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European Biopharmaceutical Review

Regulatory Challenges

 

There is no regulatory guideline that specifically addresses the quality expectations for oligonucelotides. Instead, developers need to take into account the history regulatory reviews, and the applicability of existing quality guidelines to this novel class of therapeutics. Over the past three decades, there has been an explosive growth in the number of research articles published in the area of DNA and RNA therapeutics. This already popular field was further energised with the awarding of the 2006 Nobel Prize in Physiology or Medicine to Andrew Fire and Craig C Mello for their discovery of RNA interference – gene silencing by double-stranded RNA in the nematode worm C elegans.

The first investigational new drug (IND) application for an oligonucleotide was filed in 1992. The compound was a DNA antisense oligonucleotide, ISIS 2105, administered locally to genital warts for the treatment of human papilloma virus (HPV). This application was followed in 1993 by the filing of an IND for the first systemically administered oligonucleotide, ISIS 2302, for the treatment of Crohn’s Disease.

In 1997, Vitravene became the first oligonucleotide drug to receive market approval in the US and Europe for the treatment of cytomegalo viral retinitis. Vitravene is an antisense molecule that blocks translation of viral mRNA by binding to a coding segment of a key CMV gene. In 2004, a second drug, Macugen, a PEGylated aptamer oligonucleotide was approved by the US FDA for the treatment of age related macular degeneration. This was followed by market license approvals in Canada, Europe, South America and Asia. The aptamer in Macugen is an inhibitor of the vascular endothelial growth factor (VEGF) protein, which upon binding to VEGF effectively blocks angiogenesis and prevents leakage of fluid and blood in the retina. Both of these drugs are approved for local administration by intravitreal injection. Although there are many oligonucleotides currently in development for parenteral administration, some in late stage clinical development, to date there are no approved oligonucleotide drugs for systemic indications.

Review of Oligonucleotide Therapeutics in the US and Europe

Despite the market approval of two oligonucleotide-based drugs and large numbers of other oligonucleotide drug candidates in various stages of clinical development in the US, Canada, Europe and other parts of the world, there are no formal regulatory guidelines available from any regulatory agency for the development of this class of therapeutics.

In the early 1990s there was some question as to whether oligonucleotide therapeutics should be reviewed under the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER) at the FDA. This issue was essentially put to rest with a landmark joint publication in 1993 by scientists from CBER and CDER in which they stated that “oligonucleotides are more similar to most other drugs than they are different” (1). The quality expectations outlined in this publication have been further elaborated upon in presentations made by FDA reviewers (2). Consistent with the sentiments expressed in the publication and presentations, all oligonucleotide IND and NDA applications to the FDA to date have been reviewed by CDER. The only exception may be in the use of oligonucleotides as immunostimulatory adjuvants in combination with vaccines or other biologics agents, although even in such applications the oligonucleotide portion of the dossier may still be reviewed by CDER.

In 2009, a proposal by the National Institutes of Health (NIH) required review of all NIH-sponsored clinical protocols for synthetic oligonucleotides by the Recombinant DNA Advisory Committee (RAC) within NIH. As synthetic oligonucleotides have been present in clinical trials for more than 20 years with no significant or unexpected safety issues, there was an overwhelming objection to this proposal by various industry groups and sponsor companies. This rule was subsequently revised to exempt DNA oligonucleotides (but not RNA oligonucleotides) from RAC review. In consideration of the fact that both DNA and RNA oligonucleotides have similar mechanisms of action – that is, they target the mRNA but do not impact the genome – most antisense molecules are DNA/RNA hybrids; and, as the effects are transient and are reversible upon cessation of therapy, negotiations are ongoing to also exempt RNA oligonucleotides from such review.

