Drug Development Plan Research Articles

PSS38 - Payer Needs In Emerging Markets: How Should These Needs Be Included In Dermatology Drug Development Plans?

PSS38 - Payer Needs In Emerging Markets: How Should These Needs Be Included In Dermatology Drug Development Plans?

A gift for research

An anonymous $275 million gift propels the Sanford-Burnham Medical Research Institute more than halfway to its funding goal for a newly announced 10-year drug development plan that involves speeding the development of preclinical therapies that it hopes to out-license.

Discovering human immunodeficiency virus mutational pathways using temporal Bayesian networks

The human immunodeficiency virus (HIV) is one of the fastest evolving organisms in the planet. Its remarkable variation capability makes HIV able to escape from multiple evolutionary forces naturally or artificially acting on it, through the development and selection of adaptive mutations. Although most drug resistance mutations have been well identified, the dynamics and temporal patterns of appearance of these mutations can still be further explored. The use of models to predict mutational pathways as well as temporal patterns of appearance of adaptive mutations could greatly benefit clinical management of individuals under antiretroviral therapy. We apply a temporal nodes Bayesian network (TNBN) model to data extracted from the Stanford HIV drug resistance database in order to explore the probabilistic relationships between drug resistance mutations and antiretroviral drugs unveiling possible mutational pathways and establishing their probabilistic-temporal sequence of appearance. In a first experiment, we compared the TNBN approach with other models such as static Bayesian networks, dynamic Bayesian networks and association rules. TNBN achieved a 64.2% sparser structure over the static network. In a second experiment, the TNBN model was applied to a dataset associating antiretroviral drugs with mutations developed under different antiretroviral regimes. The learned models captured previously described mutational pathways and associations between antiretroviral drugs and drug resistance mutations. Predictive accuracy reached 90.5%. Our results suggest possible applications of TNBN for studying drug-mutation and mutation-mutation networks in the context of antiretroviral therapy, with direct impact on the clinical management of patients under antiretroviral therapy. This opens new horizons for predicting HIV mutational pathways in immune selection with relevance for antiretroviral drug development and therapy plan.

Molecular Imaging PET and SPECT Approaches for Improving Productivity of Antipsychotic Drug Discovery and Development

The need for innovation in research is leading to an increased use of imaging biomarkers, which have shown to reduce timings and increase productivity, thus saving costs. PET and SPECT neurotransmission imaging has shown usefulness in the discovery and development of drugs for the central nervous system, providing unique information on drug-target interactions in the living human brain. Among the different therapeutic areas, antipsychotic drugs pioneered the application of these technologies in early phases of development. PET and SPECT radioligands for the most commonly targeted neurotransmission systems in the development of these drugs, such as the dopaminergic and serotoninergic systems are available, thus fostering the inclusion of PET and SPECT studies in the antipsychotic drug development plans. Radioligands for other neurotransmission systems more recently implicated in the pathophysiology of schizophrenia, such as the glutamatergic system, are being currently investigated. This review focuses on neurotransmission PET and SPECT aiming to serve as guidance for procedure requirements and methodology choices to be applied in antipsychotic drug development, through specific examples. Cutting-edge study designs and quantification approaches will be reviewed. Finally, some clues to get the most out of the PET and SPECT studies in the development of antipsychotic drugs will be provided.

6IN - From Landmarks of Cancer to Targeted Therapies: Lessons Learnt and Perspectives

ABSTRACT TKIs and antibodies (trastuzumab, imatinib,..) emerged as “revolutionary” drugs. Nevertheless, testing different agents in studies turned to be negative or “marginally” positive. Negative trials highlighted important issues: 1) The genetic complexity of carcinogenesis 2) Defining the implication of a target to oncogenesis is essential. 3) Due to the “plasticity” of signaling pathways, combination agents or multitargeted kinase may be needed but “cumulative” toxicities emerged. 4) A well performed early study is a prerequisite for the succes of a new agent. Marginally positive studies lead in limited circumstances to retrospective identification of subpopulations likely to benefit (e.g., WT KRAS and sensitivity to EGFR MoAbs in CRC). The sensibilisation towards tumor selection has demonstrated better results. NSCLC with ALK gene rearrangements are senstitive to ALK inhibitors. Melanoma with BRAF mutation responded to vemurafenib. A drawback would be the heterogeneity of the tumor. Moreover, modern techonologies allows the development of agents with a higher selectivity. Although advances have been achieved further, efforts are needed: Biomarkers of sensitivity have been evaluated but not optimaly validated. Mechanisms of resistance have been described, but a proper assessment is lacking. So it is fundamental to prioritize “powered” clinical trials. Prospective collection of biospecimens during disease evolution and therapies must become a standard approach. A comprehensive drug development plan (in advanced or neoadjuvant setting) has the potential to identify drugs to be tested in the adjuvant setting in subgroups where cure will be much higher. The lessons learnt so far should bring the concept of “personalized treatment” closer to the reality. A close collaboration of scientists, chemists, investigators and statisticians is needed to reach this goal. Disclosure The author has declared no conflicts of interest.

