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What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
CITATION: Malhotra S., Shafiq N. (2006), What Clinical Pharmacology Means To Us. In: What Medicine Means To Me (Ajai R. Singh, Shakuntala A. Singh Eds.), III:6, IV:1-4, p184-206.
What Clinical Pharmacology
Means To Us
S. Malhotra*
N. Shafiq**
ABSTRACT
Clinical Pharmacology is a specialty with many attributes and our association with the subject has allowed us to acquire, apply and disseminate myriad aspectsof research and practice. Though clinical pharmacologists are conspicuous byvirtue of their small number, recent years have shown a growing need for thecourse. In the review below we navigate through several aspects of the subject aswe encountered them from time to time. From critical appraisal of literature, toapplication of knowledge of drugs, to clinical practice; moving on to clinical andbasic research, to drug development process, to policy making - these are but afew of the many fields which constitute the scope of clinical pharmacology. Theimportance of the subject lies in allowing a trainee to develop a broad overview ofthe entire process, from drug generation to drug distribution to drug utilization,a process meant for the greater common goal of better health for all. We foresee abright future for the subject though with a slight skepticism thrown in. In thepresent article, we make use of personal experiences and reference from literatureto help you get a broad view of what clinical pharmacology means to us. Key Words : Clinical Pharmacology, Me-Too Drugs, Negative Studies, Informed
Consent, Research and Future of the Branch, Ethics and Pharma Relation *Corresponding author: S. Malhotra: samirmalhotra345@yahoo.com **Co-author N. Shafiq: nusrat_shafiq@hotmail.comDepartment of Pharmacology,Postgraduate Institute of Medical Education and Research, Received 1 June 2006. Editorial review 6 June 2006. Revised 15 and 30 June 2006. Accepted with corrections 10 July 2006. Modified 26 July. Final Acceptance 29 July MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us Introduction
My Name Is Clinical Pharmacology
Though it is not customary for authors of invited write-ups to introduce themselves, we would like to digress slightly from the norm.
We make use of our professional degree for describing ourselves, andhence Clinical Pharmacologists are what we are. In case some of the readersare bemused by this description, they need not feel guilty of ignorance,for we indeed belong to an endangered species. This description isoriginally not ours and has been borrowed (Vestal, 1998). Unlike our othersuper speciality brethren such as cardiologists, gastroenterologists,nephrologists etc who are virtually omnipresent, we are conspicuous byour near absence. While at the international level this means concernsregarding lesser residents opting for clinical pharmacology (Benowitz,1997), at the national level the concern is regarding aborted attempts atopening clinical pharmacology centers.
Having collectively spent a very enriching period of more than a decade in this field, we have moved from being trainees to teachers ofClinical Pharmacology. However, we were learners then and are learnersstill. Every now and then some new concept emerges. And in the processof grasping it, teaches us repeatedly that ‘becoming veterans fromamateurs’ is a Herculean task. All the same, it is heartening to know thatthe super speciality is beginning to find its place in such gatherings. Wecertainly believe in the chaos theory and the butterfly effect propoundedby Edward Lorenz. Using Ian Stewart’s words (Stewart, 1989): The flapping of a single butterfly’s wing today produces a tiny change in the state of the atmosphere. Over a period of time, what the atmosphere actuallydoes diverges from what it would have done. So, in a month’s time, a tornadothat would have devastated the Indonesian coast doesn’t happen. Or maybe onethat wasn’t going to happen, does. We were fortunate to have found an academic accommodation in one of the institutes where D.M. in Clinical Pharmacology course was thefirst of its kind in India. More importantly, it did not demonstrate aconsiderable lag from the time Clinical Pharmacology got its official birthdate from WHO in 1970 (World Health Organ Tech Rep Ser., 1970). Thedoyens of the subject, Prof. Ranjit Roy Chaudhury, Prof. P.L. Sharma, MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
Prof. V.S. Mathur, and several others, actually deserve a lot more thanmere mention for their foresight, vision and dedication, and for the factthat they continue to guide us till date.
A very commonly asked question by our peers on learning that we were clinical pharmacologists used to be, ‘Did you take up this subjectout of choice?’ The question is a good reflection on the choice of clinicalpharmacology as a speciality. Most of the people who opt for the branchhave majored in pharmacology, which, being a para-medical branch, wasnot a coveted subject for those making it through the postgraduateentrance exams. There has been a very interesting trend of late, though.
Students who score well in the exams and are among the top rankers arebeginning to opt for the subject. Till a few years back we thought it was achance happening. However, the trend has continued to stay and webelieve it is clinical pharmacology that is making pharmacology moreattractive. Two important reasons for this change are lucrative andchallenging job prospects in the pharmaceutical industry (thoughpersonally this is not our favoured reason), and increasing awareness ofthe diverse scope of this subject.
Besides being our bread and butter, the subject has meant a great deal to us. We like to see it best as the bridge between basic science andclinical science (cynics tell us we are neither pharmacologists norclinicians!): a path from bench to bedside. This bridge allows applicationof the available knowledge in patient care and policy making, and it alsohelps in generation of knowledge mainly for these two purposes.
Now this quick summary of what it means to us warrants some elaboration. We will do that by taking you through some selectiveexamples that have gone on to become our experience in clinicalpharmacology Clinical Pharmacology
A Path From Print To Bedside
As part of training during our posting in the Department of Internal Medicine, we were asked to review the prescription of patients andcomment.
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S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us Case 1: We had a case where the patient was referred to the emergency
department for haemorrhagic stroke. The medicine resident presentedfindings and we were asked to comment on the possibilities. Our tuningwith clinical pharmacology compelled us to take the medication history.
The patient had been thrombolysed with streptokinase for myocardialinfarction, which had preceded the cerebrovascular accident. Havingundertaken a cursory causality assessment for the adverse drug event wecategorized it as ‘probable’. We were immediately asked to commentwhether the option of thrombolysing the particular patient wasappropriate. This meant that we check for all the contraindications forusing a thrombolytic agent, which is what we did, and ruled out thepossibility of an irrational use of the agent. This was not the end of thestory as, following our answer, we were asked: If seeing this patient, another well informed attendant of a patient of myocardial infarction asks, ‘Is it really necessary to thrombolyse his relative?’what would our answer be?” In other words, “What is better- to let him have thepain or to lead him to a near paralytic state? Inadvertently we had treaded into the territory of evidence-based medicine when we formulated our answer and told the patient’s relative: Streptokinase reduces the risk of mortality to 6.3% as against previous 13% (The GUSTO Investigators, 1980). For each hour earlier that a patient was treated,there was decrease in absolute mortality by 1% that translated into an additional10 lives saved per 1000 patients treated (Michel and Weinfield, 2000). There aresome concerns regarding haemorrhagic stroke. These are minimal. The risk ofintracerebral haemorrhage is approximately 0.3% (Michel and Weinfield, 2000).
Weighing the risk and benefit we advocate the thrombolysis of your patient.
Moreso since you have reached the patient to the emergency within three hours,the expectation of benefit is maximum.
We realized later, at the end of the round, that clinical pharmacology was beginning to find its entry into our veins.
‘Me Too’ Drugs
There are several other aspects while writing a prescription that one is impelled to consider. Important among them being a burgeoning of‘me too’ drugs which offer no clinically relevant advantage over theprogenitor drug. The pharmaceutical companies are able to bring and MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
later push them into the market reaping colossal benefits. An example isthe case of Astra Zeneca’s Nexium, which was brought into the marketjust as Prilosec, another Astra Zeneca product, was going off patent. Thedrug hardly offers any clinical advantage over Prilosec or, for that matter,any generic version of Omeprazole.
It is often argued that ‘me-too’ drugs offer an opportunity for reduction of patented drugs by bringing down the price. This may be anexception rather than a rule as it has been noted that the ‘me-too’ versionsare introduced, if not at a higher, at an equal price.
What does one do, now that ‘me-toos’ have become a non-ignorable reality? It is a prudent exercise for a person to devise a personal formularybased on availability, cost, ease of administration, side-effect profile, druginteractions, consideration for route of elimination and choose the mostsuitable option for any given condition. Of course, the formulary shouldoffer enough flexibility to suit certain special situations. Training in clinicalpharmacology is indeed a great facilitator in converting such ideas intoroutine practice.
Clinical Pharmacology:
From Bench To New Drug Use
The second episode that we would like to tell you about helped our foray into yet another territory of clinical pharmacology.
Case 2: In one of our informal discussions on pleiotropic effect of
some drugs, we chanced upon an article, which related the antiproliferativeand anti-inflammatory action of troglitazone, an anti-diabetic drug in anexperimental model of psoriasis (Ellis, Varani, Fisher, Zeigler,Pershadsingh, Benson, Chi and Kurtz, 2000). Troglitazone had by thenbeen withdrawn but another agent from the same class, pioglitazone,demonstrated similar properties. We were immediately motivated toinitiate a pilot study of pioglitazone in patients with plaque psoriasis, acondition characterized by derangements in dermal proliferation andinflammatory processes. We wrote down the protocol and finalized it inconsort with the dermatologist. A brief tryst in a pharmaceutical companyallowed us to manage the drug and matching placebo. We drafted theCRF, generated a randomization list, developed Standard OperativeProcedures for various things and conducted the study in accordance with MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us the principles of GCP, and with funds just enough for the stationery. Thestudy showed a moderate improvement in Psoriasis Activity and SeverityIndex (PASI) at 10 weeks, which was the primary outcome (Shafiq,Malhotra, Pandhi, Gupta, Kumar and Sandhu, 2005a).
Being impoverished on resources we could not hire a biostatistician for the analyses. So we carried out the statistical analyses ourselves. Thefindings of the study warranted some additional investigations. We havepresently undertaken a study to evaluate the efficacy and safety ofcombining acitretin with pioglitazone.
So we were beginning to grow with the subject itself, exploring its Clinical Pharmacology:
Sifting The Real From Projected Truth
The very same discussion on pleiotropic effects of drugs motivated us to explore the available literature on this issue related to statins.
Case 3: The database was really vast and we realized statins were
implicated in almost everything. They seemed to have potential, or almostproven, role in conditions ranging from sickle cell anemia to rheumatoidarthritis to Alzheimer’s disease. When some of our better-informedcolleagues had started to believe that mixing statins in the drinking watersupply might well be justified, we thought of taking a closer look. Whatlay in store for us was not a pleasant surprise but exaggeration of facts,distortion of reality and overgeneralization of study findings. For instance,statins were investigated as potential beneficial agents for multiplesclerosis, on account of their anti-inflammatory properties. The title ofthe study ran as follows, ‘Oral simvastatin treatment in relapsing-remittingmultiple sclerosis’ (Vollmer, Key, Durkaisiki, Tyor, Corboy, Markovic-Plese, Preiningerova, Rizzo and Singh, 2004). The investigators evaluatedbeneficial effect of 80 mg of oral simvastatin for 6 months on gadoliniumenhancing lesions. The study was an open label study in which the post-treatment lesions were compared with baseline lesions and simvastatintreatment was shown to have beneficial effect. The results of the studyneed to be interpreted with caution as there existed a definite possibilitythat reduction in the disease severity as measured by MRI may very wellhave been due to regression to the mean. Moreover, the patient selection MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
on the basis of gadolinium enhancing lesion may have led to selection ofpatients with active disease. These patients were likely to have shown aspontaneous reduction in the disease severity anyhow. Steroid use andunblended assessment of the MRIs were additional factors that could haveinfluenced the study results.
Similar close look at several other proposed indications of statins showed that the evidence was a rather weak one. Even for the conditionsfor which randomized controlled trial results were available, the beneficialeffect had been shown either on a surrogate marker or, in several cases,had not taken care of the several biases in drawing conclusions. We werecompelled to wonder, ‘Statinth wonder of the world: a panacea for all ora bubble about to burst.” (Shafiq, Malhotra, Pandhi and Grover, 2005 b).
The review after being rejected by a few journals found a place in theJournal of Negative Results in Biomedicine (www.jnrbm.com/content/4/1/3).
We understand that now more and more people are realizing the importance of publishing so called ‘negative’ studies which should moreappropriately be studies showing a lack of statistically significant beneficialeffect (Malhotra, Shafiq and Pandhi, 2004a). There are journals, forexample, Journal of Negative Results in Biomedicine (www.jnrbm.com/home/)that are devoted exclusively to such studies. What was happening earlierwas that only studies showing a breakthrough, or which showed p<0.05for one or more of the study outcomes, found their way into medicaljournals. As a result many scientists, who were perhaps guided by factorsother than true scientific pursuit, were tempted to forge results and receivenot only accolades from their peers but also flaunt better citations. Thenagain, at the time of doing meta-analysis, ‘negative’ studies wereconspicuous by their absence, and for many years the disturbing statement,‘Publication bias cannot be ruled out,’ remained.
There have been several instances when investigators have been discouraged (and even sued) by sponsors for publishing results that maynot have been fruitful for a company. The role a sponsoring pharmaceuticalcompany may play in moulding the direction of a research work cannotbe ignored. In one study (Stelfox, Chua, O’Rourke and Detsky, 1998), theauthors scrutinized the conflicts of interest issues associated withpublications of calcium channel blockers. The authors identified 70 studiesand classified them as critical (23), supportive (30) or neutral (17%). Theythen queried the authors for financial relationships with manufactures MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us and found that 96% of those who supported the study had financialinterests with manufactures of calcium channel blockers. From amongthose who were either critical or neutral, 37% and 60% respectively hadsuch financial interests. This may just be a case in point.
Clinical Pharmacology:
A Conscientious Viewpoint
Perhaps no other speciality is as intimately associated with the pharmaceutical industry and drug regulatory authorities as is clinicalpharmacology. Not only has the branch and its older sibling,‘Pharmacology,’ been the main source of recruitment of personnel for thepharmaceutical industry, those staying on become the industry’s greatestcritics as also collaborators.
A good grounding in clinical trial methodologies, critical evaluation of literature, concepts of patents and generics, statistics, pharmacovigilanceallow many clinical pharmacologists to read between the lines and correctinterpretation of published reports of sponsored studies, of the role of‘conflicts of interests’ in obtaining drug approval or withdrawing a drug,thus making them the pharma industries’ biggest critics. The samerepository of knowledge also allows them to become a part of theindustries’ endeavour for new drug development by carrying out andinterpreting their experimental research, their toxicological studies, andconducting clinical trials either as employees of the companies or asmembers of academic institutes.
We have long been critical of the ways pharmaceutical companies promote their products. Some Greco-Latin versions of these irrational
promotional principles have been pointed out (see www.nofreelunch.org/
slide.htm):
Argumentum ad Verecundiam,’ ‘Argumentum ad Populum,’ ‘ Non
Sequitar,’ ‘ Argumentum ad Misericordiam,’
translated into English ‘appeal
to authority, ’ ‘the bandwagon effect,’ ‘ the red herring,’ and ‘appeal to
pity’, respectively (The Physician-Pharmaceutical Industry Relationship,
2006).
The point, which was largely ignored, was the fact that this is possible only because the clinician writing the product is up for sale. It is just amatter of bargaining. One of our surveys regarding the perception ofpharmaceutical company representatives brought to light some alarming MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
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facts (Malhotra, Kondal, Shafiq, Sidhu and Pandhi, 2004 b). It was notedthat pharmaceutical company representatives were of the view that theywere able to influence more than half of the prescriptions. Gifts,sponsorship of conferences and provision of scientific literature werehelpful in getting a desired drug promoted. We thus decided to at leasttrain the clinicians in critical analysis of such promotional literature atvarious low profile workshops.
Drug regulators have several important issues to handle. In developed nations, approval and disapproval of innovator molecules is the majorissue with regulators. In developing countries, other involved issues are– procurement and distribution of medicines, import of drugs, formulationof guidelines for conducting clinical trials, dealing with the problem ofthe dearth of ethics committees in a large number of health centers, and arelative lack of awareness of GCP principles. Regulatory authorities areoften at the receiving end for being under the influence of thepharmaceutical industry, and many times rightly so.
A glaring example of the same brought to light by action taken by the Arthritis Advisory Committee and the Drug Safety and Risk ManagementAdvisory Committee meeting held in February 2005, deserves specialmention here. Safety of COX-2 inhibitors was the topic of discussion. Itwas disclosed after the meeting that 10 of the 32 voting panel membershad financial associations, in some form or another, with the manufacturersof the COX-2 inhibitors. Of the 30 votes cast by these 10 members onwhether rofecoxib, celecoxib, and valdecoxib should continue to bemarketed, 28 favoured marketing of the drugs. Of the 66 votes of the other22 members, only 37 favoured their marketing. If the 10 panel memberswith the financial associations had not participated, the committee wouldhave voted 12 to 8 that valdecoxib should be withdrawn and 14 to 8 thatrofecoxib should not return to the market. However, with these votersbeing there larger than life, the tallies were 17 to 13 for keeping valdecoxibon the market and 17 to 15 for the return of rofecoxib (Harris and Berenson,2005; Center for Science, 2006). Such was the impact of the ‘Godfather’that Dr. Wood of Vanderbilt University, who had chaired the joint meeting,commented: MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us Of all the FDA advisory committee meetings I have attended, there has never been more money on the table. Some potential panel members had already beenexcluded because of conflicts. The people who were chosen had disclosed theirfinancial interests to the FDA, although it played out as though they had somethingto hide (Steinbrook, 2005). Heavy conflicts of interests of members in the drug approval reviewing committee are a major cause for concern. Though theDeclaration of Helsinki (http://www.wma.net/e/policy/b3.htm) outlinedethical principles for the conduct of research in humans several decadesago, clinical trials defying the ethical principles continue to occur inmodern times.
Two very contemporary examples, which are perhaps more blatant in flouting ethical norms than many others, are given here: 1. A study conducted by a pharmaceutical company in an African country for perinatal transmission of HIV deprived the control groupof an established treatment of proven efficacy. The control group wasgiven placebo on the pretext that ‘no treatment’ for preventingperinatal transmission was the norm in the native population (Lurieand Wolfe, 1997).
2. The other example hails from one of the more affluent and aware zones of the world. A study to elucidate the natural history of cervicalcancer was conducted in Australia. Here again the women weredeprived of the benefit of regular screening (which has already shownto have a definite role in detecting early stages of cancer) in order toupdate the existing knowledge on cervical cancer (Coney and Bunkley,1987).
Despite such examples continuing to crop up from time to time, it is heartening to note that, in general, awareness regarding ethics in medicalresearch is ever increasing. Developing countries are also taking initiativesto propagate the concept of ethics by organizing workshops, seminars,helping institutes set up ethics committee and issuing their own guidelines.
Guidelines for ethical conduct of human research, issued by Indian Councilof Medical Research are oft quoted in this regard (www.icmr.nic.in/ethical). The recent Academia-Industry Symposium by the Mens Sana Monographsis a welcome step in the direction of creating a healthier climate forinteraction between the medical profession and the pharmaceutical MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
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industry (Singh and Singh, 2005a; 2005b; 2005-2006. See also http://mensanamonographs.tripod.com/id87.html for details.) Rightly, clinical pharmacology training here and abroad lays a great deal of emphasis on the ethics of conducting research in humans. For theclinical pharmacologists involved in bench side research, training in ethicalprinciples of conducting research in animals is of as much importance asconduct of the research itself.
Informed Consent
In developing nations, the importance of conducting clinical trials is being increasingly recognized. There is more than one issue which needsattention in this regard. While conducting these studies we realizedobtaining informed consent was a rather difficult job. The main reasonwas that participants held two kinds of extreme viewpoints about clinicalresearch: one, that they would become guinea pigs; or, second, that ofleaving every decision to the investigating physician (expressed in thelocal dialect as, ‘Jo tussi theek samjho’, translated roughly as, ‘Whateveryou decide is fine with us.’).
It was interesting to note that till very recently, even in tertiary care centers conducting multi-centric trials, the importance of obtaining trulyinformed consent in the vernacular was nothing more than an interestingtopic for discussion. Fortunately, though, the trend is changing. Havingrealized the importance of the same, we started an exercise in designing atemplate consent form (Shafiq, Sidhu, Pandhi and Malhotra, 2005 c). Thistemplate is based on research in which we have tried to assess thecomprehension of research subjects after giving them a dummy consentform. Interestingly, despite explaining, both in writing and orally, termslike ‘placebo’, ‘randomization’ and ‘blinding’ were not largely understoodeven by the educated. After realizing this, we have started an exercise inwhich we allow the patient to ask questions on whatever they have notunderstood, and continue to explain it to them till it is clear. In one of themeetings of investigators for an ongoing trial, our colleagues in otherinstitutes were happy to know that we had maintained a record of patientsrefusing consent, with reasons for the same. As an experimental exercise,we make a note of the time the consent process lasted and the queries thatwere raised.
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S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us There were several other important misconceptions prevailing both in the patients as also the clinicians who participate as investigators in aclinical trial. The need for educating people regarding this was imminent.
We have made an attempt in this direction by penning down differingaspects of clinical research which may be of concern to a clinical researchparticipant in the form of a book written in a simple language (Malhotra,Shafiq and Pandhi, 2006). We are yet to see how effective our initial attemptwill be in the years to come.
Clinical Pharmacology:
From Ignorance To Knowledge
Another episode we would like to recount here is about low molecular Case 3: We had long been hearing about the superior efficacy of the
low molecular weight heparin, enoxaparin, over its other counterparts -nadroparin and dalteparin. In our earlier investigation we had seen thatenoxaparin, a low molecular weight heparin (LMWH) showed a benefitover conventional heparin therapy on the composite endpoint of death,recurrent angina and myocardial infarction (Malhotra, Bhargava, Grover,Pandhi and Sharma, 2001). It was now time to investigate the best choiceamong the three available to us in the Indian market for treating unstableangina.
We thus concluded there was an urgent need for a head to head comparison among the three most commonly used low molecular weightheparins in patients with unstable angina. We decided to compare theefficacy, safety and cost-effectiveness of enoxaparin, nadroparin anddalteparin in patients with unstable angina. As a sub study, we decidedto investigate the effect of these LMWHs on Plasminogen ActivatorInhibitor-1. Our results led to the following conclusions - the three LMWHswere similar as regards efficacy and safety. The cost minimization analysisshowed nadroparin to be superior to dalteparin and enoxaparin. We thusconcluded that cost of the LMWH should be the determining factor formaking a choice of the LMWH (Unpublished data).
The perspective of the pharmacoeconomic study was the patient.
Unlike in the West, patients here in India bear majority of the treatmentcost. Barring few exceptions, they are largely uninsured. Obtaining an MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
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indigenous cost effectiveness data is, therefore, the need of the hour. Thisthen becomes the basis for further prescriptions being written by practicingphysicians.
Clinical Pharmacology:
Making Its Heartbeats Felt
By this time the busy clinicians have started understanding the different approach of a clinical pharmacologist in answering several drugand therapeutics related questions. The need for generating local treatmentguidelines had long been realized by our fellow clinicians. The first suchguideline, which was generated in the institute by collaborative effort ofWHO, had largely overlooked clinical pharmacologists (Jindal, Gupta andAggarwal, 2006). In the generation of their next guideline for themanagement of community-acquired pneumonia, clinical pharmacologistswere invited as a part of the team of experts (Guidelines to be published).
Then, again, comes the question of interpreting clinical guidelines made by ‘experts’ in the more privileged parts of the world till one hasone’s own guideline ready. In the present era of evidence-based medicine,a prescription that does not follow the Joint National Commissionguidelines, more popularly known as JNC guidelines, for the treatmentof hypertension may well be questioned. However, blindly following itwould also mean ignoring several important points, such as the ratherdogmatic recommendation of diuretics as first line management,introduction of the term ‘prehypertensive’ and the conflict of interests ofthe people involved in generation of the guidelines (Shafiq, Malhotra andPandhi, 2003).
Again there was a suggestion sometime back of polypill therapy for the primary and secondary prevention of cardiovascular diseases. Theauthors suggested combining thiazide diuretic, angiotensin convertingenzyme inhibitor, beta-blocker, statin, aspirin and folic acid for thispurpose. The suggestion was based on the synergistic treatment effectscalculated by multiplying relative risk reductions with each of theindividual therapies (Wald and Law, 2003). Though it sounded interesting,if allowed to go unchecked and unquestioned, it may have resulted in thepharmaceutical industry grabbing the seemingly attractive opportunityof pushing such a pill into the market. Fortunately, though, such write- MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us ups are now under the scanner, and many a time voices raised aresuccessful in critically evaluating them.
It was pointed out that utility of individual pills for primary prevention could not be generalized (Fahey, 2005). The example of aspirinwas cited in this context wherein it was pointed out that low dose aspirindid not provide any benefit in prevention of rate of myocardial infarctionin women as was the case in men (Fahey, 2005). It was also argued thattreating people with low risk of cardiovascular diseases as was suggestedby the authors would lead to medicalization of the population with nopromise of sufficient benefits coming through (Mulrow and Kussmaul,2005).
Clinical Pharmacology:
Research Sans Frontiers
The members of our species have two major options for diversifying after training. They usually make a choice between either joining apharmaceutical industry or doing academics. These two have often beenseen as mutually exclusive, or rivals.
Incidentally, the clinical pharmacology community is rather a small one in India. The small size has made it a closely-knit community, with ofcourse all its internal badgering and dissensions. But it has also helped usevolve reasonably decent academia-industry collaboration rather than anacademia-industry rivalry. Many company sponsored trials andbioequivalence studies are outsourced to us with due credit to clinicalpharmacology. Other than providing us with much needed financialsupport, this has provided us hands on experience in learning to undertakesuch studies. On our part, we have been conducting national workshopsin Clinical Pharmacology yearly, and recently have initiated, with industrysupport, a workshop for training in Good Clinical Practice. We have plansof collaboration with the pharmaceutical industry to generate a core groupof clinical researchers who would train other academicians for conductingresearch. As a routine, we write protocols for investigator-initiated trialsand approach concerned industry to sponsor our study in terms ofprovision of drugs, placebo, or the comparator and other requirements.
To finalise such protocols, we have experts sitting from our department,the concerned clinician, and a person from the pharmaceutical industry.
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From that time on, a very good rhythm is established as the study movesfrom initiation to completion to analysis to publication.
Though the pharmaceutical industry is largely maligned for malpractices, we have had instances where we have gone ahead with
publishing results that may not have been very welcome to the industry.
This study aimed at comparing kinetics of a new iron formulation (iron
polymaltose complex) with the older ferrous sulphate formulation. The
manufacturers of the new formulation sponsored the study. However,
the study results showed a greater bioavailability of ferrous sulphate as
compared to the new formulation. The study results were published as
such (Malhotra, Garg, Khullar, Malhotra, Kondal, Rana and Sidhu, 2004).
