JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER  V OL
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JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER V OL

61 49 Hon Chief Physician and Director of Nuclear Medicine and ExMedical Director Jaslok Hospital and Research Centre Mumbai Director of Nuclear Medicine and RIA Dept Lilavati Hospital and Research Centre Mumbai Emeritus Professor of Medicine for li

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JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER V OL




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JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER 2013 V OL . 61 49 Hon. Chief Physician and Director of Nuclear Medicine and Ex-Medical Director, Jaslok Hospital and Research Centre, Mumbai; Director of Nuclear Medicine and RIA Dept., Lilavati Hospital and Research Centre, Mumbai; Emeritus Professor of Medicine (for life) and Ex - Dean, Grant Medical College and Sir J. J. Group of Hospitals, Mumbai; Emeritus Professor: National Academy of Medical Sciences, NDIA Received: 03.07.2012; Accepted: 14.07.2012 How to Ascertain Drug Related Deaths During Clinical Trials ? RD

Lele Abstract Recent guidelines by the Drug Controller General of India require extra care by Investigators & Sponsors of Clinical Trials in India. The author, an eminent member & Chairman of various Independent Ethics Committees in Mumbai, proposes various concrete solutions for adherence to these guidelines. Insurance cover to the subjects, use of Internet databanks for drug interactions, active involvement by the pharmacologists in Ethics Committee, review of data from animal studies, being amongst them. In case of death due to trial, autopsies, or at least verbal autopsies, are essential

in the interest of Science and Law. More importantly Anticipation and prevention of ADEs can be done by exclusion of subjects from trials by using newer technologies like cDNA in microarrays to determine several polygenic quantitative trait loci (QTLs) and tests forSingle Nucleotide Polymorphisms (SNPs). Drug manufacturers must provide prototypes of Affymetrix chips to clinicians and bear the cost in their own enlightened self-interest. Introduction A recent article: Compensation Guidelines for Research- related injury in India- (Divatia JV et al JAPI 2012;60:53-55) has raised several

important issues which I propose to address in this article, with concrete solutions. The amended Schedule Y of 2005 in the Indian Law for clinical trials, has specified the need for provision of compensation of participants for research-related injuries as an essential element of the informed consent form (ICF). The Drug Controller General of India (DCGI) now mandates that all ICFs incorporate a clause stating that in case of study- related injury or death, the sponsor will provide complete medical care as well as compensation. The Central Drugs Standards Control organisation (CDSCO), the

Directorate General of Health Services (DGHS) as well as ICMR have issued draft guidelines for compensation of research- related injuries on its website requesting feedback from all interested parties. As Chairman of an Independent Ethics Committee in Mumbai for 14 years (1998- 2012) I have successfully ensured that every sponsor of drug Trials approved by my committee takes out an insurance policy, specific for the trial, to cover all risks. Such policies are readily available from Indian insurance companies. This should be standard practice. Gray Areas Divatia et al have observed that

Mandatory Compensation for the following is not rational. a. Failure of an investigational product to provide intended therapeutic effect b. Administration of placebo providing no therapeutic benefits. c. Adverse effects due to concomitant medication. API OCTOBER 2013 V OL . 61 ] 733
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50 JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER 2013 V OL . 61 The above 3 points are specifically mentioned in the ICMR guidelines as not being entitled to compensation while the CDSCO guidelines mandate it. My suggestion is for investigators to make full use of databanks giving

drug-drug interactions which are available on the internet and make suitable adjustments for drug-drug interactions to pre-empt any adverse interactions. Every Institutional Ethics Committee has competent pharmacologists who can handle this responsible duty. Details are available in my published book Clinical Science and Clinical Research 2 nd ed. 2008. 17 Anticipation and Prevention of ADEs Data from animal studies of safety pharmacology is always available to the principal investigators of drug trials, both for lethal and non-lethal toxic effects and the NOAEL (no observed adverse effect

level) of each drug, and the LOAEL (lowest observed adverse effect level) expressed as mg/kg, along with data on human volunteers in phase I and II clinical trials and laboratory parameters are always included for monitoring during phase III (ramdomised, placebo- controlled) clinical trials. The relationship of an ADE to the investigational product should be classified using the following guidelines. Definite : Experience follows a reasonable temporal association and could not have been explained by the patient’s underlying condition or is confirmed with a positive re-challenge. Probable :

