Trial design encompasses all the processes which are essential to ensure successful outcome of the clinical trial. It starts with framing the right research question based on the hypothesis and spans trial methodology and all related processes.

A well-developed proposal and protocol helps identify the critical elements of a trial. It ensures that the necessary practical requirements are in place, adequate funds are requested and facilitates securing necessary regulatory and ethical approvals.

The sections below are key to successful trial design:

Hypothesis

A hypothesis provides justification for a clinical trial, and helps establish its direction. It is developed from the main elements of the proposed research – sampling strategy, intervention (if applicable), comparison and outcome variables. The hypothesis is stated at the beginning, to guide the objectives of the trial. The investigator must adhere to the principles of clinical equipoise. According to this principle, there must exist a genuine uncertainty regarding the comparative therapeutic merits of each proposed arm in a trial.

The hypothesis is based on the primary research question, and must be developed before the start of the trial. It will influence the development of the research objectives and study design; and drive the data collection throughout the study.

Research Question

Defining a clear and focused research question is crucial. It helps narrow down aims and objective. Furthermore, once defined, the research question helps guide the methodology, sample size calculations, instruments to be used for collection of data and tools for data analyses. Numerous authors and experts have suggested pathways / steps to developing a research question, based on area of interest, critical review of the published literature (ideally systematic review), and identifying a well-defined problem.

The researcher may have multiple research questions. However, it is imperative that the primary research question is clearly defined, because it will guide the basis for the hypothesis, aims and objectives. The research question may change or get modified, as the researcher works through the various steps of trial design and literature review. Research questions can be answered through different methodologies:

• Quantitative: These are generally precise, and can be categorised as Descriptive, Comparative or Relationship.
• Qualitative: These are generally more flexible and adaptable.
• Mixed method studies: some researchers choose to develop separate quantitative and qualitative i.e. mixed method questions depending on the type of study being conducted.

Research Objectives

Research objective is a statement on how the clinical trial is going to answer a specific research question. As compared to the aims, these are generally more specific and are directly linked to the research question. The research questions may be divided into two categories:

• Primary: likely to be achieved, and directly linked with the hypothesis.
• Secondary: incidental objectives.

The research objectives should cover all aspects of the research problem, be specific, follow a logical sequence or order, achievable, based on the available resources and be mutually exclusive of each other. Some typical research objectives could be: exploratory, descriptive, explanatory, predictive or influential. When setting a research question the following criteria may also be applied: Specific, Measurable, Appropriate, Realistic and Time-specific (SMART – given by Doran in 1981).

The research objectives can also sometimes detail on the outcome measures going to the used, help guide the development of the protocol, study design and influence sample size calculations.

Trial Design

The effectiveness of an intervention depends on the interpretation of data generated during a trial, and its strength. In other words, the more controlled is the trial, the stronger is the data generated. Considering this, the design and conduct of the trial plays an extremely important role. The following should be kept in mind, while deciding or selecting a trial design:

1. ability of the design to answer the primary research question
2. is the trial exploring or studying a new treatment for a condition for which an effective treatment already exists?
3. is the condition life-threatening or severe?
4. what is the probability and extent of risk to the participants?
5. what is the population under study: its size, availability and accessibility
6. how will the data (collected during the present trial) be utilised: to start the new treatment or collection of preliminary data to inform larger trials, etc.

The choice of design depends on the above-listed factors and others, due to which it is difficult to offer any generalised suggestions. However, one must remember that adherence to the ethical principles, thereby minimising risks and ensuring voluntary consent is of paramount importance. Designs that incorporate these considerations should be considered over others. Randomisation and blinding or masking are techniques that help in risk minimisation. Both these topics are covered in the section of Trial Set-Up of this toolkit.

It is important to note that the regulations and guidelines (in India) might differ depending on the investigational product. It is recommended that the researcher refer these, wherever applicable:

New Chemical Entity	CDSCO’s page on New Drugs
Bioavailability / Bioequivalence Studies	CDSCO (guidance document) and page on BA and BE.
Medical Devices	Medical Devices Rules, 2017 and CDSCO’s page on Medical Devices.
Stem Cell Research	National Guidelines for Stem Cell Research (ICMR & DBT, 2017) FAQ’s on Stem Cell Research in India (ICMR)
AYUSH	GCP guidelines for clinical trials of ASU Medicine. The National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017 and Chapter IVA (Provisions relating to [Ayurveda, Siddha and Unani] Drugs) in the Drugs and Cosmetic Act, must be referred to as well. More details are available on CDSCO’s page on Traditional Drugs.
Diagnostics	CDSCO’s page on Diagnostics.