In Europe, similar to any other drug, compliance with the standards defined by the EU Clinical Trial Directive 2001/20/ EC is required for initiation of all oligonucleotide clinical trials. This directive provides guidance for documentation to be submitted to the ethics committee as well as the Investigational Medicinal Product Dossier (IMPD) to be submitted to the competent authority for approval. While there are no oligonucleotide-specific guidance documents, presentations have been made by European reviewers on the general requirements for the quality of oligonucleotides intended for clinical trials (3). In the case of market license authorisations, there appears to be a preference for the use of centralised procedure over the mutual recognition procedure. Although the centralised procedure is considered optional for “medicinal products containing new active substances which constitute a significant therapeutic, scientific or technical innovation”, both oligonucleotide drugs, Vitravene and Macugen, were reviewed and approved under this procedure. In 2008, there was a proposal by the European Commission to classify synthetic oligonucleotides as advanced medicinal products (such as gene therapy) in Annex 1 to Directive 2001/83/EC. In response to objection scientists, both from academia and industry from around the world, this directive was revised in 2009 to specifically exclude synthetic oligonucleotides.

 

 

Manufacturing Process for Synthetic Oligonucleotides

A typical oligonucleotide therapeutic is a short chain DNA or RNA molecule, usually manufactured by chemical synthesis utilising automated synthesisers. The manufacturing process for a typical DNA or RNA oligonucleotide involves chemical solid phase synthesis on controlled pore glass (CPG) or polymeric solid support using 3’-O-(2-cyanoethyl) phosphoramidite chemistry. Each elongation cycle involves 5'-hydroxyl deprotection, coupling, oxidation (or sulfurisation) and capping. After the appropriate number of cycles, the crude oligonucleotide is cleaved from the solid support and the relevant protecting groups removed. Purification is commonly achieved by preparative anion exchange chromatography followed by desalting and freeze drying to yield the drug substance. For duplex oligonucleotide drugs such as siRNA, an annealing step which involves bringing together the two purified oligonucleotide strands in an equimolar ratio is required. For PEGylated oligonucleotides, the oligonucleotide containing a built-in amino linker is conjugated to the desired PEG (polyethylene glycol) moiety, which is then purified, desalted and freeze dried. The overall quality of the oligonucleotide drug is assured through the control of raw materials, in-process controls and final product testing. Special attention is paid to other factors such as facilities, equipment, personnel and systems that may affect final product quality, as described in ICH Q7 (4).

Applicability of Current Guidelines

Despite their large size (typical molecular weights of about 7000 or larger), oligonucleotide drugs are more similar to small molecule drugs or new chemical entities (NCEs) than biologics in that they are manufactured by organic chemical synthesis. Therefore, it has been general practice for regulatory agencies to apply guidelines intended for small molecules to oligonucleotide therapeutics. These include all quality-related regulatory guidelines issued by the US FDA, EMA and the ICH.

The applicability of the current ICH quality guidelines to the review of oligonucleotide therapeutics is presented in Table 1. As can be seen, all of the ICH quality guidelines intended for small molecules are applicable to oligonucleotides.

Some ICH guidelines, such as ICH Q3a and ICH Q6a, specifically exclude oligonucleotides (5,6). At times, this is misinterpreted to mean that these guidelines do not apply to oligonucleotides. On the contrary, it is often the case that the guideline is not considered comprehensive enough to apply to oligonucleotides. The spirit of these guidelines still applies to oligonucleotides, but there is some flexibility in cases where certain elements may not specifically apply. For example, in ICH Q6a, which specifically excludes oligonucleotides, drug substances are expected to be characterised for polymorphism. Most oligonucleotides are amorphous in nature, and therefore, polymorphism does not apply. On the other hand, there may be additional specification requirements for oligonucleotides that are not expected for small molecule NCEs as described in ICH Q6a. An example of this is the use of molecular sequencing as an assurance of absolute identity of an oligonucleotide sequence. For special situations, as in the case of aptamers, which are oligonucleotides that adopt well-defined three dimensional conformations and function similarly to monoclonal antibodies, it is common to use bioactivity assays in addition to the usual panel of quality tests to assure quality.

In the case of ICH Q3a, the general principles guiding the control of impurities are directly applicable to synthetic oligonucleotides. However, there is signifi cant flexibility in the limits for reporting, identification and qualification thresholds. Although considerable effort has been expended in developing a harmonised set of limits for all oligonucleotides, the results remain elusive. This is in part due to the sheer diversity in the types of oligonucleotides in clinical development, including differences in length, chemical modifications, conjugation and other features, which makes it difficult to define a single set of limits. Concurrently, considerable progress is being made in the development of novel analytical technologies which have advanced our understanding of the chemistry and our ability to control the overall quality of an oligonucleotide drug (7).

