1. Drug Development: Steps in Cancer Drug Development The development of new cancer drugs spans multiple steps that demand a substantial investment of time, professional dedication, and financial resources. The drug development process may be delayed or terminated at any point due to unfavorable findings. Progression of a successful cytotoxic compound from the laboratory to common use typically takes about 12 years and costs an average of $500 million. Candidate compounds have historically been identified through empiric approaches and screened in a murine leukemia model. More recently, however, promising natural products, “rationally synthesized” compounds, and biologic agents are identified and screened against well-characterized tumor cell lines or through mechanistic or molecular targeted assays. Compounds that pass screening must then be evaluated for activity and toxicity in preclinical animal models and analyzed for the potential for optimal production and formulation characteristics. Only then can rigorous evaluation in increasingly intensive clinical trials be initiated in patients and approval sought for use in general medical practice.
2. Drug Development: Identification of Candidate Compounds: Natural Products Approximately 30% of the anticancer agents in use are from natural sources or are derived from natural products. Because these drugs come from finite resources, however, their supply is often limited. Laboratory synthesis of these compounds addresses availability issues and may allow chemical modification of the drugs, which may improve their efficacy and safety profiles.
3. Drug Development: Identification of Candidate Compounds: Molecular-Targeted Screening Molecular-targeted screening involves identification of a molecule in the cell that is implicated in the malignant process. A computer is then used to construct a compound that will interact with this target molecule. For example, the aberrant protein produced by the translocated BCR-ABL gene in chronic myelogenous leukemia and the protein that inactivates the retinoblastoma tumor-suppressor gene in cervical cancer are possible targets for this drug discovery strategy. Compounds that mediate the actions of oncogenes, such as protein kinases and transcription activators, are also possible targets.
4. Drug Development: Screening for Anticancer Activity One approach to screening compounds for development as cancer chemotherapies involves a panel of in vitro human tumor cell lines. This approach provides information on nonspecific antitumor activity and disease-specific antitumor activity, which can be used to guide further testing and development. Compounds that show nonspecific activity on these cell lines may be evaluated in studies of in vivo tumor panels and human tumor xenograft studies before proceeding to preclinical development and broad-based clinical trials. Compounds demonstrating disease-specific activity can proceed to targeted preclinical development and possibly disease-oriented Phase I and II clinical trials. More than 55,000 compounds were screened through this approach between 1990 and 1996. Only 5% of these compounds have proceeded beyond the cell line panels, and only five agents were considered worthy of further clinical evaluation.
5. Drug Development: Preclinical Evaluation of Cytotoxic Agents Preclinical evaluation of potentially useful cytotoxic agents comprises in vitro and in vivo analyses. In vitro analysis may include assays designed to evaluate the mechanism of action of compounds against specific mechanistic or molecular targets or activity at the cellular level in terms of cytotoxicity, growth inhibition, or differentiation. Thereafter, Stage I in vivo testing is designed to identify the maximum tolerated dose and dose-limiting toxicities of the compound, in addition to preliminary efficacy findings. Stage II in vivo testing is designed to define the spectrum of activity, schedule dependency, optimal route of administration, potential for cross resistance with other agents, and potential usefulness in combination therapies.
6. Drug Development: Use of Animal Models in Evaluation of Cytotoxic Agents Although clinicians and patients are eager to have rapid access to promising new cytotoxic agents, the use of animal models is an important first step in the evaluation of cytotoxic agents in vivo. Preclinical studies in mice, rats, and dogs provide an important bridge from in vitro screening to clinical use of new drugs. The primary objectives of animal testing include defining the major toxicities of cytotoxic agents that should be anticipated in humans and identifying an initial, safe starting dose for use in clinical trials.
