therefore the costs to the patients?  
The poignancy of working on bespoke therapeutics is that the patient population is close and personal. These are not tens of thousands of patients but, instead, dozens to hundreds of patients and their families who often are actively involved in the development process. This point was emphasized very eloquently by workshop participants, such as representatives from Phoenix Nest Inc,2 a company founded by the parents of a child with the ultra-rare disease, Sanfilippo syndrome.
The goal of this workshop was to stimulate dialog around the challenges that sponsors working in therapies for ultra-rare diseases face. From these discussions, the FDA intends to develop guidances to address the challenges in the respective areas (chemistry, manufacturing, and controls [CMC], clinical, nonclinical) based on feedback from the industry. In the opening remarks to the workshop, Dr. Peter Marks, the director of the Center for Biologics Evaluation and Research (CBER), provided some points for consideration in addressing some of the manufacturing challenges, including the creation of public/private partnerships to facilitate faster development. Possible opportunities for collaboration included platform manufacturing technologies, which would enable wider access to generating novel therapeutic candidates at a lower cost, and the use of a “templated IND” model that would streamline some of the required documentation (e.g., clinical protocol templates that can be filled in, rather than created from scratch each time). In the meantime, some of the agency’s recommendations on best practices are discussed below.
Chemistry, manufacturing, and controls
Bespoke therapies are biologics, and it is, therefore, more difficult to characterize them fully. It is also challenging to use the traditional paradigm for process validation to demonstrate the means for ensuring quality, safety, and consistency across different batches. Therefore, the FDA recommends using other means, such as procedures to demonstrate consistent control of regulatory starting materials and use of in-process controls, to minimize the risk of introducing adventitious agents into the process. Instituting these controls and following the quality by design principles outlined in by the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use),3 are proposed recommendations for meeting the inherent challenges of characterization and validation.
There should be robust control of the supply chain if these requirements to are to be met. In addition, sponsors working in this therapeutic space should establish procedures early in the process for generating consistent, well-characterized regulatory starting materials and reference standards. In traditional practice, these procedures are put in place in the later stages of development.
A key element for establishing these procedures is the development of a platform suite of robust assays that should be validated early in the development process and can demonstrate batch-to-batch variation or consistency. Demonstration of stability is also essential, and the agency recommends determining a standard formulation and container closure system, early in the process, to minimize variability and allow better comparisons across batches.
The FDA has recognized that these recommendations are exacting, and it is taking a more flexible and open approach to developing and encouraging dialog with sponsors. The agency recognizes there may be limited data on assay development and qualification, but it is open to discussions based on sound scientific principles and available data. The agency is open to more flexible criteria for later-stage development, such as the conditional release of clinical batches in which potency assays that have not been fully validated have been used, and broader acceptance standards for some critical quality attributes.
The agency also recognizes there may be limited lot data for a comparability analysis, which may challenge traditional statistical analysis tools. It is open for discussion on conducting concurrent process validation while maintaining compliance with the requirements for current good manufacturing practice (CGMP) requirements, including control, release, and review procedures.
To summarize, open discussions focusing on data-driven, scientifically grounded facts and well-reasoned arguments are crucial in addressing these challenges and finding the best path forward.
In addition to the above best practices, there are several opportunities for improving the manufacturing processes for bespoke therapies. For example, the adeno-associated virus (AAV) is an important vector for targeting and delivering the therapeutic gene to the site of action. However, there are many ways in which this carrier could be enhanced, such as increasing production of enough high-potency AAV vectors, diminishing pre-existing and adaptive immunity to the transgene, improving the tissue specificity and efficacy, and regulating the expression of the gene therapy to optimize the efficacy. Currently, the average empty-to-full ratio of the vectors is nine empty vectors for every one vector loaded with the therapeutic gene capable of delivering the therapy to the site of action. Potential solutions to meet some of these challenges include improving the process scalability of vector production and using enhanced analytics to better discriminate vectors carrying the therapeutic payload from empty vectors.
There are additional opportunities for advancement besides improving the AAV vector. Those opportunities include better sharing of genetic sequencing data for ultra-rare diseases and determining the best logistics for assuring and inspecting appropriate compliance with GMP at the lab scale, because many of the manufacturing processes for these therapeutics are near, or just above, lab scale. Finally, a metric for bespoke therapies is the demonstration of manufacturing consistency over the course of treatment.
The Platform Vector Gene Therapy (PaVe-GT) project,4 which is led by the National Center for Advancing Translational Sciences, an affiliate of the National Institutes of Health, has been established to address the manufacturing bottlenecks discussed above. It is designed to develop a “tool-box” platform of technologies for the development of gene therapy for rare diseases. It addresses common concerns in gene-therapy manufacturing, such as the scale-up of gene-vector manufacturing and the delivery mechanisms to get the transgene to the right tissue, at the right time and dosage. The PaVe-GT program aims to develop plug-and-produce manufacturing processes for AAV serotypes, a compendium of standard analytical and bioanalytical methods, and common cell-suspension and cell-potentiation technology.
The program is also researching improved delivery devices to transport therapeutic vectors to the central nervous system and to widen the platform of vectors for the delivery of groups of transgenes to targeted tissues. All information developed within this program will be publicly available, with the goal of it being a representative, open-access investigation of a new drug on which sponsors can base their therapeutic programs. It is hoped these efforts will reduce the costs of developing bespoke therapies for rare and ultra-rare diseases.
