Phases of clinical research
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Types of Clinical Trials – Based on Study Design
This type of study identifies people with a disease (or another variable of interest) and compares them with an appropriate control group which does not have the disease.
An examination is made, comparing the frequency of exposure to this or other factors between the cases and the controls.
It is an analytical observational study which enables the cause-effect relationship to be followed.
If the frequency of exposure or the cause is greater in the group of cases with the disease than in the control group, we can say that there is an association between the cause and effect.
The measurement of the association which quantifies this association is called the “odds ratio“(OR).
In medicine, a case-control study is a cross-sectional type of study which is used to research the etiology of a disease or a given result.
Study in which people with a certain disease or symptom (cases) are compared with others who do not present the disease or symptom under study (controls), with regard to prior exposure to risk factors.
This has been incorrectly called Retrospective Study.
In a case-control study, a single disease but various risk factors or exposures are examined.
Epidemiology adopted this term to refer to the idea of a simultaneous advancement, in time, of a group of individuals defined for possessing a common characteristic or group of characteristics.
The common characteristic is usually exposure to a factor (environmental, pharmacological, occupational, etc).
The term “cohort” is used to designate a group of subjects with a common characteristic or group of characteristics who are monitored over a period of time.
It is an observational, analytical and longitudinal study in which two cohorts differing with regard to the exposure to the factor under study are compared in order to assess a possible cause-effect relationship.
Study in which people subjected to a certain exposure or treatment are compared with people who are not subjected or exposed.
These are studies in which there is a time lapse between the different variables, so that a time sequence can be established between them.
They can be both descriptive and analytical.
In analytical studies, it should be taken into account whether the time sequence is from the cause to the outcome (experimental studies and cohort studies), or from the outcome to the cause (case-control studies).
Any study not focused on an alleged cause-effect relationship, but whose data is used for purely descriptive purposes is considered descriptive.
This type of study is useful for generating etiological hypotheses which should subsequently be contrasted with analytical studies.
Any study which evaluates an alleged cause-effect relationship is considered analytical.
The alleged causal agent may be a factor which is suspected of being able to lead etiologically to a disease or a treatment to prevent or improve a clinical situation.
These are studies in which the data of each subject represents essentially a moment of time.
This data may correspond to the presence, absence or different degrees of a characteristic or disease.
It consists of examining the relationship between different variables in a defined population at a specific moment in time.
These designs do not permit the study of an alleged cause-effect relationship.
Cross-sectional studies are descriptive by definition.
Epidemiological strategy in which observations of numerous factors at the same time are recorded and then a comparison is made between them.
The presence or absence of a disease or other variables (or, if they are quantitative, their level) are determined in each subject.
The analysis of the results can be made in two senses: by comparing all the variables in the individuals who suffer from the disease being studied, comparing them with those who do not suffer from it, or by comparing the prevalence of the disease in different subgroups of the population.
Phase I trials are usually the first step in testing a new drug or treatment on humans after successful laboratory and animal testing: sometimes called the first in human trial. They usually involve a small scale of healthy volunteers.
The trial often includes dose escalation studies to determine the optimal dosing regime of the treatment which will be only a fraction of those found to cause harm in pre-clinical studies. There are two types of dose escalation studies Single Ascending Dose and Multiple Ascending Dose studies.
Single Ascending Dose (SAD) studies gives small group of patients a low dose of the drug and observe them for specific period of time. If no adverse events occur a different group of patients will be given a slightly higher dose of the drug. This escalation of dosing continues until intolerable adverse events begin to occur. The final tolerated dose is the Maximal Tolerated Dose.
Multiple Ascending Dose (MAD) studies are designed to test the pharmacokinetics and pharmacodynamics of multiple dose of experimental drug. In this study a group of patients are initially given a low dose of the drug. Over time the dosage is increased within this group until a predetermined dosage has been reached. Various biological samples are collected over the time and studied to help understand how the drug is processed and how well it is tolerated by the body.
This step by step approach takes a long time. Hence to make drug development more efficient in time and direct cost, more creative strategies have evolved. This includes SAD/MAD designs as well as SAD/MAD designs with arms to test for food effects and drug-drug interactions. Recently, patient cohorts are being included in SAD/MAD combination studies with the goal of collecting more relevant safety and tolerability information as well as enhancing the chance of getting early signals of efficacy.
AbbVie announced the initiation of a Phase III clinical trial evaluating the safety and efficacy of its investigational compound, veliparib (ABT-888), when added to carboplatin and paclitaxel, two chemotherapeutic medicines, in patients with advanced breast cancer. Specifically, the combination of veliparib, carboplatin and paclitaxel will be compared to treatment with carboplatin, paclitaxel and placebo in patients with human epidermal growth factor receptor 2-(HER2) negative metastatic or locally-advanced breast cancer, containing BRCA1 and/or BRCA2 gene mutations.
“Our Phase III programme for veliparib represents an innovative approach to developing this type of anti-cancer compound. By adding veliparib to DNA-damaging therapies, such as carboplatin and paclitaxel, we can evaluate its potential to provide incremental benefit to existing treatments,” said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. “This is the third Phase III trial evaluating the efficacy and safety of veliparib, and the second evaluating the addition of veliparib to chemotherapy for the treatment of patients with difficult-to-treat forms of breast cancer.”
The randomised, double-blind, Phase III clinical trial will recruit approximately 270 patients. The primary efficacy outcome of the trial is progression-free survival (PFS). The secondary pre-specified outcome measures include overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR) and duration of response (DOR).
