Masterstudiengang "Drug Regulatory Affairs"


Preclinical and clinical development of anticancer drugs - regulatory peculiarities

Dr. Wolfgang Meyer (Abschlußjahr: 2005)

The development of novel anticancer drugs has traditionally been associated with a number of differences when compared with drugs used in other therapeutic areas. Until recently, chemotherapy with cytotoxic medications has been the mainstay of drug-based anticancer treatment. In this setting, it was the ultimate therapeutic goal to kill as much of the cancer cells in the body as possible. Chemotherapy has been available since about fifty years. On the one hand cytotoxic drugs are considered to be commonly highly toxic, on the other hand cancer (in particular advanced stages) is a serious, often life-threatening disease. Therefore, the risk-benefit ratios for cytotoxic drugs are different when compared to that of drugs used in other therapeutic areas.

The preclinical requirements related to cytotoxics for entry into Phase I and later for receiving a MAA or NDA were less when compared to agents used in other indications. In the past, rodents only have been recommended as toxicology species. Today, however, mostly two species (e.g. rat and dog) are requested by regulatory agencies. In addition, usually less data are needed in respect to mutagenicity and reprotoxicity. Cancerogenicity studies are mostly not conducted for cytotoxics.

Considerable differences exist in regard to the clinical development of anticancer drugs. Typically, cytotoxics are associated with significant toxicity (e.g. bone marrow suppression, gastrointestinal side-effects such as nausea or vomiting, neurotoxicity, or renal damage). Consequently, these compounds when first administered in humans were given to terminally ill cancer patients with metastasised disease. The patients incentive to participate in Phase I trials is that he is provided with a last therapeutic option. The goal of these studies is commonly to establish a maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs), as cytotoxics should be dosed as high as possible in order to kill as much malignant cells as possible. In Phase II studies, it is typically investigated whether the new cytotoxic is able to cause tumour of a special tumour (e.g. advanced breast cancer). In the pivotal Phase III studies, the cytotoxic is tested versus an established medical and/or regulatory standard, or, if no drug is yet approved in a particular indication, against best supportive care. In some cases, e.g. if there is only a small patient population, one pivotal study may be sufficient for MAA or NDA. Typical endpoints for Phase III studies including cytotoxics are overall survival, disease-free survival, or time to tumour progression. Quality of life endpoints (QoL) play an increasing role, although there are very few cases in which QoL endpoints have been accepted as primary endpoints. In exceptional cases when there is reason to assume that the new anticancer drug has great therapeutic potential, it can be approved based on Phase II data only using response rate as surrogate endpoint. Since years it is discussed whether biochemical surrogate parameters could be accepted as primary efficacy endpoints in pivotal trials (e.g. PSA in prostate cancer), but so far there is no accepted regulatory example.

Other peculiarities in the clinical development of cytotoxic substances are that there are special adverse event reporting systems (CTC Criteria) which are still often employed in addition to the now obligatory MedDRA system. Cytotoxic drugs are mostly developed in so-called last-line indications, i.e. advanced stages of cancer for which no drug has been approved yet. Combinations with existing anticancer drugs are common.

Post approval, most anticancer drugs are used off-label in not approved indications, causing regulatory and sometimes reimbursement problems. Another area of concern is that only few anticancer drugs are registered for use in children.

In Europe and the USA, there are a number of specific regulatory guidance documents addressing the development of anticancer drugs. In the EU, there are guidelines for the preclinical and clinical development of anticancer drugs. In the US, there are guidance documents describing how to develop additional indications for already approved anticancer medications and for the clinical development of specific cancer types. In both regions there are initiatives to promote the development of anticancer drugs in the paediatric population and to address unmet medical needs.

Other substance classes which are used in addition to the classical cytotoxic compounds include hormonal agents, photosensitizers, chemoprotectives, radiosensitizers, immunomodulators, new drug delivery systems (e.g. liposomes) and preventive medications. In particular in the preclinical field there are some special aspects associated with these agents which are shortly discussed. Combination therapy also requires some special considerations. Most of these drugs are small molecules. In addition, monoclonal antibodies are increasingly used.

From a preclinical, clinical and regulatory standpoint it has to be differentiated whether a new anticancer agent is used in a palliative (mostly patients with advanced disease, no cure possible, often shorter treatment duration) or in adjuvant and neo-adjuvant settings (cure possible, often long-term treatment).

In the last decade, novel anticancer agents became available. These drugs are intended to specifically target the cell cycle, to interfere with specific biochemical reactions on a molecular level or with cellular signal transduction, to prevent angiogenesis in the tumour tissue, or to influence extracellular mechanisms playing a role in tumour metastasis. All of these drugs have in common that they are more cytostatic than cytotoxic. Therefore, they may provide new regulatory challenges. Also, many opinion leaders in cancer medicine believe that with these new agents cancer may not be cured, but it may become a “chronic disease”, comparable to diabetes mellitus or rheumatoid arthritis. This may lead to new designs of clinical trials for oncological compounds. Owing to tremendous improvements in clinical diagnostics, it may be possible to individualize anticancer therapy much more than it has been the case in the past. The downside of this development may be that the markets for new anticancer drugs become much smaller and that it may be increasingly difficult to find sufficient numbers of suitable patients for clinical trials.

Despite many overlaps, there are a number of differences in regard to the preclinical and clinical development of new anticancer drugs between the EU and the USA. In this thesis the above mentioned aspects are discussed and some of the regulatory challenges derived thereof are addressed.