Successful late-stage clinical oligonucleotide therapeutic trials could mark the maturation of a new drug development platform, but the path to commercialization is not without hurdles.

Cold Spring Harbor Laboratory molecular geneticist Adrian Krainer was at a National Institutes of Health workshop in 1999 when he first learned about the crippling neurodegenerative disease spinal muscular atrophy (SMA)—the leading genetic cause of death in infants. The disease has no treatment, and more than 90 percent of infants born with SMA die before the age of two. At the workshop, Krainer recalls, researchers presented their findings on two genes associated with the disease, SMN1 and a duplicate gene, SMN2, both coding for survival motor neuron (SMN) protein, an essential component in the production of spinal motor neurons.

Despite the apparent similarity of the genes, SMA researcher Christian Lorson, then of Tufts University School of Medicine in Boston, and colleagues had found that a single nucleotide difference was causing the RNA transcripts of each gene to be processed differently, Krainer says. While SMN1—which is usually absent or defective in SMA sufferers—produces functional protein, SMN2 contains a mutation that causes exon 7 to be regularly left out of the transcript during splicing. The resulting messenger RNA (mRNA) is unstable and quickly degraded, resulting in low levels of SMN.  Continue Reading

By Tracy TreDenick, Head of Regulatory and Quality, and Senior Consultant, and Julie Spyrison Associate Director, Regulatory Operations at BioTechLogic, Inc.

The global biopharmaceutical market is expected to grow at a compound annual growth rate (CAGR) of 9.4% from 2014 to 2020, reaching $278 billion in revenue by the end of this six-year period. Growth is being driven by numerous factors: such as aging populations in most of the Western world and an increased prevalence of chronic disease. However, likely the most important contributor to growth is biopharmaceutical drugs’ superior effectiveness in treating many disease states, including treating conditions for which there were previously few effective drug treatment options available.

Given the growth of the biopharmaceutical segment, and biopharmaceuticals’ ability to more precisely treat many disease states, the industry needs to become increasingly better at managing biopharmaceutical projects in order for more treatment options to become available to patient populations.

The objective of any project management pursuit is to complete the project on time, within budget and within required quality or performance parameters. Whether making an automobile, computer or pharmaceutical, project management is not easy. However, given the complexity and intense regulatory demands of the pharmaceutical industry, project management is more difficult than many other segments. As if pharmaceutical projects weren’t demanding enough, biopharmaceutical project management is exceptionally challenging, requiring unique experience and expertise. Read Full Article

The following is a collection of resources that will be fascinating to those interested in what is happening within the work of using adeno-associated viruses (AAV) to develop drugs that manipulate genes for desirable clinical outcomes. The resources listed below are grouped as follows: Introduction, AAV Manufacturing & Production  and Compliance & Regulatory Considerations.

Introduction – Adeno-Associated Virus (AAV)

Article: Oligonucleotides: Opportunities, Pipeline and Challenges

1970s, nearly a half century later, only three oligonucleotide drugs have been approved by the FDA. However, the field is gaining momentum and the clinical benefits of the more than 135 oligonucleotide therapeutics currently in various stages of clinical trials are extremely promising. Read article

Video: Engineering Adeno-Associated Viruses for Gene Therapy

Video: Adeno-Associated Virus (AAV) – An Introduction

Video: Making Adeno Associated Virus (AAV)

 

Manufacturing & Production – Adeno-Associated Virus (AAV)

Video: Production and Titering of Recombinant Adeno-Associated Viral Vectors

Article: Production and Titering of Recombinant Adeno-Associated Viral Vectors

In recent years recombinant adeno-associated viral vectors (AAV) have become increasingly valuable for in vivo studies in animals, and are also currently being tested in human clinical trials. Wild-type AAV is a non-pathogenic member of the parvoviridae family and inherently replicationdeficient. Read article

Article: Large-Scale Recombinant Adeno-Associated Virus Production

Since recombinant adeno-associated virus (rAAV) was first described as a potential mammalian cell transducing system, frequent reports purportedly solving the problems of scalable production have appeared. Yet few of these processes have enabled the development of robust and economical rAAV production. Two production platforms have emerged that have gained broad support for producing both research and clinical grade vectors. Read article

Article: Co-packaging of Multiple Adeno-Associated Viral Vectors in a Single Production Step

