Regulatory Harmonization of the Nonclinical Development of Anticancer Drugs and Biologics

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By Jon Daniels, PhD, DABT, ERT and Geoff Goodfellow, PhD

Introduction

Approaches to the preclinical development of new oncology drugs and biologics are not harmonized internationally and continue to be independently discussed and developed in the United States (US), the European Union (EU) and Japan. As a result of this, it has been argued that there have been delays in bringing promising new therapeutics to cancer patients as well as inefficient use of animal resources.

In order to address this, industry proposed that the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) undertake the development of harmonized guidance on this topic and, in May 2007, the ICH Steering Committee initiated a project to develop a new nonclinical safety guideline, “Preclinical Guideline on Oncology Therapeutic Development” (ICH S9), which will cover both small molecules and products of biotechnology (but will exclude therapeutic vaccines, cell and gene therapy products).

Although more information is available at www.ich.org, the ICH brings together the regulatory authorities of the United States, Europe and Japan and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration and make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.

Although not a member of ICH, Canada has Observer status and Health Canada is represented on the ICH Oncology Therapeutic Expert Working Group (EWG).

Current Guidance and Approaches to the
Development of Anticancer Therapeutics

One of the drivers of the current ICH S9 initiative is that various jurisdictions have either published or begun developing guidance documents independently related to the nonclinical development of anticancer therapeutics. The concern with this is that if these regional guidances are completed, they will not offer a harmonized approach for the nonclinical development of products needed for the treatment of cancer and industry would tend towards following the recommendations of the most conservative jurisdiction in an effort to reduce duplication of efforts. The following is an overview of current expectations and shouldn’t be used for designing a drug development program; original source documents and guidance should be consulted.

The U.S. Food and Drug Administration (FDA) doesn’t have any official guidance related to the preclinical development of anticancer products (although the ICH S6 guidance provides general guidance related to the development of biologics (ICH, 1997)).

Within FDA, the Center for Drug Evaluation and Research (CDER) had been developing an official guidance related to the development of small molecule therapeutics but these efforts were delayed by the 2003 transfer of therapeutic biological products that had been reviewed and regulated by the Center for Biologics Evaluation and Research (CBER) to CDER and the need to incorporate biologics into any formal recommendations.

Despite the lack of official FDA guidance, sponsors have for many years received unofficial guidance related to the development of anticancer agents and selection of starting clinical doses from a publication authored by senior FDA staff (DeGeorge et al., 1998) and more recently from detailed discussions on FDA’s expectations for novel anticancer drugs and biologics that took place under the auspices of the March 2006 Oncologic Drugs Advisory Committee meeting (ODAC, 2006). In order to initiate Phase I studies in patients with end-stage disease, FDA expects sponsors to conduct toxicology studies in two species, a rodent and a nonrodent, and that these studies should ideally follow the clinical schedule, route and formulation as much as possible. In addition, pivotal studies should be conducted in compliance with Good Laboratory Practice (GLP) regulations. As pointed out by FDA, some of the more common dosing schedules employed are those where the agent is administered every 21 days, studies where drugs are administered weekly, with one week off, and continuous daily administration. Table 1 summarizes current FDA recommendations for small molecules with respect to dosing schedules (ODAC, 2006).

Another area that sponsors often seek guidance on is the duration of nonclinical safety studies relative to the duration of the clinical trial. For small molecules, in the absence of documented disease progression and an acceptable safety profile, and when the agent is administered on an intermittent schedule as per Table 1, FDA generally allows multiple cycles of treatment in a clinical trial. For therapeutics that are intended to be administered continuously, then continuous dosing for 28 days in rodents and nonrodents are generally sufficient to support clinical trials longer than 28 days (ODAC, 2006).

In Japan, the Ministry of Health, Labour and Welfare (MHLW) has developed a draft preclinical guidance that addresses various mechanisms of anticancer therapy, but does not include biologics in its scope.

The European Medicines Evaluation Agency (EMEA) has official preclinical guidance for the development of cytotoxic cancer treatments (EMEA, 1998) and has also issued an addendum addressing requirements related to the development of drugs intended to treat childhood malignancies (EMEA, 2003).

In addition, the European Organization for Research and Treatment of Cancer (EORTC) has published guidance related to the nonclinical development of novel cytotoxic anticancer agents (Burtles, et al., 1995).

