Much has been discussed on regulations governing the conduction of clinical trials in India. Also there is an emerging area on conducting clinical trials with controlled drugs especially narcotics which is really an uphill task due to the stringent regulations imposed by Indian government.
Cancer pain is a problem that is estimated to affect 30-45% of patients at diagnosis and over 70% of cancer patients in later stages of the disease. Breakthrough cancer pain is a transient increase in pain intensity over background pain and it is a common and distinct component of cancer pain with studies showing a prevalence of up to 95%. The treatment of breakthrough cancer pain represents a significant problem to clinicians, carers and patients managing and living with cancer. Inadequately relieved breakthrough cancer pain can lead to additional burdens on the healthcare system with increased emergency and medical visits, more hospital admissions and longer stays.
Opium, till today, is the best-known source for relieving pain. The word "opium" is derived from Greek word "Opion". The opium poppy (Papaver Somniferum L) belonging to the family Papaveraceae, is an annual medicinal herb. It contains many alkaloids that are frequently used as an analgesic, anti-tussive and anti spasmodic in modern medicine. Besides, it is also grown as a source of edible seed and seed oil. Opioid analgesics such as Morphine, Fentanyl are the main stay of pharmacotherapy for severe pain because of their unparalleled efficacy, besides they can also present difficulties involving adverse effects, tolerance and dosing regimens.
India is the only country authorised by the United Nations Single Convention on Narcotic Drugs (1961) to produce gum opium. Eleven other countries, i.e, Australia, Austria, France, China, Hungary, the Netherlands, Poland, Slovenia, Spain Turkey and Czech Republic cultivate opium poppy, but they do not extract gum.
The use of opium for medicinal purposes in India can be traced back as far back as 1000 AD where it finds mention in ancient texts such as "Dhanwantri Nighantu" as a remedy for variety of ailments. In Emperor Akbar time (1543 to 1605) opium was cultivated extensively in the Malwa (MP) and Mewar (Rajasthan) regions. The opium poppy contains alkaloids such as morphine, codeine, thebaine, narcotine, papavarine which have analgesic, anti-tussive and anti-spasmodic properties.
After the decline of Moghuls, the Britishers controlled opium production from year 1773. During the British East India Company Rule, collection of revenue from opium was made part of fiscal policy and various opium agencies such as the Bengal, Benaras, Bihar, Malwa agencies were formed over time.
After independence the Indian government checks and monitors its production and usage. Prior to 1950, the administration of the narcotics laws, namely, the Opium Act of 1857 & 1878 and the Dangerous Drugs Act 1930 are vested with the provincial government. The amalgamation of these agencies laid the foundation of the Opium Department in November 1950, which is presently known as Central Bureau of Narcotics (CBN). The headquarters of the CBN was shifted from Shimla to Gwalior in 1960. All the three enactments mentioned above were repealed by the Narcotics Drugs & Psychotropic Substances Act, 1985 (NDPS Act, 1985).
As per the Act 1985, "narcotic drug" means coca leaf, cannabis (hemp), opium poppy straw and including all manufactured drugs.
Manufactured drugs: Means (a) all coca derivatives, medicinal cannabis, opium derivatives and poppy straw concentrate; (b) any other narcotic substance or preparation which the central government may, having regard to the available information as to its nature, or to a decision, if any, under any International Convention, by notification in the Official Gazette declare to be manufactured drug; Central Government has declared certain narcotic drugs and preparations to be manufactured drugs.
Psychotropic substances: Means any substance, natural or synthetic, or any natural material or any salt or preparation of such substance or materials included in the List of Psychotropic Substances specified in the Schedule to the NDPS Act, 1985.
Controlled substance: Means any substance which the central government may, having regard to the available information as to its possible use in the production or manufacture of narcotic drugs or psychotropic substance or to the provisions of any International Convention, by notification in the official Gazette, declare to be a controlled substance.
The movement of the narcotics drug has been watched avidly by regulatory agency of all countries due to the notorious nature of its misuse besides causing addition, depression and death. In India, the narcotic clinical trials are controlled by following authorities:
At Central level
1. DCGI at New Delhi which functions under the Ministry of Health
2. Central Bureau of Narcotics (CBN) at Gwalior which functions under the Ministry of Finance
3. Central Excise Office - Export authorisation authority of foreign country which will issue the export license to export narcotic substances to India
At State level
1. State FDA Office
2. State Excise Agency
For a CRO to conduct narcotic clinical trial in India, they have to first obtain approval from DCGI with the import license which will be valid for one year to import the investigational product into India. Then they have to approach CBN subsequently for obtaining the import certificate which will be valid for six months. In mean time, Central Excise will inspect the CRO also for its existence and authenticity.
Usually the narcotic clinical trials are conducted in the cancer treatment hospitals situated in various States of India. These hospitals will be holding an NDPS license to dispense cancer treatment drugs to the routine cancer patients. The validity of this NDPS license vary from State to State i.e. from one year to two years. This license has to be endorsed with the clinical trial investigational products and then transport permit have to be obtained from concerned zonal FDA office or state excise agency to move the medicine from depot to the hospitals. Again the transport permit validity varies from State to State i.e. from fifteen days to two months.
After obtaining all these approvals and licences, then the investigational products can be shipped to the particular hospital and clinical trial on narcotic drugs can be initiated.
The challenge in conducting narcotic clinical trial is mainly the time lines since there are several government agencies involved in controlling the narcotics and each of their licence validity will be entirely different and overlapping, besides time-limiting factor. The filing requirements also vary from State to State and even intrastate too. The success lies in understanding the holistic picture of involvement of all regulatory agencies and making efficient project management plan to bring successfully the investigational products to the hospital.
The need of the hour has been highlighted in the report published recently by Rajiv Kher task force which was constituted by prime minister Dr Manmohan Singh to find ways and means to ease the bottlenecks coming in the way of pharmaceutical exporters in the country. Its key recommendations included comprehensive measures for accelerating the growth of generic pharmaceutical industry in the country, enhancing India's R&D, promoting contract manufacturing, drug discovery and clinical trials, Indian System of Medicines and Ayush.
This task force on pharmaceuticals, headed by Rajiv Kher, joint secretary in the Union ministry of commerce, has directed the government to look at narcotics formulations as an important opportunity and not just a menace. In its report, the task force asked the government to simplify the procedure and to capture the global narcotics business in certain classes of narcotics.
In summary, the multiple regulatory agencies are involved in India for managing import and movement of narcotic drugs within the States in the well controlled environment. Pharmaceutical companies are seeking single window clearance system which will facilitate the approvals to conduct the narcotic clinical trials successfully in India. Pharma industry is working closely with both the central and state government which is very supportive in issuance of relevant licences. These clinical trials with narcotic drugs are very useful to cancer patients who have uncontrolled pain and this pain can be relieved only by taking narcotic medicines for which the benefit far outweighs the risk.
(The authors are with PharmaLeaf India Private Limited, an International Regulatory Consultancy based at Bangalore)