Human studies designed to evaluate the safety, effectiveness, or usefulness of an intervention include research on therapeutics, diagnostic procedures and preventive measures including vaccines. The type of experimental procedures that a patient is submitted to has become more complex and varied as the complexities of medical research have increased. It is clearly accepted that it is essential to carry out research on human subjects to discover better medical and therapeutic modalities for the benefit of mankind. It is equally clear that such research on normal subjects and patients is associated with some degree of risk to the individual concerned. The guidelines have been framed to carry out the evaluation of drugs, vaccines, devices and other diagnostic materials on human subjects including herbal remedies, in accordance with basic ethical principles. These guidelines are important for the protection of research subjects against any avoidable risk and to guide the researchers in the preparation of research proposals/protocols.
For the evaluation of proposed research intervention the framework of guidelines is as follows:
A. General Ethical Principles
B. Special Ethical concerns related to
- Drug Trials
- Vaccine Trials
- Medical Devices
- Diagnostic agents - with special reference to use of Radioactive Materials and X-rays
- Trials with Herbal remedies.
A. GENERAL ETHICAL PRINCIPLES
All the research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for person/subject, beneficience and justice. The guidelines laid down are directed at application of these basic principles to research involving human subjects.
An investigator is the person responsible for the clinical trial and for the rights, health and welfare of the subjects recruited for the study. He/she should have qualification and competence in clinical trial research methods for proper conduct of the trial and should be aware of and comply with the legal and ethical requirements of the study protocol.
1. Informed Consent of Subject
1.1 Individual Informed Consent
For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject or, in the case of an individual who is not capable of giving informed consent, the consent of a legal guardian.
- Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in research or not. Informed consent protects the individual's freedom of choice and respect for individual's autonomy.
- When research design involves no more than minimal risk (for example, where the research involves only collecting data from subject's records) the ethical review committee may waive some or all elements of informed consent.
1.2 Essential information for prospective research subjects
Before taking the informed consent of subject, the investigator must provide the individual with the following information in the language he or she is able to understand -
- the aims and methods of the research,
- the expected duration of the subject participation,
- the benefits that might reasonably be expected as an outcome of research to the subject or to others,
- any risk to the subject, associated with study,
- maintenence of confidentiality of records,
- responsibility of investigators,
- provision of free treatment for research related injury,
- compensation of subjects for disability or death resulting from such injury, and
- freedom of individual to participate and to withdraw from research any time without penalty or loss of benefits to which the subject would otherwise be entitled.
1.3 Obligations of investigators regarding informed consent The investigator has duty to:
- communicate with prospective subject all the information necessary for informed consent. There should not be any restriction on subject's right to ask any questions related to study, and any restriction on this undermines the validity of informed consent.
- exclude the possibility of unjustified deception, undue influence and intimidation. Deception of the subject is not permissible. However, sometimes information can be withheld till the completion of study, if such information would jeopardize the validity of research.
- seek consent only after prospective subject is adequately informed. Investigator should not give any unjustifiable assurances to prospective subject, which may influence the subject's decision to participate in the study.
- as a general rule obtain from each prospective subject a signed form as an evidence of informed consent (written informed consent) preferably witnessed by a person not related with trial, and in case of incompetence, a legal guardian or other duly authorised representative should do so.
- renew the informed consent of each subject if there are material changes in the conditions or procedures of the research along the trial.
- Intimidation in any form invalidates informed consent. The investigator must assure prospective subjects that their decision to participate or not will not affect the patient - clinician relationship or any other benefits to which they are entitled.
1.4 Inducement to participate
Subjects may be paid for the inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgement (inducement). All payments, reimbursement and medical services to be provided to research subjects should be approved by the Ethical Committee.
- When a guardian is asked to give consent on behalf of an incompetent person, no remuneration should be offered except a refund of out of pocket expenses.
- When a subject is withdrawn from research for medical reasons related to the study the subject should get the benefit for full participation. When a subject withdraws for any other reasons, he/she should be paid in proportion to the amount of participation.
2.Selection of Research Subjects
2.1 Equitable distribution of burdens and benefits
Effort may be made that individuals or communities invited for research should be selected in such a way that the burdens and benefits of the research should be equally distributed. Special justification is required for inviting vulnerable subjects, whose rights and welfare must be protected.
