Statement of Specific Principles for Clinical Evaluation of Drugs/Vaccines/Devices/Diagnostics/Herbal Remedies etc.
The recent developments in frontier areas like genome mapping, genetic recombinant engineering, assisted reproductive biology, stem cell research, have opened up hither to unknown practical applications of these technologies. However, these exciting areas also raise some delicate and sensitive issues regarding ethics in Bio-medical research. Accordingly, as a sequel to the “Policy Statement on Ethical Consideration involved in Research on Human Subjects” in the previous issue, this second issue provides a statement of specific principles for clinical evaluation of drugs/ vaccines/ devices/ diagnostics/ herbal remedies.
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 equally clear that such research on normal subjects and patients is associated with some degree of risk to the individual concerned. These 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 the basic ethical principles. These guidelines are important for protection of research subjects against any avoidable risk and to guide the researchers in the preparation of research proposals/protocols.
For the clinical evaluation of proposed research intervention, the framework of guidelines is provided for the following areas:
1. Drug trials
2. Vaccine trials
3. Surgical procedures/medical devices.
4. Diagnostic agents – with special reference to use of radioactive materials and X-rays
5. Trails with herbal remedies
General principles
All the research involving human subjects should be conducted in accordance with the four basic ethical principles, namely Autonomy or respect for person/ subject, Beneficence, Non-maleficence 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 research trial and for protection of the rights, health and welfare of the subjects recruited for the study. He/she should have qualification competence in clinical trial research methods for proper conduct of the trial and should be aware of and comply with all requirements of the study protocol as enumerated under the General Principles and General Issues.
Specific Principles
Drug trials
Clinical trial of drugs is a randomized single or double blind controlled study in human subjects, designed to evaluate prospectively the safety and effectiveness of new drugs/new formulations. The new drug as defined under the Drugs and Cosmetics Rules 1945 (DCR), and subsequent amendments include:
(a) a new chemical entity (NCE);
(b) a drug which has been approved for a certain indication, by a certain route, in a certain dosage regimen, but which is now proposed to be used for another indication, by another route, or in another dosage regimen;
© a combination of two or more drugs which, although approved individually, are proposed to be combined for the first time in a fixed dose combination (FDC). The proposed trial should be carried out, only after approval of the Drugs Controller General of India (DCGI), as is necessary under the Schedule Y of Drugs and Cosmetics Act, 1940. The investigator should also get the approval of Ethical Committee of the Institution before submitting the proposal to DCGI. All 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 or not.
Phases of clinical trials
The first three of the following four phases of clinical trials of drug require ethical clearance:
Phase I: The objective of phase 1 of clinical trial is to determine the safety of the maximum tolerated dose in healthy adults of both sexes. Healthy female volunteers could be included provided they have completed their family or do not intend to have a child in the future. At least two subjects should be administered each dose to establish the safe dose range , pharmacokinetic , pharmacodynamic effects, and adverse reactions, if any , with their intensity and nature. Investigator trained in clinical pharmacology should preferably carry out these studies. The duration of time lapsing between two trials in the same volunteer should be a minimum of 3 months. The volunteers should preferably be covered under some insurance scheme.
Phase II: These are controlled studies conducted in a limited number of patients of both sexes to determine therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics when necessary . Normally 20-25 patients should be studied for assessment of each dosage. These studies are usually limited to 3-4 centre’s.
Phase III: The purpose of these trials is to obtain adequate data about the efficacy and safety of drugs in a larger number of patients of both sexes in multiple centre’s usually in comparison with a standard drug and/or a placebo if a standard drug does not exist for the disease under study. On successful completion of phase III trials permission is granted for marketing of the drug.
Phase IV: After approval of the drug for marketing, phase IV study or post marketing surveillance is undertaken to obtain additional information about the drug’s risks, benefits and optimal use. Although this is outside the purview of the ethical committee, it is an important aspect of drug trial on the long-term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee.
Throughout the drug trials, the distinction between therapy and research should be maintained. A physician/investigator who participates in research by administering the new drug to consenting patients should ensure that the patients understand and remember that the drug is experimental and that its benefits for the condition under study are yet unproven. Use of a placebo in drug trials and sham surgery has come under severe scrutiny at the present age and requires careful consideration before approval. Denial of the available treatment to control (placebo) group of patients is unethical.
Trials of drugs without the approval of the appropriate authority should be dealt according to the law of the land and the Guidelines formulated by the country’s regulatory agencies.
After the clinical trial is over, if need be, it should be made mandatory that the sponsoring agency should provide the drug to the patient till it is marketed in the country.
The criteria for termination of a trial must be defined a priori in the proposal of the trial and plan of interim analysis must be clearly presented. This is important when on interim analysis the test drug is found to be clearly more effective or less effective than the standard drug. The trial can be discontinued thereafter and better drug should be given to patient receiving less effective drug.
