Renaissance of Phase I trials in India: Lessons from global trials and tribulations of TGN1412

Over the last decade, there has been a surge in start-up-led biopharmaceutical innovation in India. The sector received a boost during the COVID-19 pandemic, as there was an urgent need to create therapeutic options. As these products begin the journey from bench to bedside, generating Phase I clinical trial data on the safety and tolerability of new investigational products would be critical. However, the experience of conducting first-in-human (FIH) Phase 1 trials in India is limited.[1] Indian Council for Medical Research (ICMR), focusing on this national need, has embarked on creating the ICMR-Network of Phase 1 clinical trial sites.[1] For Indian investigators, the conduct of FIH trials would be uncharted territory. Hence, they should reflect on the lessons for human safety learned from the unprecedented disastrous Phase I incident of TGN1412.[2,3] On March 13, 2006, TGN1412, a novel anti-CD28 monoclonal antibody, was administered to six healthy male volunteers participating in an FIH trial at London’s Northwick Park Hospital.[3] Within 90 min of receiving an intravenous bolus of TGN1412, all suffered from a severe cytokine release syndrome with multiorgan failure.[3,4] Within 8–12 h, their condition became serious with lung injury, renal failure, and disseminated intravascular coagulation. All were treated in the intensive care unit, where they were given intensive cardiopulmonary support, dialysis, high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody.[3] Two volunteers had prolonged cardiovascular shock, developed acute respiratory distress syndrome, and required intensive organ support for a long duration. Fortunately, all volunteers survived this disastrous adverse event.[3] These life-threatening events in healthy volunteers triggered a media storm and public outcry. Medicines and Healthcare products Regulatory Agency (MHRA) promptly conducted inspections which revealed that TGN1412 adverse incidents did not involve any errors in the manufacture, formulation, dilution, or administration of TGN1412 trial participants and concluded that an unpredicted biological action of TGN1412 in human beings was the most probable cause of the adverse reactions in the trial participants.[5] An Expert Scientific Group (ESG) set up by the UK Government reviewed all data submitted by the sponsor.[6] ESG’s review did not find any failure in complying with regulatory guidance.[4,6] However, ESG opined that preclinical development studies performed with TGN1412 did not predict a safe dose for use in humans.[6] ESG made recommendations to enhance the safety of volunteers participating in the FIH of agents with higher potential risks. The recommendations cover: (a) preclinical and early clinical development, (b) process of preparation and review of clinical trial applications, (c) early access to advice for both regulators and sponsors, (d) determining and administering the initial doses in man, (e) clinical environment for first-in-man studies, and (f) developing the skills and training.[6] These recommendations have had a major worldwide impact on how FIH would be conducted. MHRA, as suggested by ESC, established accreditation system for investigators conducting FIH trials, which has important lessons for Indian investigators and institutions.[7-9] The investigator – a clinical pharmacologist – should have relevant qualifications, experience, and training to be competent in planning and conducting of FIH trial.[7,8] Phase 1 investigator should have expertise in review of the preclinical pharmacology, toxicity, pharmacokinetics and pharmacodynamics, no observed adverse effect level (NOAEL), minimally anticipated biologic effect level (MABEL) to decide maximum recommended starting dose (MRSD), dose escalation and stopping criteria, knowledge of regulatory, ethical, and good clinical practice (GCP) requirements, and oversight of participant safety. Clinical acumen, management of medical emergency, critical thinking, decision making, communication with participant, ethics committee, safety review committee (SRC), sponsor, and media would be vital skills as leader of the Phase I site team. Indian clinical pharmacologists with postgraduate medical qualification – Doctor of Medicine, have knowledge of Phase I trial. However, unless they have worked in a clinical pharmacology department actively conducting Phase I trials, they would not be able to do justice to responsibilities of FIH investigator. It would be desirable for clinical pharmacologist to develop competence as principal investigator of FIH trials by working in an experienced Phase I unit of a medical institution. Clinical Pharmacology (DM/DNB) degree in India is a super specialization after Postgraduation in Pharmacology/Medicine. Hence, the quandary in India is that those with MD Pharmacology degrees do not have the extensive clinical/intensive care experience needed to manage patients/healthy volunteers on their own and those with MD in clinical speciality degrees do not have the exposure to clinical pharmacology. Hence, both clinical pharmacologists and clinical specialty-trained investigators need to collaborate with each other for Phase I studies with high-risk compounds that have effects on the immunological system. It will take some years before India can have sufficient Phase I/Early Clinical Development work for a full-time clinical investigator. MHRA accreditation guidance emphasises the critical role of the trained Phase I unit staff and arrangements for handling medical emergencies.