Due to similarities in the manufacturing processes between peptides and oligonucleotides – both are manufactured by solid phase chemical synthesis followed by preparative chromatographic purification and downstream processing – it has been helpful to apply best industry practices utilised in the peptide arena to oligonucleotides.

Development of Oligonucleotide- Specific Position Papers

As of 2011, there were more than 100 oligonucleotide drugs in clinical development in the US, Europe and Canada. These include antisense oligonucleotides, immunostimulatory oligonucleotides, DNA duplex decoys, small interfering RNAs (siRNAs), ribozymes, microRNAs, aptamers and spiegelmers. Although most oligonucleotides in clinical development are chemically similar, DNA, RNA or LNA, often with chemical modifications to afford nuclease stability in biological matrices, the mechanisms of action vary widely. As a consequence, development of a single regulatory guideline that can adequately address the safety and quality requirements for such a diverse class of compounds with equally diverse mechanisms of action is challenging.

In an effort to bridge this gap, an Oligonucleotide Safety Working Group (OSWG), consisting of volunteer members from the industry and regulatory agencies from the US, Canada and Europe has made significant strides in unifying our understanding of the safety of various classes of oligonucleotides. They have also generated white papers outlining policy positions to assist both industry and regulatory agencies to better regulate this unique class of therapeutics. As a result of this success, a similar working group was formed to address critical policy elements related to the quality of oligonucleotide therapeutics. This group is actively engaged in developing similar white papers addressing topics such as quality specifications and impurities in synthetic oligonucleotides.

Conclusion

In spite of the nearly 20 years since the first oligonucleotide drug candidate entered the clinic, and after more than a decade since the market approval of the first oligonucleotide drug, the regulatory expectations for such products are still evolving. This is, in part, due to the various unique mechanisms of action of this class of molecules, resulting in quite a diverse group of molecular entities for which a unifi ed set of regulatory expectations is diffi cult to achieve. It is hoped that the discussion presented in this article will be helpful in forming a basis for the regulatory strategy for an oligonucleotide product intended for clinical development.

References

  1. Kambhampati R, Chiu Y-Y, Chen CW et al, Regulatory concerns for the chemistry, manufacturing, and contents of oligonucleotide therapeutics for use in clinical studies, Antisense Res Dev 3: pp405-410, 1993
  2. Kambhampati R, Points to consider for the submission of chemistry, manufacturing and controls (CMC) information in oligonucleotide-based therapeutic drug applications, Center for Drug Evaluation Research, Office of New Drug Quality Assessment, US Food and Drug Administration, DIA Industry and Health Authority Conference on Oligonucleotide Therapeutics, 2007
  3. Thürmer R, CMC Requirements for Oligonucleotides in Europe, BfArM, Federal Institute for Drugs and Medical Devices, DIA Industry and Health Authority Conference on Oligonucleotide Therapeutics, 2007
  4. ICH Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, 2001
  5. ICH Q3A, Impurities in New Drug Dubstances, 2008
  6. ICH Q6A, Specifications: Test Procedures and Acceptance criteria for new drug substances and new drug products: Chemical Substances, 2007
  7. Bonilla JV and Srivatsa GS (eds), Handbook of Analysis of Oligonucleotides and Related Products, 2011

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Susan Srivatsa is President of ElixinPharma, a scientifi c consulting fi rm dedicated to assisting pharmaceutical companies in the development of oligonucleotidebased therapeutics. Since 1999, Susan has provided strategic CMC regulatory leadership for more than 40 oligonucleotide compounds in various stages of clinical development. Susan has published widely in the area of oligonucleotide analysis including Handbook of Analysis of Oligonucleotides and Related Products. Susan received a PhD in Analytical Chemistry from the University of California in 1985, followed by post-doctoral research in NMR spectroscopy. She serves on the scientifi c advisory board of Tides, EuroTides and AsiaTides conferences.
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