Vulnerable subjects:- Equitable distribution of the burdens and benefits of research participation is generally more difficult when the intended subjects include vulnerable individuals or groups. These subjects are children, persons with mental or behavioural disorders, who are incapable of giving informed consent and prisoners, students, subordinates service personnel etc. who have reduced autonomy. Adequate justification of their involvement as research subjects is required.
The quality of the consent of certain social groups requires careful consideration, as their agreement to volunteer may be unduly influenced by the Investigator.
2.2 Selection of pregnant or nursing women as research subjects:-
As a general rule, pregnant and nursing (breast feeding) women should not be subjects of any clinical trials except such trials which are designed to protect or advance the health of pregnant or nursing women or fetuses or nursing infants, and for which drugs can be tested only in pregnant women.
The justification of participation of these women in clinical trials would be that they should not be deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines or other agents that promise therapeutic or preventive benefits. Example of such trials are, to test the efficacy and safety of a drug for reducing perinatal transmission of HIV infection from mother to child, trials for detecting fetal abnormalities, trials of therapies for conditions associated with or aggravated by pregnancy etc.
Women should not be encouraged to discontinue nursing for the sake of participation in research and in case she decides to do so, harm of cessation of breast feeding to the nursing child should be properly assessed.
Research related to termination of pregnancy:- Pregnant women who desire to undergo Medical Termination of Pregnancy (MTP) could be made subjects for research relating to termination of pregnancy, as per The Medical Termination of Pregnancy Act, 1971.
Research related to pre-natal diagnostic techniques:- In pregnant women research on prenatal diagnostic techniques should be limited to detect the fetal abnormalities. Such research should take the consideration of The Prenatal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994.
2.3 Research involving children
Before undertaking children as subjects for clinical trial, the investigator must ensure that -
- children will not be involved in research that might be carried out equally well with adults,
- the purpose of the research is to obtain knowledge relevant to health needs of children. For a new drug usually the study in children should always be after the phase III clinical trials in adults. It can be studied earlier only if the drug has a therapeutic value in a primary disease of the children,
- a parent or legal guardian of each child has given proxy consent on behalf of the child,
- the consent of the child should be obtained to the extent of the child's capabilities such as in the case of mature minors, adolescents etc.,
- research involving children should be conducted in settings in which the child and parent can obtain adequate medical and psychological support,
- interventions intended to provide direct diagnostic, therapeutic or preventive benefit for the individual child subject must be justified in relation to anticipated risks involved in the study. The risks of interventions that are not intended to be of direct benefit to the child subject must be justified in relation to anticipated benefits to society.
3. Confidentiality of Data
3.1 Safeguarding confidentiality
The investigator should safeguard the confidentiality of research data, which might lead to the identification of individual subjects.
Data of individual subjects can be disclosed only in a court of law under the orders of the presiding judge or in some cases may be required to communicate to drug registration authority or industrial sponsor of research or in cases of certain communicable diseases to health authority. Therefore, the limitations in maintaining the confidentiality of data should be anticipated and assessed.
4. Compensation of Research Subjects from Accidental Injury
4.1 Right of subjects to compensation
Research subjects who suffer physical injury as a result of their participation are entitled to financial or other assistance to compensate them equitably for any temporary or permanent impairment or disability. In case of death, their dependents are entitled to material compensation.
Obligation of the sponsor to pay:- The sponsor whether a pharmaceutical company, a government, or an institution, should agree, before the research begins, to provide compensation for any physical injury for which subjects are entitled to compensation.
5. Ethical Review Committee
All trials involving human subjects must be submitted for scientific review and approval of ethical review committee of institute before starting such research.
All the medical colleges and research institutions/centres involved in clinical research should form scientific and ethical committees which may be either combined or be two independent committees. The scientific evaluation will assess the technical excellence of the proposed clinical trial.
5.1 Composition of the Ethical Committee
The ethical committee should be able to provide complete and adequate review of the research proposals submitted to them. The committee should be headed by a chairman, who should not be head of the same institution. Other members should be - one pharmacologist preferably clinical pharmacologist if available, one pathologist, two clinicans, one or more members of non-clinical departments, one person having knolwedge of law (preferably a Judge or Lawyer) and a social scientist or philosopher. The member secretary should be from the Institute concerned.
The number of persons in an ethical committee be kept fairly small (5-7 members). The ethical committee at any institution should not hesitate to have as its members, individuals from other institutions or communities if required. If the Investigator is a member of the Institutional Ethical Committee, he/she should not be present when his/her own project is discussed.
