1. Principles of Clinical Research By: Monali Desai

2. General responsibilities of Investigators

3. Common terms used in Clinical Research By: Monali Desai

4. Book Preview - ABC of Research Methodology and Applied Biostatistics by Dr.Mahendra Parikh

Principles of Clinical Research By: Monali Desai

India is fast becoming one of the biggest hubs for conducting global clinical trials. In 2007, the country conducted around 220 clinical trials, making up for less than 2 percent of the global clinical trials. But, according to a new research report, a number of factors such as low cost, large patient pool, easy recruitment, strong government support and strengthening of its intellectual property environment will enable India to conduct nearly 5 percent of the global clinical trials by 2012. The industry will spend 1500 crore plus on clinical trials in India, as per Goldman Sachs, Centre watch, Goldman Sachs and McKinsey.

What has led to this dramatic shift in the location of clinical trials? The change was made in response to vociferous demands from multinational drug companies and private organizations that conduct clinical research for a relaxation of the rules for drug trials — those necessary hurdles whose price tags can run to 40 percent of the cost of drug development. It has become increasingly difficult to test drugs in Western countries, with their strict regulations, elaborate safety and compensation requirements, and small populations, all of which make the recruitment of research subjects slow and expensive.

India is a particularly attractive site for such trials because of its genetically diverse population of more than 1 billion people with patient pollution suffering from infectious diseases to chronic illnesses. As most of the healthcare costs in India are paid 'out of pocket', a large patient population continues to have unmet medical needs. As a result, they may readily volunteer to participate in clinical trials to get free treatment. Virtually all Indian doctors speak English, and may have acquired postgraduate qualifications abroad, primarily in Britain or the United States. Added to these attractions are cheap labor and low infrastructure costs, which can reduce expenditures for clinical trials by as much as 60 percent. We, as clinicians, are interested in bringing more clinical trials to India as, study of pharmacogenomics gives evidence that drug response and adverse effects are based on one’s genes.  

In January 2005, the government of India enacted a new rule that allows foreign pharmaceutical companies and other interested parties to conduct trials of new drugs in India at the same time that trials of the same phase are being conducted in other countries. This new rule supersedes a directive of India's Drugs and Cosmetics Rules that required a "phase lag" between India and the rest of the world. According to the old rule, if a phase 3 study had been completed elsewhere, only a phase 2 study was permitted in India. Even under the new rule, phase 1 trials will not normally be permitted in India. The old rule was designed to protect Indians from being used as guinea pigs in the testing of unproved drugs of foreign origin; trials of domestically discovered drugs were not subject to this provision.

Despite the availability of infrastructure and demand in India, the area of Clinical Research (CR) is still in its infancy here. The country has more than half a million practicing doctors, but fewer than 200 investigators have been trained in good clinical practice in regards to CR. Among some 14,000 general hospitals, no more than 150 have the adequate infrastructure to conduct trials, and there are fewer than a dozen pathology laboratories that meet the criteria for compliance with good laboratory practice. Only about half of the large hospitals have institutional review boards, and even these boards have not yet formulated standard operating procedures — and they, too, often lack the expertise with which to evaluate protocols. Information about conflicts of interest is neither sought nor voluntarily provided by investigators. Furthermore, the Drugs Controller General of India (DCGI) — the equivalent of the U.S. Food and Drug Administration (FDA) — is understaffed and lacks the expertise to evaluate protocols.

In 2001, self-styled researchers working in their own clinics formulated "vaginal pellets" of erythromycin and tried them as contraceptive agents in more than 790 poor, illiterate, rural women in West Bengal. In 2003, letrozole, an anticancer drug, was tested in more than 430 young women at a dozen private clinics to find out whether it promoted ovulation. All these trials took place without regulatory approval. Adverse coverage in the media, that trials in India are illegal and unethical trials, could mean a loss of opportunity for India to make a mark on the CR industry.

This calls for the development of its capacities and capabilities in terms of infrastructure, regulatory structure, and formulation of specialized pool of research investigators. The aim by Indian Council of Medical Research is to generate such professionals who can represent India in good light, which attracts further international collaborations. Also, this will help to organize this sector in a well-defined mould, whose interests will have to be catered at both local and international level. This will go a long way in launching and boosting India as a major player in this area of research and ensure that it does not lag behind for want of trained manpower.

Currently, per clinicaltrials.org a central registry for all clinical trials, there are 2208 clinical trials in Gynecology and 128 trials in Obstetrics, with 7 being done in India. There are over 31 pregnancy registries with minimal inputs from obstetricians from India.  While we as Investigators in developing countries could benefit from rigorous training in the design, conduct, and ethical oversight of trials, which would allow us to engage more fully in multinational clinical research at a leadership level, pressures at work and time constraints may limit us from attending professional courses.

In following few months I wish to share some topics which could help some reader’s take active part in this interesting field. The topics I have in mind are starting with some common terminologies used in clinical research, responsibilities of an Investigator, training of staff, FDA rules pertaining to an investigator, registering a trial, ethical review committees and any other topic requested by reader’s.

