Are we ready for global phase I studies?

Wednesday, March 07, 2007 08:00 IST 
Dr Arun Bhatt

Indian clinical trial industry is now entering into an exciting phase. The market has grown from $ 20 million in 2002 to $ 80-100 million in 2005. The market is continuing to grow at a rapid pace. This growth is spurred by the changes in IPR status and amendments in Schedule Y of clinical trials. These have made India more attractive to international pharma community. 

In 2004 the global CRO market was estimated to be $ 10 billion and was expected to grow at an annual rate of 14-16 % (ACRO website). The market segmentation was: Phase I 6.09%; PhaseII-III 19.13%; Phase IIIb/IV 16.52%; Preclinical 17.39%; Central Lab 12.17%; Others 28. 7%. 

The 2007 estimate for CRO market is $14.4 billion. The 2007 market size for different phases (based on 2004 segmentation) is likely to be: Phase I : $ 0.87 million; Phase II-III : $ 2.7 billion;Phase IIIb/IV : $ 2.37 billion.

The Indian CRO market, in line with global expectations, is rapidly expanding. As the amended Schedule Y permits concurrent Phase II-III studies, the focus of global trials outsourced to India is shifting from late stage Phase III/IV to early stage Phase II studies. Now the Indian CROs are looking for opportunities to participate in global Phase I studies and are requesting regulatory authorities to remove restrictions on conduct Phase I for drugs discovered outside India. As the regulatory system becomes more organized, these restrictions will be removed. However, the big question is: Are we ready for Phase I studies? 

Global pharma perspectives on phase I studies
Phase I study is the first phase in the drug development when a new medical entity (NME) first time meets the species for which it is designed. Phase I study focuses on safety of NME in healthy subjects or in patients in certain conditions e.g. cancer and pharmacokinetic studies. 

For the pharma company developing an NME, Phase I is a critical phase, when based on human safety and potential activity, critical decisions are taken to continue further development or to stop further studies. Phase I forms around 10% of overall clinical development cost and is usually completed quite rapidly (within 6 months or less). Besides, big pharma has good database and internal expertise to assess risk, benefit during planning and conduct of Phase I. For big pharma conduct of Phase I do not pose any challenge of time and/or cost. Hence, big pharma is unlikely to look for cost saving by conducting Phase I in a developing country. 

In contrast, 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 preclinical data, the valuation of NME jumps 40% higher after a successfulPhase I. As small biotech firms lack financial comfort enjoyed by big pharma, there is a pressure on them to save costs. Besides, small biotechs have little internal expertise for planning clinical development. Hence, they will usually look for outsourcing Phase I to a developing country. 

TGN 1412: Impact on phase I studies

In early 2006, six volunteers enrolled in Phase I of TGN 1412 were admitted to intensive care unit of Northwick Park Hospital. (Drazen JM Volunteers at Risk NEJM 355:1060-1061 2006). The investigational product TGN 1412 was a humanized monoclonal antibody (MAb) designed to treat leukemia and auto immune diseases such as rheumatoid arthritis by targeting a receptor CD28. 

All subjects developed multi-organ failure. Two of these needed mechanical ventilation, and all received renal-replacement therapy. All had severe hypotension, and peripheral ischemia developed in one subject requiring surgical treatment. All six volunteers, survived because of the extraordinary intensive care delivered during the critical stages of their illness.

The serious injuries to these volunteers have compelled the scientists, industry and regulators, to reassess the safety of clinical trials involving healthy volunteers. (Wood AJJ, Darbyshire J NEJM Injury to Research Volunteers - The Clinical Research Nightmare 354:1869-1871 2006). Until now,Phase I studies were considered remarkably safe, reflecting both the extent of the preclinical and animal testing that precedes them and the safeguards built into their own designs. The TGN 1412 events have impacted the way Phase I studies are planned, conducted and monitored by the industry. 

