CLINICAL TRIALS

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Clinical trials are sets of tests in medical research and drug development that generate safety and efficacy data (or more specifically, information about adverse drug reactions and adverse effects of other treatments) for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). They are conducted only after satisfactory information has been gathered on the quality of the nonclinical safety, and health authority/ethics committee approval is granted in the country where approval of the drug or device is sought. Previously, many emerging countries did not require local trials for product approvals. Now, though emerging countries still accept data from U.S./Europe, they also require some local trials.

Depending on the type of product and the stage of its development, investigators initially enroll volunteers and/or patients into small pilot studies, and subsequently conduct larger scale studies in patients that often compare the new product with others already approved for the affliction of interest. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size, and can involve a single research entity in one country or many such entities in multiple countries.

A full series of trials may incur sizable costs, and the burden of paying for all the necessary people and services is usually borne by the sponsor, which may be a governmental organization or a pharmaceutical, biotechnology or medical device company. When the diversity of required support roles exceeds the resources of the sponsor, a clinical trial is managed by an outsourced partner, such as a contract research organization or a clinical trials unit in the academic sector.

Phases

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 0, 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population.

Phase 0: Pharmacodynamics and Pharmacokinetics
Phase 1: Screening for safety
Phase 2: Establishing the testing protocol
Phase 3: Final testing
Phase 4: Postapproval studies

Each phase has a different purpose and helps scientists answer a different question:

In Phase 0 trials are the first-in-human trials. Single subtherapeutic doses of the study drug are given to a small number of subjects (10 to 15) to gather preliminary data on the agent’s pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).

In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 trials, the experimental treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 trials, the treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.

In Phase 4 trials, postmarketing studies delineate additional information, including the treatment’s risks, benefits, and optimal use.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies.

Design

A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. Types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. However, under certain conditions, causal effects can be inferred from these studies.

Under the right conditions, a randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.

Currently, some Phase 2 and most Phase 3 drug trials are designed as randomized, double-blind, and placebo-controlled.

Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This ‘blinding’ is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a “double-dummy” design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study.
Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect.

Although the term “clinical trials” is most commonly associated with the large, randomized studies typical of Phase 3, many clinical trials are small. They may be “sponsored” by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases, sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university

What is a clinical trial and how does a trial work?

Carefully conducted clinical trials are performed in human volunteers to provide answers to questions such as:

Does a treatment work?
Does it work better than other treatments?
Does it have side effects?

Clinical trials also provide important information on the cost-effectiveness of a treatment, the clinical value of a diagnostic test and how a treatment improves quality of life.

We conduct each trial according to a comprehensive plan, or protocol. The plan outlines the types of patients who can enter the trial, the schedule of tests and procedures, drugs and dosages, necessary follow up and the length of the study. It also describes the results (endpoints) that will be measured and the type of information to collect, which we then share with regulatory authorities to obtain marketing approval and with payers to get reimbursement.

Clinical trials are conducted in phases. Each phase is designed to answer certain questions, while taking steps necessary to safeguard the people taking part. Every new treatment is usually tested in three phases of clinical trials before regulatory agencies consider it safe and effective. Trials are also conducted according to Good Clinical Practice (GCP) guidelines that regulators require in order to protect patient safety.

What are clinical trials?

A clinical trial is a research study conducted in human beings with the goal of answering specific questions about new therapies, vaccines or diagnostic procedures, or new ways of using known treatments. Clinical trials are used to determine whether new drugs, diagnostics or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that help people.

After researchers test investigational new therapies or procedures in the laboratory and in animal studies, those with the most promising possibilities are moved into human clinical trials. Clinical trials are broken down into different phases. During a trial, more and more information is gained about the potential treatment, its risks and how well it may or may not work, along with aspects related to quality of life.

What are the different phases of a clinical trial?

Clinical trials are categorized as Phase I to IV trials. They are generally described as follows:

Phase I (small number of participants, normally between 6-10 healthy volunteers, or very sick patients for whom treatment options are lacking)

Phase I studies are designed to allow scientists and medical doctors to understand what effects an investigational compound has in human subjects. The goal is to study what happens to the compound in the body from a safety and tolerability point of view after it is swallowed, injected or infused. .Study participants are monitored for the occurrence and severity of any side effects that they may experience.

