In a race against time …

Will quality and ethical issues be barriers to India's clinical trial industry? No, not if the industry learns how to balance speed with quality. Viveka Roychowdhury analyses

As the number of clinical trials outsourced to India increases, Indian clinical research organisations (CROs) are no doubt seeing phenomenal growth. The rationale of outsourcing, i.e. to reduce costs, comes with an added dimension in clinical trials industry—when trials are outsourced, a CRO is considered more efficient if the trial is completed ahead of schedule. In other words, the sponsor (usually a pharmaceutical company) expects a CRO to shrink deadlines.

The benefits of expecting and adhering to aggressive timelines are obvious. But more than the usual reduction in costs, the pharma company is more interested in beating competition. In these days of unproductive drug research pipelines, the industry has several sponsors chasing the same target, taking similar products through trials. The possibility of a first-to-market launch and the add-on benefits of capturing a lion's share of the market is the real reason why the emphasis on speed is here to stay.

"Trials in India are faster because of the sheer number of patients and the disease distribution and not because of any shortcuts by CROs or pharma companies" - Dr Chetan Tamhankar Chief Operating Officer SIRO Clinpharm

The CRO industry has responded to the challenge by breaking down the trial process into components and getting each task done by specialists. In fact, this is the very reason sponsors choose to outsource their clinical trials to CROs in the first place—because CROs have developed expertise in their area and hit the ground running on day one.

As Dr Chetan Tamhankar, COO, SIRO Clinpharm points out, "CROs are able to complete clinical trials faster as it is their core area of focus and expertise. They carry more number of trials than company departments or academic institutes, hence, they master processes and develop efficiencies. It's just like a professional is likely to complete a task faster and better than an amateur."

With the focus on speed and unbridled growth, it is likely that sponsors or CROs decide to cut corners and take shortcuts. Tamhankar refutes the charge, pointing out that though the primary responsibility for a trial is with the pharmaceutical company, many CROs discuss the trial design/protocol with medical experts, during a feasibility process before entering into a contract for a trial. "If the design is unsound or not in line with GCP principles we refuse the study, we however do not track what happens to these studies later," says Tamhankar. The question is how many CROs would turn their back on opportunity?

The larger debate

In fact, a recent article in the October 3 edition of New England Journal of Medicine, titled "Commercialising Clinical Trails—Risks and Benefits of the CRO Boom" asks the question—is the commercialisation of clinical trials, in its current form, in the best interest of science or the public? The article goes on to analyse examples where CROs or sponsors have slipped up. One of the examples, the TeGenero episode, made headlines in Indian mainline press as well because most of the healthy volunteers were of Indian origin. The study was a Phase 1 trial of TeGenero's monoclonal antibody (mAB), conducted by Parexel. Of the eight male volunteers, six were given the mAB, but soon after receiving it, they had to be admitted to intensive care due to multiple organ failure.

An inspection by the UK regulator, Medicines and Healthcare Products Regulatory Agency (MHPRA) revealed that the physician concerned with the study had 'inadequate training and experience'. In addition, there was 'no formal system in place for providing round-the-clock medical coverage'. Inspite of these findings, the conclusions of the expert scientific group that investigated the episode for the UK Secretary of State for Health, stated, that it was "highly unlikely" that these shortfalls had caused these events.

Indian scenario

"The quality depends on the faculty and the students. We have shortage of talented and experienced industry faculty. The students are more focused on short term objectives of lucrative job opportunities and less on clinical research as a discipline" - Dr Arun Bhatt President ClinInvent Research

So where does India stand on this score? As of now, there are no such examples in public domain, says Dr Arun Bhatt, President, ClinInvent Research, adding that only regulatory inspections can bring to light such events. Tamhankar too says there are no incidents in India involving CROs along the lines of the examples quoted in the NEJM report. He refers to a BBC documentary (titled "The Dark Side of Clinical Trials") on clinical trials in India, which claimed that clinical trials are not carried out with due regard to the patients (informed consent). The BBC investigation involved a drug being tested by a reputed US pharma major. "Even in the case of that trial the company had documentary evidence of the informed consent from the patient/patient's guardian, as stated in the documentary itself," points out Tamhankar.

At the time the BBC documentary was screened, the Indian clinical research industry was divided as to the action to be taken. While some were in favour of putting up a defence, (i.e. that indeed there does exists a 'bright' side to doing clinical trials in India), another point of view was that this would only give more mileage to the programme. No doubt, the case of a 'bad apple in a barrel' applies to this situation as well.

