Rajiv Mahajan

Food and drug administration's critical path initiative and innovations in drug development paradigm: Challenges, progress, and controversies

During the last decade, despite increased investment in drug research and development related activity, stagnation in new drug discovery has been documented. Despite a 70% increase in investment in research and development-related activities, a 40% fall in launch of new chemical entities was seen during 1994–2004. A steep rise in the attrition rate of drug development has complicated the matter. Rising cost and increased attrition rates proved major barriers to investment in higher risk drugs or in therapies for uncommon diseases or diseases that predominantly afflict the poor. This prompted Food and Drug Administration (FDA) to highlight this problem in a 2004 white paper classified as “Critical Path Initiative” (CPI) and to initiate steps to target stagnation and rise in attrition rates. Many new drug development projects have started worldwide taking cue from CPI; adopting microdosing, adaptive designs and taking advantage of newly developed biomarkers under the CPI. This review discusses the various strategies adopted under CPI to decrease attrition rate and stagnation of new drug development, and the challenges and controversies associated with CPI.

Cysticerciasis and epilepsy: a clinical and serological study

Study of 1,038 randomly selected cases of epilepsy in Chandigarh showed the cysticercus haemagglutination test to be a useful adjunct in the diagnosis of cysticerciasis as an aetiological factor. It was positive in 25.7% of epilepsy cases but in only 2% of healthy controls. The rate of seropositivity was higher in focal than in generalized epilepsy although the difference was not statistically significant. Incidence of seropositivity was about equal in males and females but did not appear to be related to the duration of epilepsy.

Adaptive design clinical trials: Methodology, challenges and prospect

New drug development is a time-consuming and expensive process. Recently, there has been stagnation in the development of novel compounds. Moreover, the attrition rate in clinical research is also on the rise. Fearing more stagnation, the Food and Drug Administration released the critical path initiative in 2004 and critical path opportunity list in 2006 thus highlighting the need of advancing innovative trial designs. One of the innovations suggested was the adaptive designed clinical trials, a method promoting introduction of pre-specified modifications in the design or statistical procedures of an on-going trial depending on the data generated from the concerned trial thus making a trial more flexible. The adaptive design trials are proposed to boost clinical research by cutting on the cost and time factor. Although the concept of adaptive designed clinical trials is round-the-corner for the last 40 years, there is still lack of uniformity and understanding on this issue. This review highlights important adaptive designed methodologies besides covering the regulatory positions on this issue.

