ne
`
`ron
`
`Clinical
`Practice
`
`Minireview
`
`Nephron Clin Pract 2009;113:c125-c131
`DOI: 10.1159/000232592
`
`Published online: August 12, 2009
`
`Drug Development: From Concept to
`Marketing!
`
`Nihad A.M. Tamimi Peter Ellis
`
`Pfizer Inc., Sandwich, UK
`
`-
`
`Key Words
`Drug discovery • Clinical trials • Drug approval • Drug safety
`
`Abstract
`Drug development is an expensive, long and high-risk busi(cid:173)
`ness taking 10- 15 years and is associated with a high attri(cid:173)
`tion rate. It is driven by medical need, disease prevalence
`and the likelihood of success. Drug candidate selection is an
`iterative process between chemistry and biology, refining
`the molecular properties until a compound suitable for ad(cid:173)
`vancing to man is found. Typically, about one in a thousand
`synthesised compounds is ever selected for progression to
`the clinic. Prior to administration to humans, the pharmacol(cid:173)
`ogy and biochemistry of the drug is established using an
`extensive range of in vitro and in vivo test procedures. It is
`also a regulatory requirement that the drug is administered
`to animals to assess its safety. Later-stage animal testing is
`also required to assess carcinogenicity and effects on the
`reproductive system. Clinical phases of drug development
`include phase I in healthy volunteers to -assess primarily
`pharmacokinetics, safety and toleration, phase II in a cohort
`of patients with the target disease to establish efficacy and
`dose-response relationship and large-scale phase Ill studies
`to confirm safety and efficacy. Experience tells us that ap(cid:173)
`proximately only 1 in 10 drugs that start the clinical phase
`will make it to the market. Each drug must demonstrate safe-
`
`ty and efficacy in the intended patient population and its
`benefits must outweigh its risks before it will be approved
`by the regul,itory agencies. Strict regulatory standards gov(cid:173)
`ern the conduct of pre-clinical and clinical trials as well as the
`manufacturing of pharmaceutical products. The assessment
`of the new medicinal product's safety continues beyond the
`initial drug approval through post-marketing monitoring of
`adverse events.
`Copyright ~ 2009 s. Karger AG, Basel
`
`Introduction
`
`Getting drugs to the market is an expensive and high(cid:173)
`risk business which takes on average 10- 15 years to com(cid:173)
`plete. The Tufts Center for the Study of Drug Develop(cid:173)
`ment announced in November 2001 that the average cost
`to develop a new prescription drug was USD 802 million
`[l]. When the costs of failed prospective drugs are factored
`in, the actual cost for discovering, developing and launch(cid:173)
`ing a single new drug would have exceeded 1.5 billion .
`This compares with USD 4 million in 1962 and USD 231
`million in 1987 [2, 3]. The problem is compounded by the
`high attrition rate, as it is estimated that approximately
`only 1 in 10 drugs that enter clinical trials will make it to
`the market. In a recent study, it was shown that the aver(cid:173)
`age success rate for drugs to be approved for all therapeu-
`
`KARGER
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`1660-2110/09/1 133-0125S26.00/I)
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`Acces~ible onlin4l .1.t:
`www.k.3rger.com}nt!c
`
`Pfi:r.cr Laboratories(cid:173)
`Ramsgat"e Road
`So11<lwith CTl3 9N) (UK)
`Tel. +11-1 1304 611 l 627, 1-~x. +Jl •I l J01t 652 (;29
`E-Mail lomimis@gmail.com
`
`MPI EXHIBIT 1047 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0001
`
`

`

`;------....---,...----..------------
`' : Discovery
`Phase Ill
`I ________ c;__.....,,.~ _ _ ...c;. _ _ _ _ ..c.. _ _ _ _ _ _ _
`
`Fig. 1. Phases of drug development.