Experience follows a reasonable temporal association, is confirmed by improvement upon discontinuation of the investigational product, and is not reasonably explained by the patient’s underlying condition. Possible : experience follows a reasonable temporal association, but may have been produced by the patients underlying condition, environment or other factors. Unlikely : Experience does not follow a clear-cut temporal association and is probably produced by patient’s clinical state, environment or other factors. Unrelated : No relationship between the experience and administration of the

drug. Table 2 : Authomatic laboratory signals (ALS) were recorded automatically if they exceeded a dened upper or lower limit ALS limits Normal range Leucocytes < 2500/μl 4000-10000 Thrombocytes < 7000/μl 140000-400000 Eosinophils > 6% of the leukocytes >450/μl < 450/μl Haemoglobin < 9/dl or drop of >2g/dl 13.0-17.0 Lactate dehydrogenase > 450 U1 -1 50-200 Alanine amino transferase > 36 U1 -1 1-18 Aspirate amino transferase > 44 U1 -1 1-22 Gamma glutamyl transpeptidase > 56 U1 -1 6-28 Alkaline phosphatase > 330 U1 -1 33-105 Bilirubin > 1.5 mgdl -1 0.1-1 Serum

Creatinine > 1.5 mgdl -1 0.4-1.4 Serum urea > 60 mgdl -1 10-20 Potassium < 2.7 mmol 1 -1 or > 6 mmol 1 -1 3.6-4.8 Sodium < 125 mmol 1 -1 or > 160 mmol 1 -1 132-155 Calcium < 1.7 mmol 1 -1 or > 3.2 mmol 1 -1 2.3-2.8 Blood glucose < 50 mgdl -1 > 150mgdl -1 70-100 Digitoxin > 20 μg 1 -1 range 6-20 Digoxin > 2 μg 1 -1 Range 0.6-2.0 Theophylline > 20 mg 1 -1 Range 6-20 Table 1 : Groups of administered drugs found to be associated with fatal ADEs Class of Drugs No. of Times Involved Types of Fatal ADEs Observewd Cardiovascular 61 Cardiodepression, hypotension, dehydration, AV block,

bronchial obstruction, renal failure Antiasthmatic 55 Arrhythmias, myocardial infarction and cardiac arrest Antithrombotic 45 Cerebral haemorrhage, gastrointestinal haemorrhage, and cardiac tamponade Anti-infective 14 Pseudomembranous enterocolitis, renal failure, hepatic failure, pancreatitis, and bone marrow depression Antipsychotic or anxiolytic 12 Respiration depression and severe sedation Analgesic 12 Respiratory depression, hepatorenal syndrome, and severe sedation NSAID Haemorrhagic gastrointestinal ulceration Other 32 Miscellaneous The total number of drugs involved in fatal ADEs was

237. Some cases involve more than 1 drug. ADE indicates adverse drug event; AV, 734 API OCTOBER 2013 V OL . 61
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JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER 2013 V OL . 61 51 The severity of an AE - mild, moderate, severe, life-threatening, death related, should be defined according to the National Cancer Institute (NCI) Common Terminology Criteria for adverse events (CTCAE) version 4.0. Table 1 lists the group of drugs found to be associated with fatal ADEs. glucose, Hb, WBCs, platelets, eosinophils, ECG abnormalities etc. Automatic laboratory signals (ALS)

generated from laboratory data (Table 2) is one way of pre-emptying adverse drug reactions. 10 The diagnosis of ADRs, especially those that are not dose-related, is often difficult and agreement in clinical judgements is low (about 50%) both within and between physicians making diagnosis. 21 Idiosyncratic and allergic reactions cannot be predicted. Adverse Reaction Probability scale (APS) developed by Naranjo et al draws the Clinician’s attention to the possibilities of ADRs not recognised by the attending physician. Bates DW et al have shown the potential identifiability and preventability of