Bromocriptine mesylate: FDA-approved novel treatment for type-2 diabetes

The food and drug administration (FDA), on May 5, approved bromocriptine mesylate 0.8-mg tablets as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. This drug has been developed by Vero Science Inc, under the trade name Cycloset. The product is a quick-release formulation of bromocriptine, a centrally-acting dopamine D2 receptor agonist.[1] Bromocriptine is otherwise approved for the treatment of hyperprolactinemia-associated dysfunctions, acromegaly and Parkinson disease.[2] The idea of using bromocriptine for the treatment of type-2 diabetes came while studying the metabolism of migrating birds; that they develop seasonal insulin resistance and dopamine plays a role in it.[3] The results of phase 3b trial, conducted in response to a letter from FDA requesting additional data on bromocriptine cardiovascular safety, were declared in the second quarter of 2007[2] and finally approved recently. Preclinical data suggest that decreased hypothalamic dopaminergic tone may be involved in the pathogenesis of insulin resistance. The normal circadian cycle that results in a leaner body in the summer and heavier body in winter is disrupted in humans because of abundant caloric intake year-round resulting in the absence of a lean phase. Stimulation of the hypothalamus promotes the release of several hormones that respond to the traditional shift in caloric intake and storage. Quick-release bromocriptine (D2 agonist), given once in the morning, stimulates the hypothalamus to release cortisol, growth hormone, and prolactin, allowing a reset of the circadian clock permanently stuck in a winter rhythm.[2] This means there occurs resetting of abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride and free fatty acid levels in fasting and postprandial states in insulin-resistant patients[1][Figure 1]. Figure 1 Structure of bromocriptine Bromocriptine mesylate is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. It may be used as monotherapy or as adjunctive therapy to metformin/sulfonylurea and single or dual oral hypoglycemic agent therapies. It should not be used to treat type-1 diabetes or diabetic ketoacidosis. There is limited efficacy data in combination with thiazolidinediones and efficacy has not been confirmed in combination with insulin.[4] Bromocriptine is the first drug for treatment of diabetes to be approved under the FDAs new guidelines which require clinical trials to demonstrate no increased cardiovascular risk.[1] In a 52-week, double-blind, placebo-controlled safety trial (n = 3070), treatment with quick-release formulation of bromocriptine reduces the incidence of diabetic cardiovascular complications in patients with type-2 diabetes and improves glycemic control in those patients who did not achieve HbA1c of less than 7.5% with metformin plus a sulfonylurea. The incidence of the composite cardiovascular end point of myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for congestive heart failure (CHF) or unstable angina was 1.5% among patients receiving bromocriptine and three percent among patients receiving placebo.[2] The recommended starting dose of bromocriptine is 0.8 mg daily and increased in 0.8 mg increments weekly until the target range (1.6 - 4.8 mg) or till maximal tolerance is reached. Doses should be administered once daily within two hours of waking in the morning and with food to reduce the risk for gastrointestinal adverse effects such as nausea.[1] Studies suggest that one morning dose helped lower the usual post-meal blood sugar rise at breakfast, lunch and dinner. Over six months, 35% of drug users reached recommended average blood sugar levels compared with 10 per cent of diabetics given placebo.[3] The drug is contraindicated in patients with known hypersensitivity to bromocriptine or ergot-related drugs. It is also contraindicated in patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during migraine may reflect dopamine receptor hypersensitivity. Bromocriptine is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.[4] It is also contraindicated in nursing women. Bromocriptine may inhibit lactation. There are postmarketing reports of stroke in these patients although causality has not been proven.[3] The most common adverse events associated with bromocriptine mesylate are nausea, fatigue, dizziness, vomiting and headache. Clinical trial data reveal that bromocriptine mesylate at doses up to 4.8 mg per day was not associated with a different rate of all-cause adverse events compared with placebo. The incidence of hypoglycemia was 6.9% among bromocriptine mesylate-treated patients compared with 5.3% of patients receiving placebo.[5] The FDA warns that bromocriptine can cause orthostatic hypotension and syncope, particularly on initiation of therapy and dose escalation. Caution is advised when treating patients who are receiving antihypertensive therapy; orthostatic vital signs should be evaluated at baseline and periodically thereafter.[1] Several oral hypoglycemic agents are already available for type-2 diabetic patients to normalize plasma glucose concentration. However, they have not had complete and sustained success. Some benefits of quick release bromocriptine mesylate therapy include: Resetting of circadian rhythm, a novel mechanism of action very different from currently used antidiabetic drugs Use with other antidiabetic agents Ease of a single morning daily dose Lower incidence of MI, stroke, and vascular events unlike other antidiabetic agents. Due to these beneficial effects bromocriptine mesylate may prove to be a revolution in the field of treatment of type-2 diabetes.

Use of propofol as adjuvant therapy in refractory delirium tremens

Delirium tremens is recognized as a potentially fatal and debilitating complication of alcohol withdrawal. Use of sedatives, particularly benzodiazepines, is the cornerstone of therapy for delirium tremens. But sometimes, very heavy doses of benzodiazepines are required to control delirious symptoms. We are reporting one such case of delirium tremens, which required very heavy doses of benzodiazepines and was ultimately controlled by using infusion of propofol. Thus propofol should always be considered as an option to treat patients with resistant delirium tremens.

Monitoring of incidence, severity, and causality of adverse drug reactions in hospitalized patients with cardiovascular disease.

Background: Patients admitted to cardiology department are mostly on polypharmacy. So drug-drug interactions and adverse effects of drugs are quite common. Yet, there is a paucity of data regarding adverse drug reaction (ADR) monitoring in cardiology department in India. The present study is an effort to fill up these lacunae. Materials and Methods: A prospective, observational study registering 966 indoor cardiology patients according to predetermined inclusion and exclusion criteria was conducted for one year. ADR profile was noted by spontaneous reporting and intensive monitoring. Naranjo ADR probability scale was used to establish the causality. Results: A total of 208 ADRs were reported from 188 patients (19.5%). Of these 188 patients, 62 patients (33%) were hospitalized primarily due to the development of ADRs, while 126 (67%) patients developed ADRs during hospital stay. Nitrates were the most common offender drug group (17.8%). Conclusion: Development of ADR in one of every five cardiac patient points toward a grave situation, but a higher incidence of Type A reactions in cardiology department means that these can be avoided.

