Tuesday, December 16, 2008

Combination Vaccine for Kids withdrawn

A vaccine that combines conventional MMR (Measles, Mumps, Rubella) with Chikenpox has been withdrawn in the United States due to a higher rate of seizures in children. In a study children aged 12 to 23 months who received the combined MMR cum Chickenpox vaccine had double the rate of seizures compared to children who got separate vaccine for MMR and chickenpox. This equates to one additional case of convulsion per 2000 vaccinations.

The Connection Between Sedatives and Fractures in Elderly Patients

Johns Hopkins Health Alerts:
Prescription Drugs
The Connection Between Sedatives and
Fractures in Elderly Patients

All drugs have potential side effects. Indeed, at some point you've probably squinted down the laundry list of possible side effects on the package insert of your medications. Common drug-related side effects include blurred vision, drowsiness, dizziness, dry mouth, heart palpitations, erectile dysfunction, memory impairment, and nervousness. Fortunately, many of these drug side effects occur in only small numbers of people.

Now researchers have called into question the connection between sedatives which can cause dizziness and the potential for falls in elderly patients. They point out that well-meant policies discouraging sedative use in older people to prevent falls and fractures may not be necessary.

Starting in 1989, New York State required doctors to fill out prescriptions in triplicate for benzodiazepines, the most widely used class of sedatives. Twenty-one months later, use of these drugs plummeted by more than half. However, the number of hip fractures did not fall accordingly.

Benzodiazepines can make elderly people unsteady on their feet, potentially increasing the risk of falls and hip fractures. Policy makers hoped that restricting access to these drugs might help prevent these fractures. In fact, since January 2006, benzodiazepines have been excluded from coverage under the Medicare drug benefit.

But this study, which was reported in the Annals of Internal Medicine (Volume 146, page 96), did not confirm the alleged link between hip fractures and benzodiazepines. Thus, Medicare beneficiaries may not receive a class of drugs that might, in appropriate situations, benefit them. Commonly prescribed benzodiazepines include Xanax (alprazolam), Librium (chlordiazepoxide), Valium (diazepam), and Ativan (lorazepam).

Monday, December 15, 2008

Isotretinoin in India: A tragedy in the offing

Isotretinoin in India: A tragedy in the offing


Wednesday, March 28, 2007 08:00 IST 
Seema Thakral

Isotretinoin is the drug of choice for severe calcitrant cystic acne vulgaris, which often causes scarring and depression from disfigurement. Isotretinoin has been called "the greatest medical advance of the 1980's." A majority of patients with acne are permanently cleared after a four to five months course of treatment. It has also been used off-label for a variety of oncology uses including: cervical cancer, head and neck cancer, squamous cell cancer of the skin, juvenile chronic myelogenous leukemia (CML), and neuroblastoma. However, the drug is a proved teratogen and carries a significant risk of birth defects, if it taken during pregnancy. Birth defects, which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. There is an increased risk of spontaneous abortion and premature births have been reported. Hence, women who are pregnant or who might become pregnant are strictly advised against its use.

The drug was initially made available under a risk management programme -System to Manage Accutane Related Teratogenicity (SMART) - by Roche Pharmaceuticals, which marketed Accutane, the innovator isotretinoin product. Under SMART, stickers were provided by isotretinoin manufacturers to physicians who registered to become authorised prescribers of the drug and valid prescriptions for isotretinoin must bear a yellow sticker signifying that the woman presenting the prescription has twice tested negative for pregnancy before initiating therapy. To meet its goals, SMART relied on unauthorised physicians to refrain from prescribing isotretinoin and pharmacists to refuse to fill prescriptions unless they bear the sticker. Another key element was that authorised physicians must not affix the sticker to a woman's prescription unless a properly timed negative pregnancy test result was obtained.

