Special Features Pharmacokinetics – Applications PHARMACEUTICAL PHYSICIAN MHRA Case Study Brapp Education Day 2015 Pphinal Pphunnybone

IN THIS ISSUE: Special features Pharmacokinetics – Applications PHARMACEUTICAL PHYSICIAN MHRA Case Study BrAPP Education Day 2015 PPhinal PPHunnybone

JANUARY 2016 VOLUME 26 | NO4

JOURNAL OF THE BRITISH ASSOCIATION OF PHARMACEUTICAL PHYSICIANS

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This is just a selection of the current assignments with our pharmaceutical clients. For a confidential discussion please telephone Beth Thomas-Stonier at AXESS Limited on 020 8560 2300. To apply please send your CV to [email protected] quoting the reference number. Visit our website www.axess.co.uk to register for jobs by e-mail – new roles that match your criteria e-mailed to you on the same day that they are posted. Resourcing Solutions for Medical Affairs, Regulatory Affairs and Clinical Development PHARMACEUTICAL PHYSICIAN Contents EDITORIAL 3 BOOK REVIEW 26 Vie d’Or SPECIAL FEATURE 4 Pharmacokinetics – an PPHUNNYBONE 29 overview Mission Complete Applications of Hugh Gibbons Pharmacokinetics Drs RMJ Ings and CW Vose

JANUARY 2016 VOLUME 26 | NO4 SPECIAL FEATURE 14 MHRA Case Study: MSD melanoma treatment through the early access scheme (EAMS)

PEOPLE 17

MEETING REPORT 18 BrAPP Education Day 2015 EDITOR: DR MADHU DAVIES [email protected] PROFESSIONAL DEVELOPMENT 25 EDITORIAL BOARD: Benefits of being a DR JANE BARRETT medical assessor at MHRA DR HUGH BOARDMAN DR DAVID FOWLER LIZ LANGLEY [email protected] Published 6 times per annum by BrAPP Royal Station Court, Station Road DESIGN: DANA KIDSON Twyford, Reading, Berkshire RG10 9NF. [email protected] Telephone +44 (0)118 934 1943 Fax +44 (0)118 932 0981 Email [email protected] www.brapp.org

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& retentretentionion sosolutionslutions glgloballyobally fforor FForor trialtrial sites with resource constraints,constraints, the MRN also offersoffers a SiteSite NurseNurse SupportSupport service, pplacinglacing experiencedexperienced research nurses and/orand/or coordinators into the sites to ensureensure enrollment and clinical trials. HeadqHeadquartereduartered in the rretentionetention targetstargets are met.met. UK & now with a NNorthorth American DDuringuring the last 4 yyears,ears, MRN has beebeenn iinvolvednvolved iinn the coconductnduct of ooverver 111010 pprojectsroojects across a wwideide operaoperation,tion, th thee MRN N ooffers ffers SitSitee rrangeange ofof therapeutictherapeutic areas, ranging fromfrom complexcomplex trials in oncology,oncology, rheumatology,rheumatology, enzymeenzyme NNurseurse SSupportupport anandd Home TTrialrial rreplacementeplacement therapy,therapy, hematologyhematology and othersothers requiringrequiring drugdrug administration of IV therapiestherapies and otherother injectablesinjectables inin tthehe home,home, as wellwell as simplesimple bloodblood drawsdraws inin neurology,neuroloogy, antianti infectives,infectives, SSupportupport services acracrossoss the gglobe.lobe. rrespiratory,espiratory, renalrenal & manymany others.others.

ShouldShould you wish to findfind out more abouaboutt our services or discussdiscuss a specificspec project pleasepleasse contactact us.us TalonTalon House, PresleyPresley Way,Way, Milton Keynes,Keynes, BuckinghamshireBuckinghamshire MK8 0ES0ES E: [email protected]@stuar dding@@[email protected] T: +44 (0)1908(0)1908 261 153153 www.themrn.co.ukwww.themwww.t mrn.co.ukk STOCK MARKETS OPENED the year available at the regulatory agency. The with record falls around the world. But other showcases a recent Early Access the pundits predict a good year for us to Medicines Scheme and illustrates, in pharma/biotech with research and perhaps, how it could be utilised to the development productivity continuing at advantage of all stakeholders by your EDITORIAL pace. Has there ever been a better time company? to work in our industry? The recent BrAPP Annual Education Starting at the end of the journal- Hugh Day was a great success. Liz Langley Gibbons draws his series of has drafted a summary of the day for PPhunnybones to a close marking his those of you who were unable to attend 50 years in our industry. He has including a precis of the inaugural Anne witnessed change a-plenty and has Appleton lecture, given in memory of thrived on it developing one of the Anne, a relatively young PP and most interesting careers I have come enthusiastic BrAPP committee member, across yet. Over the 23 years during who passed away last year. which our paths have crossed, Hugh has demonstrated a hunger for Last but not least, Dr David Glover has development-both his own and for enjoyed a stellar career in pharma and others, contributing to the career his memoire is reviewed in this issue. trajectory of many tyro pharmaceutical As the reviewer notes “David argues physicians – an appetite for challenge that he may have enjoyed the heyday of and, above all, cheerful and intelligent the blossoming industry but for those us resilience. None of these attributes goes who remain and those of you to come it out of fashion and all remain essential behoves us to keep the banner flying. to the success of a PP today. I am sure This book may help you reflect on ways you will join me in thanking Hugh for to do that.” PPhunnybone and wishing him health and happiness. And on that positive note, I will end.

Bob Ings and Colin Vose, who many of Here’s to a great 2016. you know from the BrAPP/ University of Cardiff Postgraduate Course in Dr Madhu Davies Pharmaceutical Medicine, draw their series on pharmacokinetics to a close with a useful article summarising the practical applications of a Dr Madhu Davies pharmacokinetic approach in drug development today. The series has been very well received by this journal’s readership and I am delighted that Bob and Colin have been prepared to put in so much time and effort to share their enthusiasm and understanding of the topic more widely. Those of you taking the Dip Pharm Med exam may usefully choose to incorporate the series into your revision… For the rest of us, a welcome reminder of things we thought we knew. Thank you, Bob and Colin.

I also need to thank the MHRA for two items. The first is a timely piece on career development reminding readers of the diversity and value of the roles 3 January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 SPECIAL FEATURE: Pharmacokinetics – an overview Applications of Pharmacokinetics

By Drs R. M. J. Ings and C. W. Vose

1. INTRODUCTION • Understanding the effects of disease, THIS IS THE last of six articles aiming both that being treated and other to provide an overview and unrelated diseases such as renal and understanding of the principles, hepatic failure, and its therapeutic processes and applications of implications pharmacokinetics (PK) in Pharma R and D. This article summarises the specific 2. DRUG DISCOVERY PK studies applied and the value of SUPPORT resulting information. Some of these Historically, drug leads and applications have been mentioned in development candidates were selected other articles of the series and these and predominantly on their preclinical some additional sources of information efficacy, potency, selectivity and are listed in the bibliography[1,2,3,4,5,6,7]. toxicity. However, given high failure rates in clinical development, Factors affecting the efficacy and safety associated, in part, with poor PK of a drug can be identified, understood, properties (Figure 1)[8], PK properties and managed if its PK is well- are now assessed early in discovery characterised and the relationship programmes. The application of in vitro between the PK and the and in vivo PK in discovery was pharmacodynamics (PD) is understood. recently reviewed by McGinnity et al[9]. With this knowledge, the PK characteristics of a drug can be used in: The overall objective is to select a development candidate most likely to Bob Ings Colin Vose • Drug discovery and selection show required in vivo PK properties and desired PD in man. • Species differences and their implications such as validating the 2.1 In vitro screening choice of species for toxicology The process of understanding potential PK properties of a drug can start even • Dosage regimen design before the compound is first synthesized.Two broad fundamentals • Assessment and implications of non- will influence the PK of a drug: linear kinetics • The physico-chemical properties of • Predicting possible drug-drug the compound interactions • The physiology of the subject • For an orally administered drug, receiving the compound understanding the role of first pass metabolism as well as the effect of Drug design cannot do much about the food on absorption. latter but the former is very much in the hands of the medicinal chemist. Many • Understanding the effect of physico-chemical properties e.g.