ABPI task force report July 2006

In the wake of TGN 1412 episode, Association of British Pharmaceutical Industry (ABPI) early stage clinical trial task force made several recommendations, some of which are: 

" Investigators should have appropriate training or significant experience in first-in-human studies with close involvement of the medical monitor from the sponsor
" As healthy volunteers have nothing to gain from the study, apart from a small monetary payment, great care must be taken to ensure their safety during the study and for any period that the medicine may act afterwards.
" Early clinical studies of novel biological agents or NCEs with novel pharmacological mode of action where the acute pharmacological action may pose a material risk should be performed in a research facility on the site of a hospital with intensive care facilities. 
" The hospital in which the research facility is sited should have an intensive care facility with sufficient beds to provide care to any subjects becoming seriously unwell. For first-in-human studies with certain biological agents, for example mAbs, the hospital site and its intensive care unit should have access to specialist techniques such as plasmaphoresis that may be of use to increase clearance of the study drug and so aid management of seriously ill subjects. Specific antidotes, if they exist, and other drugs that could be helpful in managing potential adverse reactions should be available in the study unit
" The research facility should be covered by the hospital's crash team such that their help can be summoned immediately if needed. The crash team must be aware of the location of the research facility and be able to find it quickly in an emergency. 
" The resuscitation team must be aware of the location of the research facility and be able to find it quickly in an emergency. The existence of this facility at Northwick Park Hospital may well have contributed to the survival of all of the volunteers involved in the TGN1412 study. 
" The key reason for needing immediate access to the hospital crash team is to provide the capability for intubation which is best performed by a trained anesthetist with current experience of emergency intubation.


Indian experience of phase I studies
India's journey in Phase I goes back to late 60s. Several R&D centres - CIBA, Hoechst, Boots, CDRI, which were active in NCE research, conducted Phase I studies in special clinical pharmacology wards in medical institutions. Based on these studies, several NCE were taken to full development and marketed. By late 80s, the multinational companies gradually closed down the R&D centres as there were no government incentives or support to new drug research and there was tremendous generic competition. In late 90s, the Indian big pharma turned its focus to generic exports. This led to flourishing of many bioequivalence (BE) CROs. The Indian big pharma also focused on new drug research, as the country moved to a new IPR regime. For these companies, Phase I studies had strategic business significance. Hence, they outsourced Phase I to international CROs in Europe and Canada. Hence, Indian academic medical centres or BE CROs have hardly any experience of Phase I studies for NMEs of international/Indian pharma companies. 

The experience of BE volunteer studies have created a myth about our Phase I capabilities. Let's recapitulate some facts: 
" BE studies are not Phase I studies. The main objective of such studies is to establish BE between a marketed generic and a marketed reference product. In contrast, the primary objective of Phase I is to assess safety of an NME. The BE study is essentially a pharmacokinetic study; where as Phase I is a human safety study. 
" The BE study is conducted on a marketed generic drug whose risk: benefit are already established in Phase III-IV studies. Phase I studies are conducted on NME with unknown risk profile. The EC of BE centre does not have adequate expertise to judge the risk, benefit of PhaseI study. 
" The BE studies are not free from any safety risk. Some years ago, one Indian volunteer died in a BE study. Although there was a regulatory inspection of this episode, there is no information in public domain about the regulatory observations. In contrast all aspects of TGN 1412 episode are investigated and discussed in medical journals and lay press. The Indian approach to this BE mishap, casts doubt about the safety of BE studies and also about the experience of the BE team to manage such emergencies. 
" The Phase I study requires a team of medical experts - clinical pharmacologists and other specialists - who can make critical decisions. 
" BE teams in a company/CRO facility consists largely of non-medical persons and non-specialist medical doctors. The medical team consist of an MD pharmacology and some MBBS doctors. The team does not have specialist experience to handle SAEs e.g. unconsciousness, arrhythmia, shock etc and is not adequately trained in emergency procedures - cardio pulmonary resuscitation. If there is an emergency, the team is supposed to send the subject to a local hospital. In an emergency, time and expertise are vital. These are lacking in most BE centres. 

When we review our overall experience of Phase I studies, the following facts emerge.