A novel marker procalcitonin may help stem the antibiotic overuse in emergency setting

The day the wonder drugs, antibiotics, were available for cure to humans; dramatic rise of average life expectancy has been recorded compared to past. However, disease-causing microbes that have developed resistance to antibiotics are an increasing public health problem. Recently, superbug emergence was reported in some countries including India. One of the reasons quoted was misuse of antibiotics. Clinical signs and symptoms of infection often do not point towards the etiology. The dilemma occurs as diagnosis of sepsis is difficult because of nonspecificity of clinical signs and symptoms, and frequent overlapping of symptoms with other noninfectious causes of systemic inflammation. Key for improving survival rates lies in early diagnosis and treatment. Serum procalcitonin (PCT) levels measuring in sick patients during infection may be valuable in diagnosing the conditions, and its changing levels have some prognostic value too.

Current scenario of attitude and knowledge of physicians about rational prescription: A novel cross-sectional study

Background: In the last 30 years concepts in pharmacology have moved from Essential Medicines (EM) to P-drugs via the Rational Use of Medicines (RUM), but no structured study has evaluated the level of understanding among the working clinicians about these concepts. Aim: The present study was designed to assess the attitude and knowledge of clinical practitioners about the concepts of RUM, EM, P-drugs, and sources of drug-information, across North India. Materials and Methods: A cross-sectional study was carried out in and around the teaching hospitals attached to Medical Colleges, enrolling 504 clinicians from six centers across North India to fill-up a questionnaire containing 25 questions. Statistical Analysis: The results were compiled using percentages and averages. Univariate analysis, which explores each variable in a data set separately, was carried out by using the Fishers exact test. Results: Only one-fourth of the participants claimed that they always prescribed Essential Medicine; no one could correctly count the number of drugs / drug combinations in the Indian Essential Drug list; only 15.1% of the clinicians wrote the generic names of drugs on the prescription slip; about one-third of clinicians were not fully aware about the adverse effects, drug interactions, and contraindications of the drugs they prescribed; about 83% of physicians admitted to relying on information from Medical Representatives and an interest in research activities seemed to be lost. Conclusion: Results show a sorry state of affairs among clinicians, as far as the level of understanding about EM, P-drugs, and RUM is concerned, and it points toward arranging more continuing medical education (CME) for clinicians with regard to these concepts.

Professionalism and ethics: A proposed curriculum for undergraduates.

Professionalism is the attributes, behaviors, commitments, values, and goals that characterize a profession. In medical professional, it encompasses strong societal role and involves emotional component too. On the other hand, ethics is the study of morality – careful and systematic analysis of moral decisions and behaviors and practicing those decisions. Medical ethics focuses primarily on issues arising out of the practice of medicine. It is generally believed that professionalism and ethics are caught by watching your teachers and seniors and not taught formally. Professionalism and ethics are previously diffused passively to the students through “the hidden curriculum,” leaving a lot to chance. However, over the time, it has been advocated that graduates need to be formally trained in the concepts of professionalism and ethics. In this paper, we propose a formal curriculum on professionalism and ethics, tailor-made for Indian medical graduates.

Foundation programme: A student's perspective

Context: Various colleges and universities worldwide develop and implement students’ orientation programs to acclimatize them to the campus environment, familiarize them with the teaching programs and its importance has been stressed in the document “Vision 2015” planned by the Medical Council of India (MCI). Objectives: To evaluate the feedback questionnaire after conclusion of two day :Foundation Program” for MBBS 2nd Professional students, conducted by the medical education unit at a tertiary care Medical Institute. Material and Methods: After the conclusion of two day “Foundation Program”, a pre-designed, anonymous questionnaire was received from all the students who participated in the program. Results: Of the 100 participants, 67% of the participants labeled the foundation program a very good exercise. Students’ view regarding the factors that facilitated their learning were good topics (covered important aspects pertaining to the clinical phases), good presentations, good and experienced speakers, and interactive faculty. Conclusion: Such orientation programs lay a strong foundation for better understanding and learning of under-graduate courses, and should be a regular feature in the curriculum.