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`Hypertension
`Hyperlipidaemia
`Arthritis
`
`Asthma
`Psychotic disorders
`Type II diabetes mellitus
`
`Gastro-oesophageal reflux
`disease
`
`Epilepsy
`Type I diabetes mellitus
`
`Genetic storage diseases
`
`Inflammatory bowel
`disease
`Irritable bowel syndrome
`
`Chronic kidney disease
`Obesity
`Malignancy
`Stroke
`
`Heart failure
`Liver cirrhosis
`Chronic obstructive
`pulmonary disease
`AIDS
`
`Cystic fibrosis
`Multiple sclerosis
`Septic shock
`Transplant rejection
`
`Fig. 2. Drivers for discovering new drugs
`with examples.
`
`Low
`
`Medium
`
`Medical need
`
`High
`
`tic areas is approximately 11 %. The success rate varies be(cid:173)
`tween therapeutic areas ranging from 20% for cardiovas(cid:173)
`cular drugs to only 5-8% for oncology and central nervous
`system disorder drugs [4]. Improvements in predicting
`the potential success or failure of a product in clinical tri(cid:173)
`als is essential to aid in reducing the spiralling devel(cid:173)
`opment costs. Unfortunately, increasing costs combined
`with the high attrition rate are forcing pharmaceutical
`companies to reduce investment in research and develop(cid:173)
`ment, focussing on a more limited product portfolio.
`Drug development is a significant challenge. Every
`product must not only be safe and efficacious, but its ef(cid:173)
`ficacy has also to be proven across racial and ethnic
`groups as well as across different age groups. Every drug
`has to pass a global regulatory review in what is current(cid:173)
`ly the most regulated industry in the world. Once this is
`done, approved products must appeal to global markets
`across different cultures, healthcare systems and distri(cid:173)
`bution systems.
`It is interesting to note that in a recent survey, the pub(cid:173)
`lic perception was that the pharmaceutical industry dis-
`
`covers only 27% of new drugs whilst the reality is that
`more than 90% of all new drugs are discovered by the in(cid:173)
`dustry [5].
`This minireview will address the process of drug de(cid:173)
`velopment from discovery through the stages of develop(cid:173)
`ment up to approval and marketing (fig. 1).
`
`Discovery
`
`Selecting therapeutic areas or indications to invest in
`is driven by 'medical need' and the prevalence of the dis(cid:173)
`ease (fig. 2). Additional factors also include technical fea(cid:173)
`sibility, research and development costs and commercial
`considerations such as competition in the market place
`and potential market share. Even if these criteria are met,
`there is only a limited research and development budget
`and each new project must be prioritized against the
`company research and development portfolio, with only
`high priority projects within the budget being selected for
`progression. For many companies, this is typically an an-
`
`c126
`
`Nephron Clin Pract 2009;113:cl25-cl3l
`
`Tamimi/Ellis
`
`MPI EXHIBIT 1047 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0002
`
`

`

`nual review process for products at all stages of develop(cid:173)
`ment. This may lead to stopping a programme even at an
`advanced stage of development.
`Early chemical starting points have been identified
`from naturally occurring substances in plants, humans or
`animals but lead compounds are more often sourced from
`targeted chemical synthesis directed to bind to the known
`structures of receptors and enzymes or from random or
`receptor-targeted high-throughput screening [6]. This has
`become more popular in the last few years as it is helpful
`in accelerating drug discovery. Initial problems encoun(cid:173)
`tered in the last decade have eased with improving tech(cid:173)
`nology. With the advent of modern computer technology,
`robotics and multi-well assay plates (384 growing to 1,536
`wells per plate), high-throughput screening can test vast
`'libraries' of chemical compounds in multiple screens
`(which can deliver up to 120,000 assays every 24 h). An(cid:173)
`other method of lead identification is 'virtual screening'
`(also named in silico screening) which is defined as the
`'selection of compounds by evaluating their desirability in
`a computational model' [7]. Compounds testing positive
`in screening have their potency and selectivity confirmed
`by in vitro biochemical or cellular assays. This is typi(cid:173)
`cally followed by functional biochemical and pharmaco(cid:173)
`logical testing in vitro, followed by pharmacodynamic
`and pharmacokinetic testing in vitro and in vivo [8]. The
`next step is to complete pilot toxicology testing to inform
`us of the likely safety profile. Once all preclinical testing
`has satisfied the minimum selection criteria, the com(cid:173)
`pound transitions from a 'lead' to a 'candidate' and is
`nominated for progression to the clinic.