ADEs using information systems. 13 Levy M et al have shown the utility of computerised surveillance of ADRs in hospitals. 14 The same can be applied to clinical trials. This resource should be utilised by all principal investigators and the sponsors of drug trials should ensure its availability to them. Compensation for death during clinical trials : Crucial role of autopsy. The DCGI has stated that it is the duty of the Institutional Ethics Committee to ensure that due compensation for the study- related death is paid to the dependents of the deceased, by the sponsor in time. I wish to

emphasise the role of autopsy in ascertaining drug-related deaths, which is the sole responsibility of Institutional Ethics Committee “The decision of the Ethics Committee after the review shall be final. In case the research subject or legal heirs in case of death are not satisfied with the decision of the Ethics Committee, they shall retain the right to seek legal remedy through the courts”. I strongly recommended that sponsors of clinical Drug trials should ask for permission to perform autopsy in the event of death during a trial. If the permission is refused, the fact should be documented

as such – “request for autopsy was made but refused”. It would be in the best interest of the victims for the next of kin to grant the request for autopsy. An important publication in Archieves of Internal Medicine October 22, 2001 by Ebbesen J et al 1,2 entitled “Drug-related deaths in a department of Internal Medicine in Norway is an eye-opener. During a 2 year period, a multidisciplinary study group examined all 732 patients who died (5.2% of 13992 patients treated) at the Department of Internal Medicine, Central Hospital of Akershus, Norway. Decisions about the presence or absence of fatal

Adverse Drug Effects (ADEs) were based on aggregate clinical records, autopsy results and findings from pre-mortem and post-mortem drug analysis of 732 patients. In 75 out of 137 patients with fatal ADEs autopsy findings and / or drug analysis data were decisive for Table 3 : Genetic determinants of responses to drugs Polymorphism of drug-metabolising enzymes Mechanism Consequences TPMT (Thiopurine S-methyl transferase ) [Inactivation of azathioprine and 6 mercaptopurine ] = full activity enzyme EM:extensive activity enzyme PM : poor metabolism PM phenotype patients show Excessive bone marrow

toxicity with “usual” dose EM phenotype patients show undertreatment with “usual” dose of azathioprine. NAT-2 (n-acetyl transferase) Acetylation of isoniazid, hydralazine, sulphonamides, procainamide etc. “slow”, “rapid and “intermediate acetylators Slow acetylators likely to produce INH neuropathy Cytochrome P450 monooxygenases Isoforms with multiple pathways EM (extensive metabolisers) PM (poor metabolisers) IM (intermediate metabolisers) Range of activity can vary ten-fold between individuals e.g. Chlorpromazine on same dose. CYP2D6 Metabolic pathway for antiarrhythmic drugs, blockers,

tricyclic antidepressants, neuroleptic drugs, selective serotonin reuptake inhibitors PM phenotypes show exaggerated drug of blockers can be debrisoquine CYP2C19 Catalyses omeprazole Proguanil, diazepam and etalopram EM genotype patients show only 29%, cure rate for eradicating H. Pylori Vs 100% cure rate in PM genotype for same dose 20 mg omeprazole CYP2C9 Metabolism of warfarin and phenytoin, Loss of catalytic function in PM phenotype causes bleeding even with low warfarin dose. 100-200 fold of mephentoin between EM and PM phenotype Increased toxicity in PM phenotype. Genes coding ion

