Clinically Oriented blogs and news- Clinical Research

Clinical Research - An Introduction

INTRODUCTION

We define a clinical trial as a prospective study comparing the effect and value of intervention(s) against a control in human beings. Note that a clinical trial is prospective, rather than retrospective. Study participants must be followed forward in time. Each participant however, must be followed from a well-defined point in time, which becomes time zero or baseline for the study. A clinical trial must employ one or more intervention techniques. These may be single or combinations of diagnostic, preventive, or therapeutic drugs, biologics, devices, regimens, or procedures. Intervention techniques should be applied to participants in a standard fashion in an effort to change some aspect. Follow-up of people over a period of time without active intervention may measure the natural history of a disease process, but it does not constitute a clinical trial. Without active intervention the study is observational because no experiment is being performed. Early phase studies may be controlled or uncontrolled. Although common terminology refers to phase I and phase II trials, because they are sometimes uncontrolled. A trial contains a control group against which the intervention group is compared. At baseline, the control group must be sufficiently similar in relevant respects to the intervention group in order that differences in outcome may reasonably be attributed to the action of the intervention. Most often a new intervention is compared with, or used along with, best current standard therapy. Each clinical trial must incorporate participant safety considerations into its basic design. Equally important is the need for, and responsibility of, the investigator to fully inform potential participants about the trial, including information about potential benefits, harms, and treatment alternatives. Unlike animal studies, in clinical trials the investigator cannot dictate what an individual should do. He can only strongly encourage participants to avoid certain medications or procedures which might interfere with the trial. Since it may be impossible to have “pure” intervention and control groups, an investigator may not be able to compare interventions, but only intervention strategies. Strategies refer to attempts at getting all participants to adhere, to the best of their ability, to their originally assigned intervention. When planning a trial, the investigator should recognize the difficulties inherent in studies with human subjects and attempt to estimate the magnitude of participants’ failure to adhere strictly to the protocol. The ideal clinical trial is one that is randomized and double-blind. Deviation from this standard has potential drawbacks. In some clinical trials, compromise is unavoidable, but often deficiencies can be prevented by adhering to fundamental features of design, conduct, and analysis.

Fundamental Of Trial Design : Randomized Controlled Trials 

INTRODUCTION

Randomized clinical trials are scientific investigations that examine and evaluate the safety and efficacy of new drugs or therapeutic procedures using human subjects. The results that these studies generate are considered to be the most valued data in the era of evidence-based medicine. Understanding the principles behind clinical trials enables an appreciation of the validity and reliability of their results.

What is a randomized clinical trial?

A clinical trial evaluates the effect of a new drug (or device or procedure) on human volunteers. These trials can be used to evaluate the safety of a new drug in healthy human volunteers, or to assess  treatment benefits in patients with a specific disease. Clinical trials can compare a new drug against existing drugs or against dummy medications (placebo) or they may not have a comparison arm. A large proportion of clinical trials are sponsored by pharmaceutical or biotechnology companies who are developing the new drug, but some studies using older drugs in new disease areas are funded by health related government agencies, or through charitable grants.

In a randomized clinical trial, patients and trial personnel are deliberately kept unaware of which patient is on the new drug. This minimizes bias in the later evaluation so that the initial blind random allocation of patients to one or other treatment group is preserved throughout the trial. Clinical trials must be designed in an ethical manner so that patients are not denied the benefit of usual treatments. Patients must give their voluntary consent that they appreciate the purpose of the trial. Several key guidelines regarding the ethics, conduct, and reporting of clinical trials have been constructed to ensure that a patient’s rights and safety are not compromised by participating in clinical trials.

Are there different types of clinical trials?

