Getting up to speed with India

pharmafile | January 12, 2009 | Feature | Research and Development |  India, clinical trials, ethics 

On a recent trip I made to India, the resourcefulness of the country's people was demonstrated to me as soon as I arrived at Mumbai airport. I had to transfer to the domestic airport, which necessitated a taxi ride. A colleague and I duly hailed an incredibly ancient and very small vehicle that looked like a 1960s Fiat, and loaded our bags and ourselves into it – with difficulty. The boot lid would not lock, but was secured by a length of chain which also prevented the rear bumper from falling onto the road.

At the same time, I was reflecting that this was the world's largest democracy, whose last general election was run with staggering efficiency using Indian-developed computer systems that have since been marketed in other countries. Herein lies the enigma of India, where ancient meets modern, and where some things go very fast and some things don't. The problem lies in predicting which is which.

The migration of clinical trials eastwards is a trend which is well established now, but conducting trials in India remains different to working in Europe or the US. I hope to give you a flavour of the subject and alert you to a few issues that you might not spot otherwise. I have always maintained that systems don't run projects, people do, so let's start by considering the human dimension.

Education

India's universities are now producing graduates in large numbers, and indeed these might be considered a major export, as we encounter them around the world. The key point is that this is not just a commodity process, it is a quality one.

The educational level of Indian graduates is second to none, and my immediate impression as I travelled around the country was that everyone knows their own technical area inside out. This needs to be qualified of course, as we are talking about 900 million people and not everyone has the opportunity to go to university. There are still major inequalities in society. But with that size of population, there will be a lot of graduates and a good supply of very highly skilled people.

Language

Everyone, of course, is fluent in English – or are they? Professions conduct much of their business in English (so your study site documents won't need translation), but don't be misled by what you find in the cities. People in rural and poorer areas don't need English on a day-to-day basis, and there is a multitude of regional languages, as you might expect from such a large population.

Language is always one of the logistical issues that needs to be addressed in clinical trials, and naturally all patient-facing materials will need to be in local languages. For example, you will need to consider consent documents for India in much the same way that you would for multiple countries in Europe – except that in any one region there will be several languages spoken. If you are using patient-reported outcomes, the instruments (whether paper or electronic) will also need translation and verification.

The different appearances, usages and meanings of certain characters in languages such as Kanadda and Tamil can be very subtle, and you will need very close co-operation between translators and publishers of text. For those of us who use the Roman alphabet, this process can be challenging as we don't recognise the characters, so don't be surprised if you have several iterations before translations are approved.

Culture and beliefs

From this, you can see that this huge nation is highly regionalised, a feature which affects several aspects of clinical trials. The land mass is divided into 28 states, plus seven 'union territories' (former colonies of European powers). Each state has its own Food and Drug Administration (FDA) and, be warned, they may not all operate in quite the same way. For those of us who like to get clear structured plans into place, supply chain planning can be a serious challenge. Not only do practices vary from state to state, but also they can change over time as regional practices change.

Getting the necessary approvals, eg to ship drugs from customs to the country depot, or from depot to study sites, depends on the co-operation of individual officials. Nothing new about that you might say, but here the matter of culture and belief systems arises.

To illustrate this point, let me refer to a recent real-life situation. A patient in a clinical trial had run out of a study drug, which was an opiate and thus a controlled drug. The patient's pain was therefore uncontrolled, apart from rescue medication. The situation arose because of a delay in obtaining a permit from the regional FDA to transport a batch from the depot.

Representations were made to the official concerned, emphasising that the patient was receiving sub-optimal pain control. The response was that suffering was good for the patient, as it would enhance their karma and stand them in good stead for their next life. From my perspective in a largely secular Europe, this is hard to understand, but it is very important to appreciate the extent to which culture determines what happens in all societies, and especially in India.

There are many ways in which such social mores can disrupt the planning for clinical trials (or for anything else). Earlier this year I heard about a problem with arranging travel of site staff to an investigator meeting. One site was sending both the investigator and the site co-ordinator. They arrived at the airport on the same flight, but could not be picked up in the same car. This was because they were at different social levels, and it was not acceptable for them to travel together.

Presumably their seats on the aircraft were well separated. India has been striving to modernise society, but traditions die hard. The caste system has been made illegal, but is still practised quite openly. The 'untouchable' caste still exists, relegating its members to such unenviable jobs as cleaning out sewers by hand.

Technology

The nation has put huge effort into modernising its infrastructure, especially communications. As I have observed, India is among the leading countries for computer expertise, and to support this the telephone and internet networks are orders of magnitude more powerful than they were even a few years ago. So you might be reassured that your weekly teleconferences and web-based training sessions will proceed without a hitch.

Well, again, don't be misled by what you see in the major cities, as the rest of the country may be different. Even large hospitals may have telephone problems, sometimes technical but more often bureaucratic. For instance, you may want to use interactive voice response systems (IVRS) for drug supply chain management. Study sites are not going to be happy about paying for the large number of calls involved, but you may find, as I did, that the freephone number you have supplied won't work via the hospital system because numbers with certain prefixes are automatically blocked. We got round this by issuing calling cards to all the sites. The message is to test your proposed processes at all your sites before going live. Offices sometimes lose internet connections, and I am accustomed to finding that all lines are engaged when I phone – which I suspect is not because of the place I am phoning, but the result of general network overload.