5.2 Basic responsibilities
The ethical committee should meet periodically (at least twice a year) and review all research proposals and their progress reports. Ethical approval through circulation of research proposal among members should not be resorted to. The basic responsibilities of ethical committee are -
- to verify the safety, integrity and human rights of the subjects participating in the trials.
- to verify that all proposed interventions, and particularly the administration of drugs and vaccines or use of medical devices under development, have been assessed by a competent expert body as acceptably safe to be undertaken in human subjects; and
- to ensure that all other ethical and scientific concerns arising from a protocol are satisfactorily resolved both in principle and in practice.
5.3 Assessment of research proposal
The ethical committee should review every research proposal on human subjects. It should observe that the research proposal is scientifically sound, the possible risks to the subjects are justified by the expected benefits, informed consent is satisfactory and procedures for selection of subjects are equitable and properly documented.
The protocol should include -
- clear research objectives and rationale for undertaking the investigation in human subjects in light of the existing knowledge,
- precise description of methodology of the proposed research, including intended dosages of drugs and planned duration of treatment,
- a description of plans to withdraw or withhold standard therapies in the course of research,
- the plans for statistical analysis of the study,
- inclusion and exlusion criteria for admission of subjects in the study,
- procedure for seeking and obtaining informed consent,
- safety of proposed intervention and any drug or vaccine to be tested, including results of relevant laboratory and animal research, and
- for research carrying more than minimal risk, if any, an account of plans to provide medical therapy for such risk or injury should be included.
- storage and maintenance of all data collected during the trial.
The role of ethical committee is not only to permit the initiation of research but also to review research during the course of study. When there is anticipation of likely injury or detection of adverse events during the course of study the termination of study should be recommended.
6. Externally Sponsored Research
The externally sponsored research entails two ethical obligations:-
- The external sponsoring agency should submit the research proposal according to the standards applied by ethical committee of sponsoring agency/country with due approval.
- The ethical committee of host Institution/country should satisfy themselves that the proposed research meets their own ethical requirement before sanctioning approval. The decision of the host Institution where the study will be conducted is ultimate.
B. ETHICAL CONSIDERATIONS FOR SPECIFIC AREAS
I. DRUG TRIALS
Clinical trial of drugs is a controlled study in human subjects, designed to evaluate propsectively the safety and effectiveness of new drugs/new formulations.
The proposed trial should be carried out, only after approval of the Drugs Controller General of India, as is necessary under The Schedule Y of Drugs and Cosmetic Act, 1940. The investigator should also get the approval of Ethical Committee of the Institution before submitting the proposal to DCI. The guiding principles should be followed irrespective of whether the drug has been developed in this country or abroad or whether clinical trials have been carried out outside India.
1. Phases of clinical trials
The following four phases of clinical trials of drug require ethical clearance -
1.1 Phase 1 drug trials:- The objective of phase 1 of clinical trial is to determine the maximum tolerated dose in healthy adult male. To establish the safe dose range, pharmacokinetic, pharmacodynamic effects, and adverse reactions, if any, with their intensity and nature. These studies should be carried out by investigator trained in clinical pharmacology.
1.2 Phase 2 drug trials:- These are controlled studies conducted in a limited number of patients to determine therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics.
1.3 Phase 3 drug trials:- The purpose of these trials is to obtain sufficient evidence about the efficacy and safety of drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. On successful completion of phase 3 trials the permission is granted for marketing of drug.
1.4 Phase 4 drug trials:- After approval of drug for marketing, phase 4 trial or post marketing surveillance is done to delineate additional information about the drug's risks, benefits and optimal use. Although, this is outside the purview of ethical committee, it is an important aspect of drug trial on the long term effects of the drugs.
Throughout the drug trials, the distinction between therapy and research must be maintained. A physician/investigator who participates in research by administering the new drug to consenting patients must ensure that the patients understand and remember that the drug is experimental and that its benefits for the condition under study are unproven. Use of Placebo in drug trials has come under severe scrutiny at the present age and requires careful consideration before approval. Trials of drugs without approval of appropriate authority should be dealt according to law of the land and regulatory agencies.
Model protocols recommended by WHO Guidelines for Good Clinical Practices (GCP) for trials on pharmaceutical products and Drugs Controller General of India's Guidelines for Good Clinical Trial Regulations are included at the end of the text.
2. Special concerns for Multicentric Trials
A multicentric trial is conducted simultaneously by several investigators at different centres following the same protocol and proformae. Ideally, these trials should be initiated at the same time at all the centres.
