Oncology

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Introduction

From: US NCI

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:

  • Carcinoma - cancer that begins in the skin or in tissues that line or cover internal organs. There are a number of subtypes of carcinoma, including adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma.
  • Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
  • Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood.
  • Lymphoma and myeloma - cancers that begin in the cells of the immune system.
  • Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.

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

From: US NCI

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

From: Cancer Research UK

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

From: US NCI Institute

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:

  • Growing older
  • Tobacco
  • Sunlight
  • Ionizing radiation
  • Certain chemicals and other substances
  • Some viruses and bacteria
  • Certain hormones
  • Family history of cancer
  • Alcohol
  • Poor diet, lack of physical activity, or being overweight

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

From: US NCI Institute

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 (US NCI Institute)

Agency Guidelines

FDA

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:

  • Protocol and SAP design requirements
  • Data Collection for Tumor Measurement
  • Issues to consider in PFS analysis
  • Progression and Censoring Date
  • How to handle Missing Data
  • Lesions evaluation
  • Sensitivity Analysis

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

The Guideline on the evaluation of anticancer medicinal products in man [1] 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 methodologial aspects related to Progression Free Survival (PFS) and disease specific guidance.

The appendix 1 Methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials [2] gives more details / suggestions concerning the following topics:

  • interval detected progression
  • informative censoring
  • primary and sensitivity analysis
  • frequency and methods of assessment
  • blinded independent central review (BICR)
  • effect size
  • follow-up and treatment after progression

The appendix 2 for Confirmatory studies in Haematological Malignancies [3] gives specific indication for Chronic Myelogenoma Leukopenia (CML) and Myelodysplastic Syndromes (MDS) such as.....

In the appendix 4 Condition Specific Guidance [4] additional details when condcting trial on NSCLC, Prostate and haematologicl malignancies, are also provided.

Guidance for Paediatric Oncology are provided separately [5]

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 documentb Report - Oncology Workshop Party Related Quality of Life (HRQoL) [6].



Clinical Trial Endpoints

From: The Ongoing Evolution of Endpoints in Oncology - Jack Alain McCain - Supplement to Managed Care 2010[7]

Overall survival (OS) has been the gold standard for oncology clinical trial endpoints. Over the years, however, such surrogate endpoints [1] 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:

  • Progression Free Survival (PFS) defined as time from randomization/1st drug administration until objective tumor progression or death due to any cause
  • Time to Progression (TTP) similar to PFS but deaths are not considered event
  • Overall Survival (OS) defined as time from randomization/1st drug administration to date of death
  • Duration of Response (DR) defined as time from first CR/PR (whichever is first) until the first recurrent disease or PD (For subjects with BOR=CR or PR)
  • Duration of Stable Disease defined as time from the start of the treatment until the criteria for progression is met (For subjects with BOR=SD)
  • Time to Treatment Failure (TTF) defined as time from randomization/1st drug administration to treatment discontinuation for any reason (e.g., PD, AEs, death, etc.).

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

EORTC QLQ-30

From: EORTC

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 developped. These are also general questionnaires.

Consider also the EMA report from the Oncology Working Group Health Related Quality of Life (HRQoL) [10]. 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

From: Oncology Trials 101 - The Basics and Then Some - Dave Polus - PharmaSUG 2011[11]

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. [12]


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[13].
Phase I studies are the first test of the new treatment (new drug or new combination of drugs) and specifically in Oncology Trials are run on Patients who have Cancer and a lack of other treatment options usually with advanced disease (e.g. metastatic cancer patients failing to standard therapies) but good 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:

  • Single-Arm / Multi–Arm designs
  • One-Stage / Multi-Stage designs
  • Non-comparative / Comparative

Multi-Arm

  • Simultaneous exploratory screening of several different Treatments / Doses / Regimes
  • For the purpose of formal comparison or within arms evaluations

Multi-Stage

  • Gehan
  • Flemin
  • Simon

General Characteristics:

  • Frequently used in single-arm studies. Specify P0 and P1 bounds,  and .
  • In multi-arms, non-comparative trials, the design is applied independently within each arm.
  • Larger sample size in multi-stage designs



