| Oncology |
Link to US NCI Introduction Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer that begins in melanocytes of the skin is called melanoma. Cancer types can be grouped into broader categories. The main categories of cancer are:
Oncology is a branch of medicine that specializes in the diagnosis and treatment of cancer. It includes medical oncology (the use of chemotherapy, hormone therapy, and other drugs to treat cancer), radiation oncology (the use of radiation therapy to treat cancer), and surgical oncology (the use of surgery and other procedures to treat cancer). Disease Description All cancers begin in cells, the body's basic unit of life. To understand cancer, it's helpful to know what happens when normal cells become cancer cells. The body is made up of many types of cells. These cells grow and divide in a controlled way to produce more cells as they are needed to keep the body healthy. When cells become old or damaged, they die and are replaced with new cells. However, sometimes this orderly process goes wrong. The genetic material (DNA) of a cell can become damaged or changed, producing mutations that affect normal cell growth and division. When this happens, cells do not die when they should and new cells form when the body does not need them. The extra cells may form a mass of tissue called a tumor. Not all tumors are cancerous; tumors can be benign or malignant. Benign tumors aren't cancerous. They can often be removed, and, in most cases, they do not come back. Cells in benign tumors do not spread to other parts of the body. Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis. Some cancers do not form tumors. For example, leukemia is a cancer of the bone marrow and blood. Cancer Statistics Cancer is a leading cause of disease worldwide and GLOBOCAN estimates that 12.7 million new cancer cases occurred worldwide in 2008.2 Lung (1.6 million, 12.7% of the total for men and women), female breast (1.4 million, 10.9% of the total for women), colorectal (1.2 million, 9.7% of the total for men and women) and stomach cancers (1 million, 7.8% of the total for men and women) were the most common, accounting for more than 40% of all cases diagnosed. Just five cancer sites –lung, female breast, colon-rectum, stomach and prostate – accounted for half (48%) of the world’s total cancer diagnoses in 2008. More information concerning cancer statistics for the most common cancer can be found in Cancer Research UK website (Cancer Research UK). Causes and Risk Factors Doctors often cannot explain why one person develops cancer and another does not. But research shows that certain risk factors increase the chance that a person will develop cancer. These are the most common risk factors for cancer:
Many of these risk factors can be avoided. Others, such as family history, cannot be avoided. People can help protect themselves by staying away from known risk factors whenever possible. Treatments The treatment plan depends mainly on the type of cancer and the stage of the disease. Doctors also consider the patient's age and general health. Often, the goal of treatment is to cure the cancer. In other cases, the goal is to control the disease or to reduce symptoms for as long as possible. The treatment plan may change over time. Most treatment plans include surgery, radiation therapy, or chemotherapy. Some involve hormone therapy or biological therapy. In addition, stem cell transplantation may be used so that a patient can receive very high doses of chemotherapy or radiation therapy. Some cancers respond best to a single type of treatment. Others may respond best to a combination of treatments. Treatments may work in a specific area (local therapy) or throughout the body (systemic therapy): Local therapy removes or destroys cancer in just one part of the body. Surgery to remove a tumor is local therapy. Radiation to shrink or destroy a tumor also is usually local therapy. Systemic therapy sends drugs or substances through the bloodstream to destroy cancer cells all over the body. It kills or slows the growth of cancer cells that may have spread beyond the original tumor. Chemotherapy, hormone therapy, and biological therapy are usually systemic therapy. Because cancer treatments often damage healthy cells and tissues, side effects are common. Side effects depend mainly on the type and extent of the treatment. Side effects may not be the same for each person, and they may change from one treatment session to the next. More information concerning type of treatment can be found in the US NCI Institute website. Agency Guidelines FDA Link to FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 2007. The Guidance contain general regulatory requirements for efficacy with detailed description of endpoints and how they can be used in various clinical settings. Pros and Cons of the different endpoints are discussed. Details on the following topic are also provided:
The FDA has also undertake a project to evaluate potential endpoints for cancer drug approval. Endpoints were examined for the most common cancers, such as lung cancer, colon cancer, etc. For each cancer, FDA hold public workshops to identify important issues, and these issues have been discussed in meetings of the Oncologic Drugs Advisory Committee (ODAC). EMA Link to Guidelines on the evaluation of anticancer medicinal products in man. The above guidelines provides guidance on all stages of clinical drug development for the treatment of malignancies, including drug resistance modifiers or normal tissue protective compounds. Supportive measures such as anti-emetics and haematopoietic growth factors, however, are covered by separate guidelines. The guidance of 2013 is a revised version of past versions where the focus was mainly the conventional cytotoxic compounds. The current version of the guidance cover also non-cytotoxic compounds and additional indication for exploratory studies. Moreover the guidance is also now completed by a set of specific appendices covering methodological aspects related to Progression Free Survival (PFS) and disease specific guidance. The appendix Methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials gives more details / suggestions concerning the following topics:
The appendix 2 for Confirmatory studies in Haematological Malignancies gives specific indication for Chronic Myelogenoma Leukopenia (CML) and Myelodysplastic Syndromes (MDS) such as..... In the appendix 4 Condition Specific Guidance additional details when conducting trial on NSCLC, Prostate and haematological malignancies, are also provided. Guidance for Paediatric Oncology are provided separately. The EMA is also planning to provide an additional appendix for Quality of Life/Patient Reported Outcome. For this reason in May 2012 a workshop was conducted to gather information / opinions from patients, industry and health technology assessment representative. A summary of the topic discussed was summarized in the document Report - Oncology Workshop Party Related Quality of Life (HRQoL). Clinical Trial Endpoints Overall survival (OS) has been the gold standard for oncology clinical trial endpoints. Over the years, however, such surrogate endpoints as objective response rate and progression-free survival (PFS) have been employed because they can be reached faster and may offer important benefits in evaluating therapies. Categorical Measurements
Time to Event Measurements Treatment efficacy in oncology is often measured with survival analysis techniques and therefore with time to event endpoints. Several time to event endpoints are usually calculated and analysed. Duration of the event, or censoring if no events occurred, are calculated from randomisation date or from first drug administration if study is not randomised to the date of the event. Censoring methods and censoring date to be used may vary depending on the type of the event. Possible time to event endpoints are but not limited to:
PFS, or a modified version, is often the primary endpoint of most of solid tumor cancers as requested by regulatory agencies (see above about Agency Guidelines). Other Specific Indication Efficacy Endpoints For some indications / type of cancers, a variation of the standard efficacy endpoints or the evaluation of additional endpoints, usually secondary, it may be required. For example:
Patient Reported Outcomes The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. It is a copyrighted instrument, which has been translated and validated into 81 languages and is used in more than 3,000 studies worldwide. Presently QLQ-C30 Version 3.0 is the most recent version and should be used for all new studies. It is supplemented by disease specific modules for e.g. Breast, Lung, Head & Neck, Oesophageal, Ovarian, Gastric, Cervical cancer, Multiple Myeloma, Oesophago-Gastric, Prostate, Colorectal Liver Metastases, Colorectal and Brain cancer which are distributed from the EORTC Quality of Life Department. Other disease specific modules are under development but not yet validated. Satisfaction with Care measure (EORTC-IN-PATSAT32) and a Palliative Care questionnaire (QLQ-C15-PAL) have been also developed. These are also general questionnaires. Consider also the EMA report from the Oncology Working Group Health Related Quality of Life (HRQoL) The intention of this workshop was to gather information/opinion in order to generate a Health Related Quality of Life / Patient Reported Outcome appendix to the general Guideline on the 'Evaluation of anticancer medicinal products in Man'. Clinical Trial Design Oncology is somewhat more complicated than other therapeutic areas. The endpoints, for one, differ greatly. For example, rather than running a clinical trial to test the safety and efficacy of an antibiotic against an infection, an oncology trial is trying to extend and improve a subject’s quality of life. One of the main differentiators is the role of comparator drugs in oncology trials. Placebos are never used in place of treatment when an existing standard therapy exists. If a patient is given a placebo in an oncology trial, it is always in conjunction with other approved treatments. In other therapeutic areas, it is common to have a placebo arm compared to the drug being studied. Patient recruitment is often more of a challenge with oncology trials. Often more sites are needed to meet population requirements which increases costs to the sponsor incrementally. According to Applied Clinical Trials, “Lack of participation can cause an oncology trial to recruit slowly, often lengthening the trial's timeline by months or even years.” The article goes on to detail some of the challenges of recruiting for oncology trials, including the lack of patient reimbursement, recruiting older patients, negative perceptions of clinical trial treatments, logistics, and access to clinical trial opportunities. Phase I Dose Escalation Phase I studies are a critical step in cancer drug development. They are small sample size and non-randomized and they also produce early observation about the drug's safety, pharmacokinetic, and preliminary evidence of antiumour activity. The Performance Status measures the physical status of the patient; it can be used to predict how well the patient will tolerate the therapy (a very well know prognostic factor). Two main criteria are used to evaluate the performance status:
Phase II The main purpose of Phase II in oncology is to detect signals of activity for the new drugs, for further testing, in an exploratory manner and hypothesis generating setting. Also to Document Toxicity is one of the main objectives. not to: provide a definite estimate of response rate or efficacy of new drugs. The main types of phase II designs can be summarized as follows:
Multi-Arm
Multi-Stage
General Characteristics:
Phase III From: cancer.net The primary endpoints in Phase III Oncology clinical trial design typically is based on survival type endpoints such as overall survival, disease free survival/ remaining recurrence free or progression free survival. The aim of Phase III is to take a new treatment that has shown promising results in a Phase II setting with smaller number of patients and compare with current standard treatment with larger number of patients (hundreds to thousands), and therefore designed to be statistically powered for comparison. Phase III clinical trial are designed to demonstrate whether the new treatment has better clinical risk/benefit profile based on the efficacy and safety data analysis. The main types of Phase III Oncology Clinical trial designs are as follows:- • Superiority This design is used to prove that the new treatment is significantly better compared to a standard. • Non-inferiority This design is used to prove that the new treatment is not significantly worse compared to a standard but could offer other benefits or further options to patients. • Sequential This design could be special type of an adaptive design and involves a number of stages within the trail separated by an interim analysis which is used drive the second stage of the trail design or stops the study early. Once a drug has been proven successful in a phase III clinical trial, the researchers can submit an application for FDA approval. If data from the clinical trials meet the FDA's standards, the treatment is approved for a specific use. However, doctors sometimes prescribe a drug for a use not specified by the FDA, but rather based on studies published in peer-reviewed journals showing that the treatment works for other diseases, conditions, or symptoms; this is called "off-label" use. Data Challenges Overview The way data are collected and handled in Oncology studies is pretty standard, although there are some peculiarities. In the introduction section categories of cancer were introduced. Another way of classifying cancer is as follows:
More info details on the US NCI website (http://www.cancer.gov/cancertopics/types/commoncancers). Depending on the type of cancer and sometime on the location of the cancer, data to be collected and the way they are collected may differ. Prior Cancer History After having identified key demographics information, the next step in collecting clinical data in oncology trial is the identification of cancer characteristics such as diagnosis and prior treatments.
Exposure Chemotherapy (the first systemic cancer therapy) still remains one of the main therapy which is given at some point to most of the cancer patients. Administration of 2 or more agents (cytotoxic + other) is widely used nowadays for cancer treatment (often significantly improves response and cure rates over monotherapies, that is therapy where one single drug/agent is used). In most of the trials especially in phase I but also in phase II, there is no defined or specific Cycles / no. of Visits. The subject will continue the trial till the meeting of one of the trial discontinuation / treatment termination criteria as specified in the protocol. In addition after discontinuation, same subject will enter to protocol specific follow-up period till death of the respective subject and there is no specific timeline for this. Most of the oncology drug therapies are usually infused and in this case the patient is hospitalized. However some of the novel therapies may be also administered by means of tablets. In describing the exposure data of a study, the concept of Dose Intensity and Relative Dose Intensity is often used together with the description of type of Treatment Modifications (for example number of cycles reduced, delayed, interrupted, overdosed). Safety Data Laboratory Data Laboratory tests performed within clinical trials in oncology are used both to make immediate clinical decisions for patient’s care and to define the drug profile according to the trial objectives. Early oncology clinical trials, which are often performed in a population with advanced disease in centres of excellence serving a broad geographical area and testing toxic compounds, require frequent samplings, and laboratory results must be available to the treating physician in a very short time for quick decision making; as a consequence, the use of multiple local laboratories cannot be avoided mainly for patients convenience. The results are thus obtained using different equipments and assays which make reference to different ranges of normality and are expressed in different units. This heterogeneity implies great efforts to collect a series of different normal ranges and the need for some methods of conversion to ensure comparability of results. The list of laboratory parameters to be collected may vary from protocol to protocol, depending on the expected mechanism of action of the compound(s). Laboratory values are often classified using the NCI CTCAE criteria wherever applicable. For example ‘Platelets’ adverse event grade 2 is defined as an observed value between 75.000/mm3 (not included) and 50.000/mm3 , regardless of the normal range of the specific laboratories.
The latest version of the NCI CTCAE criteria (currently version 4.03) is available at the US NCI website. The Statistical Analysis Plan can be the right place where, for each collected laboratory parameter, the link to the CTCAE criteria is identified, including whether the toxicity criteria is defining either hyper or hypo toxicity or both. For example for Potassium we have both hypokalemia and hyperkalemia, this if we have to create summary statistical analysis tables by means of shit tables of baseline CTCAE value vs worst on treatment CTCAE, we will have to produce two tables, one for Potassium high values and one Potassium low value. See full details of CTCAE criteria vs laboratory parameters. An additional analysis of laboratory data in oncology, especially for the definition of the toxicity profile (e.g. neutrophils and platelets for hematological toxicity) in the early development of cytotoxic drugs (phase I), is the evaluation of the toxic effects of the drug over time. For example a commonly analyzed parameter is the time to nadir, i.e. the time elapsing from treatment / cycle start to the observation of the lowest value. Similarly also time to recovery to a defined threshold is often determined; for example, if a drug is administered once every 28 days (that is the cycle duration), we may be interested to see when the most severe toxicity is to be expected (time to nadir) and what is the duration of CTCAE grade 4 toxicity (time to recovery to grade<=3) and of the toxicity overall (time to recovery to grade 0). Adverse Events Although now also adopted by other Therapeutic Area, in oncology adverse events are scored according to the guidelines provided by the National Cancer Institute: Common Terminology Criteria for Adverse Events (NCI-CTCAE). In some cases, a grade of 1 corresponds to mild, 2 to moderate, and 3 to severe. There are also two additional grades that may be assigned; 4 is a life-threatening or disabling adverse event, and 5 is a death related to the adverse event. However not all adverse events allow all five grades. Often in oncology the following additional peculiarities in collecting adverse events are quite common:
In addition we may have:
When combination of drugs are used in the trial, onset, relationship and action taken are referred to each single drug. In some circumstances we may need to distinguish between Treatment Emergent flag for each drug if they are not administered simultaneously. The Concept of Treatment Emergent Event or On-Treatment Observations The ICH Statistical Principles for Clinical Trials (E9) defines a treatment emergent [adverse] event (TEAE) as an event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. In trials where the investigational medical product (IMP) is tested in combination with other commercial drug (e.g. chemotherapy), you may also define TEAE with respect to the IMP when for example in the sequence of drugs used the IMP is not given as first drug (e.g. on day 2). The same concept can be applied to any safety assessment, such as a laboratory. So for example defining Treatment Emergent Laboratory Assessment any sample collected after 1st drug administration and within 28 days from last drug administration. Despite SDTM contains some 'flag' variables to identify prior vs post treatment assessment, it is recommended to "re-derive" treatment emergent flags in ADaM by following the rules defined in the SAP. For example TRTEMFL in ADAE or ONTRTFL if using BDS structure for Laboratory. Efficacy Data
Data Collection The US NCI Enterprise Vocabular Sevices creates, compiles, and cross-maps biomedical terminology needed by NCI and its community. EVS is also collaborating with FDA and CDISC developing controlled terminology in different therapeutic area. SDTM Data Introduced with SDTM version 3.1.3 Oncology Disease-specific Therapeutic Area Supplement contains mapping specification for three domains:
These three domains allow the mapping of tumor assessment information as per RECIST criteria. These new standards were also presented at 2013 PHUSE SDE event in Durham. Upcoming version 3.1.4 contains several new domains that could be used for specific or recurrent oncology type of data:
More details on upcoming SDTM enanchements were presented at last 2013 PHUSE Basel SDE. ADaM Data No specific ADaM CDISC guidance have been released. However, two papers contain specific examples on how to derive and map composite time to event endpoint such Progression Free Survival. Additional example of user implementation have been also presented at conferences: PharmaSUG 2010 CD03 ref1 Statistical Analysis Background
Single Arm Trials and Parallel Trials With Two or More Treatment Arms
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