[7] The staff should be trained in Life Support measures – Basic or Advanced – depending on the risk of investigational products for the FIH study. For high-risk investigational products, medical experts with experience of handling medical emergencies should be available during and following dosing. An emergency trolley containing drugs and equipment essential for cardiopulmonary resuscitation should be easily and quickly accessible. Equipment for continuous monitoring of vital signs must be available. There should be robust arrangement for immediate resuscitation and stabilization of participants in an acute emergency situation and onward transfer of participants to the medical intensive care unit, either within the same hospital or to a hospital in close proximity, with a preagreed memorandum of understanding between the Phase I unit and the hospital where participant would be managed in emergency situation. MHRA findings from Phase 1 Accreditation Inspections[8] have highlighted critical deficiencies in (1) dose escalation process, (2) lack of procedure for risk assessment and risk management/mitigation, (3) inadequate training of staff in handling medical emergencies, (4) inadequate procedures for contacting medical doctors in an emergency, (5) expired or missing items on the emergency trolley, (6) incorrect dosing of participants, (7) lack of robust procedures to ensure all protocol assessments were performed and that staff allocated were suitably trained and competent, and (8) no formal procedure to address overvolunteering. The learnings from MHRA inspections emphasize the crucial importance of personnel training, emergency equipment, and robust systems and procedures in planning and conducting FIH trials. At the institution level, the role of the administration, ethics committee (EC), and Safety Review Committee (SRC) is crucial in the conduct of Phase I trials. The head of the institution should understand the unique nature of the Phase I trial and provide operational support to the investigator during the conduct, especially when unanticipated problems occur impacting participant safety. Phase I clinical trials are fast-paced and require EC review and turnaround in a very short duration (e.g., 72 h) before the next cohort can be dosed. Hence, EC has to be operationally efficient with a subcommittee that can undertake the review and approval process in a coordinated manner with the Phase I unit. Delays in the EC review will lead to not only operational challenges but also put participant safety at risk. ECs have the most important responsibility for the protection of rights, safety, and well-being of vulnerable participants – healthy volunteers who would be exposed to unique risks of a new investigational product with unknown safety without any therapeutic benefits. Hence, ECs should be able to understand translation of preclinical animal data to FIH starting dose and dose escalation, be trained in risk assessment, risk minimization and mitigation, safety monitoring, assess the investigator’s qualifications and experience for FIH trials, and ensure fair recruitment and compensation. Start-up companies are usually founded by basic scientists, who would depend on external medical experts and contract research organisations (CRO) for monitoring the Phase I trial. Medical monitor should have strong clinical acumen, be aware of regulatory and ethical requirements, should have an in-depth understanding of protocol, investigational product, dose initiation/escalation and stopping criteria, safety management, and serve on the SRC.[9] This committee, which includes the investigator, sponsor’s medical monitor, and other medical experts,[9] conducts an independent review of safety data, adverse events, and dose-limiting toxicities of each dose and takes crucial decisions about dose escalation, inclusion of the next cohort of participants or modification of the study protocol, or discontinuation of the trial. CRO project manager and monitor should orient themselves to the specific focus of Phase I trial – assessing and ensuring participant safety – during oversight of clinical trial conduct and should have relevant scientific knowledge and monitoring skills. The CRO team should be trained in verifying investigator site and team readiness for conducting protocol procedures, ensuring participant safety, and compliance to GCP requirements. In India, enrolment of healthy participants in the Phase I trial is arduous, time-consuming, and strenuous task. In a study by Gogtay et al., the majority >50% of participants screened for the Phase 1 trial could not be randomized because of abnormal lab test, detection of a medical condition, and withdrawal of informed consent.[10] Indian participants refuse consent because of the inconvenience of multiple blood collections, lack of ability to comply with the study protocol procedures, and perception of risks involved in clinical trials.[11] Another major issue is healthy volunteers taking part in multiple trials at the same time. In order to prevent this, the investigator site should have access to an Internet-based system along the lines of the UK’s The Over-Volunteering Prevention System.[9] Indian hospitals have been part of clinical trials for over two decades. However, Indian society’s perceptions toward clinical trials are still negative. Media’s adversarial attitude to clinical trials, reflected in frequent alarming headlines highlighting deaths in clinical trials, exploitation of unemployed youth, informed consent errors, and compensation for serious adverse events, is largely responsible for this atmosphere.[12] The government has a critical role in shaping public perceptions about clinical trials, and should make efforts to build trust and confidence amongst the public about the need for supporting Indian discovery of new products, conducting clinical trials, and enlightening the society about clinical trial participant protection measures. The government should also create awareness amongst other important stakeholders – hospitals, ethics committees, regulators, civic society, nongovernmental organizations, politicians, and media – about the new initiatives in fostering innovation. Let’s not forget the lessons of history for ensuring participant safety when we are on the threshold of creating history in developing innovative Indian products!