Challenges of paediatric drug development and impact of paediatric legislation

Medical writers are increasingly involved in designing and documenting overall plans in paediatric drug development, e.g. EU PIPs (Paediatric Investigation Plans) and individual components, e.g. protocols and study reports. It is essential to differentiate between the overall process and the individual components that together constitute paediatric drug development. Paediatric drug development does not mirror the development of drugs for adults. Drugs are developed by commercial companies. Paediatric drug development was triggered by laws dating back to 1997 (USA) and 2007 (EU) to give children better access to pharmaceutical progress. The active players are the regulatory authorities, the respective company, and the professionals involved in the planning and execution of defined development activities. For companies, participation is partially voluntary in the USA but compulsory in Europe. Key elements are assessing epidemiology and existing therapies in children, and all elements of adult drug development adapted to children's different anatomy, metabolism, and developmental stage. Paediatric drug development might include, for example, developing liquid formulations for children (vs. tablets), doing studies in juvenile animals, and paediatric clinical studies. Most key components of the paediatric drug development plan are negotiated between authority and company, and executed by paediatricians, clinical pharmacologists, and others.

Drug development in pediatric psychiatry: current status, future trends

Reflecting the fact that regulatory agencies recently required companies to initiate a pediatric drug development plan earlier in the drug development sequence for compounds first developed for adults, most psychiatric drugs for children still remain the offspring of adult drug development programs, viz., except for the psychostimulants, very few psychiatric medications have been developed for children and adolescents by first intent [1]. However, two irreversible trends are gradually shifting intervention development for psychiatric disorders away from a focus on adult organisms to a focus on developing organisms. First, epidemiological data indicate that the great majority of mentally ill adults were first mentally ill as children [2], and that this effect is evident as early as two years of age [3]. Second, recent advances in translational developmental neuroscience have shown that mental illness of all types can be referenced directly to the developing central nervous system and its interactions with the environment [4]. The knowledge that mental disorders are early onset, trajectory-based brain illnesses has enormous implications for the nature and organization of how we understand interventions for psychiatric patients of all ages [5,6]. Put succinctly, to preempt, prevent and cure psychiatric disorders, it will be necessary to translate insights about molecular pathways for mental illness into druggable targets that directly reflect key neurodevelopmental processes that form trajectories of atypical as contrasted to typical development [7]. To this end, this commentary will describe drug development in pediatric psychiatry with reference to three converging perspectives: fundamental biology and target identification, early phase clinical pharmacology, and the importance of biomarkers in the shift to personalized medicine.