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.
Usually a CRF starts by collecting subject characteristics at study entry, such as Age (and/or date of birth), Sex, Race, Weight, Height, etc., followed by information about cancer diagnosis and prior cancer therapies when subjects are previously treated, for example in trials indication for 2nd or 3rd line therapy, anything else that could help in identifying the current status of the subject including the current safety profile (e.g. vital signs, laboratory, prior and current signs and symptoms, ECG, performance status, etc.).
In studies were efficacy is evaluated, periodic tumor assessment data are collected including baseline / pre-treatment assessment.
Detailed exposure information for each experimental drugs are also collected together with repeated safety assessment. Within each 'exposure' assessment (cycles), repeated safety assessment for laboratory, ECG, vital signs, etc. could be performed (e.g. prior to drug administration, 1 hours after drug administration, 8 hours after drug administration, and so on).
It is important also to note that exposure/safety assessments usually do not have the same frequency of efficacy assessments.
Whether or not efficacy is an endpoint of the trial, follow-up information are also collected including survival status and further follow-up anti-cancer therapies.

In the introduction section categories of cancer were introduced. Another way of classifying cancer is as follows:

  • Solid Tumors Cancer involving solid tumor, typically originates in a specific body organ, such a lung, breast, ovarian, etc. Types of solid tumors includes sarcomas, carcinomas, adenocarcinomas, blastomas, carcinoid tumors
  • Hematologic malignancies Arrise in the blood-forming cells; typically present as systemic disease, as blood and lymphatic organs located throughout the body are affected. Types of Hematologic malignancies includes leukemias, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MM)

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.
As of today there is no other specific oncology SDTM standard (apart for efficacy/tumor response). Sponsors could either create ad-hoc domains or use existing standard SDTM domains. For example:

  • Prior (but also follow-up/post) anti-cancer treatments can be mapped in CM, where anti-cancer therapies are identified using the variable CMCAT (e.g. CMCAT="Previous Anti-Cancer Therapy" or CMCAT="Further Anti-Cancer Therapy"), CMSCAT the type of anti-cancer therapy (e.g. RADIOTHERAPY), the standard CM variables to specify further details such as start/end date, dosage, unit. etc. Any other related variables if not standard in CM and not relevant for the analysis, can be mapped in a SUPPQUAL dataset (e.g. mapping to SUPPCM best overall response to prior therapies). Optionally prior surgery or any other non-drug therapies can be mapped to Medical History (MH).
  • Staging or any other variables related to the diagnosis of cancer (especially if used as a covariate in the analysis) can be stored in Subject Characteristics (SC). For example TNM stage, histology, grading, etc.
  • Tumor History, such as the type of cancer (e.g. Colorectal), can be also mapped in the Medical History (MH) where start date (MHSTDTC) could contain the date the cancer was histologically confirmed.

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).
A key concept in oncology drug therapy is the concept of Cycle. A cycle is commonly defined as a Number of days (or weeks), e.g. 21 / 28 days (3/4 weeks), where treatment is administered on specific days (for example Day 1 to 5, 8 to 12, etc) of a cycle. When drugs are administered in combination, each drug within the combination may have a different schedule. For example drug A is administered on day 1 and 8, while drug B is administered only on day 1. The therapy, the sequence of treatment, is usually repeated (re-cycled) under certain condition usually safety and/or efficacy related. For example if a patient progressed or if the patient had severe toxic effect from which he/she did not recover, the patient is usually withdrawn from the study. In presence of toxic effects, for example a severe neutropenia with a CTCAE grade 3 or 4, the new cycle can be delayed until the toxic effect is solved (recovered). Usually one or two weeks of delay are allowed depending on the study protocol.

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.

  1. Assigning NCI CTC Grades To Laboratory Results [14]
  2. Analyze This? Supporting Clinical Decisions Graphically When Not Enough Data is Available A Study Case: Challenges in NCI CTCAE Version 4 Grading [15]
  3. From Local Laboratory to Standardisation and beyond [16]

A PhUSE wiki page is also available. The latest version of the NCI CTCAE criteria (currently version 4.03) [17] 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 toxicitity 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 collecing adverse events are quite common:

  • CTCAE Grade 5 not used – keep the worst grade and outcome=fatal
  • changes in severity/grade need to be tracked e.g. each change requires closing the event with the previous grade, and opening a new event with same description, with the new grade and having start date equal to the stop date (or the day after) of the stop date of the close event
  • More details in action taken (e.g dose reduction, infusion rate reduced)
  • ‘events’ such as progression are ‘obviously’ not recorded as AE

In addition we may have:

  • Different definitions of SAE (e.g. hospitalizations that are scheduled for trial related procedures)
  • DLT variable (see Phase I studies)

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) [18] 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.
Although it may change between sponsors and type of studies, it is also common to define a AE being treatment emergent, if the AE occurred within a certain nr. of days (safety follow-up period) after last drug administration.
From the data collection point of view it is therefore important to be able to get the AE start date as much complete as possible (e.g. no partial date), unless the date is clearly before the 1st drug administration (e.g. previous year or previous month), data-management should make any possible effort to clarify with the investigator whether or not the AE was already present at the time of 1st drug administration.
In case AE started the same day of the 1st drug administration, it is suggested to also collect an additional field where the investigator is asked to specify whether the AE was or not already present at the time of 1st drug administration.