" 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.
" The know-how of conducting successful Phase I trials limited.
" The training of manpower insufficient in safe guarding subject's health. 
" There is a lack of state-of-the-art infrastructure. 

It is obvious we are not yet ready for Phase I studies for drugs based on new bio-medical technologies - proteomics, genomics etc. If we want to build Phase I facilities of global standard, we need to consider global expectations of infrastructure and study team. 

Indian model for phase I public-private partnership 
At present, we have two different models for Phase I trials: 
1) Academic clinical pharmacology centres of medical institutions 
2) CRO in-house centres 
Both models have their strengths and weaknesses. 

Academic centres have relevant medical expertise and being located in hospitals can successfully handle adverse events. However, they lack good volunteer database and modern equipment for safety assessments e.g. computerized ECG, psychometry. Besides, most do not have intensive care unit (ICU) in their own facility and depend on the hospital ICU in emergencies. The staff is involved in multiple research projects and hence, lacks knowledge and skills for managing Phase I. These units are not well versed in regulatory and quality aspects of Phase I. 

The CROs have good volunteer database and can afford to set up modern phase facility. Although they have ICU facilities, the staff is not trained in basic life support. Besides, their experience of handling marketed generics creates a false sense of safety about adverse events. As the BE is primarily a pharmacokinetic study, the BE CRO invests in lab staff more than in clinical staff. Although these CROs aspire to conduct Phase I, they must remember that impact of a mishap - a serious adverse event - could impact not only their reputation but also will affect India's image and potential clinical trial business. 

It is obvious that neither of these models by itself can succeed on its own. One strategy would be to establish public-private partnership (PPP) model. The PPP model for Phase I is not a new concept. Till late 80s, the Phase I units at leading institutions - KEM and JJ Hospital were supported by CIBA and Hoechst. However, the economy had not yet liberalized and the organization was still under control of public sector with little management involvement for the private partner. We should take advantage of current liberal climate and improve this model. 

The public partner - medical institution - will provide the clinical pharmacology expertise and medical oversight. The clinical pharmacology expert will oversee the planning and conduct ofPhase I study. The availability of medical specialists and emergency services will assure that the subjects get the required life saving measures in case of a serious adverse event. The staff can get essential training in basic and advanced life support. The private partner - pharma company/CRO - will manage the set up with necessary equipment and manpower and organization volunteer logistics. The PPP model appears to be the best option to face challenges of modern day Phase I. The Phase I set up should be as per the global expectations.

Global expectations of phase I set up 
The ABPI task force (vide supra) 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. The study team should be supervised by an experienced principal investigator (PI) who has relevant postgraduate qualifications and is experienced in undertaking first-in-human trials. (Griffin JP, O'Grady John Textbook of Pharmaceutical Medicine). The PI and co-investigators providing medical care should be able to comprehend the nature of the NME being studied, any potential adverse events and how to deal with them. This would require involvement of other medical and drug development experts independent of the research institution and/or the sponsor. 

The PI and other experts should be able to take major decisions, which can affect trial conduct. These include deciding whether a volunteer meets the entry criteria for a healthy subject or should be withdrawn from a study, how to handle an unexpected adverse event and when to discontinue a study. Ideally there should be at least one physician providing dedicated support to the study for every two subjects dosed during the first few dosing occasions and at least one nurse per subject. 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.

Conclusion
The expanding Indian clinical trials market for Phase II-III have made the stakeholders look towards the next opportunity - Phase I. However, the limited past experience of Phase I in India, the potential for SAE in Phase with NME, and stress on safety of healthy subjects should make us whether we are ready for Phase I. Neither the academia public institutions nor the private industry can create a successful Phase I unit. The academia and industry should come together and form a mutually beneficial public-private-partnership to set up state-of-the-art Phase I units in hospital setting, which will meet global standards of infrastructure and trained manpower. This will provide assurance that Indian Phase I studies meet the twin objectives of establishing safety of NME and protecting safety of healthy volunteers! 

(The author is President, ClinInvent Research Pvt Ltd, Mumbai )