`At this stage, drug production is scaled up to meet the
`increased compound demand, work commences on de(cid:173)
`veloping a suitable formulation for clinical use (often a
`tablet is the preferred dosage form) and the candidate is
`progressed through the required toxicology testing (in(cid:173)
`cluding genotoxicity, safety pharmacology in all biologi(cid:173)
`cal systems, single and multiple dose toxicity and toxico(cid:173)
`kinetic studies) to enable the first in human and subse(cid:173)
`quent clinical studies. Reproductive toxicology in male
`and female animals (required prior to testing in women
`of child-bearing potential) and long-term carcinogenici(cid:173)
`ty testing are also prerequisites for filing a drug approval
`request [9].
`In parallel with lead development/candidate nomina(cid:173)
`tion, a key decision on when to patent the compound or
`chemical series is taken. Early patenting mitigates against
`competitors beating a company to a claim, but delaying
`the patent application allows for introduction of addi(cid:173)
`tional data to strengthen the patent and extends the pat-
`
`ent expiry date. The patent life is typically 25 years but as
`it takes 10-15 years to develop a drug, there could only be
`10 years remaining to sell the product and recoup the
`high development costs.
`
`Phases of Clinical Drug Development
`
`Phase I. Phase I starts with the first administration of
`the new medicinal product to humans. Usually this phase
`involves healthy volunteers with the exception of cyto(cid:173)
`toxic drugs (e.g. oncology drugs) which get tested in pa(cid:173)
`tients without the requirement to test in healthy volun(cid:173)
`teers first. The purpose of this stage is to evaluate the safe(cid:173)
`ty, tolerability, pharmacodynamic (effect of the drug on
`the body e.g. effect on heart rate, blood pressure, electro(cid:173)
`cardiogram (ECG), etc.) and pharmacokinetic (effect of
`the body on the drug i.e. absorption, distribution, metab(cid:173)
`olism and excretion) effects of the tested drug. Phase I
`studies are usually conducted in dedicated phase I units
`which are research units attached to a general or teaching
`hospital and manned by research physicians who are fa(cid:173)
`miliar with conducting such studies. Full resuscitation fa(cid:173)
`cilities are available at these units. Phase I studies require
`approval from an ethics committee and the relevant regu(cid:173)
`latory agency. In the United States, an Investigational
`New Drug (IND) application, which summarises the es(cid:173)
`tablished preclinical and manufacturing information
`along with investigator guidance, must be in place prior
`to starting clinical trials. A pre-IND consultation pro(cid:173)
`gramme is offered by the US Food and Drug Administra(cid:173)
`tion (FDA) to provide guidance on the data necessary for
`the IND submission. Subjects are usually compensated for
`participating in these studies. Development of the drug
`could be stopped if it is found that the half-life of the drug
`is too short or too long or if it has poor bioavailability.
`Similarly, if the drug is not well tolerated at effective con(cid:173)
`centrations it is dropped from development. Phase I stud(cid:173)
`ies usually start with single sub-pharmacological doses
`which are escalated gradually and followed by multiple
`doses. Stopping rules to dose escalation include severe ad(cid:173)
`verse events, clinically significant ECG abnormalities and
`clinically significant laboratory abnormalities.
`Other phase I studies to support drug development are
`conducted throughout phase II and II of development.
`These include drug-drug interaction studies, effect of
`food on absorption, age and genetic influences. A typical
`phase I study can cost up to USD 500,000, with speciality
`studies (such as detailed QTc ECG assessments) costing
`up to USD 1.5 million.
`
`Drug Development
`
`Nephron Clin Pract 2009;113:cl25-cl31
`
`c127
`
`-
`
`MPI EXHIBIT 1047 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0003
`
`

`

`Role of Translational Medicine/Bio markers
`The American Physiological Society has defined trans(cid:173)
`lational research as 'the transfer of knowledge gained
`from basic research to new and improved methods of pre(cid:173)
`venting, diagnosing, or treating disease, as well as the
`transfer of clinical insights into hypotheses that can be
`tested and validated in the basic research laboratory' [10].