physiological factors such as age, molecular weight, Log P, Log D, pKa, 4 weight, gender etc. polar surface area (P.S.A), number of January 2016 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN | FIGURE 1: Reasons for failure of drug candidates in development SPECIAL FEATURE: (Redrawn based on information from T. Kennedy, Drug Discov. Pharmacokinetics – an overview Today, 2, 435-444, 1997) Applications of Pharmacokinetics

0 ADME (39%) Efficacy * Pre-Clin Human Commercial Misc (7% excluding (30%) Tox (11%) ADRs* (5%) (5%) anti-infectives) (10%)

Kennedy, T. 1997, DDT 2: 436-444 chance of success in further development. Based on the properties of the early drug leads, new analogues | TABLE 1: Physico-Chemical Properties of Drugs and Pharmacokinetics with modified structures and physico- chemical properties will be prepared. Property Influences The aim is to find compounds with a clearance, volume of distribution, and Structure Molecular weight (Size) half-life, that together with appropriate Partition/distribution coefficient (Ratio of solubility in lipids and water) Chemical stability absorption and bioavailability will, using pKa (acid/base/non-ionic) a simple dosage regimen, provide steady-state plasma levels (Css) with low Partition Coefficient (logP) Solubility in biological fluids, Absorption Distribution Coefficient (logD) Protein binding to moderate within- and between- Distribution subject variability, yielding the required Elimination pathways (excretion vs metabolism) PD. pKa (Acid/Base/Non-ionic) Absorption Distribution However, at this stage of the process the Elimination tendency can be to view each of these Molecular Weight Membrane transport screens as a filter with sharp cut-off Biliary excretion criteria, optimizing one property and then moving to the next. This approach can be protracted and costly and hydrogen bond donors and acceptors Once compounds have been invariably leads to very few or no can be calculated in silico from the synthesized, their physico-chemical potential development candidates, proposed chemical structure, even properties can be further evaluated by a especially as optimizing one property before its synthesis. This is important series of relatively high throughput can easily compromise another. It is far since the relationship between chemical exploratory in vitro screens. Initially better, periodically, to assemble all the structure, physico-chemical properties these properties include solubility, data and evaluate it in a and PK is the basis of chemical permeability (PAMPA), metabolic multidimensional manner using modification(s) to optimize PK stability using microsomes, plasma programs such as Spotfire (TIBCO, CA) properties. The influence of the relevant protein binding and cytochrome P450 to visualize the overall profile and physico-chemical properties on PK are (CYP-450) inhibition. These screens determine if it is worth further summarized in Table 1. weed out those compounds having little evaluation.

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 5 Continues from page 5

As the compound moves from hit to models, looking for possible drug-drug SPECIAL FEATURE: lead and lead optimization, more interactions and the PK in special Pharmacokinetics – an overview detailed, lower throughput in vitro patient populations by employing assays can be introduced, including programs such as SimCyp (Certara, CA) Applications of Pharmacokinetics dissolution, Caco-2 cell monolayer or GastroPlus (Simulations Plus, CA). assessment of permeability and any P- gp efflux transporter involvement, more 2.2 In vivo Preclinical detailed plasma protein binding the The in vitro assays described above CYP-450 Ki (inhibition constant), and indicate the potential PK of a time- and mechanism-based inhibition compound which must be tested in a and transporter inhibition. variety of in vivo animal models since the early safety assessment will be Metabolite profiling comparisons in liver performed in a rodent (usually rat) and microsomes/cells of the non-rodent species (usually dog or pharmacological and toxicology species monkey). Initially single dose PK studies and man will support interpretation of are performed to evaluate exposure in pharmacology activity and toxicity. In the species of interest and combined addition, reaction phenotyping can with some formulation development if identify the human enzymes and/or exposure is inadequate e.g. poor oral transporters eliminating the drug, whilst, absorption due to poor dissolution. binding to the PXR and CAR nuclear receptors and functional hepatocyte These studies are followed by repeated assays of specific CYP-450 isozymes can dose PK studies, commonly performed assess enzyme induction potential. in conjunction with toxicokinetic studies Covalent binding studies and used to ensure adequate exposure to glutathione adduct formation can be the drug and/or specific metabolite(s) in evaluated looking for reactive the toxicology studies. The single dose metabolites. If appropriate, these more PK data from the different species can detailed assays can be performed with be used to predict the likely PK in man

the regulatory submission in mind. Also, (Cl, VD and t1/2), prior to dosing to man,

intrinsic clearance (Clint) calculations using allometric scaling. This relies on (equation 1) can be made to predict the the relationship between parameters of human clearance (equation 2) as various physiological processes[11] e.g. described by Houston[10] to avoid high liver blood flow, creatinine clearance (a first pass metabolism of orally measure of kidney function), heart rate, administered compounds. respiratory rate, maximum lifespan potential, and bodyweight (BW) in When concentrations are animal species as described in equation

Where Vmax = Maximum metabolic rate; similar relationship.

Km = Michaelis constant Physiological or PK parameter = α In vivo Cl = ______Fu *Clint *Qh A* BW ...... (3) ...... (2) Fu *Clint +Qh The values of A and the power function

Where Fu = Fraction unbound in (α) depend on the physiological or PK

plasma; Clint = intrinsic clearance; parameters being studied.

Qh = Liver (hepatic) blood flow Examples of this relationship are shown More sophisticated and robust human for clearance of cyclophosphamide predictions can be made by bringing (Figure 2) and methotrexate (Figure 3) much of these data together using which are eliminated mainly by physiologically-based pharmacokinetic metabolism and urinary excretion,

January 2016 6 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN respectively. Volume of distribution can to scale directly with BW (power also be scaled with bodyweight but function ~1.0). The approach works SPECIAL FEATURE: whereas clearance tends to scale better well for drugs eliminated by renal Pharmacokinetics – an overview with body surface area (BSA; power excretion or high clearance drugs function ~0.75), the volume term tends eliminated by metabolism. Liu and Applications of Pharmacokinetics

| FIGURE 2: Allometric relationship of cyclophosphamide clearance to bodyweight in animals and man (Redrawn from R. M. J. Ings, Xenobiotica, 20, (11), 1201-1231, 1990)

Methotrexate (Renal CL)

Man 200

100 Monkey

Dog 10 Rat

1 Mouse

Plasma Clearance (mL/min) Plasma [12] Chen showed that clearance in man ≤ 0.1 was predicted well (average error 2-

0.01 0.1 110100 fold vs observed values) for some 20 of 31 drugs using the relationship with BSA Body Weight (Kg) and BW. It is generally much less Passive renal filtration, logD7.4 ≤ 0 accurate for low clearance drugs, particularly when eliminated predominantly by CYP-450 metabolism. Moreover, this in vivo approach can be | FIGURE 3: Allometric relationship of methotrexate clearance to combined with the in vitro approach bodyweight in animals and man described previously to provide (Redrawn from R. M. J. Ings, Xenobiotica, 20, (11), 1201-1231, 1990) reasonably robust predictions of human PK prior to the first dose to man.