- All the Investigators should give a written acceptance of the protocol to be followed for the trial duly approved by the ethics committee of the host institutes.
- Meetings to be organised at the initial and intermediary stages of the trial to follow uniform procedures at all centres.
- Training to be imparted to participating centres to familiarise with the uniform procedure.
- Standardisation of methods for recruitment, evaluation and laboratory procedures.
- Control of adherence to protocol including measures to terminate the participation of some centres, if necessary.
- Specific role of coordinators and monitors.
- Centralised data management and analysis.
- Drafting of a common final report and publication procedure.
2.1 Monitoring and reporting Adverse Events
Any serious adverse events occurring during the course of the trial should be immediately brought to the attention of ethics committee, sponsors and Drug Controller of India. At the end of the trial, all adverse events are to be listed, evaluated and discussed in detail in the final report.
II. CLINICAL EVALUATION OF VACCINES
The guidelines to conduct the clinical trial on investigational vaccines are similar to those governing a drug trial.
1. Phases of vaccine trial
1.1 Phase I trial refers to the first introduction of a vaccine into a human population for determination of its safety and biological effects including immunogenicity. This phase includes study of dose and route of administration and involves less than 100 volunteers. Phase I trial should involve low risk subjects. For example, immunogenicity to hepatitis B vaccine should not be determined in high risk subjects.
1.2 Phase II trial refers to the initial trials examining effectiveness (immunogenicity) in a limited number (200-500) of volunteers. It may be ethically justified to involve HIV-seropositive individuals as subjects in phase II trial for HIV vaccines.
1.3 Phase III trials focus on assessment of safety and effectiveness in the prevention of disease, involving controlled study on a larger number of volunteers in multicentres.
2. Points to be noted in vaccine trials
- 2.1 Some vaccines that contain active or live - attenuated micro-organisms have a small risk of producing that particular infection. Subject to be informed of the same.
- 2.2 The subjects in control groups or in case of ineffective vaccines, are at risk of contracting the disease.
- 2.3 The risks associated with vaccines produced by recombinant DNA techniques are yet unknown.
- 2.4 Trials should be designed to involve subjects who stand to benefit most from the protection afforded by the vaccine.
- 2.5 Exact information about what to do and whom to contact in case of a serious adverse reaction or research related injury, should be given to the participants.
III. CLINICAL TRIALS WITH MEDICAL DEVICES
The concept of regulations governing investigations involving medical devices is relatively new. Recently it has been realised that the risk involved in the use of such devices should be identified before they are put to public use.
A medical device is defined as an inert diagnostic or therapeutic article that does not achieve any of its principal intended purposes through chemical action, within or on the body unlike the medicated devices which contain pharmacologically active substances which are treated as drugs. Such devices include diagnostic test kits, crutches, electrodes, pacemakers, arterial grafts, intraocular lenses, orthopedic pins and other orthopedic accessories.
Depending upon risks involved these devices could be classified as follows -
a) Non significant risk devices - An investigational device that does not present significant risk to the patients
b) Significant risk devices - An investigational medical device that presents a potential serious risk to the health, safety or welfare of the subject - for example, heart valve.
All the general principles of clinical trials described for drug trials should also be considered for trials of medical devices. However, the following important factors which are unique to medical devices should be taken into consideration while evaluating the related research project.
- Medical device should have been cleared for trial by Drugs Controller of India.
- Safety data of the medical device in animals should be obtained and likely risks posed by the device should be considered.
- Clinical trial of medical devices are different from drug trials, as former cannot be done in healthy volunteers. Hence Phase I of Drug Trials is not necessary for Device trial.
- Medical devices used within the body may have greater risk potential than those used on the body - for example, orthopedic pins vs crutches.
- Medical devices not used regularly have less risk potential than those used regularly. For example: Intraocular lens vs contact lenses.
- Safety of the procedure to introduce a medical device in the patient should be considered, as the procedure itself may cause harm to the patient.
IV. DIAGNOSTIC AGENTS - USE OF RADIOACTIVE MATERIALS AND X-RAYS
In human beings, for investigation and treatment, different radiations - X-ray, gamma rays and beta rays, radiopaque contrast agents and radioactive materials are used. The relative risks and benefits of research proposal utilising radioactive materials or X-rays should be evaluated. Radiation limits for the use of such materials and X-rays should be in accordance with the limits set forth by the regulatory authority (BARC) for such materials.