7. Drug Development: Clinical Evaluation of Cytotoxic Agents The clinical evaluation of cytotoxic agents spans four phases, each with defined objectives and patient populations. In Phase I, noncomparative clinical studies are designed to identify the maximum tolerated dose and key toxicities in small groups of patients with various tumor types. Phase II studies are noncomparative trials conducted to evaluate tumor response and determine if the drug is sufficiently promising to warrant Phase III studies; Phase II studies are somewhat larger than Phase I studies and enroll patients with more uniform disease characteristics. Phase III studies expand the experience with new agents through efficacy and safety comparisons with standard therapies, which support marketing approval; these studies typically involve hundreds of patients who have a single tumor type, but represent a broader patient pool than do Phase II studies. Phase IV studies are conducted post-approval to integrate findings from earlier clinical studies into general clinical practice with particular emphasis on safety monitoring in very large cohorts of hundreds or thousands of patients who represent the general clinical population.
8. Drug Development: Clinical Trials: Efficacy Endpoints Patients’ responses to chemotherapy can be evaluated based on several efficacy endpoints in clinical studies. Tumor response and overall response rates are typically addressed in short-term studies. These responses, however, may not be reflective of broader patient benefits, which can be better evaluated in long-term trials and expressed in terms of survival and disease-free survival. Other terms, such as time to progression and duration of response, may be reported in clinical studies. Quality-of-life measures have come into broader use recently in an effort to more fully characterize the impact of therapy on patients’ lives. And, pharmacoeconomic analyses may provide insight into cost-benefits and consequences of various treatments.
9. Drug Development: Clinical Endpoints: Complete Remission One criterion for evaluating response to chemotherapy involves degrees of remission from the signs of disease. A complete remission is a response to treatment in which all clinical, radiologic, and biologic signs of a tumor have been observed to disappear. All fields demonstrating the primary tumor, node-positive disease, and metastatic disease must be confirmed to be disease-free for designation as a complete remission.
10. Drug Development: Clinical Endpoints: Partial Remission Remission that is less than complete may be designated as partial remission if the tumor bulk has been reduced by at least 50%.
11. Drug Development: Clinical Endpoints: Disease Progression A response designation of disease progression indicates failure of therapy to arrest tumor growth. Specifically, tumor growth must exceed the multiple of two tumor diameters by at least 25%.
12. Drug Development: Clinical Trials: Safety Analyses Since all cytotoxic compounds impose certain risks, safety analyses are critical components in clinical studies of new agents. The major toxicities, which are typically revealed in animal studies, need to be quantified in terms of causative relationship to treatment, incidence, and severity in clinical studies.
13. Drug Development: Summary of Organization and Reporting of Clinical Studies Clinical studies of cytotoxic agents are essential for the continued progress of cancer therapy. An understanding of the organization and reporting of clinical studies is important for the thoughtful and critical review of the quality and implications of data from these studies. This illustration summarizes the collaboration of the ethics committee and investigator in designing studies, as well as the cooperation of the investigator and patients during study. At the outset, appropriate documents, such as the study objectives and protocol, documentation of Institutional Review Board approval, and various methods for capturing and analyzing data, need to be prepared, as clinical supplies are gathered. During study, the investigator needs to work closely with patients for appropriate enrollment, treatment administration, and timely evaluation of prespecified efficacy and safety data parameters. Study monitoring is also required to ensure adherence to protocol or the need for protocol modifications, with written accounts of study conduct. A final study report is prepared to reflect the conduct, outcomes, and implications of the study, with consideration for publication in the medical literature, as appropriate.