However, trials involving vulnerable patient groups like paediatric, geriatric or psychiatric patients, did present a practical and ethical problem. However, today we do have a system in place to protect the interests of these groups as well. Explaining the procedure, Tamhankar says, "In many cases, like when the patient in not in a mental state to respond or afflicted with some psychiatric problem that leaves him/her in a state not fit to understand and respond to the implications of participating in a trial, the consent is sought from the patient's guardian. This is the right and the ethical method, as seeking consent from a mentally unsound patient has no value." He adds that the patient's consent is sought by the doctor (investigator) and not directly by the CRO or the pharmaceutical company, though these may help the investigator with patient recruitment. This, therefore, serves as an additional insulating layer between the patient and sponsor.

Another solution to the hurdles of the informed consent process is to translate the IC document into relevant Indian languages, so that the patient can choose to refer to the document in a language familiar to him. Another solution for illiterate patients is that the documents are read out to them by an authorised and trained person. "Hence there is no basis to claim that patients do not understand the implications, or the procedures are not up to the mark, says Tamhankar

Given the competitive scenario, the mushrooming of CROs all hoping to bag the same clinical studies, aren't CROs tempted to take shortcuts? Tamhankar counters this stand with the statement, "Malpractice is possible everywhere, how-ever, since reputation and regulation is critical to CROs; it does not make business sense for them to indulge in such practices."

Genuine strengths

Inspite of these barriers, there is no denying the fact that India offers genuine benefits. The first is obviously faster patient recruitment rates. "Trials in India are faster because of the sheer number of patients and the disease distribution and not because of any shortcuts by CROs or pharma companies," states Tamhankar. But other countries offer the same advantage. Countries in Africa and some like Bangladesh have the same volunteer/patient profile (economic and disease profile wise). In fact some of these countries have more relaxed or no regulatory hurdles as well. As Tamhankar avers, "There are genuine strengths like well educated doctors, world class medical infrastructure at a number of centres, a talented clinical research workforce and many more" to justify the steadily increasing flow of clinical trials to India.

Raising the bar

The Indian government's regulatory mechanism is playing its role, aware that even a single incident may do long term harm and tarnish the image of the Indian clinical research industry. Therefore they are being ultra-cautious about regulations. In fact, India's drug regulatory mechanism is known to be conservative. As Tamhankar says, "The Indian government is highly risk averse in permitting clinical studies. It is very difficult if not impossible for MNCs/CROs to get approval for first in man studies in India. The government wants to know if a new drug has been tested in any other developed country before giving the approval. The Drug Controller General India (DCGI) generally awards faster approval if studies of the drug have already been carried out in developed countries like the USA and countries in Western Europe. As India has a limited staff for reviewing studies for approval, this acts like an automatic safety mechanism, and also allows the DCGI to focus more attention on the higher risk areas."

Industry players have their own way to track quality. Tamhankar points out that top domestic/MNC CROs have faced several international audits from clients as well as regulatory authorities from western countries and no serious audit findings have been noted or are at least part of public knowledge.

Solutions

So what are the solutions? Listing the ways to prevent such incidents, Bhatt puts regular effective oversight from ethics committees and inspections from regulatory authorities top on the list. Second is the extensive training of sponsor staff and investigator site team in regulatory compliance, ethics, GCP. And third is to encourage and reward whistleblowers. In addition, accreditation of researchers or research sites work would help in establishing uniform minimum quality standards for trial conduct. Tamhankar further points out that a clinical registry has been set up and it should be mandatory to register all trials.

Ultimately an industry is only as good as its people; therefore, the emphasis has to shift to training industry professionals to man the trials moving to India. India has no dearth of clinical education institutes or graduates to enroll for these courses. But the hype surrounding the clinical research industry could work against it.

With the mushrooming of clinical training institutes in India, the year ahead could see concerns about the quality of these institutes, the training imparted and the curricula followed. According to Bhatt, "The quality depends on the faculty and the students. We have shortage of talented and experienced industry faculty. The students are more focused on the short term objectives of lucrative job opportunities and less on clinical research as a discipline."

At present, there is no way to gauge the system, except on the industry-worthiness of past students. By that standard, Bhatt opines that based on recruitment process interviews, only about ten percent of students get jobs in reputed companies/CROs. Does this mean that the industry is trying to run a marathon before mastering the sprint? One thing is very clear—India will continue to attract clinical trials because of the genuine strengths. It is now a question of multiplying these skills and balancing quality with speed.

viveka.r@expressindia.com