Cyclophosphamide (High CL) The preclinical PK and metabolism 500 studies do not stop here. In non-clinical Dog development, the toxicology species 100 Man have to be shown to be sufficiently Monkey exposed (AUC and Cmax) to the same chemical species (drug and metabolites) Hamster 10 as expected in man to provide confidence in the relevance of the safety Rat data to man. Typically, this involves

1 Mouse dosing a radiolabelled form of the drug

Plasma Clearance (mL/min) Plasma (normally 14C but sometimes 3H) to each of the toxicology species, so that all 0.1 drug-related material can be accounted 0.01 0.1 110100 for. The recovery of excreted Body Weight (Kg) radioactivity (excretion balance) in urine

High first pass Cl, low F and feces, over an appropriate period based on the anticipated half-life, should ideally be close to 100% of the dose,

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 7 Continues from page 7

and indicates the extent to which drug- those of the respective toxicology SPECIAL FEATURE: related material has remained in the species. Pharmacokinetics – an overview body. The plasma and/or blood concentration-time profiles of 3. CLINICAL Applications of Pharmacokinetics radioactivity can be compared with PHARMACOKINETICS those of the drug to provide an Dovetailing into the later portion of the assessment of the extent of circulating preclinical DMPK program with in vitro metabolites. Also, if a large amount of and in vivo studies will be the start of radioactivity is found in feces, especially the clinical program. Preclinical after iv, dosing, a separate biliary PK/ADME and toxicology data, should excretion study may be required. provide a rational estimate for the starting dose and probable PK profile The quantitative profile using for the first-in-human study. This is radioactivity, and identification using primarily a safety study, but should mass spectrometry and possibly also always include PK, starting with a NMR, of metabolites in the collected single ascending dose (SAD) and urine, feces, bile, and plasma samples moving to a multiple ascending dose should then be determined. An (MAD) study. In the clinical additional radiolabelled study examines pharmacology program, these studies the tissue distribution of radioactivity have the widest range of doses since usually in the rodent species used for they are designed to start at a relatively toxicology, most commonly by low, very safe, dose and escalate to a quantitative whole body point where side effects are seen. Thus, autoradiography. These data help they are the best studies to evaluate interpretation of the toxicology findings linearity of kinetics, to determine if

and allow dosimetry calculations for a exposure (AUC and Cmax) increase in a human radiolabelled study. Eventually, dose-proportional manner. Ideally drug when there are sufficient clinical data, exposure (AUC) should increase dose an excretion balance study, including proportionally but it may increase less plasma profiling, metabolite than dose proportionally if there is identification and quantitation in urine, dissolution rate limitation so the extent feces and plasma, will be performed of absorption decreases at higher doses dosing radiolabelled compound to man e.g. griseofulvin. On the other hand, so that the data can be compared with increases in AUC greater than dose

| FIGURE 4: PK/PD relationship for repeated oral dosing of a drug

10000 Toxic

Therapeutc 1000 Therapeutic } Window

Plasma Conc 100 Ineffective

10 04896144 Time (h)

January 2016 8 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN proportionality can occur when there is • The optimum amount/concentration saturation of one or more elimination of drug in the body - appropriate SPECIAL FEATURE: pathways e.g. carbamazepine. This may desired activity with low risk of Pharmacokinetics – an overview even lead to formation of a toxic undesired effects. metabolite not seen at lower doses e.g. Applications of Pharmacokinetics paracetamol. At the very least it may • Excessive amount/concentration of amplify effects caused by inhibitory drug in the body - maximum desired drug-drug interactions or disease states. effects but with high risk of undesired These early PK studies will identify the effects. risk so that appropriate dose escalation regimens can be designed for drugs Most drugs are administered with non-linear PK. chronically and at steady-state the average unbound drug plasma Also, although these studies are usually, concentration over one dosing but not always, conducted in healthy interval equals the unbound drug volunteers, it is often possible to obtain concentration at the target some measure of the intended receptor/enzyme site. Thus, plasma pharmacology (PD) which can help in drug concentrations can be used to predicting target plasma concentrations follow the drug concentration profile at for future efficacy studies. the target site. This is summarised in Figure 4 for repeated low, moderate As previously described in this series[13,14] and high oral doses of a drug and their the PK/PD relationship can be relationship to the intensity of PD summarised as: effects. and/or from PK/PD modeling, effective dosage regimen(s) can be calculated • No amount/concentration of drug in If the target Css concentration(s) since at steady-state: the body - no effects. associated with optimal activity and with a low risk of toxicity have been Rate in (Dosage regimen) =

• Insufficient amount/concentration of identified, either from in vitro or in vivo Rate out = CL * Css drug in the bo dy - inadequate activity pharmacology data combined with =CL___ * Css...... (4) and no undesired effects. knowledge of plasma protein binding F

where CL = clearance, Css = steady-state | TABLE 2: Factors affecting drug pharmacokinetics and disposition concentration, F = bioavailability

This offers a more rational basis for Factor Outcome dosage regimen design than empirical Dose Saturation of absorption and/or elimination testing of dose-effect relationships.

Age Decreased renal, hepatic and respiratory function An important facet of the clinical Decreased plasma drug protein binding pharmacokinetic/pharmacology Liver disease Changes in drug metabolism capacity program is to understand the sources of Kidney disease Decreased urinary elimination of drugs, variability of the PK of a drug in normal metabolites and endogenous components; clinical use so as to maintain efficacy decreased hepatic metabolism capacity and minimize unwanted side effects by Respiratory disease Increased hepatic metabolic capacity the rational adjustment of dosage regimen. There are many sources of Heart disease Reduced blood flow to all organs/tissues with variability (Table 2) and several of them potential effects on drug elimination will have already been identified from Gastro-intestinal disease Decreased drug absorption the in vitro studies described earlier. Drug interaction Modify clearance, increase or decrease steady- state concentrations • Effect of Food Food interaction Modify rate and extent of absorption for some The rate and extent of absorption of drugs some drugs can be affected by food. It can delay gastric emptying and access to

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 9 Continues from page 9

absorption sites in the small intestine and the inhibition by probenecid of active SPECIAL FEATURE: thus drug absorption. A high fat meal renal secretion increasing drug plasma Pharmacokinetics – an overview shows the largest effect on gastric levels of penicillins and cephalosporins. emptying. Thus, for orally administered Cimetidine and trimethoprim have a Applications of Pharmacokinetics drugs a food effect study is usually similar effect on pramipexole and performed comparing the PK of a drug dofetilide. Also, renal and hepatic in the fasted state with that when a high function decrease with age and fat meal is given, typically using a potentially with disease leading to crossover design. decreased clearance of a drug and increased plasma drug Css in elderly The effect on extent of absorption patients and in those with renal or depends on physico-chemical properties hepatic failure if the dose is not adjusted. of the drug, with high fat meals often Age and disease may also modify the enhancing the absorption of highly plasma protein binding of a drug, with a lipophilic drugs e.g. saquinavir, by consequent effect on volume of stimulating secretion of bile. However, distribution and potentially half-life. food effects for a given drug may vary, with the absorption of propentophylline Inhibition or induction of metabolising decreased and that of spironolactone enzymes e.g. glucuronyl transferases, and increased when given with food. most CYP450s are well known[15]. Grapefruit juice inhibits CYP3A4/5 • Effects on clearance decreasing the metabolic clearance and The mean steady-state drug plasma increasing Css of atorvastatin and concentration (Css) for total or free drug omeprazole. Cimetidine has a similar is inversely proportional to the effect on diazepam. Ketoconazole corresponding total clearance, where inhibition of terfenadine metabolism by total clearance is the sum of the CYP3A4, reduced its clearance, increased clearance for each pathway i.e. its Css, and led to its withdrawal from the market because of the resulting QTc

Cltot = Clrenal + Clmetab + Clbiliary + ...... (5) prolongation, torsades de pointe and death in some patients. Inhibition of A change in clearance of any pathway metabolism of a drug by another can also will change total clearance, leading to a be used therapeutically to reduce its change of the mean Css, and ultimately, clearance and prolong its duration of the PD of the drug. Thus, it is essential effect e.g. ritonavir has this effect in HIV to identify the major routes of drug combinations. Enzyme induction elimination of a candidate drug in order can increase levels of some metabolising to predict factors that could impact its enzymes e.g. CYP3A4, CYP2C9, total clearance. glucuronyl transferases. Carbamazepine and rifampicin induce CYP2C9, CYP2C19 This is accomplished using a and CYP3A4, and can thereby increase combination of data from many of the in the clearance, decrease Css of many vitro studies described earlier and the drugs metabolised by these enzymes. data from a human radiolabelled excretion-balance/plasma Thus, one of the important aspects of profiling/metabolite identification study. any clinical pharmacology program is The latter study will show the major the identification and mitigation of routes of elimination of the drug. If it is possible drug-drug interactions. There primarily renal or biliary (feces) are two facets to this, the first being a excretion, transporters will play an co-administered drug interacting with important role and identifying those the candidate drug where the latter is involved will allow appropriate clinical the victim and the second is the studies to be performed evaluating candidate drug interacting with a co- possible drug-drug interactions. administered drug where the candidate Examples of transporter interactions are drug is the perpetrator.