Strengthened distribution programme for isotretinoin
The generic versions of the drug entered into the market in late 2002, with each manufacturer providing the drug through separate risk management programmes modelled after SMART. Recently, the United States Food and Drug Administration (US FDA) announced approval of a strengthened distribution programme for isotretinoin, called iPLEDGE, aimed at preventing use of the drug during pregnancy. The iPLEDGE programme is a computer-based risk management programme, designed to further the public health goal to eliminate fetal exposure to isotretinoin through a special restricted distribution programme approved by the US FDA and has been fully implemented on March 1, 2006. The programme strives to ensure that:

No female patient starts isotretinoin therapy if pregnant; 
No female patient on isotretinoin therapy becomes pregnant. 

Thus, the iPLEDGE programme requires registration of all wholesalers distributing isotretinoin, all healthcare professionals prescribing isotretinoin, all pharmacies dispensing isotretinoin, and all patients prescribed isotretinoin. To obtain the drug, patients must comply with a number of key requirements that include:

(1) Being registered with iPLEDGE, 
(2) Completing an informed consent form, 
(3) Obtaining counselling about the risks and requirements for safe use of the drug, 
(4) And, for women of childbearing age, complying with necessary pregnancy testing. A female of childbearing potential selects and commits to use two forms of effective contraception simultaneously for one month before, during, and for one month after isotretinoin therapy. She must have two negative urine or blood (serum) pregnancy tests with a sensitivity of at least 25 mIU/ml before receiving the initial isotretinoin prescription.

Each month, the prescriber must enter the female patient's pregnancy results and the two forms of contraception she has been using in the iPLEDGE system. The iPLEDGE system verifies that all criteria have been met by the prescriber, patient, and pharmacy prior to granting the pharmacy authorization to fill and dispense isotretinoin. The pharmacist must obtain authorization from the iPLEDGE system via the programme website prior to dispensing each isotretinoin prescription for all the patients. The FDA approved this programme under its regulations, known as Subpart H, that require restrictions on the distribution of a drug to assure safe use. 

After patent expiry of the drug in February 2002, a number of generic versions of isotretinoin were launched in India and the drug was made available for the treatment of acne. But, the fact that isotretinoin is a wonder drug for treatment of acne and that its formulation is so easily accessible in India without even a prescription, raises concern. Implementation of a web-based programme on the lines of iPLEDGE is neither feasible nor practical in India. Though isotretinoin manufacturers have taken care to warn the patients regarding teratogenic potential of the drug by including the details in package insert and with the help of appropriate warning on labels, this simply does not suffice the purpose. It is the moral responsibility of all the formulation manufacturers in India to forward the information regarding risk potential of isotretinoin to dermatologist as well as patients. Both the manufacturing concerns as well as dermatologists should make sure that the important information should be passed on to the patient especially woman of childbearing age. Thus, before the patient receives his/her isotretinoin prescription, the prescriber must counsel the patient about the risks of isotretinoin. The drug authorities will have to gear up all the isotretinoin manufacturing concerns to come together and to make sure that the drug is used safely and with all precautionary measures being taken especially for patients of childbearing age. If adequate measures are not taken early and the drug is continued to be freely available in our country, we may be heading for a thalidomide-like tragedy of 1960s. Hence, this delicate issue must not be ignored any further and the availability of this valuable, effective medication should be regularised through a restrictive distribution programme.

Relevant websites
Douglas Pharmaceuticals Ltd. Oratane data sheet 24 May 2001. http://www.medsafe.govt.nz/Profs/Datasheet/o/oratanecap.htm 
Roche Products (New Zealand) Ltd. Roaccutane data sheet 24 May 2001. http://www.medsafe.govt.nz/Profs/Datasheet/r/Roaccutanecap.htm
Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992;26(4):599-606. 
https://www.ipledgeprogram.com

(The author is an assistant professor,GVM College of Pharmacy,Murthal Road, Sonipat)

An important discovery

"Gene therapy strategies will come in with a major cost advantage since DNA interference technology will act at the DNA level at lower doses, reduce toxicity and only one or two copies of the DNA"

- Dr Ramanand Nadig 
President Operations and  
Deputy Dean 
Clinical Research Education and Management Academy (CREMA)


Genes are segments of DNA present in the chromosomes in the nucleus of every cell. Genes carry instructions for making proteins, which are then copied by special enzymes into many copies of messenger RNA (mRNA). The mRNA then comes out of the nucleus, into the body of the cell; where it goes on to create the proteins needed for everyday life. Faulty or mutated genes lead to malfunctioning proteins that cause disease. Gene expression can be blocked by restricting the ability of chromosomal DNA to be copied into RNA and made into proteins. This research has given the lead wherein the ways to correct genetic disease by changing mutant gene sequences to its normal has been made possible.