Issues of partner notification and discordant couples should be taken care of before initiating any HIV/AIDS related trial.
Good Clinical Practices (GCP) Provide operative guidelines for ethical and scientific standards for the designing of a trial protocol including conduct, recording and reporting procedures and should be strictly adhered to while carrying out a trial. Till such time that the Standard Operating Procedures (SOP) for Indian GCP are formulated, the international guidelines issued by World Health Organizations (WHO) and International Committee on Harmonization (ICH) should be followed.
Special concerns
I. Multicentric Trials
A multicentric trial is conducted simultaneously by several investigators at different centre’s following the same protocol and proformae. Ideally, these trials should be initiated at the same time at all the centre’s.
- 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 should be organized at the initial and intermediary stages of the trial to ensure uniform procedures at the all centre’s.
- Training should be imparted to research staff at the participating centre’s. to familiarize them with the uniform procedures.
- Standardization of methods for recruitment and evaluation/ monitoring of laboratory procedures and conduct of trial should be carried out.
- There should be monitoring of adherence to protocol including measures to terminate the participation of some centre’s., if necessary.
- Specific role of coordinators and monitors should be defined.
- Centralized data management and analysis should be planned.
- Drafting of a common final report and publication procedure should be decided at the outset. No individual centre should publish any data till appropriate authorities accept the combined report.
- The code of the administered drug could be broken in the event of a severe adverse reaction occurring during the conduct of a double blind trial necessitating such a step.
Contraceptives
- All procedures for clinical trials are applicable. Subjects should be clearly informed about the alternatives available.
- In women where implant has been used as a contraceptive for trial, a proper follow up for removal of the implant should be done, whether the trial is over or the subject has withdrawn from the trial.
- Children born due to failure of contraceptives under study should be followed up for any abnormalities if the woman does not opt for medical termination of pregnancy.
Monitoring and reporting adverse reactions or 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 General of India. At the end of the trial, all adverse events whether related to trial or not are to be listed, evaluated and discussed in detail in the final report.
II. Vaccine trials
The guidelines to conduct the clinical trial on investigational vaccines are similar to those governing a drug trial. The phases of these trials differ from drug trials as given below:
Phase I: The 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 should involve low risk subjects. For example, immunogenicity to hepatitis B vaccine should not be determined in high risk subjects.
Phase II: This refers to the initial trials examining effectiveness (immunogenicity) in a limited number of volunteers. Vaccines can be prophylactic and therapeutic in nature. While prophylactic vaccines are given to normal subjects, therapeutic or curative vaccines may be given to patients suffering from particular disease.
Phase III: This focuses on assessment of safety and effectiveness in the prevention of disease, involving controlled study on a larger number of volunteer (in thousands) in multicentres.
Special concerns
- Some vaccines that contain active or live – attenuated micro organisms can possibly possess a small risk of producing that particular infection. The subject to be vaccinated should be informed of the same.
- The subjects in control groups or when subjected to ineffective vaccines run a risk of contracting the disease.
- The risks associated with vaccines produced by recombinant DNA techniques are not completely known. However, for all the recombinant vaccines/products the Guidelines issued by the Department of Biotechnology should be strictly followed.
III. Clinical trials with surgical procedures/medical devices
Of late, biomedical technology has made considerable progress in the conceptualization and designing of bio-equipments. Several medical devices and critical care equipments have been developed and many more are in various stages of development. However, only through good manufacturing practices (GMP) can the end products reach the stage of utilization by society. Most of these products are only evaluated by Central Excise testing for taxation purposes which discourages entrepreneurs to venture in this area with quality products especially when they do not come under the strict purview of the existing regulatory bodies like ISI, BSI and Drugs Controller General. This is evidenced by the very low number of patents or propriety medical equipments manufactured and produced in the country. As the capacity of the county in this area is improving day by day the need for a regulatory mechanism/authority is increasingly obvious. The concept of regulations governing investigations involving biomedical devices is therefore relatively new in India. At present, except for needles and syringes these are not covered by the Drugs and cosmetics Act, 1940. The Chief Executive of the Society of Biomedical Technology (SBMT) set up under the Defence Research Development Organization (DRDO) has drafted a proposal for the setting up of a regulatory authority, tentatively named as the Indian Medical Devices Regulatory Authority (IMDRA). Until the guidelines are formulated and implemented by this Regulatory Authority clinical trials with biomedical devices should be approved on case to case basis by committees constituted for the specific purpose.
DefinitionsMedical devices: 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, intra-ocular lenses, orthopaedic pins and other orthopaedic accessories.
Depending upon risks involved the devices could be classified as follows:
a) Non critical devices – An investigational device that does not present significant risk to the patients eg. Thermometer, BP apparatus.
b) Critical devices – An investigational medical device that presents a potential serious risk to the health, safety or welfare of the subject – for example, pace markers, implants, internal catheters.