Limiting factors in large pre-clinical and clinical studies utilizing adeno-associated virus (AAV) for gene therapy are focused on the restrictive packaging capacity, the overall yields, and the versatility of the production methods for single AAV vector production. Furthermore, applications where multiple vectors are needed to provide long expression cassettes, whether because of long cDNA sequences or the need of different regulatory elements, require that each vector be packaged and characterized separately, directly affecting labor and cost associated with such manufacturing strategies. Read article

Article: Cross-Packaging of a Single Adeno-Associated Virus (AAV) Type 2 Vector Genome into Multiple AAV Serotypes Enables Transduction with Broad Specificity

The serotypes of adeno-associated virus (AAV) have the potential to become important resources for clinical gene therapy. In an effort to compare the role of serotype-specific virion shells on vector transduction, we cloned each of the serotype capsid coding domains into a common vector backbone containing AAV type 2 replication genes. This strategy allowed the packaging of AAV2 inverted terminal repeat vectors into each serotype-specific virions. Read article

Sample Protocol: A Protocol for AAV Vector Production and Purification

The protocol describe at below is typical of methods that are used to propagate and purify AAV vectors for experiments both in vitro and in vivo. Read Article

Article: Transient Transfection Methods for Clinical Adeno-Associated Viral Vector Production

Recombinant adeno-associated virus (AAV)-based vectors expressing therapeutic gene products have shown great potential for human gene therapy. One major challenge for translation of promising research to clinical development is the manufacture of sufficient quantities of AAV vectors that meet stringent standards for purity, potency, and safety required for human parenteral administration. Several methods have been developed to generate recombinant AAV in cell culture, each offering distinct advantages. Transient transfection-based methods for vector production are reviewed here, with a focus on specific considerations for development of AAV vectors as clinical products. Read article

Article: Manufacturing of Recombinant Adeno-Associated Viral Vectors: New Technologies Are Welcome

Recombinant adeno-associated viral vectors (rAAV) are probably the most powerful tools for in vivo gene delivery. Encouraging preclinical data have been followed by successful gene therapy clinical trials including Leber’s congenital amaurosis type 2, hemophilia B,and recently choroideremia. These results together with the market authorization of Glybera, an AAV-based product for the treatment of lipoprotein lipase deficiency,  has prompted skeptical investors and biotechnology and pharmaceuticals companies to move into this field. Read article

Compliance & Regulatory – Adeno-Associated Virus (AAV)

U.S. Pharmacopeia: Manufacturing of Gene Therapy Products

Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events

Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

FDA Grants Breakthrough Status to Gene Therapy for First Time

Rare Disease Advocacy Groups Receiving FDA Orphan Designations

 

Regulators are tightening up on post-marketing monitoring of biological medicines to detect deficiencies caused by manufacturing problems, particularly those stemming from post-authorization changes in the manufacturing process.

The European Union introduced a guideline in August 2016 on the monitoring of the safety of biological medicines on the market amidst industry worries about the ability of regulators to deal with quality deficiencies due to manufacturing variations in biopharmaceuticals. Manufacturing standards can have a bigger impact on the post-marketing safety and efficacy of biological medicines than those of chemically synthesized pharmaceuticals with which different producers can achieve a uniform quality.

“[With biologicals], the manufacturing process–including choice of cell line, raw or starting materials, fermentation and purification process, final formulation–is as much a determinant of the product’s quality as the active substance,” states the guideline. “Minor changes in any manufacturing step can affect the product quality and subsequently its safety and efficacy.” As a result, the guideline, published by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA), constantly highlights the need to find the “root cause” of a suspected adverse drug reaction (ADRs) by tracing the product back not only to its manufacturer but also to its batch and the individual medicines within it. Read full article

Combination drug products are high on everyone’s radar screen, as seen in continuing discussion about appropriate testing and regulation of self-injectors, such as EpiPen, and emerging cellular and gene therapies. Manufacturers complain of delays in decisions by FDA’s Office of Combination Products (OCP) about which FDA center should take the lead in evaluating a new combo. Medical device makers are particularly unhappy that most stents and transdermal patches are classified as drugs based on primary mode of action. At the same time, biopharma companies struggle with designing human-factors studies and evaluating risks related to intended use. A hot issue is how much the device portion of a generic drug–device combo has to be the “same” as the innovator product.