Channel proteins Mutant genes, remain subclinical until challenged by drugs such as quinidine prolonged QT and polymorphic V Tachycardia API OCTOBER 2013 V OL . 61 ] 735
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52 JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA OCTOBER 2013 V OL . 61 recognising the ADEs. In 595 patients, autopsy studies excluded the suspicion of fatal ADEs in 62 patients. Without an autopsy it is not possible to ascertain the cause of death due to ADE of drugs as against the natural course of the main disease for which the drugs were given. Drugs may be causal or contributing to fatal ADEs, being

highest among patients who, died of gastro- intestinal disease (42.4%) – gastrointestinal ulcerations and haemorrhage caused by anti-coagulants, or antibiotics-associated pseudomembranous enterocolitis. Antithrombotic agents, sympathomimetic drugs given for lung disease and cardiovascular drugs (ACEIs Calcium channel blockers and diuretics) were the most common drugs associated with fatal ADEs. Table 1 lists the groups of drugs associated with fatal ADEs (Ebbesen J et al 2001). Without an autopsy many drug-related ADEs may be missed (e.g. Potassium tablet given to a dehydrated patient with

difficulty in swallowing leading a bleeding oesophageal ulcer). Verbal Autopsy Pacque –Margolis S et al showed the utility of verbal autopsy questionnaire to determine cause of death and mortality during a community-based treatment trial of onchocerciasis with ivermectin. 18 During the 8 months of surveillance 25 individual died and it was found that in 80% of adult deaths the verbal autopsy and death certificate diagnoses of underlying cause of death agreed. If permission for regular autopsy is not obtainable in a drug trial –related death, the next best approach is to conduct a verbal

autopsy, by the principal investigator or by a medical member of the IEC. There is extensive literature on the utility of verbal autopsy in ascertaining causes of deaths in infants and children (WHO/CDS/CSR/ISR/9904). 19 Martha Anken et al used verbal autopsy as a method of finding out the cause of death based on an interview with next of kin or other care givers. An underlying assumption in the verbal autopsy method is that by development of expert verbal autopsy algorithms and asking a series of questions it is possible to ascertain common causes of death: diarrhoaea, dysentery, tetanus,

measles, pneumonia, meningitis (fever and bulging fontanelle) malnutrition and accidents in children. The next of kin are asked to tell all they observed about the patients illness till his / her death in their own words. This is followed by a detailed questionnaire e.g. Gastroenterological, cardiovascular, respiratory or nervous system etc. Verbal autopsy methods to ascertain multiple causes of death in adults have been validated by Gary 5-7 Lee (Statistical Science 2008), and by Soloman, Chandramohan and Shibuya (2006). Yang et al (2005) have coded 13 causes of death and 58 (yes or No)

symptoms elicited from care-takers. Symptoms need to occur with particular patterns more for some causes of deaths than others. It has to be ensured that different types of respondents interpret the same symptoms questions in similar ways. Open source software that implements all the http:/gking,harvard.edu/va and should be utilised by all Principal Investigators. Gajalaxmi V and Peto (2004) did verbal autopsy of 80000 adult deaths in Tamilnadu, South India. Design of Future Drug Trials Paradigm Shift The greatest impact of the Human Genome Project on Clinical medicine is the appreciation of

the extra- ordinary molecular and biochemical individuality of each patient. 15 Gene polymorphism occurs in one in 1000 DNA base pairs in the human genome. This is reflected in the diversity of the gene products -- structural proteins, enzymes, channel proteins, transporters and binding proteins, receptors and post-receptor signal cascades. Polymorphism in the upstream gene promoter sequences can influence the activities of many enzyme mediated processes. New technologies such as cDNA microarrays will facilitate analysis of individual variations via determining several polygenic quantitative

triat loci (QTLs). An elaborate tool box for QTL mapping is now available (Lynch and Walsh 1998, Jansen 2001. Flint and Mott 2001) Mapped SNPs are being placed regularly in the public domain website http://snp.cshl.org. Particularly important for drug trials is the Cytochrome P450, and its numerus subtypes e.g. CYPIA2, 3A4, 2A6, CYP2C8 and 2C9, 2C19, CYP2D6, CYP2E1 play particularly critical roles in genetically determined response to a broad spectrum of drugs. For example patients homozygous for CYP2D6 null allele exhibit a poor metaboliser (PM) phenotype with impaired degradation and

excretion of many dugs leading to ADEs. More than 40 drugs used in clinical practice especially cardiovascular and psychiatric disorder follow the same pattern as the antihypertensive drug debrisoquine Tests to determine debrisoquine metabolism pattern are now available and should be employed by sponsors of clinical drug trials as a mandatory requirement. The protocol of many drug trials currently used in India involve sending patient’s blood samples abroad for genetic analysis. The sponsors must share the results 736 API OCTOBER 2013 V OL . 61
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JOURNAL OF THE ASSOCIATION OF

