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1) What is the definition of a Contract Research Organization (CRO)?
A CRO can be defined as an organization which specializes in research which it offers to undertake for a client in return for payment.
2) What is preclinical research?
Preclinical research takes place before a compound is deemed safe or effective enough to be tested on humans. The preclinical research can take the form of efficacy studies in in vivo and in vitro disease models, basic pharmacology, toxicology or safety studies.
3) Where do preclinical services of Ethix fit into the drug development “value chain”?
Once a compound has been identified as a potential drug from a chemical series, its actions against receptors, cells, tissues, organs and whole animal systems has to be determined. If the organization or the originators of the drug under development do not have the internal resource to explore these actions ‘in house’ a reliable CRO can be employed to undertake the preclinical development that is essential prior to entering the compound into clinical development. In addition a reliable CRO like Ethix Pharma can be used as an independent validation body to confirm in-house results.
4) How regulated are preclinical services in Ethix?
It is important that a CRO is self regulating and that if they undertake in vivo studies that these are done under the auspices of an ethical review board. At Ethix we are able to provide client references that speak to the high standards of their work as well as all regional and national standards related to the nature of the research performed in their laboratories. Final reports always comply with ICH, FDA, OECD and EMEA regulations for non clinical studies.
5) How are the ethical issues handled?
Ethical issues concerning animal welfare should be dealt with by the local governmental ethical review board (CPCSEA). Governmental ethical review boards differ greatly from region to region and a potential client should always ensure that the strictest ethical guidelines are observed at all times. Ethix also has an internal ethical committee that works to ensure that all studies are carried out in accordance with the highest possible ethical standards.
6) How are issues of Intellectual Property Handled?
All IPR is owned by the study originator. Ethix Pharma works to ensure that there is no discrepancy about this issue. Ethix Pharma works exclusively for, and on behalf of, the client. The research services contract that Ethix Pharma signs will be explicit with regards to client ownership of results, IPR and publication rights. Since Ethix Pharma is not an academic organization there are none of the ownership issues that traditionally surround academic research.
7) How are issues of confidentiality handled?
A non disclosure agreement (NDA) is always signed before discussion of project details takes place. This NDA will ensure that all matters discussed remain in strictest confidence.
8) Can results be published on without authorship of Ethix Pharma?
The results belong to the client and can therefore be published in any form and with any authorship the client sees fit. However, Ethix Pharma service extends much further than simply generating results and we are enthusiastic to be involved in all aspects of data reporting and communication. We feel this reflects the strong relationships we build with our clients which allows them to avail themselves of the wealth of experience within the company. However, as with items 6 and 7 above the final decision on these issues always resides with the client.
9) What about the independent validation of in-house generated results?
Before moving a compound into clinical development many investigators will demand the reproduction of ‘in house’ data in another laboratory. A preclinical CRO is ideally placed to provide an unbiased study based on the original which can validate existing efficacy data and so allow the compound to be developed with the confidence that the efficacy data is robust and reproducible.
· What about cost?
Prices charged for preclinical contract work can vary dramatically. A client should be aware of the cost of the resources involved in undertaking the experiment and also the value placed on the difficulty of the model and experience needed to successfully execute the study design.
10) What can I tell about the overall efficacy of the compound after an Ethix Pharma study?
Ethix Pharma studies will always apply the most pertinent statistical analysis to data sets so a client can be confident that when a statistical difference is observed it is reflected in the results reported. Ethix Pharma scientists are continually striving to generate the maximum value from any given assay and the creativity and innovation we apply to our model platforms is geared toward reflecting compound efficacy in each assay.
11) What about translational factors or “bridging to the clinic”?
The generation of data in animal models that can be directly comparable to the data generated in patients is becoming an essential part of a preclinical data package. Ethix Pharma is acutely aware of this concept and as such work very hard to include parameters seen in the clinic, such as behavioral testing, imaging and biomarkers analysis in preclinical studies so that we deliver maximum value to the client. This translational strategy aims to maximize the potential of success of a client’s compound in the clinic.
12) How quickly can studies be started?