Interestingly, our relationship with the concerned person never got jeopardized: instead what happened was rather to the contrary.
The foundation of a good working relationship between the two has led us into more such joint ventures.
Clinical Pharmacology:
The Help Line
We steer you through another scenario that has been a part of our Case 4: A phone call comes to the drug information unit located in
our institute. It is a query from a private dermatology clinic. A femalepatient of the dermatologist had used dextromethorphan, Augmentin andflucanozole within the first five weeks of pregnancy. The dermatologistwanted to know if it was advisable to continue the pregnancy.
The resident on call, though a fresh postgraduate student, was tuned to clinical pharmacology. He reported, ‘High doses of fluconazole inpregnancy cause teratogenicity in animals’. He cited a case report ofcraniofacial abnormality in the foetus of a mother who had taken 400 mgof fluconazole daily (Pursley et al, 1996). It was added, further, thatprescription event monitoring found no such increase in teratogenicitybut reports of teratogenicity with high dose fluconazole use were available.
Cardiac abnormality had been observed in females taking high dosesduring pregnancy. However, dextromethorphan and Augmentin have not MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us been shown to have any teratogenic effects (Brunton, Lazo and Parker,2006).
These findings were presented to the dermatologist who in turn conveyed it to the parents. So services provided by a clinicalpharmacologist come handy in multiple ways.
Roadblocks And The Future
Though we see a bright future for the subject, we also foresee a number of roadblocks. For instance, at the moment, there are only a limited numberof institutes imparting the degree. More importantly, the number of trainedfaculty at these institutes is even fewer. Funds for more such centers areslow to come by.
However, with the government and pharmaceutical industry showing renewed interest in the subject, the pattern is likely to change. Judicioususe of drugs, development of new formulations, reaching treatment to allconcerned is no longer confined to discussion by the intelligentsia, but isbeing felt as the need of the hour. The ‘10-90’ gap (ten per cent ofworldwide expenditure on health research and development is devotedto the problems that primarily affect the poorest 90 per cent of the world’spopulation) is increasingly being seen as a reason of some serious action.
(In this connection, see http://www.who.int/intellectualpropery/submission/InternationalPolicyNetwork.pdf.) The clinical pharmacologist, sitting at the hub of all drug related activities, is the right person to lead the team of individuals getting togetherto deal with this inequation. While the optimistic picture presented abovespeaks of events in the next two or three decades at best, a time is boundto come when unmet medical needs will remain countable on fingertips.
What will be the future of clinical pharmacologists in the next half of the century may send shudders down the spine of quite a few. Fortunately,though, the human body, with its ever-unfolding mysteries and aspects,has been able to keep alive the need for research in therapeutics so far.
But like other sciences, the focus may shift from research in ischaemicheart diseases to anti-ageing medication, to treatment for male patternbaldness, or one-time injections for rheumatoid arthritis.
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What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
On second thoughts, leads are slow to come in certain fields, and clinical pharmacology may guide and accompany humanity towards abetter and healthy living, what with quality of life studies alreadybecoming an integral part of research (Shah, Ananth, Sohal et al, 2006;Bradshaw, Jamrozik and Gilfillan, 2006).
A few concerns remain, such as how to increase the number of institutes who provide clinical pharmacology training. Most of the ongoingtalk is about incorporating clinical pharmacology into the undergraduatecurriculum. Indeed, orientation towards some concepts of clinicalpharmacology could start at the undergraduate level. For instance,teaching clinical application of pharmacokinetic knowledge would bemore appropriate than making it into a boring exercise of rote learning offormulae. Again, it would be more prudent to help students generate theirown formularies based on the available drugs for a particular condition.
Also, training in searching for evidence for any fact mentioned in theirtextbooks could be a good exercise. This should pave the way forgenerating a greater motivation in students to opt for clinicalpharmacology later.
The paucity of institutes giving training in clinical pharmacology at the super speciality level is an important issue. Even if more such instituteswere opened, absence of good trained faculty would be another roadblock.
More important would be retaining the faculty in academic institutes, asthe lure of pharmaceutical industry pay packets is a great force to reckonwith. Of late, some pharmaceutical companies have started their owncourses in clinical pharmacology. However, these courses deal with onlysome aspects of the subject, such as clinical trials, not clinical pharmacologyin totality. The importance of the subject lies in its capacity to integratetranslational and clinical research.