 References:

A K Nair (2009) Retrieved on 23 Feb 2009 from http://www.expresspharmaonline.com/20090215/management02.shtml

Samiran Nundy, M.Chir, Chandra M. Gulhati (2005).A New Colonialism? — Conducting Clinical Trials in India. New England Journal of Medicine.  Volume 352, Number 16:1633-1636

Seth W. Glickman et al.( 2009)  Ethical and Scientific Implications of the Globalization of Clinical Research. New England Journal of Medicine. Volume 360, Number 8 :816-823

General responsibilities of Investigators:

An Investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall, in accordance with the Code of Federal Regulations and ICH/GCP Guidelines, obtain the informed consent of each human subject to whom the drug is administered, except as provided in CFR50.23.

The Investigator shall:

• Maintain IRB approval to conduct the clinical trial and report to the IRB as required. The IRB must assume continued responsibility for the study and review the research on at least an annual basis.

• Maintain a file of all communications with the IRB on issues related to the clinical trial.

• Complete, sign, and return to Kendle a Form FDA 1572 including a current CV for the Principal Investigator, Sub-Investigator(s), and any study personnel involved, if listed.

• Conduct the study in strict adherence to the protocol.

• Supervise the use of the study drug as outlined in the protocol. The study drug may be provided by medical doctors or study staff working under the supervision of an Investigator who is a medical doctor.

• Store the study drug in a secure and locked area with limited access. The storage and custody of the study drug are responsibilities of the Investigator.

• Maintain adequate records of the receipt and disposition of all study drug (including dates, quantities and use by the study subjects).

• Inform each subject of the risks and benefits of participating in the study and obtain a properly signed, dated and witnessed (if applicable) informed consent form for each subject before he or she begins any study–related procedures.

• Document all adverse events on the CRF; document all Serious Adverse Events (SAEs) on the SAE Form and immediately notify Kendle via phone and fax.

• Report all SAEs to the IRB.

• Maintain a master log of all subjects screened for the study and establish a system to alert clinic staff of scheduled follow-up visits; provide clinic staff with a system for contacting study subjects who do not return for scheduled follow-up.

• Document and maintain accurate CRFs for all subjects. As required, sign forms ascertaining the accuracy of data recorded. Storage and custody of all study related records are the responsibility of the Investigator.

• Retain the copies of the CRFs, the original informed consent forms and all study-related documentation of the study site for at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.

• Make available all study subjects’ records to staff and representatives from monitoring or regulatory office.

• Be thoroughly familiar with the properties of the investigational agent as described in the Clinical Investigator Brochure.

• Ensure that sufficient time is allotted to conduct and complete the study; ensure adequate staff and facilities are available for the duration of the study; and ensure that other studies do not divert essential subjects or facilities from the study at hand.

• Provide information to all staff members involved with the study or with other elements of the subject’s management.

• Ensure that the confidentiality of all information about the subjects and the information supplied by Kendle is respected by all persons.

Common terms used in Clinical Research:

Rules and principles for Clinical trials were first introduced in Avicenna's The Canon of Medicine in 1025 AD, which still form the basis of modern clinical trials:

1. "The drug must be free from any extraneous accidental quality."
2. "It must be used on a simple, not a composite, disease."
3. "The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones."
4. "The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them."
5. "The time of action must be observed, so that essence and accident are not confused."
6. "The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect."
7. "The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man."

Coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ICH HARMONISED TRIPARTITE GUIDELINE. The guidelines are continuously being updated and are have open excess to all at http://www.ich.org/cache/compo/276-254-1.html

Following are some common terms used in clinical trials.

ADVERSE REACTION: (Adverse Event.) An unwanted effect caused by the administration of drugs. Onset may be sudden or develop over time.

CLINICAL: Pertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science.

CLINICAL INVESTIGATOR/ Principal Investigator: A medical researcher in charge of carrying out a clinical trial's protocol. Sub Investigator: A medical researcher assisting the PI.

CLINICAL TRIAL: A clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments. Clinical trials (also called medical research and research studies) are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. Trials are in four phases: Phase I –IV.

COMMUNITY-BASED CLINICAL TRIAL (CBCT): A clinical trial conducted primarily through primary-care physicians rather than academic research facilities.

COMPASSIONATE USE: A method of providing experimental therapeutics prior to final FDA approval for use in humans. This procedure is used with very sick individuals who have no other treatment options. Often, case-by-case approval must be obtained from the FDA for "compassionate use" of a drug or therapy.

COMPLEMENTARY AND ALTERNATIVE THERAPY: Broad range of healing philosophies, approaches, and therapies that Western (conventional) medicine does not commonly use to promote well-being or treat health conditions. Examples include acupuncture, herbs, etc.

CRA: A clinical research associate ensures compliance with the clinical trial protocol, checks clinical site activities, makes on-site visits, reviews Case Report Forms (CRFs) and communicates with clinical research investigators. A clinical research associate is usually required to possess an academic degree in Life Sciences and needs to have a good knowledge of Good clinical practice and local regulations.