Industry concerns have generated efforts by FDA commissioner Robert Califf to streamline the OCP system for designating the lead center to regulate a new combination product. A newly formed Combination Products Council, composed of senior-level officials from OCP, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices & Radiological Health (CDRH), was established in April 2016 to address cross-cutting issues and resolve disagreements. OCP also has established…read full article on BioPharm International

As more biosimilars gain FDA approval for marketing in the United States, and more manufacturers launch programs to develop additional competitive biotech therapies, concerns have emerged that continued growth in this area could be limited by mounting pressure to push down on prescription drug outlays. Even though payers and insurers anticipate savings from alternative biotech therapies, the threat is that aggressive cost-cutting measures could raise the demand for truncated biosimilar development, eroding the confidence of physicians and patients about biosimilar safety and efficacy.

FDA is aware that mounting rage over drug pricing could have repercussion for biosimilar development. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), observed at a recent conference sponsored by the Biosimilars Council that gaining public trust in biosimilar safety and efficacy is key to building broad acceptance for these products, especially when patients are being asked to switch from a life-sustaining medicine that is working well. Woodcock emphasized the importance of requiring sufficient analytics and testing to convince prescribers and patients that new biosimilars are products that “can be relied upon.” FDA’s regulatory framework is based on a “totality of evidence” standard that she feels will help industry “earn the trust and confidence” of payers and prescribers.

FDA has approved three biosimilars for market, the latest just a week ago. As of the end of July 2016, … click to read full article on BioPharm International.

Stop by Booth 1116 to discuss your process validation, analytical and CMC regulatory needs at the BioProcess International (BPI) Conference & Exposition. BPI is the largest bioprocessing event bringing you the science, technologies and partners needed to accelerate promising biologics towards commercial success. BPI will be held October 4-7, 2016 at the Boston Convention and Exhibition Center..

Combination drug products are complex to both develop and to manage from a compliance perspective. This presentation discusses five critical areas of combination drug compliance including:

• What is 21 CFR Part 4?
• FDA’s Office of Combination Products
• Legacy Combination Drug Products – Compliance with 21 CFR Part 4
• Product Stability Studies Strategy
• Streamlined Approach for Review and Approval of Some Combination Products

Combination drug products (i.e., products that are a combination of a medical device and/or a drug and/or a biologic) are inherently complex to manage, particularly due to regulatory approval processes. Three different FDA centers—the CDRH, the CBER, and the CDER—are involved in regulating these products, and although a lead center is assigned to a specific drug, the needed coordination and knowledge base required to manage the process is not easy.

In April 2016, the FDA announced its first Combination Products Policy Council. The Combination Products Policy Council will include senior-level team members who will focus on holding agency-wide discussions and making decisions on issues related to combination drug products. This council will “have decision-making authority on issues relating to combination products, cross-labeled products, and medical product classification.”

A lead center will still be designated based on the combination product’s determined primary mode of action (PMOA), but it appears the Combination Products Policy Council will take a more hands-on role in tapping required resources and expertise across the agency as the complexity of combination products increases. Ultimately, the goal is to increase efficiency in line with the agency’s announced dedication to lean process mapping initiatives.

This new organization will not replace or override existing processes for the review and approval of combination products. However, the council will have the authority to resolve any issues and conflicts that often arise between CDRH, CBER, or CDER regarding the review, classification, and clearance or approval of combination products.

Per the FDA’s efficiency goals mentioned earlier in this post, the formation of the Combination Product Policy Council will hopefully improve the delays that often occur in reviews of combination products. In fact, the Combination Products Coalition (CPC), an industry group that the FDA regularly consults, states that 70 percent of innovators experience delays as a result of problems during combination product reviews. Of greater concern, up to 85 percent of respondents stated that when a combination product-related conflict arose, the lead center communicated its position without offering scientific and regulatory support for its position.

Given the senior-level resources being assigned to the council, it is expected that many more strategic, scientifically grounded decisions will be facilitated. In addition, discussion, guidance, and insight will be facilitated if needed. This move is much needed since combination drugs will only increase in complexity as new technologies and innovations come online.

At the CASSS CMC Strategy Forum in July of this year, BioTechLogic’s Tracy TreDenick, Head of Regulatory and Quality and Senior Consultant, delivered a presentation discussing how to bring legacy combination products into compliance with 21 CFR Part 4. BioTechLogic has a wealth of experience in this area and have successfully helped a number of combination product manufacturers with this very issue. We hope you find the presentation deck to be informative and let us know if we can help you. Also, stay tuned for more on this topic.