The time to commence a study depends on the nature of the CRO and the study. Ethix Pharma works within its own proprietary laboratories with its own dedicated staff so studies can be scheduled within weeks of an agreement being reached with the client. As the nature of studies varies so does the time to commence studies, for example, if the study involves transgenic subjects then one must take into account the time needed to breed the requisite number of subjects for the study unless, as is often the case, there are cohorts of these animals readily available.
13) Can models be customized?
Virtually every study which Ethix Pharma undertakes has been tailored to the requirements of the client. Studies differ with regards to route of administration (I.V, I.M, I.P, ICV, Intrathecal administration etc.) Every client has different needs and an effective CRO should always look to tailor a study to suit the needs of a client, and more importantly, to the premise behind the clients compound
14) The issue of the positive control?
There are some models for which there are very effective positive controls or reference compounds. These can be used to great effect to validate the assay and compare efficacy with a compound under development. Not all assays, however, have a compound that can be relied upon to produce consistent results. This is due either to the complexity and severity of the assay or the quality of available pharmacological tools.
15) What is a clinical trial?
A clinical trial is a research study to answer specific questions about vaccines, 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.
16) Why participate in a clinical trial?
Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.
17) Where do the ideas for trials come from?
Ideas for clinical trials usually come from researchers. After researchers test new therapies or procedures in the laboratory and in animal studies, the treatments with the most promising laboratory results are moved into clinical trials. During a trial, more and more information is gained about a new treatment, its risks and how well it may or may not work.
18) Who sponsors clinical trials?
Clinical trials are sponsored or funded by a variety of organizations or individuals such as physicians, voluntary groups, and pharmaceutical companies, in addition to medical institutions such as the All India Institute of Medical Sciences (AIIMS). Trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics.
19) What is a protocol?
A protocol is 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.
20) What is a placebo?
A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment.
What is a control or control group?
A control is the standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.
21) What are the different types of clinical trials?
Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes. Screening trials test the best way to detect certain diseases or health conditions. Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
22) What are the phases of clinical trials?
Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: In Phase I trials, researchers test a new 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 II trials, the study drug or 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 III trials, the study drug or 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 the drug or treatment to be used safely. In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
23) Participation in Clinical Trials
For those considering participation in a clinical trial, the following frequently asked questions are important in understanding the role of the participant and the unique process of clinical trials.
24) Who can participate in a clinical trial?
All clinical trials have guidelines about who can participate. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results. The factors that allow someone to participate in a clinical trial are called "inclusion criteria" and those that disallow someone from participating are called "exclusion criteria". These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.
25) What happens during a clinical trial?
The clinical trial process depends on the kind of trial being conducted (See what the different types of clinical trials are?) The clinical trial team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed.
Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team. Clinical trial participation is most successful when the protocol is carefully followed and there is frequent contact with the research staff.
26) What is informed consent?
Consent is the process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in the trial explain the details of the study. If the participant's native language is not English, translation assistance can be provided. Then the research team provides an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time.
27) What kind of preparation should a potential participant make for the meeting with the research coordinator or doctor?
Plan ahead and write down possible questions to ask. Ask a friend or relative to come along for support and to hear the responses to the questions.
28) What should people consider before participating in a trial?
People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial. The following questions might be helpful for the participant to discuss with the health care team. Some of the answers to these questions are found in the informed consent document.
What is the purpose of the study?
Who is going to be in the study?
Why do researchers believe the new treatment being tested may be effective?
Has it been tested before?
What kinds of tests and treatments are involved?
How do the possible risks, side effects, and benefits in the study compare with my current treatment?
How might this trial affect my daily life?
How long will the trial last?
Will hospitalization be required?
What type of long-term follow up care is part of this study?
Who will pay for the treatment?
Will I be reimbursed for other expenses?
How will I know that the treatment is working?
Will results of the trials be provided to me?
Who will be in charge of my care?
29) Does a participant continue to work with a primary health care provider while in a trial?
Yes. Most clinical trials provide short-term treatments related to a designated illness or condition, but do not provide extended or complete primary health care. In addition, by having the health care provider work with the research team, the participant can ensure that other medications or treatments will not conflict with the protocol.
30) What are side effects and adverse reactions?