`Biomarkers are quantitative measures of biological ef(cid:173)
`fects that provide informative links between mechanisms
`of action and clinical effectiveness [11]. Effectively apply(cid:173)
`ing translational research measures to a development
`programme in phase I and phase II results in earlier iden(cid:173)
`tification of efficacy (or just as important, lack of effica(cid:173)
`cy) resulting in increased overall productivity and poten(cid:173)
`tially a quicker route to drug approval. There are 3 fun(cid:173)
`damental classifications of biomarkers: (1) markers of
`disease e.g. proteinuria as a biomarker of chronic kidney
`disease (CKD); (2) markers of pharmacological activity of
`a drug e.g. inhibition of angiotensin-converting enzyme
`increases plasma levels of angiotensin-1 and decreases
`plasma levels of angiotensin-2; (3) surrogate biomarkers
`of efficacy e.g. using a measure of penile rigidity mea(cid:173)
`sured by plethysmography (Rigiscan) as a surrogate for
`sexual intercourse. An example of a biomarker with di(cid:173)
`agnostic rather than efficacy potential is neutrophil gela(cid:173)
`tinase-associated lipocalin or NGAL, which serves as
`biomarker of acute renal injury as increased levels are de(cid:173)
`tected in urine and blood within hours of kidney injury.
`Taking the example of proteinuria in CKD, interven(cid:173)
`tions that reduce proteinuria can be potentially beneficial
`in the treatment of CKD. Therefore measuring changes
`in the biomarker in both preclinical models (e.g. sub-total
`nephrectomy model in the rat) and the clinic can be in(cid:173)
`dicative of activity of a potentially new drug for treating
`that indication (i.e. slowing progression of non-diabetic
`CKD). The challenge is to use or develop a biomarker in
`which we have confidence that it will reflect changes in
`the important registrable endpoints that we will assess in
`phase III trials and which are essential to gain regulatory
`approval.
`Phase II. Once the drug's safety, pharmacokinetics and
`dose selection has been established in healthy volunteers,
`the next step is to investigate the efficacy and safety of the
`drug in the target population. For example, if a drug is
`being developed for the treatment of hypertension, phase
`II trials will involve investigating the drug in a hyperten(cid:173)
`sive patient population. Phase II is usually divided into
`phase Ila and phase Ilb. Phase Ila is when the drug (usu(cid:173)
`ally limited to a single high/maximal tolerated dose level)
`is tested in a small cohort (12-100) of patients; this is
`
`called the 'proof of concept'. Phase Ilb follows on from
`the proof of concept in which several dose levels are test(cid:173)
`ed in the target population (dose-ranging studies) to de(cid:173)
`fine the minimally effective or non-effective dose and to
`decide the optimal dose, based on clinical efficacy and
`safety, to take to the next stage. Occasionally phases Ila
`and Ilb are combined in one large study. A complete
`phase II programme could involve several hundred pa(cid:173)
`tients and can cost several million dollars.
`With ever increasing development costs and expiry of
`valuable patents on major products, the pharmaceutical
`industry is compelled to develop more efficient and cost(cid:173)
`effective ways of doing drug development. These include
`the use of biomarkers, as discussed, but also application
`of enhanced quantitative drug design 'EQDD' to under(cid:173)
`stand exposure-response relationships and optimise dose
`selection, thus facilitating regulatory review and maxi(cid:173)
`mising the commercial value of the drug.
`However, positive phase II data is no guarantee of pro(cid:173)
`gression to phase III. At this key stage of development,
`costs will increase significantly and detailed analyses of
`the drug candidate and the market (patient, payer and
`physician perspectives) are conducted. This will include
`drug efficacy relative to the competitors, safety profile,
`probability of technical and regulatory success, remain(cid:173)
`ing patent life of the drug, cost of goods to produce the
`drug, potential market share and pricing and reimburse(cid:173)
`ment. Once again, the drug will be prioritised against all
`other candidates in the portfolio and only if the outlook
`is favourable and the priority is within the research and
`development budget will it go forward.
`A successful phase II is followed by an 'end of phase II'
`meeting with regulatory agencies such as the FDA to dis(cid:173)
`cuss the results from phase II and discuss and agree the
`clinical and statistical analysis plans for phase III. This
`negotiation, which also includes the target labelling, is
`critical to ensure alignment between the regulatory agen(cid:173)
`cy and sponsor.
`Phase III. This is the final stage of drug development
`prior to registration and will confirm the clinical doses,
`frequency and timing of administration for approval. Be(cid:173)
`fore embarking on a costly phase III programme, the
`sponsor should have a high level of confidence in the
`drug's safety and efficacy in the target patient population
`and the dose range to be tested. Phase III trials (usually a
`minimum of 2) can involve up to several thousands of
`patients, depending on the indication, so that an ade(cid:173)
`quate database (with 90% power to detect statistically sig(cid:173)
`nificant differences) is created to assess the efficacy and
`safety profile, in addition to enabling accurate drug label-
`
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`Tamimi/Ellis
`
`MPI EXHIBIT 1047 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0004
`
`

`

`ling. Phase III trials are primarily designed and powered
`to test the hypothesis of efficacy but at the same time, ad(cid:173)
`verse events are collected to assess benefit-risk potential
`of the drug. Use of novel endpoints in phase III is a high(cid:173)
`risk strategy, but can prove valuable in demonstrating
`benefits relative to competitors or established therapies;
`however, these endpoints do require validation and
`should be included in phase II and discussed with the
`regulatory authorities prior to the start of phase III.
`Clinical studies that use mortality and morbidity end(cid:173)
`points are often very large and can take several years to
`complete. Oncology is an exception, with phase III stud(cid:173)
`ies often limited to a few hundred patients. In diseases in
`which there is an established 'gold standard' treatment,
`European regulatory authorities will require phase III
`studies to include a comparator arm to demonstrate non(cid:173)
`inferiority or superiority compared to the standard ther(cid:173)
`apy. Efficacy can be demonstrated either by demonstrat(cid:173)
`ing superiority to placebo in placebo-controlled trials or
`by showing superiority to an active-control treatment.
`Sometimes the new drug entity is compared to a reference
`treatment without the objective of showing superiority.
`This can be either an equivalence trial, which shows that
`the response to treatments differs by an amount which is
`clinically not significant (specify upper and lower equiv(cid:173)
`alence margins), or a non-inferiority trial which has the
`objective of showing that the new drug is not clinically
`inferior to the comparator (only lower equivalence mar(cid:173)
`gin is specified). The choice of specified margins should
`be clinically justified.
`Depending on the nature of the study and the end(cid:173)
`points used for the indication, a 'Data Safety Monitoring
`Board' (DSMB) may be required throughout the conduct
`of the trial. This is especially so in studies that incorpo(cid:173)
`rate mortality and morbidity as primary or secondary
`endpoints. DSMB members must include a clinician with
`expertise in the disease area under investigation as well
`as a biostatistician as a minimum. Each DSMB must have
`a charter and written operating procedures detailing
`members' responsibilities and the plan of communica(cid:173)
`tion. DSMB members must disclose potential conflict of
`interest to the sponsor.
`For the sponsor, phase III trials involve a large cross(cid:173)
`functional team which involves, amongst others, clini(cid:173)
`cians, project management, data management, drug safe(cid:173)
`ty monitoring, document management, regulatory sup(cid:173)
`port and clinical quality assurance. A key consideration
`for phase III is selection of study centres to ensure appro(cid:173)
`priate patient recruitment and timely completion of the
`study. Estimations of patient drop-out rates are made, but
`
`if the rate is too high, additional study centres will be re(cid:173)
`cruited. This ensures adequate patient numbers for ap(cid:173)
`proval, but is costly in incurring delays to the programme.