January 2016 10 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN When evaluating drug-drug interactions to be a strong inhibitor or inducer of a where the candidate drug is the victim, specific CYP-450 or transporter, SPECIAL FEATURE: identification of the in vivo human appropriately designed in vivo clinical Pharmacokinetics – an overview metabolites from the human studies should be performed either using radiolabelled study combined with the model substrates or drugs that are known Applications of Pharmacokinetics data from the reaction phenotyping substrates that are likely to be co- studies are used to quantify the extent of administered. Again, recommendations transporter and/or enzyme involvement should be made as to whether to avoid in the elimination of the candidate drug co-administration of drugs or dosage and which enzyme(s) is associated with regimen adjustment where such the production of individual metabolites. interactions are shown to be clinically All major pathways (>25% of the total relevant. clearance) should be evaluated with appropriately designed in vivo clinical Despite all the studies described above, studies, usually under steady-state this not the end to the understanding of conditions, using either a known strong the clinical PK and PD of a candidate model inhibitor/inducer or a known drug, as other sources of variability can strong inhibitor/inducer that is likely to occur such as gender, weight, ethnicity, be co-prescribed. If there is a clinically disease severity, genotype (e.g. significant interaction, recommendations CYP2D6), various physiological should be made on the appropriate dose parameters (e.g. creatinine clearance) adjustment or drug exclusions. and unanticipated drug-drug interactions. Although many of these When evaluating if the candidate drug is can be examined using separate participating in the Phase 2 and Phase 3 a perpetrator of a drug-drug interaction, traditionally designed studies, they can trials, examining the factors of interest in vitro data are again used as a guide as also be investigated using a population as covariates and using Bayesian to what in vivo clinical studies are PK approach with sparse plasma feedback to optimize dosage regimen. required. If the candidate drug is found sampling from the patient population However, to use this approach, the

| FIGURE 5: A summary of the input of drug metabolism and pharmacokinetics in the drug discovery and development process

More detailed New indic. TK Modelling & simulation PXR/ Phase Hepat. IIb Phase NDA React. Control Transporters ppb Pheno. Ind. Phase I/IIa III GSH/ Release IC /TDI Cl Met. id PK/PD formulation CaCo 2 50 int Coval. FIH Bind.

Target Early Full Life Cycle charact HTS Hit to Lead Lead Opt. Development Development Management

PK/PD Sol. Cyp Met. IV/PO IV/PO Radiosyn/ Biomarkers Stab. inhib. Long term rodent non - ADME TK Metabolite/ rodent Enantomer M.W. ppb Pharm PAMPA Development LogP/D PK/PD pK a P.S.A higher throughput Formulation In silico Modeling & support Simulation (SimCyp/Gastro+)

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 11 Continues from page 11

studies must be designed prospectively substrate/inhibition are adequately SPECIAL FEATURE: with the appropriate experimental described and not just the in vivo Pharmacokinetics – an overview design built into the protocol to ensure clinical pharmacology so that the the true dosing history, sampling times reviewer is able to follow the rationale Applications of Pharmacokinetics and covariates are accurately recorded, of the clinical pharmacology program. even if they deviate from protocol. 4. CONCLUSIONS Once all the non-clinical and clinical As can be seen from the overview PK/ADME data have been obtained they above and from Figure 5, PK impacts all will have to be collated, interpreted and stages of the discovery and summarized in the respective regulatory development of a drug. This input does marketing authorization (e.g. NDA, not stop after approval of the MMA) documents. It is key, when NDA/MMA, but continues into life cycle preparing the clinical pharmacology management with novel formulation section to ensure that all aspects of the development, new indications with clinical pharmacology, including possibly different dosage regimens, new relevant in vitro assays such as the dosing routes and even the plasma protein binding, cytochrome development of active metabolites or a inhibition, cytochrome induction, single enantiomer where appropriate, reaction phenotyping, transporter perhaps in a different indication.

| REFERENCES 1. M. Rowland and T. N. Tozer, Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 4th Edition: Philadelphia: Lippincott Williams and Wilkins 2010.

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5. M. E. Winter, Basic Clinical Pharmacokinetics, 4th Edition: Philadelphia: Lippincott Williams and Wilkins 2004.

6. R. M. J. Ings, in Medicinal Chemistry: Principles and Practice. F. D. King (ed), Cambridge: Royal Society of Chemistry, pp 67-85, 1994.

7. C. W. Vose, in Medicinal Chemistry: Principles and Practice. F. D. King (ed), Cambridge: Royal Society of Chemistry, pp 86-97, 1994.

8. T. Kennedy, Drug Discov. Today, 2, 436-444, 1997.

9. D. F. McGinnity, K. Grime and P. J. H. Webborn, The Handbook of Medicinal Chemistry: Principles and Practice, A. Davies and S. E. Ward (eds), Royal Society of Chemistry, Cambridge pp 208-238, 2015.

10. J. B. Houston, Biochem. Pharmacol.47, (9), 1469-1479, 1994.

11. H. Boxenbaum, J. Pharmacokin. Biopharm., 10, 201-207, 1982.

12. X. D. Liu and J. Chen, Europ. J. Drug Metab. Pharmacokin., 26, (4), 249-256, 2001.

13. R. M. J. Ings and C. W. Vose, Pharmac. Physician, 25, (4), 14-18, 2015.

14. R. M. J. Ings and C. W. Vose, Pharmac. Physician, 26, (3), 23-29, 2015.

15. R. M. J. Ings and C. W. Vose, Drug Metabolism pp 197-200, in The Handbook of Medicinal Chemistry: Principles and Practice. A. Davis and S. E. Ward (eds).

January 2016 12 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN CARDIFF UNIVERSITY/BRAPP POSTGRADUATE COURSE IN PHARMACEUTICAL MEDICINE An interactive, modular course providing broad knowledge-based learning across the specialty of pharmaceutical medicine; run by BrAPP working closely with Cardiff University.

Modules are mapped to the syllabus for the UK Diploma in Pharmaceutical Medicine exam. Ten two-day, non-residential modules run in central London from January 2016 to July 2017. (The exception is Module 1 which is held at Cardiff University.) Expert teaching is provided by a wide spectrum of industry and academic experts and includes an Integral Revision module and a Critical Appraisal workshop run by Dr Gurpal Gosall. Places are limited to 25 delegates.

For further information and to register please contact: [email protected] or visit www.brapp.org or call +44 (0) 118 934 1943 MHRA CASE STUDY:

MSD successfully put their advanced new melanoma treatment through MHRA’s early access to medicine scheme (EAMS).