Side effects are any undesired actions or effects of drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental treatments must be evaluated for both immediate and long-term side effects.
31) What are the benefits and risks of participating in a clinical trial?
Clinical trials that are well-designed and well-executed are the best treatment approach for eligible participants to:
Play an active role in their health care
Gain access to new research treatments before they are widely available
Obtain expert medical care at leading health care facilities during the trial
Help others by contributing to medical research
There are risks to clinical trials
There may be unpleasant, serious or even life-threatening side effects to treatment.
The treatment may not be effective for the participant
The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements
32) How is the safety of the participant protected?
The ethical and legal codes that govern medical practice also apply to clinical trials. In addition, most clinical research is federally regulated with built in safeguards to protect the participants. The trial follows a carefully controlled protocol, a study plan which details what researchers will do in the study. As a clinical trial progresses, researchers report the results of the trial at scientific meetings, to medical journals, and to various government agencies. Individual participants' names will remain secret and will not be mentioned in these reports. Every clinical trial in India must be approved and monitored by an Institutional Review Board (IRB) to make sure the risks are as low as possible and are worth any potential benefits. An IRB is an independent committee of physicians, statisticians, community advocates, and others that ensures that a clinical trial is ethical and the rights of study participants are protected. All institutions that conduct or support biomedical research involving people must, by Indian regulation (Schedule Y), have an IRB that initially approves and periodically reviews the research.
33) Can a participant leave a clinical trial after it has begun?
Yes. A participant can leave a clinical trial, at any time. When withdrawing from the trial, the participant should let the research team know about it, and the reasons for leaving the study.
34) Adverse Drug Reaction (ADR)
An unintended reaction to a drug taken at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. In clinical trials, an ADR would include any injuries by overdosing, abuse/dependence, and unintended interactions with other medicinal products.
35) Adverse Event (AE)
A negative experience encountered by an individual during the course of a clinical trial that is associated with the drug. An AE can include previously undetected symptoms, or the exacerbation of a pre-existing condition. When an AE has been determined to be related to the investigational product, it is considered an Adverse Drug Reaction.
36) Adverse Event Reports
Investigator reports of all serious and adverse events, injury and deaths given to the sponsor, the IRB and the FDA.
The process through which one or more parties to a clinical trial are unaware of the treatment assignments. In a single-blinded study, usually the subjects are unaware of the treatment assignments. In a double-blinded study, both the subjects and the investigators are unaware of the treatment assignments. Also, in a double-blinded study, the monitors and sometimes the data analysts are unaware. "Blinded" studies are conducted to prevent the unintentional biases that can affect subject data when treatment assignments are known.
38) Case Report Form (CRF)
A record of pertinent information collected on each subject during a clinical trial, as outlined in the study protocol.
39) Clinical Investigation
A systematic study designed to evaluate a product (drug, device, or biologic) using human subjects, in the treatment, prevention, or diagnosis of a disease or condition, as determined by the product's benefits relative to its risks. Clinical investigations can only be conducted with the approval of the Food and Drug Administration (FDA).
40) Clinical Research
Study of drug, biologic or device in human subjects with the intent to discover potential beneficial effects and/or determine its safety and efficacy. It is also called clinical study and clinical investigation.
41) Clinical Research Associate (CRA)
Person employed by the study sponsor or CRO to monitor a clinical study at all participating sites. See also, monitor.
42) Clinical Research Coordinator (CRC)
Site administer for the clinical study. Duties are delegated by the investigator. Also called research, study or healthcare coordinator
43) Clinical Study Materials
Study supplies (i.e., study test article, laboratory supplies, case report forms) provided by the study sponsor to the investigator.
44) Clinical Trial
Any investigation in human subjects intended to determine the clinical pharmacological, pharmacokinetic, and/or other pharmacodynamic effects of an investigational agent, and/or to identify any adverse reactions to an investigational agent to assess the agent's safety and efficacy.
45) Consent Form
A document explaining all relevant study information to assist the study volunteer in understanding the expectations and requirements of participation in a clinical trial. This document is presented to and signed by the study subject.