ONCOLOGY Drug Development
ONCOLOGY Drug development Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation Phase I, II, III, IV Clinical Trials General Medical Practice Steps in cancer drug development Toxicology Pharmacology Biochemistry
ONCOLOGY Drug development Identification of candidate compounds: Natural products Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;387-388. Haskell CM. Cancer Treatment . 1995;35-36. Drug Type Source Antitumor antibiotic (daunorubicin, doxorubicin) Streptomyces fungus Vinca alkyloid (vincristine, vinblastine) Vinca rosea plant Taxane Yew tree Camptothecin (topotecan, CPT-11) Camptotheca accuminata tree Podophyllin (etoposide, teniposide) Podophyllum peltatum plant Bryostatin, dolastatin, halichondrin Marine organisms
ONCOLOGY Drug development <ul><li>Computer-aided construction of molecules </li></ul><ul><li>Mutant oncogenes (BCR-ABL) </li></ul><ul><li>Aberrant tumor suppressor genes (RB) </li></ul><ul><li>Protein kinases </li></ul><ul><li>Transcription activators </li></ul>Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;385-394. Identification of candidate compounds: Molecular-targeted screening
ONCOLOGY Drug development Prostate IN VITRO HUMAN TUMOR CELL LINE PANELS Ovarian Melanoma CNS Breast Colon Lung Preclinical development followed by broad-based clinical trials In Vivo “tumor panel” human tumor xenograft studies Specific “disease-oriented” Phase I/II trials Targeted preclinical development “ Nonspecific” antitumor activity “Highly specific” antitumor activity Adapted from NCI drug screening strategy,1985. Screening for anticancer activity
ONCOLOGY Drug development <ul><li> Target level Maximum tolerated dose Spectrum of activity </li></ul><ul><li> Cellular level Dose-limiting toxicities Schedule dependency </li></ul><ul><li> Efficacy Route of administration </li></ul><ul><li> Cross resistance </li></ul><ul><li> Combination therapies </li></ul>IN VITRO IN VIVO Preclinical evaluation of cytotoxic agents Mechanism of action Stage I Stage II
ONCOLOGY Drug development <ul><li>Preclinical studies in mice, rats, and dogs provide an important bridge from in vitro studies to clinical studies </li></ul><ul><li>Objectives </li></ul><ul><ul><li>Define major toxicities </li></ul></ul><ul><ul><li>Identify initial safe starting dose for clinical trials </li></ul></ul>Use of animal models in evaluation of cytotoxic agents
ONCOLOGY Drug development Clinical evaluation of cytotoxic agents Study Phase Objectives Patient Population Phase I Identify maximum tolerated dose Small (3-6 patients/dose level) Define key toxicities Various tumor types Phase II Evaluate tumor response Larger than Phase I (10-50 Determine whether drug patients/treatment group) warrants Phase III study More uniform disease characteristics Phase III Compare new treatment with Larger than Phase II (100s of standard patients/treatment group) Support marketing approval Same tumor type Broader patient pool Phase IV Integrate clinical study experience Very large cohorts (100s-1000s) into general clinical practice Represent general patient Monitor safety after approval population
ONCOLOGY Drug development <ul><li>Response rate </li></ul><ul><li>Survival </li></ul><ul><li>Disease-free survival </li></ul><ul><li>Time to disease progression </li></ul><ul><li>Duration of response </li></ul><ul><li>Quality of life </li></ul><ul><li>Pharmacoeconomics </li></ul>Clinical trials: Efficacy endpoints
ONCOLOGY Drug development Adapted from World Health Organization, 1980. Clinical endpoints: Complete remission Primary Tumor Nodes Metastases Disappearance of all clinical, radiologic and biologic signs of tumor Treatment
ONCOLOGY Drug development Treatment Decrease of the multiple of two tumor diameters by at least 50% Clinical endpoints: Partial remission Adapted from World Health Organization, 1980.
ONCOLOGY Drug development Increase of the multiple of two tumor diameters by at least 25% Clinical endpoints: Disease progression Adapted from World Health Organization, 1980. Treatment
ONCOLOGY Drug development <ul><li>Major toxicities </li></ul><ul><ul><li>Adverse effects </li></ul></ul><ul><ul><li>Need for dose/schedule modifications </li></ul></ul><ul><ul><li>Discontinuation of therapy during study </li></ul></ul>Clinical trials: Safety analyses
ONCOLOGY Drug development Summary of organization and reporting of clinical studies ETHICS COMMITTEE INVESTIGATOR PATIENTS PREPARATION OF DOCUMENTS CLINICAL SUPPLIES DATA ON ADVERSE EVENTS DATA PROCESSING WRITTEN ACCOUNTS MONITORING STUDY REPORT