India on Phase I
Similar to other phases of clinical trials, India has huge opportunity in Phase I clinical trials but it is largely an untapped market as of now. Sushmi Dey discerns what India needs to walk ahead.
One of the most important phases of clinical trials is the phase where the new medical entity (NME) for the first time, meets the species for which the molecule is designed for. “Phase I are the first in human studies conducted to determine the safety and the pharmacokinetics of a new drug in human subjects,” says Dr Anurita Mazumdar, Medical Advisor, Oncology, Eli Lilly India. Phase I is considered very crucial in order to observe the behaviour of the drug in the human body. The drug is tested in minimum of two healthy volunteers at each dose level. With the exception of anti-cancer and HIV drugs, Phase I trials are conducted in healthy volunteers in a clinical pharmacology unit which has facilities for housing of volunteers in a controlled environment.
Phase I trials give vital information on the safety of the drug in healthy volunteers. This phase is also instrumental in determining the maximum tolerated dose of the particular drug in patients and if there can be any adverse reactions.
What it needs?
According to global expectations, a clinical pharmacology unit (CPU) preferably based in a hospital set-up with special infrastructure for clinical safety and bio-analytical lab, competent investigators with a background in clinical pharmacology, trained team of clinical and lab personnel, expertise for handling medical emergencies and a pool of healthy volunteers are the basic requirements for conducting Phase I clinical trials. “The ABPI task force has recommended that the Phase I unit should be in a hospital setting with intensive care facilities and access to an expert emergency management team,” informs Dr Arun Bhatt, President, ClinInvent Research.
Apart from the facility, Phase I trials require experienced manpower and technology to conduct complex studies. The ABPI taskforce also recommends that the study team should be supervised by principal investigator with relevant experience and qualification for conducting first in human trials. “Knowledge of animal pharmacology and data on toxicology is essential to decide dose and dosage interval including blood sampling times. Then an appropriate safe dose calculation is done on the basis of toxicity data available on the molecule. There are regulations on how to do this,” says Rathnam. An experience in pharmacokinetics and study design capabilities is added advantage while conducting Phase I trials. The principal investigator should also have the potential to deal with any adverse event. A qualified staff of clinical pharmacologists, physicians and paramedical staff along with an ICU set up is also necessary during Phase I trials to handle any kind of medical emergencies.
According to Mazumdar, the CPU should also have a volunteer registration area where subjects can be explained about study procedure and consent can be taken for the trials. “The sponsor of the study should prepare a protocol well designed to answer the scientific questions as well as ensuring the safety of the trial subjects,” suggests Mazumdar. Before initiating the trial, the sponsor will also have to get the Investigational New Drug (IND) approval from the regulatory authority (DCGI in India) and the institutional ethics committee. Mazumdar adds that the IND approval from DCGI will be based on review of all essential trial documents like protocol, investigator’s brochure containing safety and efficacy information on the drug, rationale for development and chemistry and manufacturing details, informed consent document (and translations), letter of intent and curriculum vitae of the investigators doing the study and names and accreditation certificates of the CPU and the laboratory to be used.
However, once the approval is obtained, the sponsor can carry on with the study. “The trial should be strictly conducted as per the approved protocol. All safety data should be periodically submitted to the ethical committee. All volunteers should be kept in close surveillance until study completion,” suggests Mazumdar.
Is it risky?
Phase I studies are conducted on NME with an unknown risk profile. Phase I is a critical phase for the pharmacos developing an NME because it is based on human safety and potential activity. “The major risk factor associated with Phase I trial is adverse event. These may be minor to life threatening situations,” says Rathnam. Critical decisions are taken to continue further development or to stop further studies. The Phase I study, therefore, requires a team of medical experts including clinical pharmacologists and other specialists who are capable of making critical decisions.
|Although, with large pool of patients and swanky five star hospitals, India has emerged as a major location for clinical trials, the Indian regulatory (Schedule Y) does not permit Phase I trials for drug substances discovered outside India, unless the disease has specific relevance to Indian population. This is because they do not want Indian subjects to be exposed to new drug substances for first time in the world.
However, the industry has its own side of the story. According to Rathnam, India needs to have more proactive regulation to encourage research in the country from not only Indian companies but also MNCs, to share knowledge and exchange capabilities. “It is presumed that the Indian subjects are used as guinea pigs in testing the new molecules. It is the mind set of some people. I do not subscribe to this idea. Indian drug discovery companies are conducting Phase I studies in other countries and the people in those countries cannot complain the same way not to allow Indian companies to use their people as guinea pigs in testing the molecules. India at this point do not need to do all these things in not allowing Phase I studies for foreign molecules and stricter animal experiments controls,” emphasises Rathanam.