From a nonclinical and safety perspective, bespoke therapies offer a different set of challenges. Most notable among those challenges is the determination of what comprises sufficient manufacturing and safety information to allow the trial to proceed for a single patient or a small group of patients. Often, in the case of ultra-rare diseases, the patient population is pediatric. In addition, there are often no relevant animal models or species for these types of diseases, which complicates the determination of the dose level, route of administration, and clinical monitoring variables for the therapies. Nonclinical means of addressing these concerns are needed. Bioinformatics and artificial intelligence are gaining traction, but there are concerns about the robustness of the algorithms used to make these determinations because different challenges arise when applying these learnings to traditional clinical trials with humans.
However, as with CMC concerns, there are many opportunities for nonclinical advancement. These include novel in vitro methods that can provide key safety information in the absence of a nonhuman model species, flexibility in ongoing or adaptive trial design, and development of more robust in vivo models.
Collaboration at all practical levels is elemental in taking advantage of these opportunities. Ongoing interactions with regulators are crucial during the development process, such as through FDA’s INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER producTs) program.5 An INTERACT meeting allows sponsors to obtain preliminary, informal advice from the agency at an early stage of the drug development process and ahead of the pre-investigational new drug (IND) meeting, depending on the agency’s available resources. During the INTERACT meeting, both sponsor and the agency agree on a feasible path forward to facilitate the nonclinical program. In addition, opportunities to share precompetitive information on fundamental data in open-access portals will allow sponsors to leverage nonclinical and, ultimately, clinical data, such as data about AAV biodistribution; nonproprietary, platform-specific commercial assays; and common manufacturing assays, which can be publicly available. These measures can facilitate faster translation from the bench to the patient. Key factors that need to be addressed are assay sensitivity to detect manufacturing-related differences that could affect the safety profile of the therapeutic agent and determine the off-target effects of gene therapy.
Just as the paradigms for CMC development and nonclinical safety studies need to change, so do the paradigms for clinical studies and evaluations. Novel approaches are needed to perform efficacy assessments in individual patients and small groups of patients. Dose determination is often a challenge if there are no relevant animal models on which to base starting points. Innovative study designs could maximize leverage of the clinical data. Researchers need to address the establishment of a platform protocol to assess common themes of these treatments, which may signal safety concerns for a given disease treatment, even though each specific treatment is individualized. This platform protocol will enable meta-analytical activities during several different bespoke therapy trials and provide a better understanding of the global development needs for these therapies.
FDA recognizes the need in these development programs for regulatory flexibility and the critical importance of patient-physician interactions to capture and record clinically important data on safety and efficacy. Furthermore, in these individualized trials, there is a much higher expectation that the therapeutic will have an effect. In that context, there is significant opportunity for the development of sophisticated, effective tools that can consistently measure efficacy in single patients.
These opportunities could be in the form of advanced analytical methodologies or advanced computer algorithms to sort out faint signals. Regulatory flexibility is essential because the development plan often will evolve during the trial, depending on the data obtained. For those reasons, collaboration and communication are critical elements of the successful development of these types of therapies. As with nonclinical and CMC aspects, FDA urges the sharing of precompetitive information across platforms. Often, this information will be related to CMC, but novel means of understanding safety or efficacy signals for a given type of therapy, such as common delivery vehicle and means of administration, are important.
Traditional drug development paradigms are being significantly challenged as we enter a new era of highly individualized therapies. As with any new technology, there are opportunities and challenges. A recurring theme in this landscape is the importance of open communication and collaboration between the FDA and sponsors, as well as between academic and biotechnology company sponsors. The best news is that there is hope for patients suffering from rare diseases, where previously there was none.
AAV, adeno-associated virus; CBER, Center for Biologics Evaluation and Research; cGMP, current good manufacturing practice; CMC, chemistry, manufacturing, and controls; CRISPR, clustered regularly interspace short palindromic repeats; FDA, Food and Drug Administration; GMP, good manufacturing practice; NCATS, National Center for Advancing Translational Sciences; NIH, National Institutes of Health; PaVe-GT, Program Platform Vector Gene Therapy; RNAi, RNA interference
  1. FDA Center for Biologics Evaluation and Research. Food and Drug Administration website. Facilitating end-to-end development of individualized therapeutics. Public workshop. https://www.fda.gov/media/137875/download. Presented 3 March 2020. Accessed 22 May 2020.
  2. Phoenix Nest Inc website. http://www.phoenixnestbiotech.com/.
  3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use website. ICH harmonised tripartite guideline pharmaceutical development Q8(R2). https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf. August 2009, Accessed 29 May 2020.
  4.  National Institutes of Health: National Center for Advancing Translational Sciences. PaVe-GT: Paving the way for rare disease gene therapies. https://pave-gt.ncats.nih.gov/. Updated 2020. Accessed 22 May 2020.
  5.  Food and Drug Administration. INTERACT Meetings (Initial Targeted Engagement for Regulatory Advice on CBER products). https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings-initial-targeted-engagement-regulatory-advice-cber-products. Updated 3 May 2020. Accessed 26 May 2019.
About the author
Shawn Roach PhD, RAC, is a consultant with the Halloran Consulting Group. He has more than 19 years’ experience in analytical chemistry and regulatory affairs in the biotech and pharmaceutical industry and has worked in regulatory affairs, with an emphasis in chemistry and manufacturing controls, since 2012. Roach worked for more than a decade in development for nucleic acid-based (oligonucleotide) therapies before entering regulatory affairs. He has a PhD in analytical chemistry and has obtained RAC certification through RAPS. He can be contacted at sroach@hallorancg.com.
Cite as: Roach S. Bespoke therapies – opportunities, challenges, and hope. Regulatory Focus. May 2020. Regulatory Affairs Professionals Society.

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