However, cytotoxic/cytostatic agents are becoming a class of therapeutics that are decreasing overall with respect to development as newer, non-cytotoxic (signalling pathways) and context dependent (tumour mutation specific) mechanisms for treatment of cancer now make up the bulk of the agents in development. Although it is generally acknowledged that the nonclinical testing strategies for new agents designed to treat life threatening diseases, such as cancer, should be viewed on a case-by-case basis, the situation in Europe is that regulators are requesting toxicology studies (typically one month studies using daily dosing prior to Phase I) in two species for targeted anticancer therapeutics (i.e., new, non-cytotoxic therapies with a “novel mechanism of action”) that cover the duration of dosing in the clinic and that to extend treatment of patients past one month, a 1:1 duration of nonclinical studies are requested, essentially the type of nonclinical recommendations conveyed to Sponsors of non-oncology agents in the ICH M3 guidance (ICH, 2000). As a result of these expectations, chronic animal toxicology studies have been required earlier during clinical development of novel anticancer agents.

Table 2 highlights some of the current differences in regulatory expectations between the US and the EU with respect to the generation of nonclinical safety data.

Status of the ICH S9 Guidance

As previously mentioned, a concept paper and business plan were both endorsed by the ICH Steering Committee in May, 2007 and the topic was discussed at the October 2007 ICH meeting in Yokohama, Japan. In preparation for the Yokohama meeting, members of the EWG from the EU, Japan and US provided draft and finalized guidances as a framework for discussion and developing a unified working document. It was agreed that the FDA document (FDA, 2007), the most comprehensive provided to the EWG, would serve as the primary basis for discussion. A subsequent meeting of the EWG took place in Portland, Oregon in June, 2008 with the main topics covered being approaches to selecting starting doses in the clinic, the duration and timing of general toxicology studies to support marketing authorization, and the need for reproductive toxicology studies.

One of the important items that arose from these discussions was acknowledgement that toxicology studies should not limit the clinical dose studied or continued treatment of patients receiving benefit from the investigative therapy. A Step 2 guidance, reached when the ICH Steering Committee agrees, based on the report of the EWG, that there is sufficient scientific consensus on the technical issues for the draft guideline or recommendation to proceed to the next stage of regulatory consultation, is planned for release by late 2008 (around the time of the November 2008 EWG meeting in Brussels, Belgium) and the current ICH schedule calls for completion of the harmonised tripartite Step 4 guidance by early 2010.


Considerable effort is being made to develop the harmonized ICH S9 nonclinical guidance on oncology therapeutic development so that it will cover both small molecules and products of biotechnology. It is expected that the ultimate S9 guidance will look quite different from the preliminary discussion document that has been shared with stakeholders (FDA, 2007), but the guidance will undoubtedly reduce the inconsistencies in approaches experienced when conducting clinical trials and seeking marketing authorization in the various regulatory jurisdictions.

References

Burtles, S., et al. (1995). Revisions of general guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe. The Cancer Research Campaign (CRC) Phase I/II Clinical Trials Committee and the European Organization for Research and Treatment of Cancer (EORTC) New Drug Development Office. European Journal of Cancer 31(3):408-410.

DeGeorge J., et al. (1998). Regulatory Considerations for Preclinical Development of Anticancer Drugs. Cancer Chemother Pharmacol 41:173-185.

EMEA (1998). Note for Guidance on the Pre-Clinical Evaluation of Anticancer Medicinal Products. The European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, January 1998.

EMEA (2003). Addendum on Paediatric Oncology. Note for Guidance on the Pre-Clinical Evaluation of Anticancer Medicinal Products. The European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, July, 2003.

FDA (2007). Preliminary Draft Recommendations for the Purpose of ICH Discussions. Nonclinical Studies for Anticancer Drugs and Biologicals. Office of Oncology Drug Products, US Food and Drug Administration.

ICH (1997). S6. Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (July, 1997).

ICH (2000). M3(R1). Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct Of Human Clinical Trials For Pharmaceuticals (November 9, 2000).

ODAC (2006). Oncologic Drugs Advisory Committee. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Gaithersburg, MD, March 13, 2006.

The authors are senior consultants with Intrinsik Health Sciences, a toxicology, product development and regulatory affairs consulting company. Dr. Daniels recently chaired a workshop in Boston entitled “Harmonization of Requirements for the Preclinical Development of Anticancer Drugs” that included speakers from FDA and industry. For more information about the development of anticancer drugs or any of the guidelines cited in this article, please contact jdaniels@intrinsikscience.com or visit www.intrinsikscience.com/health.

		Table 1
		Table 2