`The overall success rate of phase III is around 70% and
`depending on the size can cost up to USD 100 million. A
`successful phase III is usually recognised by the financial
`markets with an impact on the sponsor's share price.
`
`Regulatory Submission/Approval
`
`Once the phase III studies have completed and deliv(cid:173)
`ered a positive outcome, compilation of the data to sub(cid:173)
`mit to the regulatory agencies starts. This usually takes
`several months and can be done by one region at a time,
`e.g. in the United States, or could be done globally, target(cid:173)
`ing major regions simultaneously. Classically, the major
`markets include the United States, the European Union
`and Japan. However, recently more attention is given to
`the 'emerging markets' such as Latin America, India and
`China, amongst others. As for the United States, a routine
`New Drug Application 'NDA' can take up to 15 months
`for review. However, in cases of particularly high medical
`need or in areas lacking treatments (e.g. oncology and hu(cid:173)
`man immunodeficiency virus), an expedited review can
`be granted. If the new drug is a biologic, then a biologic
`license application 'BLA' rather than a 'NDA', is submit(cid:173)
`ted.
`In Europe, the sponsor submits a marketing authori(cid:173)
`sation application (MAA), which could be granted either
`under the centralised procedure (valid for the entire com(cid:173)
`munity market) or through the mutual recognition pro(cid:173)
`cess.
`During the review by the regulatory agencies, ques(cid:173)
`tions are referred back to the sponsor. To facilitate the
`review process, the sponsor will typically establish a rap(cid:173)
`id response team to coordinate the responses to the au(cid:173)
`thority. Drug label negotiations take place during the re(cid:173)
`view process. Regulatory agencies could request post-ap(cid:173)
`proval studies from the drug companies to address any
`safety concerns that the regulatory agencies may have. At
`the same time, the drug company will have presented its
`plans to detect, assess and report adverse events.
`Pharmacovigilance is the term used in Europe de(cid:173)
`scribing the ongoing evaluation of the safety of the drug
`in the post-marketing period; it is a requirement that all
`pharmaceutical companies with a post marketed product
`must comply. The drug company will also provide peri(cid:173)
`odic safety update reports on the new drug after its ap(cid:173)
`proval. Post-marketing or safety surveillance trials are
`
`Drug Development
`
`Nephron Clin Pract 2009;113:cl25-cl31
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`c129
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`-
`
`MPI EXHIBIT 1047 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0005
`
`

`

`sometimes referred to as phase IV clinical trials. Harmful
`effects discovered during phase IV trials can lead to the
`withdrawal of the drug from the market as seen in the
`example of rofecoxib (Vioxx) and cerivastatin (Lipobay,
`also known as Baycol in the United States).
`Orphan Drug Status. Pharmaceutical products devel(cid:173)
`oped to treat rare diseases have been referred to as orphan
`drugs. The FDA Orphan Drug Act specifies the require(cid:173)
`ments for granting a drug orphan status. The disease that
`the drug is intended for should affect less than 200,000
`people in the United States. This designation grants the
`company fast-track review process as well as market ex(cid:173)
`clusivity for a period of 7 years. In addition, it will be eli(cid:173)
`gible for direct guidance from the FDA for the design of
`a clinical plan to further develop the drug. In Europe,
`some drugs used to treat tropical diseases that are pri(cid:173)
`marily found in developing countries can also be desig(cid:173)
`nated as orphan drugs. For the drug companies, the cost
`of developing such drugs and marketing them will not be
`covered by the expected sales. Hence, the economic and
`regulatory incentives to encourage pharmaceutical com(cid:173)
`panies to develop such drugs are needed.
`
`Regulatory Standards
`
`Preclinical studies are conducted according to good
`laboratory practice ( GLP) guidelines, which regulate how
`laboratory studies are performed. Clinical trials are con(cid:173)
`ducted according to good clinical practice (GCP) guide(cid:173)
`lines, which are internationally required quality and safe(cid:173)
`ty standards for designing, conducting and reporting
`clinical trials. GCP-compliant clinical trials are essential
`to ensure the rights and safety of clinical trial subjects.