Phase II (once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups of patients, generally 20-300 depending on the type of disease)

Phase II studies are designed to begin to evaluate the safety and efficacy of an investigational medicine in patients, and often used to determine if different dosages of the treatment have different effects. The patients are given various doses of the compound and closely monitored to compare the effects and to determine the safest and most effective dosing regimen. In many instances, multiple Phase II studies are conducted to test the compound in a variety of patient populations or indications.

Phase III (carried out on large patient groups, 300–3,000 or more depending upon the disease being studied)

Phase III studies are designed to confirm the safety and efficacy of an investigational medicine. Large numbers of patients are generally involved in order to adequately confirm benefit and safety. These studies, as in the earlier phases, may involve one or more ‘treatment arms’, which allow for the safety and efficacy of the new investigational drug to be compared to other available treatments, or to be tested in combination with other therapies. Information obtained from Phase III studies is used to determine how the compound is best prescribed to patients in the future.

Phase IV (also known as Post-Marketing Surveillance Trials)

Phase IV studies take place after the medicine has received regulatory approval (market authorization) and are designed to provide broader efficacy and safety information about the new medicine in large numbers of patients, subpopulations of patients, and to compare and/or combine it with other available treatments. These studies are designed to evaluate the long-term effects of the drug. Under these circumstances, less common adverse events may be detected.

Why does Roche conduct clinical trials?

Clinical trials are an integral part of the drug and diagnostics discovery and development process. Before a new medicine or diagnostic test can be made available, evidence of its safety and effectiveness must be provided by well-designed, well-controlled, and carefully monitored clinical studies in patients consenting to participate.

Ethical clinical research is guided by the principles of nonmalificence, respect, beneficence and justice.

Nonmalificence is the duty to cause no harm. This principle has its roots in the Hippocratic Oath. The ethical issue at the core of clinical research is whether the outcome of the research can be reasonably expected to provide benefit to society without doing any harm to the individuals enrolled in the trial.
Respect for persons is embodied in informed consent, dictating that information is exhaustive and provided in a manner that is understandable, that the subject’s cooperation is voluntary, and that all information pertaining to the subject is held in confidence.
Beneficence is demonstrated by a thorough risk/benefit assessment, recognizing that benefits can be direct, collateral, and/or altruistic. Similarly, risks are considered in physiologic, psychological, and socioeconomic terms. For a clinical trial to be considered ethical, there must exist a sufficient body of scientific/medical evidence to justify exposure of individuals to the risks of the trial. There must be clear medical need, and the potential benefits to be gained by the research must be weighed against the possible risks to the participating person in both safety and effectiveness of the drug or intervention being studied.
The principle of justice takes into account all the processes by which populations are selected for study to ensure that the results benefit the community, avoid exploiting vulnerable populations, and include individuals who may be likely to benefit.

Which legal and ethical standards does Roche apply for its clinical trials?

The basic right of every person is to be treated with respect as an independent moral being. The dignity, rights, safety, and well-being of individuals participating in clinical research must be promoted and protected at all times and in any part of the world where clinical trials take place. Since participants in clinical research willingly provide information that cannot be obtained in any other way, they clearly deserve the gratitude and respect of the world community.

Roche is committed to following all international guidelines as well as local laws and regulations in the conduct of its clinical research programs. All Roche clinical studies are conducted in full conformance with the principles of the Declaration of Helsinki and with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The principles outlined in the “Guideline for Good Clinical Practice” ICH Tripartite Guideline (January 1997) are considered to be the minimum standard for Roche clinical trials. The Good Clinical Practice (GCP) guidelines includes standards on how clinical trials should be conducted, defines the roles and responsibilities of clinical trial sponsors, clinical research investigators and monitors. They also include protection of human rights of people participating in trials and provides assurance of the safety and efficacy of the newly developed compounds.

An especially important aspect of the Declaration of Helsinki is informed consent. The informed consent process should be one of shared information and decision making in which physicians and participants of the clinical research study openly discuss the research to be done and communicate their goals and values to each other. In this way, the process accommodates both the personal values and the well-being of the research participants as well as the responsibilities of physicians to make clear the risks and benefits of the research.

How is the adherence to legal and ethical standards controlled externally?

Roche respects human rights, human dignity, patient safety, and ethical principles. The company is committed to act ethically and to provide the highest standards of care to individuals participating in Roche sponsored clinical trials. Roche commits to protect the privacy of all individuals participating in Roche trials. This commitment aims at safeguarding all personal data protection rights and will ensure that no patients suffer any emotional or physical harm because of having participated in a Roche clinical trial.