Points for consideration:
- can the information to be gained be gathered using methods that do not expose subjects to more radiation than exposed normally,
- the research be performed on patients undergoing the procedures for diagnostic or therapeutic purposes,
- safety measures to be taken to protect research subjects and others who may be exposed to radiation,
- the protocol should make adequate provisions for detecting pregnancies to avoid risks of exposure to embryo,
- information to subject about possible, if any genetic damage to offspring,
- non-radioactive diagnostic agents are considered as drugs and same guidelines should be followed when using them.
V. CLINICAL EVALUATION OF HERBAL REMEDIES AND MEDICINAL PLANTS
The guidelines given below relate to herbal remedies and medicinal plants which are to be clinically evaluated for use in the allopathic system of medicine and which will be used in allopathic hospitals. The evaluation also will be carried out in allopathic hospitals and the registration of the plant extract or compound will follow the procedure laid down by the office of the Drugs Controller General of India for allopathic drugs. This does not pertain to guidelines for ayurvedic drugs or unani drugs to be clinically evaluated by experts in those systems of medicine to be eventually used by ayurvedic and unani physicians in their own hospitals and clinics.
All the general principles of clinical trials described earlier pertain also to herbal remedies. However, there are special features regarding herbal remedies which need to be kept in mind during their clinical evaluation.
The first feature is that at the time of clinical evaluation a lot may be known about the plant or its extract. There could be extensive literature about use of this in ancient Ayurvedic or Unani literature and other organised systems or, indeed, the plant may actually be in use by physicians of the traditional systems of medicine for a number of years. The substance to be clinically evaluated will be used as is being used now or as has been described in the texts.
The second consideration is that it is possible that clinical evaluation of a plant extract or a compound isolated from an extract has to be carried out which has never been in use before and has not ever been mentioned in ancient literature.
The guidelines for these two types of substances cannot be the same and therefore, given below are specific guidelines for substances which could fall into either group.
A. For plants and herbal remedies currently in use or mentioned in literature of any organised system of medicine
It is important that the herbal preparation to be clinically evaluated has been described in an authentic and recognised text of the particular system of medicine and prepared strictly in the same way, incorporating GMP norms or standardisation as far as possible. It may not be necessary to undertake phase I studies. No toxicity study may be needed for phase II trial unless there are reports suggesting toxicity or the use is to be for more than 3 months. It should be necessary to undertake 2-4 weeks toxicity study in 2 species of animals in the circumstances pointed out in the preceding sentence or when a larger multicentric phase III trial is subsequently planned based on results of phase II study.
Clinical trials with herbal preparations should be carried out only after these have been standardised and markers identified to ensure that the substances being evaluated are always the same. The recommendations made earlier regarding informed consent, inducements for participation, information to be provided to the subject, withdrawal from study and research involving children or persons not in full control of their senses all apply to these trials. These trials have also got to be approved by the appropriate scientific and ethical committees of the concerned Institutes.
There is one special aspect which needs to be emphasised. Since the substance to be tested is already in use in the Ayurvedic or Unani System of medicine or has been mentioned in these texts, toxicity testing in animals has been considerably reduced. However, it is essential that such clinical trials are carried out only when a competent ayurvedic or unani physician is co-investigator in this clinical trial and the clinical evaluation is carried out jointly by the allopathic physician and the specialist from the traditional system of medicine. It would not be ethically acceptable nor morally justifiable, if an allopathic physician, based on references in ayurvedic literature, carries out clinical evaluation of the plant without any concept or training in Ayurveda or the Unani System of medicine - hence the necessity for association of a specialist from these systems of medicine.
B. For new plants and extracts not in use or mentioned in literature
The other situation would be when an extract of a plant or a compound isolated from the plant has to be clinically evaluated for its therapeutic effect. This is, for all purposes, a new substance never been tested before. All the acute, subacute and chronic toxicity tests which need to be carried out with any new synthetic compound would need to be carried out with this preparation before clinical evaluation.
When the toxicity tests have been completed, and there is no evidence of undue toxicity a decision has to be taken whether the substance should be clinically evaluated. If the decision is made to carry out a clinical evaluation, this has to be carried out by a physician of the modern system of medicine i.e. allopathy. There is no need nor necessity to have a specialist in the traditional systems of medicine involved as a co-investigator in these trials as this is not an ayurvedic or unani drug and, in its present form, has not been used in the traditional systems of medicine. It should be tested just as any new synthetic drug would be tested and all the observations made earlier would also apply to this compound or extract.