46) Site Management Organization (SMO)
A person or an organization (commercial, academic or other) contracted by the sponsor to perform all study related duties limited to the trial site. SMO also works closely with the Investigators/Doctors and Hospitals enabling them to organize perform and execute successful clinical trials
47) Control Group
A comparison group of study subjects who are not treated with the investigational agent. The subjects in this group may receive no therapy, a different therapy, or a placebo.
This term is legally defined according to the institution. It generally refers to recorded information regardless of form. Most institutions hold title to data while researchers have rights to access the data.
49) Data Management
The process of handling the data gathered during a clinical trial. May also refer to the department responsible for managing data entry and database generation and/or maintenance.
50) Demographic Data
Refers to the characteristics of study participants, including sex, age, family medical history, and other characteristics relevant to the study in which they are enrolled.
An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is intended for use in the diagnosis, cure, treatment or prevention of disease. A device does not achieve its intended purpose through chemical action in the body and is not dependent upon being metabolized to achieve its purpose.
All forms of records that describe or document study methods, conduct and results, including any adverse events and actions taken.
The design of a study in which neither the investigator nor the subject knows which medication (or placebo) the subject is receiving.
As defined by the Food, Drug and Cosmetic Act, drugs are "articles (other than food) intended for the use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or to affect the structure or any function of the body of man or other animals."
55) Drug Product
A finished dosage form (e.g. tablet, capsule, or solution) that contains the active drug ingredient usually combined with inactive ingredients.
56) Drug or Device Accountability Records (DAR)
Required documentation for material accountability, quantity used and left over, and date of disposal.
57) Effective Dose
The dose of an investigational agent that produces the outcome considered "effective," as defined in the study protocol. This could mean a cure of the disease in question or simply the mitigation of symptoms.
A product's ability to produce beneficial effects on the duration or course of a disease. Efficacy is measured by evaluating the clinical and statistical results of clinical tests.
59) Ethics Committee
An independent group of both medical and non-medical professionals who are responsible for verifying the integrity of a study and ensuring the safety, integrity, and human rights of the study participants.
60) Exclusion Criteria
Refers to the characteristics that would prevent a subject from participating in a clinical trial, as outlined in the study protocol.
61) Good Clinical Practice (GCP)
International ethical and scientific quality standard for designing, conducting, monitoring, recording, auditing, analyzing and reporting studies. The guidelines are to ensure that the data reported is credible and accurate, and that subject's rights and confidentiality are protected.
62) Human Subject
A patient or healthy individual participating in a research study. A living individual about whom an investigator obtains private information or data through intervention or interaction.
63) Inclusion Criteria
A list of criteria that must be met by all study subjects.
64) Informed Consent
Voluntary verification of a patient’s willingness to participate in a clinical trial and along with the documentation. This verification is requested only after complete, objective information has been given about the trial, including an explanation of the study's objectives, potential benefits, risks and inconveniences, alternative therapies available, and of the subject's rights and responsibilities in accordance with the current revision of the Declaration of Helsinki.
Location of research. Retains ultimate responsibility for human subject regulation compliance.
66) Institutional Review Board (IRB)
An independent group of professionals designated to review and approve the clinical protocol, informed consent forms, study advertisements, and patient brochures, to ensure that the study is safe and effective for human participation. It is also the IRB's responsibility to ensure that the study adheres to the Schedule Y regulations.
A medical professional, usually a physician but may also be a nurse, pharmacist or other health care professional, under whose direction an investigational drug is administered or dispensed. A principal investigator is responsible for the overall conduct of the clinical trial at his/her site.
68) Investigator's Brochure
Relevant clinical and non-clinical data compiled on the investigational drug, biologic or device being studied.
Person employed by the sponsor or CRO who reviews study records to determine that a study is being conducted in accordance with the protocol. A monitor's duties may include, but are not limited to, helping to plan and initiate a study, and assessing the conduct of studies. Monitors work with the clinical research coordinator to check all data and documentation from the study. See also CRA
Reviewing a clinical study, ensuring conduct, proper records and reports are performed as stated in the clinical protocol, standard operating procedures, GCP and by regulatory requirements.