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.
Usually safety outputs (e.g. a shift table of worst observed toxicity grade) are based on treatment emergent / on-treatment observations.

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 [19] creates, compiles, and cross-maps biomedical terminology needed by NCI and its community. EVS is also collaborating with FDA and CDISC developping controlled terminology in different therapeutic area.

SDTM Data

Introduced with SDTM version 3.1.3 Oncology Disease-specific Therapeutic Area Supplement [20] contains mapping specification for three domains:

  • TU Tumor Identification
  • TR Tumor Results
  • RS Response

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[21]

Upcoming version 3.1.4 contains several new domains that could be used for specific or recurrent oncology type of data:

  • PR Procedures could be used to map specific oncology procedures and/or prior prior/post anti-cancer treatments and procedures such surgeries, radiotherapies and other specific oncology drug therapies such chemotherapies, immunotherapies, endocrine therapies, etc. Currently it is common accpeted standard to map all these procedures/treatments in the CM domain.
  • SS Subject Status could be used to stored follow-up update currently mapped either in specific ad-hoc sponsor domains or in a SUPQUAL dataset.
  • TD Trial Disease Assessments will be a new special domain where efficacy assessment schedule could be also planned as this assessments do not have the same schedule of the standard trial visits/cycles assessments

More details on upcoming SDTM enanchements were presented at last 2013 PhUSE Basel SDE [22]

ADaM Data

No specific ADaM CDISC guidance have been released. However two papers [23] contains specific example 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 [24] and PhUSE ????? [25]

Statistical Analysis

Background


Single-Arm Trials and Parallel Trials With Two or More Treatment Arms



References

  1. EMA Guideline on the evaluation of anticancer medicinal products in man
  2. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man Methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials
  3. Appendix 2 to the Guideline on the evaluation of Anticancer Medicinal Products in Man (CPMP/EWP/205/95 Rev. 3) on Confirmatory studies in Haematological Malignancies
  4. Appendix 4 to the guideline on the evaluation of anticancer medicinal products in man - Condition Specific Guidance
  5. Addendum on Pediatric Oncology
  6. Report - Oncology Workshop Party Related Quality of Life (HRQoL) workshop 2nd May 2012
  7. The Ongoing Evolution of Endpoints in Oncology, JA McCain, (Supplement to Managed Care 2010), Volume 19, No. 5
  8. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
  9. Revised Response Criteria for Acute Myeloid Leukemia CHESON Criteria
  10. Oncology Working Group Health Related Quality of Life (HRQoL)
  11. Oncology Trials 101 - The Basics and Then Some, D Polus, (PharmaSUG 2011), IB03
  12. applied clinical trial ref to be defined
  13. Phase I Clinical Trials - A practical guide, EA Eisenhauer C Twelves M Buyse (Oxford University Press 2006)
  14. Assigning NCI CTC Grades To Laboratory Results, ?????, PhUSE, (Basel 2010), PO03
  15. Analyze This? Supporting Clinical Decisions Graphically When Not Enough Data is Available A Study Case: Challenges in NCI CTCAE Version 4 Grading, ????, WUSS, (???? 2011), ????
  16. From Local Laboratory to Standardization and beyond, A. Tinazzi, PhUSE, (Dublin 2007), DM01
  17. NCI CTCAE criteria (currently version 4.03)
  18. ICH Statistical Principles for Clinical Trials (E9)
  19. US NCI Enterprise Vocular Sevices
  20. CDISC Oncology Disease-specific Therapeutic Area Supplement
  21. 2013 PhUSE SDE event in Durham Ref
  22. 2013 PhUSE Basel SDE ref
  23. ADaM Basic Data Structure for Time-to-event analysis ADaM Basic Data Structure for Time-to-event analysis, M Dey L Pyle (PharmaSUG 2010) CD03
  24. PharmaSUG 2010 CD03 ref
  25. PhUSE ???? ref

Project Team

Name Company Project Team Role
Angelo Tinazzi Cytel Inc Lead
.... .... ....
.... .... ....

Last revision by Lisopasi,04/1/2014