Model list of items to be contained in a clinical trial protocol as suggested by WHO Guidelines for General Clinical Practices (GCP)
The trial protocol should, where relevant, be required to cover the following points:-
- Title and justification for the trial.
- Statement of rationale, objectives and purpose of the trial.
- Site of the trial, name and address of the sponsor.
- Name, address and qualifications of each investigator.
- Description of the type of trial (randomised, blinded, open), trial design (parallel groups, cross over technique), blinding technique (double blind, single blind), and randomization (method and procedure).
- Description of trial subjects. Criteria for inclusion and exclusion of potential trial subjects and process of recruitment, types, methods and time of allocation of subjects.
- Number of trial subjects needed to achieve the trial objective based on statistical considerations.
- Description of and justification for route of administration, dosage, dosage interval and treatment period for the pharmaceutical product being tested and the product being used as a control. Dose-response relationships should be considered.
- Any other treatment that may be given or permitted concomitantly.
- Clinical and laboratory tests, pharmcokinetic analysis, etc. that are to be carried out.
- Description of how responses are recorded. Description and evaluation of methods of measurement, times of measurements, follow-up procedures. Measures to control patients' compliance with the treatments.
- Discontinuation criteria for trial subjects and instructions on terminating the whole study or a part of the study.
- Methods of recording and reporting adverse events/reactions, provisions for dealing with complications.
- Procedures for the maintenance of subject identification code lists, treatment records, randomisation list and/or case report form (CRF). Records should permit easy identification of individual patients/participants and permit auditing and reconstruction of data.
- Information on establishment of the trial code, where it will be kept and when, and how and by whom it can be broken in the event of an emergency.
- Measures to be implemented to ensure the safe handling and storage of pharmaceutical products, and to promote and control compliance with the prescibed and other instructions.
- Description of methodology on the evaluation of results (e.g. statistical methods) and on the report on patients/participants withdrawn from the trial.
- Time schedule for completion of the trial.
- Information to be presented to the trial subjects including how they will be informed about the trial and how and when consent will be obtained.
- Staff instructions, i.e. statement of how the staff involved are to be informed about the way the trial is to be conducted and about the procedures for drug usage and administration.
- Ethical considerations and measures relating to the trial.
- Medical care after the trial and modalities of post-trial treatment should be defined.
- Statements regarding financing, insurance, liability, delegation/distribution of responsibilities, and publication policy, i.e. when serving as a contract.
- List of literature referred to in the protocol.
Drugs Controller General of India's Guidelines for Good Clinical Trial Protocol
1. Title: including statement of confidentality.
2. Unique identity code: with date of version.
3. Investigator(s): name(s), degree(s), title(s), address(es), phone number(s), fax number(s).
4. Study site: name, address, phone number, fax number.
5. Statement of confidentality and bona fide disclosure.
6. Sponsor: name, address, phone number.
7. Introduction: background of and justification for the trial; appropriate references.
8. Objectives: questions to be answered.
9. Design of study: noncomparative or comparative; open, single-blind, or double blind; parallel-group or cross-over.
10. Study subjects: target population; sample size; criteria of diagnosis, selection and exclusion; subject information sheets; informed consent form and procedure; rules for replacement of droptouts and withdrawals.
11. Study drugs: dosage forms and strengths; lot numbers; packing and labelling; method of randomisation; supply, storage, dispensing and accounting; dosage regimens; method of administration; rules for breaking the code, if any; concomitant treatments allowed and not allowed.
12. Observations to be made: clinical and investigational; method, place, and frequency
- a) Screening and baseline.
- b) Efficacy.
- c) Safety: requirements of reporting non-serious and serious adverse events.
- d) Quality of life assessment, if any.
- f) Healthcare economics, if any.
13. Data recording: source documents; retention and archiving policy.
14. Statistics: sample size justification; response definitions; data to be analysed with methods and frequency of analyses.
15. Administrative matters: ethics committee approval; regulatory approval; risk coverage for subjects, investigator, and institution (with limitations, if any); source document verification; nature and frequency of audit for protocol compliance; policy about preparation of final report, authorship and presentation/publication; confidentiality; investigator's and sponsor's agreement.
16. Appendices: Case Report Form: specimen and instructions for completion; authorised signatories and their specimen signatures; Declaration of Helsinki; study flow chart; other aid memoirs for reference materials.
Note:Any amendment to any section should be approved by the ethics committee, dated, and appended to the protocol.