India, once again the jewel in the clinical trial crown

India is the seventh largest country in the world by total area, with the second highest population at 1.2 billion, and is bordered by the countries of Bangladesh, Bhutan, Burma, China, Nepal, and Pakistan. India has the largest postal network in the world with over 1.5 million post offices, and the name 'India' is derived from the River Indus, the valleys around which were the home to the early settlers. According to Census of India of 2001, India has 122 major languages and 1599 other languages of which 30 are spoken by more than a million native speakers. Generally Hindi and English are used for administrative, government and business purposes.

The healthcare environment

Healthcare issues and diseases include tuberculosis, malaria, HIV, Vascular Diseases, Cancers, and diabetes. Childhood mortality is high and the WHO estimated that total diarrheal deaths in India among children aged 0-6 years to be 158,209 in 2013. Infant mortality stood at 39 per 1000 live births as of 2013. Clearly there are significant challenges to be faced. India is home to more than 17 per cent of world population and around one‐fifth of the global burden of disease According to the 2012 WHO report, non-communicable diseases (NCD) are responsible for two‐thirds of the total morbidity burden and 53% per cent of total deaths in India. Due to financial constraints, the sick and the suffering poor have restricted access to healthcare.

Government expenditure on health and provision of state funded facilities has fallen over the years, standing at approximately 4.7% of GDP. This has lead to a rise in the private health care sector, which successfully services the higher levels of society. Most health care in India is conducted through private health provision, with expenses paid direct by patients and their families, rather than through any system of insurance. Public healthcare is free for those below the poverty line, but there is just one hospital bed per thousand persons. The total number of registered doctors in the country was 936,488 as of December 31, 2014. Average expectancy is 68.45 years which is 167th on the global league tables.

Private insurance is available in India, as are various government-sponsored health insurance schemes. According to the World Bank, about 25% of India's population had some form of health insurance in 2010. A 2014 Indian government study found this to be an over-estimate, and claimed that only about 17% of India's population was insured. Insurance generally does not cover consultations or medication. Over 35% of poor Indian households have incurred Catastrophic Health Expenditure (CHE) which can be defined as health expenditure that threatens a household's capacity to maintain a basic standard of living

Clinical trial infrastructure

The India government invested significantly in the early 2000s in order to encourage foreign investment and clinical trials. The money was used to create systems and to recruit and train personnel to process applications, conduct ethics reviews, etc.; this proved a serious draw for pharmaceutical companies. Global share of CTs in India grew from 0.9 per cent in 2008 to 5 per cent in 2013

Issues were reported between 2011-2013, culminating in the Supreme Court of India requiring information from the Health Ministry concerning etiquette and ethical conduct for clinical trials.  The government responded to the issues by enacting a series of amendments to the clinical trial regulations under the Drugs and Cosmetics Rules (Third Amendment) in February 2013. The objective was to improve patient safety, reporting timeliness of serious adverse events including deaths during clinical trials, and the payment of compensation to patients. These amendments led to many multinationals companies choosing to withdraw their clinical studies from India, and a suspension across all clinical areas and phases.

Resolution was reached following the formation of Subject Experts Committees (SEC) and additional safeguards for each therapeutic area and studies have resumed. The responsibility of reporting serious adverse events has been moved by the licensing authority from the sponsor to the investigator and must happen within 14 days. There are currently 440 open clinical trials in India as per Clinicaltrial.gov, a major upturn over the last two years.

The import process

It takes about 180 days to get Clinical Trials approved in India. Reviewing and approval timelines for all types of applications must occur in consultation with the SEC. Only institutional ethics committees can review and grant approval for the conduct of clinical studies at any site.

The Drugs Controller General of India (DCGI) issues an approval letter to conduct Clinical Trial, to an accredited principal investigator of the trial and the ethics committee of the Institute. This is needed for clearance together with an import license which the consignee needs to apply for after getting a No Objection Certificate from the DCGI.  The permit usually takes 12 - 14 weeks and requires the importer of record to complete extensive amounts of documentation. Customs also require IEC Code.(Import Export Code Number) and an invoice for clearance, which generally takes 24-48 hours.

The invoice must be original, on shipper's official letterhead and should clearly state:

• Importer of Record if different from Consignee
• Reference to Protocol or Study ID
• The name of the drug must match the "Name of the Drugs" on the import licence
• The 'mg' or 'ml' of the drug unit (capsule or vial) mustmatch the stated unit amount on the Import licence
• Customs must be able to easily tally the exact amount of drugs that the invoice represents in order to debit the correct amount from the tally section of the licence.
• Value must be provided at a unit (per tablet, capsule) level in addition to the total
• Value of the shipment is (which is a definite number and not a value for customs
• Manufacturing date, expiry date and batch number.These must be identical on Invoice, Packing List andProduct Label.
• A Value Evidence Certificate (VEC) for customs is required stating that the invoice value is true & correct. This should be on company letterhead of the shipper, in duplicate

Facilities en route and logistic needs

Major ports like Delhi, Mumbai, Bangalore & Hyderabad have temperature control facilities at the airports for storage during customs clearance. The second Saturday of each month is a customs holiday, if a shipment is due to arrive on Sunday then pre-clearance documents need to be received by midday Saturday (Midday Friday for every 2nd Saturday of month).

Caution should be taken around monsoon season to avoid spoilage of goods if the warehouses are full. Shrink wrapping should always be used to reduce water ingress. Simple pack outs are recommended in case customs decide to remove and count each component in a shipment. Temperature monitors should always be declared on the invoice.

The future for India in the global landscape

So India has returned to the fold of clinical trial countries which, with the additional safeguards in place can only be a positive step for all concerned, sponsors patients and CROs alike. Looking forwards given the ability of Indian pharmaceutical companies to routinely re-engineer processes for manufacturing generic drugs to make medication available at much lower costs, (which is a result of Indian patent law which only protects formulation rather than composition of a drug) it would be foolhardy to exclude them. 

Biosimilars and generic drugs are big business in India and they typically become available very quickly once patent protections expire. This will be the way forwards for this exciting sub-continent, who once again is taking its place in the global pharmaceutical marketplace.