Cancer patients will be the prime beneficiaries of gene silencing. Dr Rohit Joshi, Medical Oncology, Assistant Professor, Department of Medicine, Christian Medical College, Ludhiana, says, "The process of gene silencing is important for the differentiation of many different types of cells. Gene silencing or Ribonucleic Acid Interference (RNAi) has been described as one of the major science breakthroughs. It is a revolutionary technology, but it has many limitations. The exaggerated hope is that it will cure everything. Most of the research in this field has been in botany, with major potential seen in human research. Every few months a newer and better way to do something is revealed, but it is every few years that something of real worth is discovered or invented. Gene silencing is meant to fit into the latter category." He adds, "The prospects for this technology in developing therapeutic applications for diseases including cancers, autoimmune dysfunctions and viral infections are enormous. Additionally, it can be used as a tool for determining gene function. If you can selectively switch off a gene, you can then observe its biological function."

Controversy's child

Safety and quality issues have always dogged the vaccine sector, and when the National Regulatory Authority was recently de-recognised by the World Health Organisation, it took down the reputation of domestic vaccine players with it. Aashruti Kak reviews past and present vaccine controversies

Your browser may not support display of this image.Since the inception of vaccination in the late 18th century, there have always been concerns over the morality, ethics, effectiveness, or safety of vaccination. However, the general medical belief has been that the benefits of preventing various diseases, and therefore, death from infectious diseases offset the risks of adverse effects following immunisation. This reasoning is justified, as prevention is always better than cure. Vaccines have proved to be a much more cost-effective strategy to promote and protect health compared to treatments of acute and chronic diseases. In fact, vaccines have saved more lives than all the 'wonder drugs' put together.

It is only in the 1990s that vaccines started to attract controversies because of certain rumours about various side-effects, that they may cause, including auto immune disorders, autism and so on. Safety will always be a primary concern, but it is normally understood that all vaccines may cause side-effects. One such controversy that has managed to stay alive till date is the presence of thiomersal (International Nonproprietary Names—INN), commonly known as thimerosal, in vaccines. This is a mercury containing antifungal widely used as a preservative to prevent life threatening microbial contamination. Although US Food and Drug Administration (USFDA) has found no evidence of harm from the use of thimerosal as a vaccine preservative, other than local hypersensitivity reactions, there is a theoretical possibility of thimerosal being neurotoxic. However, with frequent modifications in manufacturing technology, the need to add preservatives during manufacturing has gone down.

There are still many companies that use the preservatives in their drugs and biologicals. Dr Suresh Jadhav, Executive Director, Serum Institute of India Limited (SIIL), says, "Some of our vaccines and those of other companies available in the market do still contain thimerosal as a preservative. There is a clear Position Paper of WHO, and now even the Centre for Disease Control and Prevention (CDC) of USA, that acknowledges the fact that thimerosal has not been found to be responsible for any of the adverse events or neurotoxicity, which has been caused following the use of vaccines containing the organomercurial." He adds, "There is a clear guidance as per WHO that a vaccine that is distributed in multi-dose containers must contain preservatives. However, some vaccines which are available in mono dose/single dose containers are preferred without preservatives." SIIL is currently working on meningococcal A conjugate vaccine, measles aerosol vaccine, rotavirus vaccine and seasonal pandemic influenza vaccine.

In today’s safety conscious world, it becomes imperative for companies and governments to be extra cautious to earn the trust of the population they are serving, otherwise incidents like the measles vaccine deaths in Tamil Nadu (April 2008) and Aurangabad (September 2008) cannot be controlled or curbed. It becomes even more important during an outbreak of a disease, where one of the most vital steps in ensuring protection is to monitor vaccine safety, because during an emergency, more vaccines are given, which could lead to more adverse events; more rare and serious adverse events may occur because people of all ages and health conditions would be vaccinated; and most importantly, the usual testing of a vaccine before its widespread use may be shortened to speed up its availability.