Veliparib is an investigational oral poly (adenosine diphosphate [ADP]–ribose) polymerases (PARP) inhibitor being evaluated in multiple tumour types. PARP is a naturally-occurring enzyme in the body that repairs damage to DNA, and in certain types of cancers, repairs cancer cells. Discovered and developed by AbbVie researchers, veliparib is being developed to help prevent DNA repair in cancer cells and increase the effectiveness of common DNA-damaging therapies like chemotherapy or radiation. Veliparib is currently being studied in more than a dozen cancers and tumour types, including Phase III studies in non-small cell lung cancer and breast cancer.
Breast cancer is the second most common cancer in the world and the most commonly diagnosed cancer in women worldwide.1 The HER2 gene, which normally helps cells in the breast remain healthy and function normally, can play a role in the development of breast cancer. Specifically, in approximately 25 per cent of breast cancers, the HER2 gene does not work properly, causing cells in the breast to grow and divide in an uncontrolled way. This process, known as HER2 gene amplification or over expression, results in HER2-positive breast cancer. HER2-positive breast cancers tend to grow faster, metastasize more quickly and are more likely to recur, compared to patients diagnosed with HER2-negative breast cancer.
It is estimated that at least five percent of breast cancer cases result from inherited mutations or alterations in the BRCA1 and BRCA2 breast cancer susceptibility genes. Women with these mutations have a 40- to 85-per cent lifetime risk of developing breast cancer. Additionally, men with BRCA2 mutations carry an increased risk of breast cancer.
Merrimack Pharmaceuticals, announced it will present clinical data on four novel antibody cancer therapeutics at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, May 30-June 3, 2014 at McCormick Place in Chicago. These presentations showcase Merrimack’s broad oncology pipeline.
“ASCO is an exciting opportunity for us to share the first Phase 2 clinical data from our systems biology-driven MM-121 programme. We believe these data identify a biomarker-positive set of patients across multiple cancers who do not perform well on standard of care therapies but who may significantly benefit from co-administration of MM-121,” said Gavin MacBeath, Co-Founder and senior vice president at Merrimack. “These data also increase our confidence in our ongoing Phase 2 study of MM-111 in gastric cancer, where we are now prospectively evaluating a biomarker-positive population based on these new insights into ErbB3 biology. We also look forward to sharing Phase 1 data from our MM-141 and MM-151 programmes as we seek to advance these therapies to Phase 2 development, along with our targeted nanoliposome MM-302.”
Merrimack’s systems biology platform integrates the fields of biology, computing and engineering to gain a more comprehensive understanding of the key drivers of tumour growth and survival and the best ways to counteract them therapeutically. These insights allow Merrimack to deploy proprietary antibody and nanoliposomal technologies to enable the precise targeting of cancers, based on signaling pathways and the tumour microenvironment.
“We believe that our rigorous understanding of cancer biology will enable us to transform cancer care over time. Our systems biology approach, nanoliposomal and antibody technologies, and diagnostic capabilities have broad applications and offer opportunities for significant treatment advances for patients,” said Robert Mulroy, president and chief executive officer at Merrimack. “The presentations at ASCO, along with our recently reported positive data for MM-398 combination therapy in metastatic pancreatic cancer, highlight the progress we are making across our entire clinical pipeline.”
The European Commission has granted Marketing Authorisation (MA) for Finox Biotech’s bemfola (follitropin alfa solution for injection in pre-filled pens), a recombinant follicle stimulating hormone used for the treatment of infertility. This marketing authorisation follows a positive opinion by the European Medicines Agency, and allows for the marketing of bemfola in all of the 31 countries of the European Union (EU) and European Economic Area (EEA).
To date, nearly 400 patients have received at least one dose of bemfola in phase I or III studies. The MA for bemfola was supported by data from a large phase III study, in which bemfola therapy was found to be similar to the currently available treatment – GONAL-f , based on the numbers of oocytes retrieved after completing FSH therapy. In this phase III study, similar efficacy and safety profiles were observed between the two study arms and similar numbers of live babies were born to patients who became pregnant following completion of therapy.
Gavin Jelic-Masterton, chief executive officer of Finox Biotech commented, “the marketing authorisation of bemfola is an important step forward in the management of infertility in Europe, enabling many more patients the opportunity to obtain the treatment they need. We are confident that IVF Patients and Doctors across Europe will benefit from Finox Biotech’s commitment to quality, cost effectiveness and easy-to-use fertility medicines. bemfola will be a great success for our company”.
Dr. h.c. Willy Michel, president of the board of Finox Biotech added, “This is the culmination of many years commitment to bringing a Swiss Quality r-FSH to the market in Europe and I believe that with the cost effectiveness of the product and sour state-of-the-art delivery system bemfola will be very popular with physicians and patients. This also gives us the positive impetus to our ongoing development and registration efforts for the USA and Rest of World”
Bemfola was produced using recombinant DNA technology. Both bemfola and the reference product GONAL-f are formulations of the naturally occurring hormone FSH, which plays a key role in human reproduction. bemfola is the result of a targeted drug development process aimed to replicate as closely as possible the reference product. The brief to the development engineers when designing the bemfola injector device was to produce a Pen that absolutely minimised the number of steps a patient needs to take when preparing the injection and to ensure that the patient and physician had maximum control and the least chance of a patient error. The result, the bemfola Pen, is therefore a simple, single-use, once-a-day disposable device, which allows the patient to self-inject.
Finox Biotech has agreed with the US FDA to conduct a pivotal phase III study (FIN3002) for registration of bemfola (AFOLIA) in the USA. A US IND has been opened and the FIN3002 study is now in progress.
Finox Biotech was founded in 2007 with a vision to become a leading company in the field of fertility therapies, by combining high quality Swiss medicines with innovative, award-winning delivery devices.