Clinical trials vary depending on who is conducting the trial. Pharmaceutical companies typically conduct trials involving new drugs or established drugs in disease areas where their drug may gain a new license. Device manufacturers use trials to prove the safety and efficacy of their new device. Clinical trials conducted by clinical investigators unrelated to pharmaceutical companies might have other aims. They might use established or older drugs in new disease areas, often without commercial support, given that older drugs are

unlikely to generate much profit. Clinical investigators might also:

• look at the best way to give or withdraw drugs
• investigate the best duration of treatment to maximize outcome
• assess the benefits of prevention with vaccination or screening programs

Thus, different types of trials are needed to cover these needs; these can be classified under the following headings:

Phases:

The pharmaceutical industry has adopted a specific trial classification based on the four clinical phases of development of a particular drug (Phases I–IV). In Phase I, manufacturers usually test the effects of a new drug in healthy volunteers or patients unresponsive to usual therapies. They look at how the drug is handled in the human body (pharmacokinetics/pharmacodynamics), particularly with respect to the immediate short-term safety of higher doses. Clinical trials in Phase II examine dose–response curves in patients and what benefits might be seen in a small group of patients with a particular disease. In Phase III, a new drug is tested in a controlled fashion in a large patient population against a placebo or standard therapy. This is a key phase, where a drug will either make or break its reputation with respect to safety and efficacy before marketing begins. A positive study in Phase III is often known as a landmark study for a drug, through which it might gain a license to be prescribed for a specific disease. A study in Phase IV is often called a post-marketing study as the drug has already been granted regulatory approval/license. These studies are crucial for gathering additional safety information from a larger group of patients in order to understand the long-term safety of the drug and appreciate drug interactions.

Trial design:

Trials can be further classified by design. This classification is more descriptive in terms of how patients are randomized to treatment. The most common design is the parallel-group trial. Patients are randomized to the new treatment or to the standard treatment and followed-up to determine the effect of each treatment in parallel groups. Other trial designs include, amongst others, crossover trials, factorial trials, and cluster randomized trials.

Crossover trials randomize patients to different sequences of treatments, but all patients eventually get all treatments in varying order, i.e., the patient is his/her own control. Factorial trials assign patients to more than one treatment-comparison group. These are randomized in one trial at the same time, i.e., while drug A is being tested against placebo, patients are re-randomized to drug B or placebo, making four possible treatment combinations in total. Cluster randomized trials are performed when larger groups (e.g., patients of a single practitioner or hospital) are randomized instead of individual patients.


Number of centers:
Clinical trials can also be classified as single-center or multicenter studies according to the number of sites involved. While single-center studies are mainly used for Phase I and II studies, multicenter studies can be carried out at any stage of clinical development. Multicenter studies are necessary for two
major reasons:

• to evaluate a new medication or procedure more efficiently in terms of accruing sufficient subjects over a shorter period of time
• to provide a better basis for the subsequent generalization of the trial’s findings, i.e., the effects of the treatment are evaluated in many types of centers.

CLINICAL TRIAL PROTOCOL DEVELOPMENT AND KEY COMPONENTS OF TRIAL PROTOCOL

CLINICAL TRIAL PROTOCOL DEVELOPMENT

Once a clinical question has been postulated, the first step in the conception of a clinical trial to answer that question is to develop a trial protocol. A well-designed protocol reflects the scientific and  methodological integrity of a trial. Protocol development has evolved in a complex way over the last 20 years to reflect the care and attention given to undertaking clinical experiments with human volunteers, reflecting the high standards of safety and ethics involved as well as the complex statistical issues.

Questions addressed by a protocol:

• What is the clinical question being asked by the trial?
• How should it be answered, in compliance with the standard ethical and regulatory requirements?
• What analyses should be performed in order to produce meaningful results?
• How will the results be presented?

Qualities of a good protocol:

• Clear, comprehensive, easy to navigate, and unambiguous.
• Designed in accordance with the current principles of Good Clinical Practice and other regulatory requirements.
• Gives a sound scientific background of the trial.
• Clearly identifies the benefits and risks of being recruited into the trial.
• Plainly describes trial methodology and practicalities.
• Ensures that the rights, safety, and well-being of trial participants are not unduly compromised.
• Gives enough relevant information to make the trial and its results reproducible.
• Indicates all features that assure the quality of every aspect of the the trial.