"In case of an epidemic/outbreak, to the best of my knowledge the Indian Government has a system in place. They have various laboratories under their control such as National Institute of Communicable Diseases (NICD), National Institute of Virology (NIV), National Aids Research Institute (NARI), and several laboratories working under Indian Council of Medical Research (ICMR)," says Jadhav. He continues to say that with respect to the benefits of vaccination, if a vaccine is already available against the outbreak/disease, then it can be used in the population in and around the centre of outbreak. "There is no question of using a vaccine, which is 'hurriedly' tested. All the vaccines need to be fully tested by the manufacturing laboratories, and then, are also to be tested/released by the National Control Laboratory; only then the product can be actually distributed and used. In view of this, the question of causing more adverse events using hurriedly tested vaccine does not arise," he adds.

In the US, it has the the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance programme co-sponsored by the FDA and the Centers for Disease Control and Prevention (CDC), that detects and analyses possible adverse events that occur after the administration of US licensed vaccines so scientists can find out if it is the vaccine that is causing health problems.

Regulatory compliance issues in India

Your browser may not support display of this image.As of today, there are five Indian vaccine manufacturers who are pre-qualified by WHO for supplies to UN agencies, says Jadhav. These manufacturers, in addition to catering to the Indian requirements, both in the private market as well as government programmes, also meet 65 to 70 percent requirement of UN agencies for Bacillus Calmette-Guérin (BCG), tetanus toxoid (TT), diphtheria and tetanus toxoid (DT), diphtheria, tetanus and pertussis (DTP), measles, rubella, measles and rubella (MR), measles, mumps and rubella (MMR), polio, rabies, hepatitis-B and haemophilus influenza type-B vaccines. "In fact, one of the UN Millennium Development Goals was to reduce mortality due to measles by 50 percent in Africa by 2010 as against what was in 1997. In reality, this has been achieved much earlier ie before November 2007, and that too not only 50 percent.

Mesenchymal stem cells might be the answer to spinal cord injury  
In India, 20,000 new cases of spinal cord injury are added to the list every year, as compared to 11,000 in US and 700 in UK. Stempeutics Research has done a pilot study on the application of mesenchymal stem cells in spinal cord injury. Patients with fresh injuries have responded well to this therapy. Although many cell types contribute to organ repair in spinal cord injury, bone marrow mesenchymal stem cells have the greatest potential for repairing the spinal cord injury. Stempeutics has collaborated with Manipal Hospital for these pilot studies.

GSK adds CHF boxed warning on Avandia label

GSK adds CHF boxed warning on Avandia label


Friday, August 17, 2007 10:00 IST 
Philadelphia, Pennsylvania

GlaxoSmithKline announced that the US Food and Drug Administration (FDA) has approved updated US prescribing information for the thiazolidinediones (TZD) class of medicines used in the treatment of type 2 diabetes. This approval allows GSK to implement changes in the label for Avandia (rosiglitazone maleate) as previously committed. 

The label will contain a boxed warning, which increases the prominence of an already existing warning for all medicines in the TZD class on the risk of congestive heart failure (CHF), a well known and well characterized risk in this class of medicine. The boxed warning also will note that TZDs are not recommended in patients with symptomatic heart failure, and that initiation of TZDs in patients with established NYHA class III or IV heart failure is contraindicated. 

The contraindications have also been updated regarding initiation of Avandia in patients with Nyha class III or IV heart failure. 

Information about CHF has been included in the prescribing information for Avandia since 1999, when the medicine was first approved by the US Food and Drug Administration. Since 2001, US prescribing information for Avandia has included a warning for "Cardiac Failure and Other Cardiac Effects" with a recommendation that use of Avandia be discontinued in patients if their cardiac status worsened. 

The changes related to CHF are being implemented on the labels of all rosiglitazone-containing products: Avandia, Avandamet (rosiglitazone maleate and metformin hydrochloride) and Avandaryl (rosiglitazone maleate and glimepiride). 

Are we ready for global phase I studies?

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 )