PHYSICIANS OF INDIA OCTOBER 2013 V OL . 61 53 with the principal investigators on a prospective on-going basis, not a retrospective analysis after the trial is over. There is urgent need for a paradigm shift in future clinical drug trials. Illustrative examples are given in Table 3. Affymetrix (Santa Clara, California) have developed a tiny chip that can analyse 20000 SNPs to probe 6817 genes in 15 minutes. 16 Drug manufacturers spend billions of dollars for the promotion of their products and also billions of dollars to compensate for deaths attributed to their products. Drug manufactures

have an enlightened self-interest in making this chip available to Principal Investigators of drug trials as the best way of anticipating and preventing ADEs. References 1. Ebbesen J. et al : Drug related deaths in a department of Internal Medicine in Norway. Arch Int Med 2001. 2. Ebbesen J. et al Fatal adverse drug events: the paradox of drug treatment. Arch Intern Med 2001;161:2317-23. 3. Pacque-Margolis S et al Application of Verbal autopsy during a clinical trial. Soc Sci Med 1990;31:585-591. 4. Martha Anken et al A standard verbal autopsy method for investigating causes of death in

infants and children. WHO/CDS/ CSR/ISR/9904. 5. Gary king and Ying Lu. Verbal autopsy methods with multiple causes of death statistical science 2008;2391:78-91 6. Soleman N., Chandramohan D. Shibuya K. 2005 WHO Technical Consultation on verbal Autopsy tools. Geneva http://www.who.int./ healthinfo/statistics/mort_verbalautopsy.pdf 7. Soleman N., Chandramohan D. Shibuya K. Verbal autopsy: current practices and challenges, Bulletin of the WHO 2006;84:239-245. 8. Yang et al validation of verbal autopsy procedures for adult deaths in China. Internal J Epidemiology 2005;35:741-748. 9. Gajalaxmi V.

Peto R Verbal autopsy of 80,000 adult deaths in Tamilnadi, South India BMC Public Health 4. 10. Tegeder Levy et al Retrospective analysis of the frequency and recognition of adverse drug reactions by means of automatically recorded laboratory signals. Br J Clin Pharmacol 1999;47;557-564. 11. Naranjo CA et al A method for estimating the probability of adverse drug reactions. Clin Pharma Therapy 1981;30:239-245. 12. Naranjo CA et al A Bayesian assessment of idiosyncratic adverse reactions to new drugs-Guillain Barre Syndrome and Zimeldino. J Clin Pharma 1990;30:174-80. 13. Bates DW et al

Potential identiability and preventability of ADEs using information systems. J Am Med Inform Asso 1994;1:404-11 14. Levy M et al Computarized Surveillance of adverse drug reactions in hospitals: implementation. Eur J Clin Pharm 1999;54:887-92. 15. Lele RD; The Human Genome Project : Its Implications in Clinical Medicine. JAPI 2003;51:380. 16. International SNP working Group. Nature 2001;409:929-933. 17. R. D. Lele Clinical Science and Clinical Research 2nd ed. 2008. 18. Pacqu-Margolis S, Pacqu M, Dukuly Z, Boateng J, Taylor HR; Application of the verbal autopsy during

a clinical trial. Soc Sci Med 1990;31:585-91. 19. WHO/CDS/CSR/ISR/9904 - A Standard Verbal Autopsy Method for Investigating Causes of Death in Infants and Children http://www. who.int/csr/resources/publications/surveillance/whocdscsrisr994. pdf). 20. Flint and Molt 2001. http://sup.cshl.org. API OCTOBER 2013 V OL . 61 ] 737