All the general principles of clinical trials described for drug trials should also be considered for trials of medical devices. As for the drugs, safety evaluation and pre-market efficacy of devices for 1-3 years with data on adverse reactions should be obtained before pre-market certification. The duration of the trial and extent of use may by decided in case to case basis by the appropriate authorities. However, the following important factors that are unique to medical devices should be taken into consideration while evaluating the related research projects:
- 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 is different from drug trials, as former cannot be done in healthy volunteers. Hence Phase of drug trials is not necessary for trial on devices.
- Medical devices used within the body may have greater risk potential than those used on or outside the body, for example orthopaedic pins vs crutches.
- Medical devices not used regularly have less risk potential than those used regularly, for example, contact lens vs intraocular lenses.
- Safety procedures to introduce a medical device in the patient should also be followed as the procedure itself may cause harm to the patient.
- Informed consent procedures should be followed as in drug trials. The Patient information sheet should contain information on following procedures to be adopted if the patient decides to withdraw from the trail.
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 or research proposal utilizing 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. (BARC – Bhabha Atomic Research Centre, Mumbai).
Special concerns
- Informed consent should be obtained before any diagnostic procedures.
- Information to be gained should be gathered using methods that do not expose subjects to more radiation than exposed normally.
- Research should be performed on patients undergoing the procedures for diagnostic or therapeutic purposes.
- Safety measures should 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 the embryo.
- Information to subject about possible genetic damage to offspring should be given.
- Non-radioactive diagnostic agents are considered as drugs and the same guidelines should be followed when using them.
- Ultrasound to be substituted wherever feasible.
V. Clinical Evaluation of Herbal Remedies and Medicinal Plants
For the herbal remedies and medicinal plants that are to be clinically evaluated for use in the Allopathic System and which may later be used in allopathic hospitals, the procedures laid down by the office of the Drugs Controller General of India for allopathic drugs should be followed. This does not pertain to guidelines issued for clinical evaluation of Ayurveda, Siddha or Unani drugs by experts in hospitals and clinics. All the general principles of clinical trials described earlier pertain also to herbal remedies. However, when clinical trials of herbal drugs used in recognized Indian Systems of Medicine and Homeopathy are to be undertaken in Allopathic Hospitals, association of physicians from the concerned system as co-investigators/collaborators/members of the expert group is desirable for designing and evaluating the study.
Special concerns
The herbal products can belong to either of the three categories given below:
1. A lot is known about the use of a plant or its extract in the ancient Ayurveda, Siddha or Unani literature or the plant may actually be regularly used by physicians of the traditional systems of medicine for a number of years. The substance is being clinically evaluated for same indication for which it is being used or as has been described in the texts.
2. When an extract of a plant or a compound isolated from the plant has to be clinically evaluated for a therapeutic effect not originally described in the texts of traditional systems or, the method of preparation is different, it has to be treated as a new substance or new chemical entity (NCE) and the same type of acute, subacute and chronic toxicity data will have to be generated as required by the regulatory authority before it is cleared for clinical evaluation.
3. An extract or a compound isolated from a plant which has never been in use before and has not ever been mentioned in ancient literature, should be treated as a new drug, and therefore, should undergo all regulatory requirements before being evaluated clinically.
It is important that plants and herbal remedies currently in use or mentioned in literature of recognized Traditional System of Medicine is prepared strictly in the same way as described in the literature while incorporating GMP norms for Standardization It may not be necessary to undertake phase I studies. However, it needs to be emphasis ed that since the substance to be tested is already in use in Indian Systems of Medicine or has been described in their texts, the need for testing its toxicity in animals has been considerably reduced. Neither would any toxicity study be needed for phase II trial unless there are reports suggesting toxicity or when the herbal preparation is to be used for more than 3 months. It should be necessary to undertake 4-6 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 preparation should be carried out only after these have been standardized 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 with diminished autonomy, all apply to trials on plant drugs also. These trials have also got to be approved by the appropriate scientific and ethical committees of the concerned Institutes. However, it is essential that such clinical trials be carried out only when a competent Ayurvedic, Siddha or Unani physician is a co-investigator in such a clinical trial. It would neither ethically acceptable nor morally justifiable, if an allopathic physician, based on references in ancient literature of above-mentioned traditional systems of Medicine, carries out clinical evaluation of the plant without any concept or training in these systems of medicine. Hence, it is necessary to associate a specialist from these systems and the clinical evaluation should be carried out jointly.
When a Folklore medicine/Ethnomedicine is ready for commercialization after it has been scientifically found to be effective, then the legitimate rights/share of the Tribe or Community from whom the knowledge was gathered should be taken care of appropriately while applying for the Intellectual Property Rights and/Patents for the product