From: MHRA December 2015

THE CHALLENGE treatment for advanced melanoma. SPEEDING UP PATIENT access to new, These exciting results helped to confirm promising, innovative treatments is a that pembrolizumab could address an current priority for the UK government, unmet medical need. regulatory agencies and the pharmaceutical industry. However, patients who required the treatment would need access to MHRA’s early access to medicines pembrolizumab in the intervening time scheme (EAMS) aims to offer patients between clinical trials completing, when with life-threatening or seriously the treatment meets with regulatory debilitating conditions access to approval and is licensed, and when the medicines that do not yet have a treatment is finally available for routine marketing authorisation when there is a use – a process that can often take clear unmet medical need. several months and that can affect seriously-ill patients who cannot afford MSD (known as Merck & Co Inc. in the the time to wait for treatment. United States and Canada), works to address unmet health needs through the In October 2014, MSD requested that development of innovative medicines, MHRA consider accepting vaccines, biological therapies and pembrolizumab into EAMS and worked animal health products. Pembrolizumab with a series of co-ordinated was being developed as a treatment for stakeholders to progress their treatment advanced melanoma (skin cancer), through the scheme, including: MHRA, where MSD had identified an unmet National Institute for Health and Care clinical need. Excellence (NICE), NHS in England, Northern Ireland, Scotland and Wales. Through EAMS, MHRA has been able to work with MSD to ensure that UK HOW MHRA HELPED patients with advanced melanoma have MSD was clear about the intrinsic been among the first in the world to benefits EAMS offered. However, as the access the breakthrough treatment, first medicine through the 2-step pembrolizumab. This has enabled process, there were a number of approximately 500 patients with practical issues that required interaction advanced melanoma with limited between MHRA and MSD to ensure that treatment options to benefit from the the review was concluded within the treatment prior to licence and paved the expected timeframe. These included: way for accelerated routine access in the NHS. • reviewing pembrolizumab against EAMS criteria to ensure it was a In June 2014, phase 1 clinical trial data suitable and acceptable candidate at published by the American Society of the face-to-face pre-submission Clinical Oncology (ASCO) pointed to meeting the significant health improvements exhibited by patients who had been • condensing the timelines around 14 provided with pembrolizumab as awarding the promising innovative January 2016 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN MHRA CASE STUDY:

MSD successfully put their advanced new melanoma MHRA’S EARLY ACCESS TO MEDICINES SCHEME AIMS TO OFFER treatment through MHRA’s early PATIENTS WITH LIFE-THREATENING OR SERIOUSLY DEBILITATING CONDITIONS ACCESS TO MEDICINES THAT DO NOT YET HAVE A MARKETING AUTHORISATION access to medicine scheme (EAMS). WHEN THERE IS A CLEAR UNMET MEDICAL NEED.

medicine (PIM) designation and the participating in and helping to develop assessment of the scientific opinion EAMS, and in being awarded the first step, which helped to reduce the positive opinion. overall duration of the process and ensure the right resources were THE OUTCOME allocated at the right time EAMS has enabled approximately 500 advanced-melanoma patients in the UK • offering availability for regular to be among the first in the world to interactions with the EAMS assessment benefit from access to pembrolizumab pembrolizumab in treating team, to help with data reviews, ahead of a European licence, indicating unresectable, metastatic melanoma speeding up analysis and the value of fast-tracking innovative after progression with ipilimumab interpretation medicines so that they reach patients with high unmet medical need more • 7 September 2015 – NICE final • agreeing to be flexible and accept quickly. appraisal determination (FAD) summaries of data that MSD was guidance recommended at the already preparing for their licence Submission through EAMS accelerated shortened 30 day implementation, application dossier, rather than re- patient access to the treatment by down from the standard 90 days writing and submitting specifically for around 4 months. Early engagement of EAMS, helping to reduce the burden stakeholders through the scheme Pembrolizumab was the first medicine of the submission secured priority scheduling from NICE to be awarded an EAMS positive for review. Important milestone dates scientific opinion by MHRA. The • clarifying pharmacovigilance criteria include: application procedure with MSD helped and future regulatory requirements. to identify and resolve some practical • 10 October 2014: PIM designation issues including data content, Ben Lucas, Business Unit Director, awarded appropriate labelling, optimising Oncology, MSD said: timelines, clarification of • 9 March 2015: MHRA issued Scientific pharmacovigilance requirements and EAMS undoubtedly accelerated access to Opinion for pembrolizumab through appropriate monitoring and risk pembrolizumab for patients with EAMS management. advanced melanoma and demonstrates a world-leading example of how • 17 July 2015: European Commission Learning these lessons has helped to healthcare agencies and industry can (EC) granted an EU licence for refine EAMS and to demonstrate that the work together to get treatments to pembrolizumab which marked the scheme offers a genuinely accelerated patients more quickly. trigger for the closing of EAMS to new process for patients in the UK to access patients - existing EAMS patients new medicines that work to satisfy We’re proud of what we achieved: early continued to gain access to the unmet medical need, as well as showing patient access to our breakthrough medicine until routine reimbursement that UK health agencies can offer a very treatment, as well as extensive streamlined process that supports early collaboration with MHRA, NICE and • 29 July 2015 - first NICE appraisal access to critical treatments. NHS England, and industry firsts – in committee meeting for

January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 15 Continues from page 15 MHRA CASE STUDY: Dr Siu Ping Lam, Director of Licensing, EAMS aims to give patients with life MHRA said: threatening or seriously debilitating MSD successfully put their conditions access to medicines that do EAMS is an important step in ensuring not yet have a marketing authorisation advanced new melanoma patients gain access to innovative when there is a clear unmet medical treatment through MHRA’s early medicines as soon as possible, need. Visit EAMS to find out more and access to medicine scheme (EAMS). improving health outcomes in patients how to submit your medicine. that urgently need new treatments. MSD’s decision to submit pembrolizumab meant that we awarded our first positive opinion ahead of a licensing decision, thoroughly tested EAMS’ principles and processes, and learned much along the way.

HOW CAN WE HELP YOU Contact the Innovation Office to find out more about accessing expert knowledge, guidance and experience that could help you develop ideas and save time and money #HealthInnovation

Boehringer Ingelheim ranks amongst the world’s top 20 leading pharmaceutical corporations. With nearly 41,000 employees in 47 countries we are a global team sharing knowledge and ambition to foster a healthier life. In the UK and Ireland together we are creating excellence, living our principles of pride, valuing people and trust and we are proud to have been placed in the Sunday Times 100 Best Companies to Work for Survey 2014 and to have been listed by Pharma Field as an Employer of Choice 6 years in a row.

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January 2016 16 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN PEOPLE

Dr Mark Edwards implement projects which will create Many of you know Dr Mark Edwards in new cross- sector opportunities in his ongoing capacity as the Ethical biomedical research. Medicines Industry Group (EMIG) R&D Director. GMEC wishes to announce that, after six years in the role, Dr Jim Hagan is The Global Medical Excellence Cluster stepping down as CEO of GMEC to (GMEC) is a not-for-profit company pursue other interests and will be formed by its founder universities to replaced by Dr Mark Edwards, who has develop a framework within which been appointed Interim Executive universities, commercial organisations Director. Reflecting on his time as the and National Health Service Trusts can founding CEO, Jim commented “The life collaborate to accelerate progress in sciences are critically important to the Translational Medicine, bolster the UK’s health of the nation and the economy globally competitive position in and it has been a privilege to work with biomedical research, attract inward the shareholder Universities of GMEC investment and improve patient on initiatives which delivered real value outcomes. in both domains. Our work in helping to establish Imanova and the GMEC- Founded by five of the world’s top Pfizer Rare Disease consortium shows universities, Cambridge University, what can be achieved when these great Imperial College London, King’s College Universities work together. I’m London, Oxford University and extremely grateful to the GMEC Board University College London the company for their support and to have had the was joined by Queen Mary University of opportunity to work with so many London in 2012. outstanding people during my time at GMEC. I wish Mark every success in GMEC is open for proposals from taking the company forward.” healthcare companies to devise and On behalf of all the GMEC members, the Board expressed sincere thanks and appreciation to Jim for all his efforts and commitment and welcomed Mark to the Leadership team.

Dr Mark Edwards 17 January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 MEETING REPORT: 8th BrAPP Education Day, 26 November 2015

Report by Liz Langley

IN 2008, THE then BrAPP committee sat expert on sarcoma, who had met Anne down to discuss our meetings on a number of occasions at the Royal programme in the light of anticipated Marsden agreed to give the inaugural revalidation and the CPD imperative. It lecture. resolved that those “in” education ie HMT (as was) were well served but the Members and colleagues gathered at a remaining majority and perhaps new location for the meeting. Not our independent physicians in particular usual college environment but perhaps might find it difficult and expensive to one better suited to the fast moving and maintain their training portfolios. innovative industry and one that BrAPP is using to deliver the London modules Training, education and development of the PostGraduate Course in are the main platforms for BrAPP’s Pharmaceutical Medicine. activities and the committee felt it was important to develop an annual one- Prof Ian Judson rather provocatively day, cost-effective “Hot Topic” meeting entitled his lecture “Molecularly which would be attractive to busy targeted therapy for sarcoma – has it physicians. And so the BrAPP Education fulfilled its promise? His subtitle was Day was born. One of the leading “is there a magic bullet?” and the brief exponents of the event was a then very answer to that is “no”. Sarcomas are new pharmaceutical physician called rare malignancies of connective and Anne Appleton. other non-epithelial tissue and their chief characteristic is heterogeneity. It is therefore fitting, if very sad, that the Their aetiology remains largely obscure 8th Education Day should see the and, although some risk factors have delivery of the first Anne Appleton been described and are largely Lecture following her sad death in April associated with mutation of DNA, only 2015. Professor Ian Judson, a global 3 out of 500 mutations identified can be

18 Prof Ian Judson January 2016 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN said to be actionable. In other words the patients may assist the cause of majority, as yet, seem not to be useful availability. MEETING REPORT: for targeting purposes. 8th BrAPP Education Day, Patient care and well-being was stressed Imatinib is known to highly effective in throughout. Prof Judson’s frustration 26 November 2015 advanced GIST (gastrointestinal stromal that the development of scientific tumour) and mean survival rates have theory, followed by identification of been extended to 6 years. This specific changes at molecular level and compares extremely favourably with then the much needed proof-of-concept the previously used and essentially are parts of such a long process often ineffective doxorubicin therapy. The without a positive result was plain to newer therapies also have patient hear. He cited an example of the time benefits too because shrinkage of lag in the case of translocation driven tumour often occurs very quickly thus sarcomas. These were first identified in improving comfort and well-being. The 1987. In 1995 researchers revealed that latest molecule, regorafenib is proving they had something to do with useful as a 3rd line rescue therapy transcription of cellular DNA. It was not extending relapse-free survival (RFS) until 2013 that the process could be rates in advanced patients from less properly described. In that period of than one month to 5 months. Used as time useful agents can come and go. In adjuvant therapy, Prof Judson stated the case of Ewing’s Sarcoma, another that there is a survival advantage of up rare bone condition which affects to three years compared to one year children and adolescents, IGF-1R has more impenetrable. The relatively small on single therapy regimens. He been found to deliver amazing (Prof numbers of patients affected by sarcoma suggested this is a REAL advantage and Judson’s word) results – albeit short- and the heterogeneity of the conditions this is reflected by NICE approval. lived. When used with linsitinib early are currently commercially unattractive. Regorafenib currently remains available studies looked good – until the IGF-1R But this does not quench his desire to via the Cancer Drug Fund but its future ran out. When IGF-1R was shown to be find answers for his patients. Prof is questionable. What concerns ineffective against lung or colorectal Judson does feel that we may be on the researchers is the regulatory authority cancer, pharmaceutical development cusp of new understanding as “obsession” with median survival rates ceased and experimental supplies soon translocation increasingly appears to be and the apparent desire of the industry ran out. Prof Judson believes that if a primary aetiology of many sarcomas. only to develop “blockbuster” only there had been time to understand His clarion cries were for a) more medicines. Judson says that it must be how IGF-1R worked in Ewing’s Sarcoma biochemists to work deep within the accepted that patients will die and so it could have been a life-saving drug. Kreb’s cycle and other loci which might clinicians must have the ability to affect chromatin regulation, b) pharma select which patients, to their For many of us the humanity and of whatever size to engage to supply knowledge, are likely to do best on humility of the presenter shone through medicines whether or not they will such regimes. Selection of suitable especially as the biochemistry became ultimately be profitable and c) clinicians to listen to their patients.

After a reflective break, David Watson, ABPI Director of Pricing and Reimbursement brought us back to the hard reality of money. His presentation title, Value, Access and Reimbursement, has been a recurring one for BrAPP Education Day. David gave us a useful overview of the current NHS structure remarking that whilst our global pharma colleagues may be under the misapprehension that there is one system in play the reality is far more David Watson complex than that! For example, there are between six and ten thousand

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people employed by NHS England consultation is currently underway. The MEETING REPORT: alone (85% of the system) involved CDF is generally regarded as a political 8th BrAPP Education Day, directly in Medicines Review. sticking plaster and industry’s view is Centralised it is not. that it probably should not be necessary. 26 November 2015 In November 2014, the Government’s David would contend that most of Office for Life Sciences announced the industry’s customers in the UK do not Accelerated Access Review (AAR) understand pricing. They tend to initiative to recommend how to get believe that medicines come to market innovative medicines and technologies with the highest price and will, when to patients as quickly as possible. An pressed, be negotiated downwards. interim review was published in Perhaps not the best position for October 2015 but it did not define the collective and cooperative working pathway for access to new products nor between supplier, assessor, is it yet clear how “transformative commissioner, prescriber and end-user. medicines” will be paid for. It is David then reminded us of the current anticipated that the mandate of NICE PPRS mechanism. The 2014 PPRS which will be revised sometime in 2016 on the runs until 2019 is very different to back of the AAR. This will perhaps lead previous schemes. One of the drivers to a conditional approval system in ahead of negotiation was a desired which assessment of cost will play an double-digit cut in prices by the increased role. Government. The outturn allowed free pricing at launch, no price cuts, a Patient access to new medicines is the growth in the medicines bill (with political imperative but currently it is felt exclusions) underwritten by industry at that very few new introductions will get agreed rates. It also agreed the immediate (list price) funding and maintenance of the status quo re NICE. companies will have to develop creative NICE would not determine price or and transparent arrangements with the lower thresholds for use. The money NHS to enable usage. The published “going back” to the Government, findings of the Cancer Drugs Fund however, does not appear to be (CDF) Consultation highlighted the need improving access or uptake and to review access and funding right industry is now seeking to improve the across the board. (reference: Operations system. of the CDF 2014/15 Consultation Report. NHS England. November 2014). There David responded to a number of was some dissonance between industry questions or comments from the floor. responders and other participants in the Whilst he hoped that the AAR would published consultation. The 2015/16 produce useful outcomes he cautioned

Dr Paul Robinson

January 2016 20 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN that truly centralised decision-making the Code. Over a period of time the might risk a reduction in ABPI Code is also being brought into MEETING REPORT: competitiveness and the effective line with the EFPIA Codes as well as UK 8th BrAPP Education Day, locking-out of any second-to-market law, MHRA Blue Guide, plus other medicines. regulations. The change to single 26 November 2015 signatory in the forthcoming edition is a Dr Paul Robinson’s presentation was case in point. Certification will not be entitled “When all else fails …. go ask required for Joint Working agreements the patient!” His slides presented a nor for contracts with patient number of case studies in which the organisations. Clause 26.5 (Relations patient-viewpoint, collected in detail and with the Public) is deleted from the early in development, may have 2016 Code and all representatives influenced the decision-making process employed after October 2014 must now for the benefit of all parties. These sit an accredited examination. included the impracticability of inhaled Disclosures and transfer of value with insulin in everyday usage, the regard to Health Professionals and preparedness of patients to understand Healthcare Organisations are also and accept risk when a medication procedurally tightened with defined solves a condition which severely reporting times. Companies are also impairs normal daily activity, and the required to publish a summary of the acceptance by patients of relatively methodologies used to prepare small but sustained weight loss via use disclosures. In a candid moment, of an implantable device despite a Heather revealed that the disclosure possible higher risk profile for the data goes live on the central platform by implant. The first was licensed after 10 1 July, she believes the early summer Bina Rawal is also a regular delegate years development with huge industry 2016 is going to be very busy at the and speaker at Education Day and this expectations but voluntarily withdrawn PMCPA. year came to follow up on one of her after 9 months, the second was initially particular spheres of interest – the EMA withdrawn but later reapproved after We took a little time to review some and Clinical Trial Transparency. It patient feedback and demand and the published cases from 2015 to usefully seems a long time since Ben Goldacre third was approved following an FDA- illustrate current issues and finally published Bad Pharma: How Drug sponsored survey of patient preferences. Heather reviewed a number of the other Companies Mislead Doctors and Harm And it is not only the FDA taking an activities of the PMCPA. She highlighted Patients. In fact it is little more than 3 interest in patient opinion. The EMA Advisory Boards and the UK Sunshine years ago. The new EU Clinical Trials published a document called “Working Rule which comes into force in 2016 Regulation (EUCTR) was published on with patients and consumers” in 2015. and further seeks to increase 27 May 2014 and it seeks to streamline Paul’s point to his fellow industry transparency amongst HCPs in relation processes via the new EU portal and EU professionals was that we should not to their industry interactions. database including increased get left behind. He showed the audience transparency on clinical trials and their a 2-minute video from Patient Research outcomes. The development of the Exchange which illustrates that thinking portal and database have proved https://vimeo.com/128992520 challenging. The most recent meeting of the EMA Management Board in October In keeping with the original idea of 2015 reported that, following significant Education Day, we welcome some on- trials and subject to successful going presentations and that from the independent audit at the end of the PMCPA is one of those. This year, third quarter of 2016, it expects the Heather Simmonds who stepped into Regulation to come into application by the breach to present 2016 Code of the end of 2017. From that point Practice. Heather talked about the work onwards sponsors and Members States of the Review Group and reminded us will use it for all new clinical trial that an assessment of the clauses to applications in the EU and the retain was also accompanied by a information from the database will be process to simplify and delete content publicly available. where this improves the functionality of Heather Simmonds

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 21 Continues from page 21

Meanwhile EudraCT – the database for Phase 2 of the data release will seek to MEETING REPORT: all clinical trials commenced in the EU publish anonymised individual patient 8th BrAPP Education Day, from 1 May 2004 – is enshrined in data but this phase is currently delayed legislation and continues to report on a and the details of the process are yet 26 November 2015 monthly basis. Provision of results to be fully fleshed out. Sponsors became mandatory from 21 July 2014. should note that the default position of Studies which ended prior to July 2013 the EMA is that nothing is confidential must be entered by July 2016. The or commercially sensitive so any posting date is considered to be the redactions need to be legitimate. compliance date and three months after Access to the data is stratified and it is the anticipated due date studies with given that users must not use overdue reporting will be publically information for unfair commercial highlighted. Each version of the data reasons or to identify entry will be stored and new postings patients/individuals. A level 1 of will NOT result in deletion of the access, members of the public having previous versions. Adult Phase 1 made a suitable declaration obtain a studies, not part of a PIP, do not have user ID and password. They will then to be made public retrospectively. be able to see CSRs in a searchable Looking forwards all summary results view-only mode. At level 2 of access, must be published within one year of bona fide academic researchers provide completion (6 months for paediatric more detailed information about studies). A lay summary is required for themselves which if approved will all studies and all must be submitted allow CSRs to be downloaded, saved regardless of outcome, including and printed. Using ICH E3 format for terminated studies. Deferral of CSRs it will be important for sponsors publication of trial information may be who wish to redact to be very clear requested until 12 months after the end that their requirements meet the of trial but it must published along with expectations of the EMA. the summary of results. Deferral must be justified on the grounds of serious Sounding similar in process to drug commercial risk etc. Redacted clinical safety/pharmacovigilance reporting study reports (CSRs) must be published timelines or the ticking clock of 30 days after marketing authorisation regulatory approval, sponsors have approval (MAA). another set of critical mileposts to satisfactorily negotiate before a new It is anticipated that first sets of CSRs drug can successfully come to market in will be published in 2016 – all the EU. redactions must be approved by EMA. Sarah Eglington, Healthcare Intelligence Director at Binley’s Wilmington Insight, and her team have recently conducted a research project entitled “What healthcare professionals think of the UK pharma industry”. Market research is not an area that pharmaceutical physicians and other industry professionals feel very comfortable with. Validity and relevance are always important. Market research can give direction to further customer relationship building. Based on 2000 responses and conducted independently, the report has some useful insights into opinions in the Bina Rawal marketplace.

January 2016 22 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN GPs said they were generally under Essentially, Sarah, suggested there were pressure (although they still participated four main areas of focus for industry; MEETING REPORT: in the study) with 40% of respondents 8th BrAPP Education Day, claiming that the pharma industry as a • Partnerships not products whole was poor at understanding the 26 November 2015 challenges they faced. 74% of • Educational support and delivery responders claimed never to visit company website and 83% never used • Sponsored learning and meetings apps of any kind with their patients. Overwhelmingly (84%) they thought • Mutual respect and understanding of their biggest challenge was rising each other’s aims and objectives in patient expectations. 66% of responders the transaction claimed not see representatives. The research data suggests there is an Their practice managers felt the opportunity for industry not only to get pressure of patient expectations too better but to be perceived as better – (87%) and also thought that industry surely a goal to strive for. Binley’s report could help more through funding of will be published soon and repeated in specific personnel (medicines years to come. management facilitator) but more broadly through training for practice The final session of the day was staff. The practice nurses, on the other delivered by Ralph Carter of hand, were more forthcoming and PharmaReview. Just how much time considered themselves in need of does industry and the Med Affairs Team training and prescribing information particularly spend on reviewing copy? compared with less than 40% for brand created specifically for their use. This In a nutshell the answer was too much. managers. The impact of reworking kind of support requirement was Entitled “Copy Review: An industry copy creates friction, leads to late echoed by the NHS manager cohort within the industry”, Ralph reported working, missed deadlines and cost who felt that industry could provide on his benchmarking studies with over-runs. It does not build good and sponsored nurses (not a new idea), clients in 2014. Surprisingly highly rewarding interdisciplinary working general training for HCPs and reduced qualified and well-paid professionals relationships. prices for medicines. This group (physicians and pharmacists) in Medical identified limited resources as their Affairs are spending around 45% of One of the saddest aspects of this biggest daily challenge (75%). Hospital their time working on copy. Brand presentation was that despite all the doctors were apparently more receptive managers claim only to be spending advances of Zinc etc little has changed to the efforts of industry with 40% 25% of their time. The same Medical since to days of the lowly manila folder saying industry understood their Affairs people say that just under 50% which was hawked physically around problems but within a portmanteau of of the jobbags “go round again” the various collaborating departments concerns (75%) felt tired of the NHS of the company. Too much expensive being used a political football, wanted executive time is wasted providing new drugs to be added to formularies opinion but not taking responsibility. and wanted more training and Involving a sensible (small) number of opportunity to attend courses. Specialist opinion formers and decision makers nurses felt industry had a role in early on does not appear to happen providing patient information but also and the world and his wife like to have this group thought it could do better in a dabble. The agency may go off on understanding how patients feel about frolics of their own rather receiving a drugs. Pharmacists broke naturally into definitive brief which is accompanied retail (not participating in numbers in by all the supporting material – this survey and saying they need messages are surely generated from the incentives to see pharma reps) and evidence so why not provide the hospital (wanting sponsored education evidence upfront. form industry with 47% of responders believing that industry understand Ralph was keen to advocate smaller secondary care well). Ralph Carter numbers of decision makers who take

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January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 23 Continues from page 23

absolute responsibility for each job. This • Hold planning meetings for big items MEETING REPORT: might mean it will go wrong on occasion and major campaigns 8th BrAPP Education Day, but if the person who owns the job is forced to decide, definitively, on each • Reduce the number of reviewers 26 November 2015 comment the debate and the opportunity to “go round again” should fall away. • Define reviewer roles The right person does need to be in the right role so once again this puts • Close the feedback loop before it pressure on up front. And they need to goes back to the agency be trained. Ralph offered the audience a top seven take home proposals: How simple it sounds and how long has the industry been striving to get this • Ensure quality is high before the job right. New Year’s resolution – let’s all enters the system try harder and smarter.