Consequently, the company welcomes external controls of its clinical trials. The concept of independent oversight requires the review of proposed clinical research projects by qualified individuals independent from the investigators and sponsors. Independent review boards approve and provide oversight to studies involving human beings. In the US, these are known as Institutional Review Boards (IRBs), and in other parts of the world, they are called Independent Ethics Committees (IECs). These boards are composed of researchers, ethicists, legal experts, and community members. Such independent oversight helps ensure the integrity of the clinical research, both from the standpoint of scientific validity and the protection of participating individuals. Thus, there is a system in place that strives to provide scientific validity while protecting patients’ interests through meaningful informed consent, justice and independent oversight and review.

How does Roche ensure that clinical trials are carried out according to legal and ethical standards?

Roche has developed internal standards and systems to ensure that we comply with or exceed all guidelines, regulations, and legal requirements. All Roche employees who work on clinical trials for Roche products, as well as external contractors working with Roche, are required to strictly adhere to local laws and international guidelines, conduct their research with integrity, and apply the highest standards of medical care and respect for patients at all times.

To ensure this compliance, Roche will ensure that Good Clinical Practice (GCP) training is provided to employees working in clinical research and related areas. In addition, Roche has established internal processes to facilitate early discussion of and consultation on issues. This support mechanism allows employees to obtain independent advice if they need it. In addition, Roche staff is obligated to report any suspected issue of noncompliance with regulatory or ethical standards.

Roche has also established a process for discussing and resolving potential ethical issues that may arise during the course of everyday work in drug development. This framework incorporates a central point of contact for Roche staff and an escalation process to facilitate the consideration of alternative perspectives when appropriate.1 Any Roche employee, who is faced with an ethical dilemma or question can contact the Science and Ethics Advisory Group (SEAG) which is independent of the clinical teams. The SEAG will help clinical teams to find an appropriate answer or will escalate the issue, first, to an internal committee of experts. If need be, advice may be requested from an independent external advisory group composed of ethicists and experts from academia and the patient community.2

There is a deep understanding of, and belief in high ethical standards by all members of the Roche community. This translates into the practical application of these high ethical standards by each employee in his or her daily work responsibilities.

1) This process was formalized within Pharma Development in July 2003
2) For further information see Resolving Ethical Issues in Human Subject Research

What are the rights of participants in a clinical trial?

Participants are entitled to a clinical trial that adheres to all legal and ethical standards. In addition, participants have a right to:

A clear, transparent Informed Consent process before they agree to join the trial
Withdraw from the trial at any point in time

The Informed Consent process aims at answering any and all questions that might be relevant to a participant’s decision to agree or decline to join a trial. Only participants who, after having all their questions answered, sign an Informed Consent form can enter the trial. With their signature, participants confirm that they believe they have been given all the important facts about a trial, that they understand them, and that they decided to take part in the trial of their own free will.

An Informed Consent document is not a contract. Therefore, a participant may change his or her decision – any participant has the right to withdraw at any point of the trial. A withdrawal will not affect the participant’s relationship with their doctor nor will it result in a loss of benefits to which the participant is otherwise entitled. Potential medical risks of a sudden withdrawal from the trial should be detailed in the Informed Consent document.

How is the privacy of participants protected?

If a patient agrees to join a trial, some people will need to be told about the participation. These people are:

The patient’s primary physician who is responsible for their healthcare on a day-to-day basis
The doctor and research team looking after the patient in the trial

The fact that someone is taking part in a trial will be written in that patient’s medical notes. Investigators cannot tell anyone else about a participation in a trial unless the patient gives his or her permission.

During the trial, all of the information collected about the participants will be kept confidential, as with any other medical records. When investigators publish the results of a trial, they are not allowed to include any information that would identify people – a patient’s name will not be used in any reports or publications.

The clinical trial protocol will define what is to be done with samples and information of participants. Specific sections within this document will detail for how long samples and information must be kept before they are destroyed. If samples and/or information are to be used further, then this will be either:

included in the original trial protocol
be part of the informed consent a patient signs prior to his participation in the trial
be written up in a specific informed consent which the patient will also be asked to sign.

What kind of information does Roche publish on clinical trials?