CASE REPORT FORM: A Case Report Form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site. All data on each patient participating in a clinical trial are held and/or documented in the CRF, including adverse events

CRO: A Contract Research Organization (CRO) is a service organization that provides support to the pharmaceutical/biotech industry in the drug and medical device research & development process.

DATA SAFETY AND MONITORING BOARD (DSMB): An independent committee, composed of community representatives and clinical research experts, that reviews data while a clinical trial is in progress to ensure that participants are not exposed to undue risk. A DSMB may recommend that a trial be stopped if there are safety concerns or if the trial objectives have been achieved.

DOSE-RANGING STUDY: A clinical trial in which two or more doses of an agent (such as a drug) are tested against each other to determine which dose works best and is least harmful.

DOUBLE-BLIND STUDY: A clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo (or another therapy). Double-blind trials are thought to produce objective results, since the expectations of the doctor and the participant about the experimental drug do not affect the outcome; also called double-masked study.

DRUG-DRUG INTERACTION: A modification of the effect of a drug when administered with another drug. The effect may be an increase or a decrease in the action of either substance, or it may be an adverse effect that is not normally associated with either drug.

EFFICACY: (Of a drug or treatment). The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the procedure mandated by the FDA, Phase II clinical trials gauge efficacy, and Phase III trials confirm it .

ENDPOINT: Overall outcome that the protocol is designed to evaluate. Common endpoints are severe toxicity, disease progression, or death.

ENROLLING: The act of signing up participants into a study. Generally this process involves evaluating a participant with respect to the eligibility criteria of the study and going through the informed consent process.

EXPERIMENTAL DRUG: A drug that is not FDA licensed for use in humans, or as a treatment for a particular condition

FROM 1572: Form submitted by Principal Investigator which contains contact details, CV, financial disclosure, conflict of interest and agreement to conduct the study with ICH GCP guidelines

INCLUSION/EXCLUSION CRITERIA: The medical or social standards determining whether a person may or may not be allowed to enter a clinical trial. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. It is important to note that inclusion and exclusion criteria are not used to reject people personally, but rather to identify appropriate participants and keep them safe.

INSTITUTIONAL REVIEW BOARD (IRB): 1. A committee of physicians, statisticians, researchers, community advocates, and others that ensures that a clinical trial is ethical and that the rights of study participants are protected. All clinical trials in the U.S. must be approved by an IRB before they begin. 2. Every institution that conducts or supports biomedical or behavioral research involving human participants must, by federal regulation, have an IRB that initially approves and periodically reviews the research in order to protect the rights of human participants.

INTENT TO TREAT: Analysis of clinical trial results that includes all data from participants in the groups to which they were randomized even if they never received the treatment.

INVESTIGATIONAL NEW DRUG: A new drug, antibiotic drug, or biological drug that is used in a clinical investigation. It also includes a biological product used in vitro for diagnostic purposes.

NEW DRUG APPLICATION (NDA): An application submitted by the manufacturer of a drug to the FDA - after clinical trials have been completed - for a license to market the drug for a specified indication.

OFF-LABEL USE: A drug prescribed for conditions other than those approved by the FDA.

ORPHAN DRUGS: An FDA category that refers to medications used to treat diseases and conditions that occur rarely. There is little financial incentive for the pharmaceutical industry to develop medications for these diseases or conditions. Orphan drug status, however, gives a manufacturer specific financial incentives to develop and provide such medications.

PEER REVIEW: Review of a clinical trial by experts chosen by the study sponsor. These experts review the trials for scientific merit, participant safety, and ethical considerations.

PHARMACOKINETICS: The processes (in a living organism) of absorption, distribution, metabolism, and excretion of a drug or vaccine.

PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients.

PHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks.

PHASE III TRIALS: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling.

PHASE IV TRIALS: Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use.

PRECLINICAL: Refers to the testing of experimental drugs in the test tube or in animals - the testing that occurs before trials in humans may be carried out.

PROTOCOL: A study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

QUERY: Any clarification sought from the clinical monitor, data associates or sponsor

RECRUITING: The period, during which a trial is attempting to identify and enroll participants for the study. Recruitment activities can include advertising and other ways of solicting interest from possible participants.

RISK-BENEFIT RATIO: The risk to individual participants versus the potential benefits. The risk/benefit ratio may differ depending on the condition being treated. .

STUDY CORDINATOR: They are employed by Principal investigators. Study coordinators work directly with study volunteers, providing them safety and protection while collecting and managing the study data. They promote, advertise, and conduct telephone and face-to-face screenings to recruit volunteers. During the study process, they assess volunteer condition and coordinate ongoing clinical/laboratory testing and physical exams.

STUDY ENDPOINT: A primary or secondary outcome used to judge the effectiveness of a treatment.

STUDY TYPE: The primary investigative techniques used in an observational protocol; types are Purpose, Duration, Selection, and Timing.

TOXICITY: An adverse effect produced by a drug that is detrimental to the participant's health. The level of toxicity associated with a drug will vary depending on the condition which the drug is used to treat.

TREATMENT IND: IND stands for Investigational New Drug application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the U.S. It makes promising new drugs available to desperately ill participants as early in the drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial.