Jeff Settleman|Robert Cohen
Communication in Drug Development: “Translating” Scientific Discovery
Enzo Life Sciences (United States)|Enzo Life Sciences (United States)
discovery development new medicines promote human health potentially extend natural life remains remarkably challenging endeavor commentary identify key elements communication required successfully translate promising biological findings novel approved drug therapies discuss attendant challenges opportunities discovery development new medicines promote human health potentially extend natural life remains remarkably challenging endeavor commentary identify key elements communication required successfully translate promising biological findings novel approved drug therapies discuss attendant challenges opportunities successful development numerous drugs manage wide variety maladies improved quality length life countless people remains large unmet need therapeutics especially challenging diseases including various cancers cardiovascular disease metabolic disorders neurodegenerative diseases psychiatric disorders infectious diseases numerous genetic syndromes key factors limit ability tackle diseases novel medicines one disease biology immensely complex despite everincreasing understanding basic disease biology ability identify relevant therapeutic targets discover drugs selectively effectively safely modulate targets produce clinical benefit remains frustratingly limited furthermore recent advances various omic technologies enable precise molecular characterization diseased tissue revealed substantial interpatient heterogeneity prompting efforts personalize drug treatment new paradigm presents opportunity match patients right medicines well challenge develop sufficiently diverse arsenal drugs benefit growing number subsets biomarkerstratified patients also challenge drug discovery development process itselfa byzantine expensive undertaking fails far often succeeds typical program culminating regulatory approval involves dozens hundreds workers requires 1015 years costs hundreds millions dollars dimasi et al 2016dimasi ja grabowski hg hansen rw innovation pharmaceutical industry new estimates rd costsjournal health economics 2016 published online 12 february 2016httpsdoiorg101016jjhealeco201601012crossref pubmed scopus 1645 google scholar several recent trends converged highlight role effective forthright communication among many participants process important element success discovery development currently approved drugs proceeded various paths somewhat standard approach underlies successful programs figure 1 typically drug discovery campaign begins biological observation associated therapeutic hypothesis cases identification targets reflects cumulative findings multiple investigators whose independent efforts eventually converge however even single especially provocative discovery prompt efforts prosecute target therapeutic development initial findings usually reported academic researchers peerreviewed publications especially promising reports prompt efforts validate target therapeutic hypothesis promising target deemed validated often prosecuted drug discovery development highthroughput screening approaches improvements medicinal chemistry antibody engineering methods 1980s 1990s revolutionized pharmaceutical industry greatly enabling discovery candidate therapeutic molecules underlying technology moved beyond pharmaceutical companies screening also conducted usually smaller scale many academic research institutions academic laboratories pursuing efforts discover drugsor least tool compounds serve potential starting points drug development efforts yielded numerous tantalizing publications well many licensing agreements academic institutions biopharmaceutical companies unfortunately many published claims regarding candidate therapeutic targets lead compounds prove problematic revealing study amgen scientists described efforts replicate results dozens landmark cancer research publications begley ellis 2012begley cg ellis lm drug development raise standards preclinical cancer researchnature 2012 483 531533crossref pubmed scopus 1895 google scholar result disappointingfindings could replicated six 53 cases surprising many experience industry scientists many colleagues similar number root causes contributing factors suggested continue widely discussed event basic failure scientific communication made plain experiment ensuing discussion issues generally productive changes manuscript review process implemented early assess impact one approach implemented journals checklist authors life sciences articles intended document rigor experiments conducted including statistical methods measures taken address potential bias nature editors 2013nature editorsreporting checklist life sciences articlesnature 2013 496 398crossref google scholar see also checklist available httpwwwnaturecomauthorspolicieschecklistpdf editors journals also indicated willingness commission statisticians consultants certain manuscriptsnoting training young biologists often inadequate regard statistics quantitative analysis potentially resulting invalid conclusions context drug discovery reports especially coming academic biologists many underestimate rigorous evaluation required adequately credential novel pharmacologic agent journal editors routinely engage industrybased scientists relevant technical expertise review studies would analogous aforementioned enhanced use statisticians consultants review process one reason industry reviewers particularly attentive robustness recognition cost alltoofrequent clinical development failures prior publication even early stages drug discovery project academic biologists encouraged seek guidance technical experts soliciting consultation industry scientists likely challenging many experts relevant knowledge fact embedded within academic biomedical research institutions days notably academic technology transfer departments within institutions clear incentive foster interactions considering interest developing licensing intellectual property resulting drug discovery projects experience industry reviewers licensing opportunities often uncover flaws perhaps missed journal reviewers investigators fundamentally communicating information regarding novel candidate targets therapeutics journal articles problematic many claims simply oversold authors failing note potential caveats limitations analysis contributing factors include peerreview journal publication process sometimes favors luster rigor evolving nih mission increasingly emphasizes translational potential well occasionally blind optimism characterizes human nature however considering importance target drug discoveries future development medicines address important human diseases additional scrutiny appropriate claims published also suggest published claims regarding novel targets inhibitors include specific communication regarding potential caveats journal editors consider mandating discussion section reports includes honest complete listing limitations disclaimers preclude publication unless limitations substantial rather set realistic foundation next important steps process adequately credentialing validating candidate target molecule short benefit enhanced process manuscript review publication improve communication genuine biomedical advances potential provide foundation eventual drug development seems clear drug discovery paradigm introduces variety communication challenges typically target validated project team formed within biotechnology pharmaceutical company initiate laborious process discovering evaluating candidate molecules therapeutic potential teams include biologists medicinal chemists biochemists structural biologists pharmacologists safety toxicologists clinicians marketing professionals group charged oversight carefully orchestrated effort involving various technical functions although share common goal experts team measure specialist trained many years develop competence arcane discipline biologists talk membrane blebs mitotic catastrophe chemists describe chiral centers rotational bonds structural biologists refer steric hindrance nmr spectroscopy biochemists speak hill coefficients noncompetitive inhibition pharmacologists relate bioequivalence hepatic clearance toxicologists make note exposure limits genotoxicity clinicians describe marrow suppression edema short various team members speak different language unlike united nations meeting usually interpreter table given high level specialization among participants drug discovery paradigm faces inherent communication challenge operating backdrop innumerable decisions required project teams suggest team experts make concerted effort describe vital information using language readily understandable everyone team conscious effort made avoid jargon neither necessary practical everyone team understands technical nuances discipline use jargon often bundles assumptions shorthand obscure essential points others effective project teams use shared understanding facilitated genuine efforts develop common informative language enable optimal decisionmaking engaging key participants conscious effort clear forthright communication thus likely increase chance program success consider drug discovery engineering problemwhich large degree iswe examine role communication context ambitious engineering feats putting man moon required teams highly specialized aeronautical mechanical electrical chemical computer engineers carefully coordinated activities ensure mission success failure appropriately link functions could catastrophic communication breakdown due language differences could problematic forms miscommunication among scientists scientists managers also play role fact nasa substantial experience area many ambitious programs uniformly successful example apollo 13 explosion ultimately attributed series poor communications engineers managers led bad decisions mission even began similar communication problems contributed two space shuttle disasters flawed hubble telescope construction infamous metric conversion error doomed mars orbiter analogy successful engineering new drug depends critically effective communication innumerable bits information among large number experts managers includes everpresent risk catastrophic failure one noteworthy distinction drug discovery programs conventional engineering projects relates role magnitude attendant uncertainty putting man moon required good luckrather required accurate calculations quantitative measurements wellunderstood physical systems biology hand still much incompletely understood result various perturbations biological systems remains largely unpredictable consequently much new knowledge determined empirically iterative trialanderror process underlies much biology discovery communicating experimental failure important communicating success moving beyond discovery candidate drugs drug development process required evaluate clinical potential novel drug candidate similarly associated communication challenges appropriate scrutiny early stage translate greater probability future success surprisingly however recent analysis astrazenecas drug development pipeline revealed among projects classified efficacy failures phase ii 40 associated fundamental failure link supposed molecular target intended indication cook et al 2014cook brown alexander r march r morgan p satterthwaite g pangalos mn lessons learned fate astrazenecas drug pipeline fivedimensional frameworknat rev drug discov 2014 13 419431crossref pubmed scopus 858 google scholar many failures could probably avoided focusing early stage issues strength evidence supporting drug target adequate pharmacodynamics measures robust activity wellvalidated animal model ensuring relevant information clearly communicated among project team members evidence failed communication implied another finding astrazeneca analysisdevelopment plans targeting wrong patient population cited reason failure demonstrate clinical efficacy third cases authors suggested teams may overvalued commercial considerations relative targeting appropriate patient populations based underlying