CLINICAL TRIAL PROTOCOL

The contents of a trial protocol should generally include the following topics. However,  site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.

General Information:

• Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
• Name and address of the sponsor and monitor (if other than the sponsor).
• Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
• Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial.
• Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
• Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
• Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.

Background Information:

• Name and description of the investigational product(s).
• A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
• Summary of the known and potential risks and benefits, if any, to human subjects.
• Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
• A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
• Description of the population to be studied.
• References to literature and data that are relevant to the trial, and that provide background for the trial.

Trial Objectives and Purpose:

• A detailed description of the objectives and the purpose of the trial.

Trial Design:
The scientific integrity of the trial and the credibility of the data from the trial depend
substantially on the trial design. A description of the trial design, should include:

• A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
• A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
• A description of the measures taken to minimize/avoid bias, including:

                    (a) Randomization.
                    (b) Blinding.

• A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
• The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
• A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
• Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
• Maintenance of trial treatment randomization codes and procedures for breaking codes.
• The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.

Selection and Withdrawal of Subjects:

• Subject inclusion criteria.
• Subject exclusion criteria.
• Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:

1. When and how to withdraw subjects from the trial/ investigational product treatment.
2. The type and timing of the data to be collected for withdrawn subjects.
3. Whether and how subjects are to be replaced.
4. The follow-up for subjects withdrawn from investigational product treatment/trial treatment.

Treatment of Subjects:

• The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
• Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
• Procedures for monitoring subject compliance. 

Assessment of Efficacy:

• Specification of the efficacy parameters.
• Methods and timing for assessing, recording, and analysing of efficacy parameters.

Assessment of Safety:

• Specification of safety parameters.
• The methods and timing for assessing, recording, and analyzing safety parameters.
• Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
• The type and duration of the follow-up of subjects after adverse events. 

Statistics:

• A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
• The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
• The level of significance to be used.
• Criteria for the termination of the trial.
• Procedure for accounting for missing, unused, and spurious data.
• Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final  report, as appropriate).
• The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).

Direct Access to Source Data/Documents:

• The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.

Quality Control and Quality Assurance:

Ethics:

• Description of ethical considerations relating to the trial.

Data Handling and Record Keeping:

Financing and Insurance:

• Financing and insurance if not addressed in a separate agreement. 

Publication Policy:

• Publication policy, if not addressed in a separate agreement. 

Supplements:
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)

When considering the above items, special attention must be given to designing a protocol that eliminates bias and reduces variance.

Key components of a trial protocol

The trial protocol is a comprehensive document and the core structure of the protocol should be adapted according to the type of trial. ICH–GCP can be used as a reference document when developing a protocol for pharmaceutical clinical trials (Phase I to Phase IV) involving a pharmaceutical substance (the investigational medicinal product [IMP]). Most institutions and pharmaceutical companies use a standard set of rules to define the main protocol outline, structure, format, and naming/numbering methods for their trials. In this section, we briefly describe the main components of a typical protocol.

Protocol information page:

The front page gives the:

• trial title
• trial identification number
• protocol version number
• date prepared

The descriptive title of the protocol should be kept as short as possible, but at the same time it should reflect the design, type of population, and aim of the trial. ICH–GCP suggests that the title of a pharmaceutical trial should additionally include the medicinal product(s), the nature of the treatment (eg, treatment, prophylaxis, diagnosis, radiosensitizer), any comparator(s) and/or placebo(s), indication, and setting (outpatient or inpatient). The key investigational site, investigator, and sponsor should also be detailed on the title page.

Trial summary or synopsis:

A synopsis should provide the key aspects of the protocol in no more than two pages, and can be prepared in a table format. The main components of the protocol summary include:

full title

• principal investigator
• planned study dates
• objectives
• study design
• study population
• treatments
• procedures
• sample size
• outcome measures
• statistical methods