Similarly it's vital to do your homework if you are using any other special technology. Let's consider again patient-reported outcomes tools such as electronic diaries. Principal investigators in India will probably assure you that there will be no problems in uploading data, either at clinics or at patients' homes, but my experience is different, even if using cellular network connectivity. As so many people have a mobile phone, it's natural to imagine that most of the world has signal coverage, but away from the cities in India this may be a problem. In smaller villages most homes won't have landline telephones and may be out of range of the nearest cellular transceiver, so you will need a back-up process to ensure that you don't lose data between clinic visits.

Administrative systems

The Indian political, legal and administrative systems are modelled on the British ones. Not only that, but they can seem remarkably Victorian at times! This means that, in general, the way things work appears at first sight familiar to us, if rather cumbersome, but at a deeper level the cultural clashes can make an already complex system even more difficult to navigate. This is all part of the highly ambivalent attitude that educated Indians have towards British culture, and by extension to western culture in general. The English language (and India has its own version, as in the US and Australia) is seen as a window into the world in general, but the nation is fiercely non-aligned while remaining a member of the British Commonwealth. This is a good example of Indian adaptability and pragmatism.

The administrative challenges of India are presented no more strongly than in the area of drug supplies. It must be remembered that, whereas Indian investigators are mostly highly conversant with Good Clinical Practice (GCP), and certainly the regulatory authority is compliant with international standards, experience in international clinical trials is fairly recent. Up to a few months ago, for example, no trials with controlled drugs had been carried out in India, so if your drug falls into that category you must expect several more layers of control. Shipments between states, which will always be needed for multi-site studies, need transport permits which have a limited life, and then you find that unused, returned and expired drugs can't be transported back to the depot. Much of this seems to relate to the federal model of government, although the latter is rather more centralised than in the US where there is more legislation at state level.

You should by now have received two main messages: firstly, do not expect less work if you run your trials in India – there will probably be more; and secondly, do not expect a shorter start-up – it will most likely be longer. But my experience so far is that, once sites are started up, patients appear more quickly, so it is worth the effort. As a bonus, costs will be lower but the bigger financial benefit will be in faster completion of the study.

Of course, to capitalise on this potential for faster completion, you will need teams on the ground. Many of the major CROs have subsidiaries in India, and the emergence of home-grown CROs reminds me of the heady days of the late 1980s when CROs were appearing in the UK one after the other. Pharmaceutical companies are also setting up R&D functions in the subcontinent, and there is a proliferating range of support functions as well, including data management, regulatory, and manufacturing/supply chain specialists, both subsidiaries and independents.

Patients

I will conclude with some ethical considerations. The main reason for going to India for our clinical trials is to tap into a largely unexplored resource of patients. You may also be thinking that such a vast population represents a market for your drug, once it receives approval, and that running some of your trials in India will help towards approval in that country.

But you may not be quite right, because of the huge difference between India and the economies within which most pharmaceutical companies operate. To be brutally frank, Indian people may not be able to afford to buy your drug. I think it is worth considering this dilemma; here we are using this resource of patients in India, who will most likely benefit from the drug (if they are on active treatment) during the trial, but they are the lucky few.

Others with the same condition won't get access to it, unless the sponsor is prepared to cut prices by very big factors. At the same time, there is migration of clinical trials even further east, and especially into China which is making huge strides in becoming a major economic power. In mitigation of a preference for India is the fact that, for all its cultural challenges, it is a parliamentary democracy. My strictly personal view is that I would be a lot less comfortable if I were tapping into the patient pool in the world's last major totalitarian state.

INDIA'S REGULATORY ENVIRONMENT

The Indian equivalent of the FDA is the Central Drugs Standard Control Organisation (CDSCO). Approval to carry out a trial is given by the Drugs Controller General (India) or DCGI

* The governing law is Schedule Y of the Drugs and Cosmetics Rules, within the Drugs and Cosmetics Act

* In 2005, Rule 122 of schedule Y was introduced, with several sections covering clinical trials and definitions of new drugs

* Schedule 7 has been harmonised with current advances in science and technology, and with the global drug regulatory environment. This includes the ICH GCP

* Rule 122E of Schedule Y defines a new drug as a new therapeutic substance, or as an already approved drug with modified or new therapeutic claims, indications, dosage forms or routes of administration

* Phase I trials were previously only allowed for drugs discovered in India. They are now permitted for drugs discovered outside India if phase I data are available from the other countries

* From phase II onwards, trials can be conducted concurrently in India and the rest of the world (previously they had to lag behind in India by one phase)

* National GCP guidelines were introduced in 2007

* Ethics committees operate to normal international standards

* Serious adverse events must be reported by the sponsor to the regulators within 14 days

* Legislation is before Parliament to reform drug regulation, creating a central authority. This centralises many hitherto separate functions and caters for various new technologies, such as microdosing phase I studies which are currently not.

Les Rose is a freelance writer and clinical science consultant with Pharmavision Consulting. For more information e-mail: lesrose@ntlworld.com