disease biology one example development olaparib parp inhibitor originally shown confer synthetic lethality cancer cells brca1 brca2 mutations bryant et al 2005bryant schultz n thomas hd parker km flower lopez e kyle meuth curtin nj helleday specific killing brca2deficient tumours inhibitors polyadpribose polymerasenature 2005 434 913917crossref pubmed scopus 3647 google scholar despite obvious clinical development path informed early results patients brca mutations later clinical development focused much larger heterogeneous population selected basis brca mutations inhibitor failed demonstrate sufficient efficacy clinical development brcadeficient tumors ultimately continued proved highly efficacious unfortunate delay drug approved suggest focus translational biology forthright communication therapeutic hypothesis project team might avoided delays expense resulted targeting wrong patient population central drug development enterprise need translate underlying biological discovery relevant patient population use word translate context implies challenge effectively communicating potential impact basic biomedical discoveries therapies based effectively evaluated humans terms translational biology translational medicine suggest one language spoken highlights need core understanding indeed national center advancing translational science ncats httpwwwncatsnihgovabout established within nih transform translational science process new treatments cures disease delivered patients faster collins 2011collins fs reengineering translational science time rightsci transl med 2011 3 90cm17crossref pubmed scopus 338 google scholar key part mission ensure training education focuses teambased interdisciplinary science outside traditionallydefined fields appears momentum gathering develop future researchers well versed core translational curriculum individuals make next generation drug developers hopefully develop lingua franca facilitate communication deeply intuitively mere attempt translation believe success precision medicine depend developing rewarding similar competencies among biomedical scientists physicians iom report toward precision medicine building knowledge network biomedical research new taxonomy disease authors note new system require healthcare providers develop great literacy interpretation application molecular data biomedical education need adjust accommodate emerging need committee framework development new taxonomy disease et al 2011committee framework development new taxonomy disease board life sciences division earth life studies national research counciltoward precision medicine building knowledge network biomedical research new taxonomy disease national academies press 2011httpsdoiorg101722613284httpwwwnapeducatalogphprecordid13284crossref scopus 58 google scholar example cited authors system characterized vertical integration biomedical information rather disciplinespecific training goal would future physicians develop holistic view biological processes one prepares successfully integrate genomics new taxonomy disease promotes far informed decisionmaking clinical practice fundamental change medical education type would additional benefit preparing students pursuing research careers function biomedical milieu increasingly requires multidisciplinary approaches realizing full benefits precision medicine drug development require integrated approach communicating genuine discoveries well prosaic results ensuring appropriate degree scientific rigor disseminating key discoveries ongoing institutional barriers biases tend discourage publishing negative data confirmatory data still exist progress toward openness come form commitment several pharmaceutical companies make available raw clinical trial data exploratory analyses thirdparty researchers httpwwwphrmaorgphrmapediaresponsibleclinicaltrialdatasharing regulatory agencies including fda expressed enthusiasm enhanced communication drug sponsors improve efficiency drug development process us department health human servicesfood drug administrationcenter drug evaluation research cderand center biologics evaluation research cber 2015us department health human services food drug administration center drug evaluation research cder center biologics evaluation research cberdraft guidance best practices communication ind sponsors fda drug developmentguidance industry review staff us department health human services food drug administration center drug evaluation research center biologics evaluation research 2015httpwwwfdagovucmgroupsfdagovpublicfdagovdrugsgendocumentsdocumentucm475586pdfgoogle scholar fda regularly provides advice adequacy technical data support ind filing design clinical trial information needed meet regulatory requirements drugs developed expedited programs fda offers intensive guidance increased interactions communications including meetings final analysis biomedical community must communicate effectively public large given enormous public investment drug development together high cost new treatments public right understand question current practices people seek build bridge even send someone moon envision process succeeds rarely many dismayed seemingly feeble pace progress developing treatments many common diseases certainly require collective communication skills explain disappointing reality many expensive drug development efforts viewed simply shots goal solid scientific hypothesis thoughtful decisionmaking highquality experimental execution generally regarded essential components successful drug development campaign however much biology remains poorly understood even believe mitigated potential risks associated new investigational agent best abilities well understood outcome clinical experimentation unpredictable cases development unfortunately fails good fortune notwithstanding suggest effective communication among many participants throughout long course complex process yet another important element one relatively straightforward steps could taken make significant improvements thereby increase likelihood success vitally important programs