Regulations and guidelines for clinical research in India

National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (2017) – ICMR

Drugs and Cosmetics Act ,1940 and Rules, 1945 (as amended up to the 31st December, 2016)

New Drugs and Clinical Trial Rules, 2019, G.S.R. 227(E)

Good Clinical Practice guidelines – India (CDSCO)

Good Clinical Practice guidelines – ICH E6(R2)

National Ethical Guidelines for Biomedical Research Involving Children (2017) – ICMR

CDSCO’s page on Clinical Trials.

Handbook for Applicants and Reviewers of Clinical Trials of New Drugs in India, 2017 (ICMR & CDSCO)

Handbook on National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (2018) – ICMR.

It is also recommended that during discussions on trial design and during protocol development the researcher is aware of the following three parameters that are utilised by the Indian Central Licensing Authority (CDSCO) for evaluation of clinical trial applications:

• Assessment of risk versus benefit to the patient,
• Innovation vis-à-vis existing therapeutic option,
• Unmet medical need in the country.

Risk Benefit Analysis

Any favourable or advantageous outcome to the participant (or individual), community or society, due to the research is considered as a benefit. Benefits due to research could be both direct and indirect. The social and scientific value of research should justify the risk. In the context of research, risk is considered as the probability of causing harm or discomfort to the participant or community or the society. These risks could be physical, psychological, economic, social or legal.

The researcher, sponsor and the ethics committee (assessing the research) should aim to minimise these anticipated risks and maximise the benefits, at individual, societal and community levels. The risks and benefits should be assessed in order to ensure a favourable balance between the two.

The risk benefit analysis is a section in the trial design (and the research protocol), that details on the proposed plan for minimising the risks and discomforts of the research. The ethics committee evaluates the merit of the research on the basis of the details in this section, before approving it.

The type of review by the ethics committee is based on the category of risks, as below:

1. Less than minimal risk: probability of harm or discomfort is nil or not expected.
2. Minimal risk: probability of harm or discomfort is not greater than that ordinarily encountered in everyday life or routine tests, where the occurrence of serious harm or any adverse event is unlikely.
3. Minor increase over minimal risk or Low risk: increment in probability of harm during the research is only a little more than the minimal. Examples of this are: inclusion of participants who are not capable of giving consent, use of minimally invasive procedures during research, delaying or withholding a proven intervention or standard of care in a control or placebo group during randomized trials, etc.
4. More than minimal risk or High risk: probability of harm or discomfort is more than minimal. Examples of this are: use of invasive procedures (lumbar puncture, lung or liver biopsies, endoscopic procedures) during research, drugs.

Statistician / Biostatistician Involvement

Robust trials are often designed comprehensively and methodically, with input from various experts, including a statistician. Thus, trial design should be considered in collaboration with a statistician before the development of a protocol. It is advisable that the statistician’s input be sought during the following (not an exhaustive list):

1. Designing the trial.
2. Selection of appropriate outcomes.
3. Justification of study sample size.
4. Development of statistical plan.
5. Randomisation methodology (if applicable).
6. Handling of all data.
7. Preparation of reports to be sent to the Data Safety Monitoring Committees (if applicable) and other committees as appropriate.
8. Analysis and interpretation of interim and final analyses.

The scientific integrity of a study and the credibility of the data generated, relies heavily on its design. Therefore, it is imperative to include a biostatistician during the initial planning / designing phase of the study.

References and Further reading

• National Ethical Guidelines for Biomedical and Health Research involving Human Participants, Indian Council of Medical Research, 2017, available online (last accessed on 26.02.2019).
• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• New Drugs and Clinical Trial Rules, 2019, G.S.R. 227(E), Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, available online (last accessed on 01.04.2019).
• Farrugia P, Petrisor B.A, Farrokhyar F, Bhandari M, 2010, Research questions, hypothesis and objectives, Canadian Journal of Surgery, 53, 4 pages 278 – 81. [PubMed Link – last accessed 27.09.2018].
• Doody O, Bailey ME, 2016, Setting a research question, aim and objective, Nurse Researcher, vol. 23 (4), 19 – 23. [PubMed Link – last accessed 27.09.2018].
• Lipowski EE, 2008, Developing great research questions, American Journal of Health-System Pharmacy, vol. 65 (17), 1667-70, [available online – last accessed on 27.09.2018].
• Onwuegbuzie A.J., Leech N.L, 2006, Linking Research Questions to Mixed Methods Data Analysis Procedures 1, The Qualitative Report, vol. 11 (3), 474-498. [Google Scholar Link – last accessed on 27.09.2018].
• Lieberman, J.A., 2001, Hypothesis and hypothesis testing in the clinical trial, The Journal of Clinical Psychiatry, vol. 62, suppl. 9, pages 5-8, available online (last accessed 15.03.2019).
• Freedman, B., 1987, Equipoise and the ethics of clinical research, New England Journal of Medicine, vol. 317 (3), pages 141-5, available online (last accessed 15.03.2019).