Though clinical pharmacologists have been providing good insights into several drug related issues, such as rational use of drugs, essentialdrugs list, pricing, regulatory issues, the branch per se remains low on thepriority list of policy makers. Funds are therefore, slow to come by. In thefew centers where it has grown, it has remained an offshoot ofpharmacology. When it is time to opt between a trained clinician and aclinical pharmacologist for an emerging institute, majority of the times MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us the former wins while the latter struggles for survival. This may soundlike a disgruntled voice, well, but a realistic disgruntled voice it is.
Keeping in mind the value a clinical pharmacologist provides in various health related aspects, it is important that these problems are takencare of and a roadmap for increasing the number of centers providingstate of the art training in clinical pharmacology is created.
Concluding Remarks
1. Clinical Pharmacology, though hitherto not a very coveted super speciality subject, is increasingly being opted for by top rankers inentrance exams.
2. Though the number of clinical pharmacologists has declined worldwide, there has been a revival in understanding the importanceof training in the subject.
3. Clinical pharmacologists have several important roles to play such as identifying new drug targets, development of new drugs, correctapplication of available knowledge about drugs, regulatory issuesand policymaking regarding therapeutics.
4. In the current era, where the pharmaceutical industry is trying all means to increase their profit (‘me too’ drugs, data dredging,unhealthy promotional practices, concealing unfavourable results,exaggerating potential uses, not declaring conflicts of interests,conducting unethical trials, ignoring the diseases which ail the poorand the majority), a clinical pharmacologist has an important role toplay as an informed critic of such practices.
5. Clinical pharmacology provides a platform for collaborative efforts between academia and the pharmaceutical industry. Academia-Industry collaboration would lead to a healthy growth of bothacademia and industry for the purpose of innovation in health relatedproducts, technologies and rational utilization of these facilities in ajust manner by all.
6. Certain apprehensions remain regarding the future of clinical pharmacology. These are mainly because of paucity of institutesgiving training in clinical pharmacology, shortage of trained faculty, MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
and academia holding against the monetary incentives that theindustry offers to clinical pharmacologists. All the same, there aresigns of revival of the speciality and it is already beginning to makeits presence felt.
Take Home Message
Clinical pharmacology, though a relatively young specialty, is a branch which is of utmost importance in this era of modern medicine. Aclinical pharmacologist with his or her knowledge about various aspectsrelated to new drug development, regulatory requirements pertinent tothe same, ethical conduct of clinical trials, interpretation of trial results,conflicts of interest, promotional activities of pharmaceutical companies,neglect of research in diseases afflicting the large majority of population,is a person best suited for providing his or her intellectual input into manydrug and therapeutics related aspects.
Conflict of Interest
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S. Malhotra, N. Shafiq (2006), What Clinical Pharmacology Means To Us Questions That This Paper Raises
1. What is the future of clinical pharmacologists especially in developing countries where the branch is restricted to only a few academicinstitutes? 2. Will raising the number of clinical pharmacologists improve the quality and quantity of basic and clinical research? 3. Will a good, conscientious rapport between academia and industry contribute towards narrowing the 10-90 gap? 4. What should be the benchmarks for clinical pharmacology units in 5. How can policy makers be made to understand the value of a clinical About the Authors
Dr Samir Malhotra is currently working as Assistant Professor in the
Department of Pharmacology at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. After doing his M.D in Pharmacology, he passed his D.M, Clinical Pharmacology, from PGIMER, Chandigarh. He has undertaken several basic and clinical research projects, guided M.D, D.M, M.Sc. and Ph.D. theses and organized workshops on Good Clinical Practice. He has published nearly hundred articles in national and international journals. In the field of research, he has been bestowed with several awards. He has served as Editor or sub-editor for medical journals. He has authored a book titled, ‘All that you wanted to know about Clinical Research.’ He is Fellow, American College of Clinical Pharmacology, and Member of several other scientific societies. MSM : www.msmonographs.org l http://mensanamonographs.tripod.com
What Medicine Means To Me, Mens Sana Monographs, Vol. III:6, Vol. IV:1-4.
Dr Nusrat Shafiq has done her M.D. (Pharmacology), D.M. (Clinical
Pharmacology) from the Postgraduate Institute of Medical Education and Research, Chandigarh. She is currently working as Senior Research Associate in the same department. She has over thirty national and international publications and is the co-author of the book titled, “All that you wanted to know about Clinical During her training in M.D and D.M, she has undertaken several investigator- and sponsor-initiated trials. She is simultaneously pursuing basic science research and is currently working on heat shock proteins. During her training period, she received several best paper presented and published awards. She is Member of American College of Clinical Pharmacology, Indian Pharmacology Society, Association of Physiologists and Pharmacologists of India etc. MSM : www.msmonographs.org l http://mensanamonographs.tripod.com

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