• Work closely with the agencies and A great day, enjoyed by all. Thank you agree service levels to our speakers and see you all next year. • Work on consistency of review criteria and standards

Reach your target market

PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley or Karen Young [email protected] 0118 934 1943

Advertise here or on the BrAPP website.

January 2016 24 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN PROFESSIONAL DEVELOPMENT: Benefits of being a medical assessor at MHRA

From the MHRA

MHRA HAS LAUNCHED campaign to See what other medical assessors have show people what's involved in the to say about the role and find out about medical assessor role, including the benefits of working for MHRA and experiences from current assessors. see available vacancies visit https://mhramedicalassessors.pgtb.me/86f In November 2015, the MHRA launched lvg for more information. a campaign highlighting what medical assessors do and the difference they As the medicines regulator, MHRA offers make to public health. The campaign a unique experience in the UK and aims to attract people with a medical assessors gain an early insight into background considering a career move. medical research, new medicines and new uses for existing medicines. Medical assessors play a key role in medicines licensing and post marketing The agency also offers employees surveillance ensuring medicines are as training opportunities to excel in their safe as possible for patients and deliver role - for example some medical their intended benefits. assessors are now members of the Faculty of Pharmaceutical Medicine. As Staff at MHRA say that variety is one of a medical assessor you are helping to the main positives of the role. Kirsty shape the industry from the inside out. Wydenbach, Medical Assessor, said:

“The timelines we work to are very short in the clinical trials unit, but this means no 2 days are the same: one day it’s a trial for a new cancer agent, the next it’s the latest gene therapy product.”

The roles the MHRA offer can involve all aspects of the regulatory process, including making decisions and advising industry.

Another medical assessor Dr Dervla Quinn was previously a GP trainee and clinical pharmacology physician. She says the diversity of work includes “reviewing both potential and confirmed drug safety issues, preparing reports based on safety issues, presenting at UK expert committees, collaborating with colleagues from other European regulatory agencies…” 23 January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4 BOOK REVIEW

VIE D’OR: MEMOIRS OF A career and an enjoyable retirement PHARMACEUTICAL PHYSICIAN. could safely allow some of the less David R Glover enjoyable aspects of corporate life. Matador 2015 ISBN 978 1784623 111 Surviving these and making one’s mark Kindle version (£9.99). are attributes of great benefit to all aspiring pharmaceutical physicians and Pharmaceutical industry memoirs are David gives the reader the chance to like buses, you don’t see any for ages see how he steered his career towards and then suddenly two come along good outcomes. He looks back and together. In the last issue of PP, Ron remarks in hindsight that a different Stark’s entertaining and insightful dosing regimen might have seen a drug volume From Farms to Pharma was be more successful in development reviewed and now is the turn of David phase and on the other hand how the Glover’s tantalisingly titled book, Vie cut and thrust of venture capital world d’Or. Before venturing forth, I should and floating on the stock market add say that the reviewer was privileged to extra flavour and excitement to an work with both authors already hugely varied whilst they were imparting medical career. the benefit of their experiences to new recruits Vie d’Or is a very personal to pharmaceutical medicine. memoir and offers us an They are tremendous insight into the minutiae of communicators and first- life in industry too. It is class exponents of our none the worse for that. relatively young specialty. From a traumatic bout of These books are good food poisoning at the end reads. of an international meeting held in the UK on the one In reflective mood towards hand, nearly meeting his the end of his memoir, maker in a taxi in Seattle David, offers us some thoughts on just and the degree of disgruntlement how golden his life in medicine and in amongst non-invitees to an award particular the twenty years of full time ceremony on the other; these are the employment within the pharmaceutical joys. David has had the resilience to industry actually was. Like us all he can grow his career, makes friends along clearly identify the many highlights, the way and not to be bruised by any launching new useful medicines, misplaced slings or arrows. learning new science as biotechnology takes hold, building teams that really The text is peppered with entertaining work together and for the common pictures and cartoons much as were good and on acquiring and developing David’s training presentations. Running a unique skills set which brought has always been an important part of fulfilment, frustration and ultimately a his life and I am sure the delegates at little fame. He also recounts with a one particular BrAPP Survival Guide will 24 degree of candour that only a successful recall an early evening workshop January 2016 volume 26 | No 4 PHARMACEUTICAL PHYSICIAN session conducted in Lycra! He was never boring and Vie d’Or makes that very clear. Joining MSD in 1984, David argues that he may have enjoyed the heyday of the blossoming industry but BOOK REVIEW for those us who remain and those of you to come it behoves us to keep the banner flying. This book may help you reflect on ways to do that. There is no spoiler in this review – you need to read the book to discover from what its title is actually derived. A clue – we wouldn’t get away with now! Mrs E Langley

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By Hugh Gibbons

FIFTY YEARS AGO this very month, I met Just a leg sprain, since you ask. And my first pharmaceutical physician - when I PTSD. joined Riker Laboratories (a precursor of today’s 3M Healthcare) in Loughborough. Unlike socks or bells or sofas, pharma products are rarely seen by their office Eric was typical of the many affable staff. But one day I found a cache of members of medical departments I small packs hidden behind a radiator, REFERENCES, FURTHER INFORMATION encountered over the next three decades presumably stored for some private AND SOME GOOD-HUMOURED or so. Offset by a few banana-heads. enterprise marketing. They were GP GOODIES ARE AT HUGH’S SPECIAL samples of, ahem, Durophet-M - the phet I’d spent two years as an advertising writer reflecting the main ingredient. Fetching a WEBSITE FOR PP READERS, at Notleys, a leading London agency pound a capsule down the pub, Eric COLLEAGUES, COUNTERPARTS AND famous for its creativity and poets on the said... ACQUAINTANCES. payroll; in an office shared with two designers, the novelist William Trevor, and The world of office work had a few WWW.JUST1.ORG.UK/PPHUNNYBONUS an executive’s usually continent corgi, significant differences from now. Most parked for the day under our desks. As noticeable, no keyboard or screen on your the only job applicant turning up with a desk. For document production, many pen, at Riker I was a shoe-in for Chief executives shared an Audiotyping Pool. Copywriter in Marketing. You dictated thoughts into a tape recorder and took the cassette along to Edith, in My new office home appealed. Allegedly charge of the team of typists (some of a former sock factory, it had wavy whom doubled up as babysitters). She’d wooden floors where machines had sometimes have to remind you to ask for Hugh Gibbons clacked energetically for decades. From 3 carbon copies at the beginning of the the big windows there was the Grand tape rather than the end, please. But Junction canal and coal-dust-spiked dictating gave you the long-lost benefit of sunsets over Charnwood Forest on one hearing the words, and speaking short side, and a vista towards rural sentences, and organising thoughts before Leicestershire on the other. On Streetview committing them to cassette and paper. it still looks a cheerfully characterful head And it lent you a crucial second mind, that office. of someone with secretarial training prepared to say Did You Really Mean I found it a warm-hearted workplace, That? where people made time to talk face-to- face and share their family and local When us male executives volunteered for community lives beyond the office. They some in-house clinical research for Eric, were proud that Loughborough is the we had to carry our urine samples past home of Taylor’s, the world’s biggest bell the Pool, while the audiotypists laughed foundry, whose work you can hear in the their headphones off. But it proved that a town’s carillon and St Paul’s Cathedral. pharmaceutical physician could organise a And in Clemerson’s furniture department piss up in a sock factory. Nick Alkemade was to be found, famous for falling 18000 feet without his RAF (Having waited 50 years for the chance to parachute on to a snow-covered forest. write that, for me it’s Mission Complete). 29 January 2016 PHARMACEUTICAL PHYSICIAN volume 26 | No 4