MEDLINE INDIA - GOOD CLINICAL PRACTICE GUIDELINES

The guidelines to conduct the clinical trial on investigational vaccines are similar to those governing a clinical trial. The phase of these trials differ from drug trials as given below:

Phase I: This 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 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 assessments of safety and effectiveness in the prevention of disease, involving controlled study on a larger number of volunteers (in thousands) in multi-centres.

7.1.2. Guidelines

· The sponsor and investigator should be aware of the approval process(es) involved in conducting clinical trials of vaccines. They should familiarize themselves with the guidelines provided by Drug Controller General (India), Department of Biotechnology (DBT) and Ministry of Environment and Genetic Engineering Approval Committee (GEAC) in the case of vaccines produced by recombinant DNA technology. See Appendix III.

· Some vaccines that contain active or live-attenuated microorganisms can possibly possess a small risk of producing that particular infection. The subjects 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.

· Trials should be conducted by investigator with the requisite experience and having necessary infrastructure for the laboratory evaluation of seroconversion.

· Protocols for such trials should include appropriate criteria for selection of subjects, plan of frequency of administration of the test vaccine in comparison with the reference vaccine. It should accompany detailed validation of testing method to detect the antibody titter levels.

· It should specify methodology to be adopted for prevention of centrifuged serum for the purpose of testing.

· The investigator should be provided with Quality Control data of the experimental batch of the vaccine made for the purpose of clinical trials.

· The sponsor should provide the Independent Ethics Committee approval of the nodal body (ies) to carry out clinical trials with the vaccine.

· The generic version of new vaccines already introduced in the other markets after step up clinical trials including extensive Phase III trials should be compared with the reference vaccine with regard to seroconversion in a comparative manner in a significant sample size.

· Post Marketing Surveillance (PMS) should be required following seroconversion studies. PMS data should be generated in a significant sample size sensitive to detect side effects and address other safety issues.

· Protocols for test of new vaccine should contain a section giving details of steps of manufacture, in-process quality control measures, storage conditions, stability data and a flow chart of various steps taken into consideration for manufacture of vaccine. It should also contain detailed method of quality control procedure with the relevant references.

7.2. Clinical Trials of Contraceptives

· All procedures for clinical trials are applicable. Subjects should be clearly informed about the alternative 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 borne 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.

7.3 Clinical trials with surgical procedures/ medical devices

Of late, biomedical technology has made considerable progress in the conceptualisation 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 Drug 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 country 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 Organisation (DRDO) has drafted a proposal for the setting up of a regulatory, 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.

7.3.1. Definitions:

Medical devices: A medical device is defined as an inert diagnostic of 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’ e.g. Thermometer, B.P. apparatus.

b. Critical devices: An investigational device that presents a potential risk to the health, safety, welfare of the subject- for example, pacemakers, implants, internal catheters.

All the general principles of clinical trials described for clinical 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 be 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.

7.3.2. Guidelines

o Safety data of the medical device in animals should be obtained and likely risks posed by the device should be considered.

o A clinical trial of medical devices is different from drug trials, as former can not be done in healthy volunteers. Hence phase I of drug trial is not necessary for trial on devices.

o 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.

o Medical device not used regularly have less risk potential than those used regularly, for example, contact lens Vs intraocular lenses.

o Safety procedures to introduce a medical device in the patient should also be followed as the procedure itself may cause harm to the patient.

o 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 trial.

7.4. Clinical trials for Diagnostic Agents - Use of Radio-active Materials and X- Rays

In human beings, for investigation and treatment, different radiations- X-rays, gamma rays and beta rays, radio opaque contrast agents and radioactive materials are used. The relative risks and benefits of 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).

7.4.1. Guidelines

§ 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 submitted wherever possible.

7.5 Clinical trials 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 DCG (I) 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 those systems of medicine which may be used later in their own 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 Homoeopathy are to be undertaken in Allopathic Hospitals, associations of physicians from the concerned system as co-investigators/ collaborators/ members of the expert group is desirable for designing and evaluating the Study.

7.5.1. Categories of Herbal Products

The herbal products can belong to any of the three categories given below:

a. 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.

b. 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.

c. 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.

7.5.2. Guidelines

· 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 emphasized that since the substance to be tested is already in used 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 preparations 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, subject, 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 / Ethno-medicine is ready for commercialisation 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.

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