However, the reasons why Phase I trials are not allowed in India could be attributed to:
Since the drug is administered for the first time in humans, the primary objective of Phase I study is to assess the safety of the drug in humans and the task is obviously not very easy. “Prior to this, the only data available is in animal species. Hence, it is difficult to predict drug’s side-effects in man,” says Bhatt. Agrees Mazumdar, “All previous information on the drug are on animal subjects based on which precautions are taken. However, humans can behave differently from animal species.” To overcome such challenges dose escalating studies are designed where in very limited number of subjects are exposed to any dose. “Phase I trials are designed to give very low doses to small group of subjects (cohorts), observe them very closely for any side-effects and then proceed to the next higher dose,” adds Mazumdar.
Although Phase I are generally considered safe, there are instances where serious adverse reactions occurred even with a single dose. Keeping this in mind, infrastructure protocol development, management of adverse events, compensation, insurance, regulatory approval and experienced and trained physicians are other major challenges for conducting Phase I trials in India.
Have(s) or have not(s)
In developed countries, Phase I is conducted in hospital or CRO setting. However, the units are geared to handle medical emergencies
The industry believes that India has trained doctors and clinical pharmacologists to ensure the well-being and safety of patients participating in Phase I trials. India also has state-of-the-art hospitals with infrastructure to handle human safety at par with international standards.
However, since Phase I trials are not permitted in India, the experience with such trials is limited. The only experience stems from Phase I trials conducted by Indian pharmaceutical companies like DRL, Ranbaxy, Torrent and Dabur. “India requires the experience and technical know-how to conduct these trials which will come through training and exposure to such projects,” avers Mazumdar. According to Bhatt, the training of manpower in India is insufficient in safe guarding subject’s health. In developed countries, Phase I is conducted in hospital or CRO setting. However, the units are geared to handle medical emergencies as they have long experience and excellent support from sponsor’s medical team. “In India, the main risk in a CRO setting is experience and capability of handling a serious medical emergency,” says Bhatt. He suggests, “Non-clinical as well as clinical staff should be trained in basic cardio-pulmonary resuscitation with frequent regular updates. Medical and nursing staff should also receive training in advanced life support. Mock emergency call sessions should be run frequently.”
Another major need of Indian pharma industry is to have required regulatory experience in auditing Phase I studies. “The experience of regulatory, scientific and ethical issues for Phase I studies is inadequate. There are also delays in regulatory and ethics approval of Phase I trials,” says Bhatt. According to Mazumdar, regulatory and ethics committee should also be trained to understand Phase I trials so that they can review and take correct and appropriate decisions.
Its all about business
However, Phase 1 trials are also significant from strategic business point of view because it does not pose any challenge of cost and time. Instead, it prevents from wasting valuable time and resources by eliminating poor candidates from development pipelines. “Phase I studies have become the fastest growing phase of drug development in the United States. The high costs and risks of drug development have led companies to increase investments in Phase I projects,” says Mazumdar.
According to Bhatt, Phase I forms around 10 percent of overall clinical development cost. And though the number of subjects depends on the protocol specifications, Phase I trials are usually completed rapidly within four to six months since the number of subjects is less during the phase. This enables the big pharma to conduct Phase I studies. According to Bhatt, this is one reason that the big pharma is unlikely to look for cost saving by conducting Phase I in a developing country. However, Mazumdar feels that India still has opportunity to gain business out of Phase I trials. “According to Reliance Clinical Research Services (Media news 10 May 2004), the average cost for conducting a Phase I study in the US is $20 million. It is expected that the average cost for conducting a Phase I study in India is 50 percent cheaper i.e. $10 million,” adds Mazumdar.
However, for small biotech firms the equations are different. Unlike big pharma, small biotech firms lack financial comfort. Hence, there is a pressure on them to save costs. For small biotech firms, successful Phase I represents an opportunity to improve valuation of NME and obtaining funding from investors. “As compared to valuation at discovery stage without any pre-clinical data, the valuation of NME jumps 40 percent higher after a successful Phase I,” informs Bhatt. Besides, small biotechs have little internal expertise for planning clinical development. Hence, they will usually look for outsourcing Phase I to a developing country where they can conduct the Phase I trials at a low cost with better clinical expertise.