**2. Conventional clinical development paradigm for anti-cancer chemotherapeutics**

Cancer drugs development paradigms have been based on criteria adjusted to cytotoxic agents. These criteria were not always transparent in the literature, but they basically are the following:


According these criteria, clinical trials have been designed and classified into different phases, covering the different questions to be answered about drugs under development.

Considering the high toxicity of cytotoxic agents, and considering the concept that maximizing doses should maximize efficacy, Phase I are dose escalation trials, designed for testing pharmacokinetics and MTD. Dose escalation in Phase I trials gives data about the maximal dose which could exert a therapeutic effect without severe damage due to

Accelerated approval (AA) regulations were established by the US Food and Drug Administration (FDA) designed to shorten development times of drugs for serious medical diseases, i.e. cancer (Dagher et al, 2004; Richey et al, 2009). According these, drugs received AA based in Phase II trials and sponsors must confirm efficacy in post-approval trials. Since the first AA for an oncology indication was granted between 1995 and 2008, 51 new molecular entities have received FDA approval for cancer therapeutic indications: 32 with

In some way, regulations have moved towards faster access to patients of even the very

Biotechnology development has provided new therapeutic weapons for cancer therapy. According Pharma 2009 report, there are currently 633 biotechnology medicines under development, from which 254 are for cancer therapy (109 monoclonal antibodies and 63

These Biotechnological products have the characteristics of being highly specific which in

 Biotechnology anticancer drugs are not just more drugs, they are different drugs; and their entrance into cancer therapy high lightened the limitations of the prevalent paradigm for drug development. The enormous differences between the new biotechnological products and chemotherapeutic agents, makes necessary changes in established clinical development paradigms. Specifically, for cancer vaccines, more flexible and focused developmental

In this report we use the case of CIMAvax-EGF® to illustrate the operation of the emerging

Cancer drugs development paradigms have been based on criteria adjusted to cytotoxic agents. These criteria were not always transparent in the literature, but they basically are the

Objective progression indicates treatment failure (drugs are not active if the tumor is

Drugs must be tested first in advanced disease and moved to ¨adjuvant setting¨

According these criteria, clinical trials have been designed and classified into different phases, covering the different questions to be answered about drugs under development. Considering the high toxicity of cytotoxic agents, and considering the concept that maximizing doses should maximize efficacy, Phase I are dose escalation trials, designed for testing pharmacokinetics and MTD. Dose escalation in Phase I trials gives data about the maximal dose which could exert a therapeutic effect without severe damage due to

cancer vaccines). That means, 40% of worldwide biotechnology is cancer therapy.

turn causes a low toxicity, long-term usability and usability in combinations.

guidelines are needed to address their unique characteristics (Hoos et al, 2007).

**2. Conventional clinical development paradigm for anti-cancer** 

Objective response predicts survival (SV) and clinical benefit.

Drugs to be tested in combination must be active as single agents.

Patient population for clinical trials must be as homogeneous as possible.

regular approval and 19 with AA (Richey et al, 2009).

toxic chemotherapies.

paradigms.

following:

**chemotherapeutics** 

growing).

(seeking cures).

 Maximizing dose should maximize efficacy. Pharmacokinetics is relevant to dose finding.

Tumor shrinkage is expected to occur fast.

excessive toxicity. The effective time of the drug in circulation has to be studied in pharmacokinetics studies, and this has been an additional goal of Phase I clinical trials.

Once defined the drug dose, a proof of clinical benefit is the next step. Currently, this is measured as objective response (assessing tumor shrinkage), because cytotoxic drugs are expected to decrease the tumor mass. Phase II trials are designed and conducted to find this kind of anti-tumor activity in some specific patient population. These trials are usually not randomized and evaluate the tumor response according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). They include the minimal patient population required to show statistical significance of a given percentage of tumor response which is different from zero.

When the product under study demonstrates to have anti-tumor activity, randomized Phase III trials are then designed to compare the new drug with the currently accepted standard therapy.

If a novel chemotherapeutic agent is more efficient and/or has better safety profile than a previous one, it is considered to substitute the previous therapy or to add on it. Usually, a large number of patients are required to achieve statistical power to detect small differences between randomized groups.

It is this statistical significance of therapeutic effect in Phase III clinical trials which guarantee the Regulatory Approval. Nevertheless, the limitations of this stepwise process have driven regulatory adaptations such as the concept of AA after an obviously successful Phase II Trial. This concept has had diverse expressions and nuances in different regulatory authorities.