The study of cost-benefit ratios of drugs with other therapies or with similar drugs. Pharmacoeconomic studies compare various treatment options in terms of their cost, both financial and quality-of-life. Also referred to as "outcomes research".
72) Phase I Study
The first of four phases of clinical trials, Phase I studies are designed to establish the effects of a new drug in humans. These studies are usually conducted on small populations of healthy humans to specifically determine a drug's toxicity, absorption, distribution and metabolism.
73) Phase II Study
After the successful completion of phase I trials, a drug is then tested for safety and efficacy in a slightly larger population of individuals who are afflicted with the disease or condition for which the drug was developed.
74) Phase III Study
The third and last pre-approval round of testing of a drug is conducted on large populations of afflicted patients. Phase III studies usually test the new drug in comparison with the standard therapy currently being used for the disease in question. The results of these trials usually provide the information that is included in the package insert and labeling.
75) Phase IV Study
After a drug has been approved by the FDA/Local Regulatory Bodies, phase IV studies are conducted to compare the drug to a competitor, explore additional patient populations, or to further study any adverse events.
76) Pivotal Study
Usually a phase III study which presents the data that the FDA/ Local Regulatory Bodies uses to decide whether or not to approve a drug. A pivotal study will generally be well-controlled, randomized, of adequate size, and whenever possible, double-blind.
An inactive substance designed to resemble the drug being tested. It is used as a control to rule out any psychological effects testing may present. Most well-designed studies include a control group which is unwittingly taking a placebo.
78) Pre-Clinical Testing
Before a drug may be tested on humans, pre-clinical studies must be conducted either in vitro but usually in vivo on animals to determine that the drug is safe.
A detailed plan that sets forth the objectives, study design, and methodology for a clinical trial. A study protocol must be approved by an IRB before investigational drugs may be administered to humans.
80) Protocol Amendment
Changes or clarifications made in writing to the original protocol.
81) Quality Assurance
Systems and procedures designed to ensure that a study is being performed in compliance with Good Clinical Practice (GCP) guidelines and that the data being generated is accurate.
Study participants are usually assigned to groups in such a way that each participant has an equal chance of being assigned to each treatment (or control) group. Since randomization ensures that no specific criteria are used to assign any patients to a particular group, all the groups will be equally comparable.
Act of enrolling subjects with the proper inclusion criteria.
84) Recruitment Period
Time allowed to recruit all subjects for a study.
85) Regulatory Affairs
In clinical trials, the department or function that is responsible for ensuring compliance with government regulations and interacts with the regulatory agencies. Each drug sponsor has a regulatory affairs department that manages the entire drug approval process.
86) Research Team
Investigator, sub-investigator and clinical research coordinator involved with study.
87) Risk-Benefit Ratio
Risk to individual subject vs. potential benefits. Also called Risk-Benefit Analysis.
88) Safety Reports
FDA report required by investigator for any serious and unexpected adverse experience.
89) Serious Adverse Event (SAE)
Any adverse event (AE) that is fatal, life-threatening, permanently disabling, or which results in hospitalization, initial or prolonged.
90) Source Data
All information contained in original records and certified copies of results, observations or other facets required for the reconstruction and evaluation of the study that is contained in source documents.
91) Source Documentation
Location where information is first recorded including original documents, data and records.
Individual, company, institution or organization taking responsibility for initiation, management and financing of study.
93) Standard Operating Procedure (SOP)
Official, detailed, written instructions for the management of clinical trials. SOPs ensure that all the functions and activities of a clinical trial are carried out in a consistent and efficient manner.
94) Standard Treatment
The currently accepted treatment or intervention considered to be effective in the treatment of a specific disease or condition.
Helps design and conduct investigation at a study site.
96) Unexpected Adverse Drug Reaction
A reaction that is not consistent in nature or severity with study application.
97) Vulnerable Subjects
Group/individual that cannot give informed consent because of limited autonomy (e.g., children, mentally ill and prisoners). Also refers to subjects who may be unduly influenced to participate (e.g., students, subordinates and patients).
Subject's physical and mental soundness
99) Withdrawal Application
Investigator/sponsor letter to FDA requesting application withdrawal when no additional work is envisioned.