Firstly, we will provide, upon request, clinical study reports (CSRs), periodic safety reports, and clinical trial summary reports, either through regulatory bodies such as the EMA, or directly. CSRs contain summaries of data and trial results regarding the safety and efficacy of the medicine but will not include any information that allows the identification of individual patients.

For requests for patient-level anonymised data (rather than CSRs), Roche will ask an independent panel of experts to review such requests. Access will be based on good scientific merit that will help patients and doctors in using our medicines.

All of Roche’s trial protocols are posted along with the results of trials once they are completed on two websites that are available to the public: clinicaltrials.gov and roche-trials.com. Finally we are also committed to publishing all of our global studies in medical journals.

This commitment is reflected in the Roche Global Policy on Sharing of Clinical Trials Data, which governs Roche’s Clinical Trial Protocol Registry and Clinical Trial Results Database. This global, public database was launched on April 15, 2005 and updated in 2013. The registry and the results database both contain information on all Roche- sponsored clinical trials in patients, worldwide, for marketed products, as well as interventional clinical studies sponsored by Roche Diagnostics. For further information see Registration of Clinical Trial Protocols and Publication of Clinical Trial Results Policy. For access to Roche’s Clinical Trial Protocol Registry and Clinical Trial Results Database, visit http://www.roche-trials.com/. Information on Roche clinical trial protocols can also be accessed via http://clinicaltrials.gov/.

What does the end of a clinical trial mean for participants?

Roche is obliged by Good Clinical Practice (GCP) international quality standard, regulations and laws to store the records of its clinical trials for a certain period of time (e.g.15 and more years). The end of a clinical trial has no impact on the confidentiality of those records; they will still be protected from disclosure to third parties.

We are committed to a high standard of quality and ethical conduct in all aspects of conducting clinical trials. For Roche sponsored trials, Roche commits to provide the investigational medicinal product free for the duration of the study, as required by GCP and in accordance with the regulatory requirements of the country. As part of this commitment and in accordance with the Declaration of Helsinki, Roche offers patients who participate in Roche-sponsored clinical trials continued access to the investigational medicinal product that they received after trial completion, when appropriate.

Does Roche work with contractors to carry out clinical trials?

Roche will work with qualified Contract Research Organizations (CROs) and other types of contractors whenever needed. In this context, Roche will apply the Roche Guidelines on Dealing with Suppliers and Service Providers (in force since October, 2004). In particular, the external organizations will be audited regularly to assure compliance with all Roche policies and procedures. All contractors with which Roche collaborates will be held to the same high ethical standards to which Roche adheres, and their work will be carefully supervised by Roche employees.

How do you select sites for your clinical trials?

We conduct our clinical trials at multiple investigational sites (e.g. hospitals) and in many different countries. The geographic diversity of these sites helps to ensure that the participants are representative of those who need and will benefit from the new medicine. However, we only perform trials in countries where we plan to market the medicine being tested.

We consider several factors when selecting sites for a trial:

Infrastructure – the country/site(s) should demonstrate experiences in clinical trial management activities which include independent ethics committees and a strong regulatory framework.
Facilities and training – Healthcare Professionals (investigators and their staff) selection criteria should be based on scientific expertise, training (clinical trial management and applicable laws and regulations) and qualifications as well as site-specific competency and feasibility.
Patient availability – adequate patient population should be available and willing to participate in the clinical trials.

Are the standards for clinical trials in developing countries different?

Conduct of clinical trials in developing countries presents a unique set of ethical issues. Where Roche undertakes clinical trials in developing countries, the same high standards of ethical conduct and scientific integrity will be adhered to, with the ultimate goal of delivering relaible results at the conclusion of the clinical research. For further information see Clinical Trials in Low and Middle Income Developing Countries.1

Where the results from a Roche Sponsored Clinical Trial in a low or middle income country are used for the purposes of registering the Roche medicinal product in another country, Roche commits to apply for marketing authorization of the medicinal product in the low or middle income country in which the trial was conducted.

DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,

Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.

Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now Sanofi Aventis, & Searle India ltd, now Rpg lifesciences, etc. He has worked in Basic research, Neutraceuticals, Natural products, Flavors, Fragrances, Pheromones, Vet Drugs, Drugs, formulation, GMP etc. He has total 29 yrs exp in this field, he is now helping millions, has million hits on google on all organic chemistry websites.

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