`These standards are subject to inspection by regulatory
`agencies at any time; regulatory agencies have the right to
`halt ongoing clinical studies if they have concerns that
`the studies are not GCP-compliant. Finally drug manu(cid:173)
`facturing is done according to good manufacturing prac(cid:173)
`tice (GMP) guidelines, which dictates the standards for
`manufacturing and quality control of pharmaceutical
`products. This is also subject to regulatory inspection.
`
`Lifecycle Management
`
`The drug company will plan the lifecycle of the drug
`throughout the patent life and beyond into the future ge(cid:173)
`neric marketplace. This may include different drug deliv(cid:173)
`ery systems such as prolonged release formulations ver-
`
`sus immediate release, combinations with other drugs for
`improved efficacy, as well as seeking new indications.
`Once a new indication is confirmed, the drug company
`can apply for a supplementary new drug application (s(cid:173)
`NDA). Publication strategies are also another important
`part oflifecycle management, as additional benefits of the
`drug that cannot be added to the label, such as patient(cid:173)
`reported outcome measures, are published in peer-re(cid:173)
`viewed journals.
`
`Interaction between Pharmaceutical Industry and
`Healthcare Professionals
`
`The Pharmaceutical Research and Manufacturers of
`America (PhRMA) represent research-based pharma(cid:173)
`ceutical and biotechnology companies. PhRMA have de(cid:173)
`veloped guidelines on the basis of interactions between
`US healthcare professionals and the pharmaceutical in(cid:173)
`dustry. The PhRMA code was last updated in January
`2009 and regulates amongst other things: informational
`presentations by pharmaceutical company representa(cid:173)
`tives and accompanying meals, prohibition on entertain(cid:173)
`ment and recreation, pharmaceutical company support
`for continuing medical education, pharmaceutical com(cid:173)
`pany support for third-party educational or professional
`meetings, the employment of healthcare professionals as
`consultants, speaker programmes and speaker training
`meetings, prohibition of non-educational and practice(cid:173)
`related items as well as scholarships and educational
`funds. In the United Kingdom, the Association of the
`British Pharmaceutical Industry (ABPI) code was estab(cid:173)
`lished in 1958 and covers advertising, activities of repre(cid:173)
`sentatives, supply of samples, provision of hospitality,
`promotional meetings and the sponsorship of scientific
`and other meetings, including payment of travelling and
`accommodation expenses. The ABPI code does not apply
`to the promotion of over-the-counter medicines to the
`general public [12].
`
`Conclusion
`
`Drug development is a long, expensive and highly reg(cid:173)
`ulated process. The risks are high, but continued invest(cid:173)
`ment in pharmaceuticals is vital if we are to enjoy the
`benefits of long-term improvements in patient health(cid:173)
`care.
`
`c130
`
`Nephron Clin Pract 2009;113:cl25-cl31
`
`Tamimi/Ellis
`
`MPI EXHIBIT 1047 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1047-0006
`
`

`

`References
`
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`
`Editorial Comment
`M. El Nahas, Sheffield
`
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`
`-
`
`This minireview by Tamimi and Ellis, 2 senior execu(cid:173)
`tives at Pfizer UK with considerable experience in drug
`development and with a genuine interest in nephrology
`and chronic kidney disease (CKD), is timely. It reminds
`the reader of the huge and often prohibitive cost of new
`drug developments. It highlights the fact that thousands
`of new potentially promising products never make it to
`the bedside. Giving the cost associated with drug develop(cid:173)
`ment and the current global financial situation, this mini(cid:173)
`review sheds considerable light on the direction major
`pharmaceutical companies may be taking. First, the drug
`industry is re-evaluating its research priorities moving to(cid:173)
`wards safer clinical areas with projected quicker financial
`return. Pfizer has moved away from its prior top research
`priorities and successful drug development areas, namely
`atherosclerosis and heart failure research. Instead, re(cid:173)
`search and development of drugs to tackle the growing
`market of Alzheimer's disease are gathering pace.