Drug development perspectives considerations, challenges, and strategies

The falling productivity of the global pharmaceutical industry is a matter of record and a concern for those both within industry and in the life science sector more broadly. Seeking to reverse this trend, industry is looking much more widely for sources of innovation, moving away from a centralized closed innovation model. As a result those in drug development are tending to work in much smaller groups on novel targets with individuals taking much wider responsibility for multiple aspects of early drug development. A book that provides a broad overview with relevant examples is potentially very valuable to those working in this environment. Dr Srinivas has over 20 years experience in many phases of early drug development and has published widely. In this book he has selected five areas for detailed review: bioanalysis, allometry, CYP metabolism, PK simulations, drug combinations and genetic polymorphisms. Selection of these topics seems to have been driven by the availability of suitable examples. An introductory section on why these have been selected and how they fit into an overall drug development plan would have been helpful. Each chapter follows the same general plan: an introduction, a series of detailed examples, and a concluding summary section. The summary sections at the end of the chapter are the best feature of the book and provide useful practical and strategic insights. Unfortunately some of the detailed examples seem to reflect the information available on the subject drug rather than addressing specific aspects relevant to the chapter. As a result some of the key messages are lost in the detail. The introductory sections are rather short and serve more as a summary of the information in that chapter rather than an overview of the topic. This is a particular weakness as the topics are highly selected and readers new to drug development will need more information on the other tools or techniques available to address the question in hand. For example the chapter on allometry discusses the strengths and weaknesses of this technique but has very little information on what other options are available for human PK prediction. This is important because allometry is no longer widely used as the primary method for human PK prediction. It may be beyond the scope of this book to discuss detailed alternative examples but an outline of key concepts such as the minimal anticipated biological effect level (MABEL) would provide important context for readers. Overall this book provides a useful reference for those seeking specific examples to illustrate identified issues in drug development but it lacks the broad overview and guidance for it to be used as a practical guide to drug development.

Accelerated Approval of Oncology Products: The Food and Drug Administration Experience

We reviewed the regulatory history of the accelerated approval process and the US Food and Drug Administration (FDA) experience with accelerated approval of oncology products from its initiation in December 11, 1992, to July 1, 2010. The accelerated approval regulations allowed accelerated approval of products to treat serious or life-threatening diseases based on surrogate endpoints that are reasonably likely to predict clinical benefit. Failure to complete postapproval trials to confirm clinical benefit with due diligence could result in removal of the accelerated approval indication from the market. From December 11, 1992, to July 1, 2010, the FDA granted accelerated approval to 35 oncology products for 47 new indications. Clinical benefit was confirmed in postapproval trials for 26 of the 47 new indications, resulting in conversion to regular approval. The median time between accelerated approval and regular approval of oncology products was 3.9 years (range = 0.8-12.6 years) and the mean time was 4.7 years, representing a substantial time savings in terms of earlier availability of drugs to cancer patients. Three new indications did not show clinical benefit when confirmatory postapproval trials were completed and were subsequently removed from the market or had restricted distribution plans implemented. Confirmatory trials were not completed for 14 new indications. The five longest intervals from receipt of accelerated approval to July 1, 2010, without completion of trials to confirm clinical benefit were 10.5, 6.4, 5.5, 5.5, and 4.7 years. The five longest intervals between accelerated approval and successful conversion to regular approval were 12.6, 9.7, 8.1, 7.5, and 7.4 years. Trials to confirm clinical benefit should be part of the drug development plan and should be in progress at the time of an application seeking accelerated approval to prevent an ineffective drug from remaining on the market for an unacceptable time.

Revealing Atropisomer Axial Chirality in Drug Discovery

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.

Predictions of Metabolic Drug-Drug Interactions Using Physiologically Based Modelling

Nowadays, evaluation of potential risk of metabolic drug-drug interactions (mDDIs) is of high importance within the pharmaceutical industry, in order to improve safety and reduce the attrition rate of new drugs. Accurate and early prediction of mDDIs has become essential for drug research and development, and in vitro experiments designed to evaluate potential mDDIs are systematically included in the drug development plan prior to clinical assessment. The aim of this study was to illustrate the value and limitations of the classical and new approaches available to predict risks of DDIs in the research and development processes. The interaction of cytochrome P450 (CYP) 3A4 inhibitors (ketoconazole and verapamil) with midazolam was predicted using the inhibitor concentration/inhibition constant ([I]/K(i)) approach, the static approach with added variability (Simcyp(R)), and whole-body physiologically based pharmacokinetic (WB-PBPK) modelling (acslXtreme(R)). Then an in-house reference drug was used to challenge the different approaches based on the midazolam experience. Predicted values (pharmacokinetic parameters, the area under the plasma concentration-time curve [AUC] ratio and plasma concentrations) were compared with observed values obtained after intravenous and oral administration in order to assess the accuracy of the prediction methods. With the [I]/K(i) approach, the interaction risk was always overpredicted for the midazolam substrate, regardless of its route of administration and the coadministered inhibitor. However, the predictions were always satisfactory (within 2-fold) for the reference drug. For the Simcyp(R) calculations, two of the three interaction results for midazolam were overpredicted, both when midazolam was given orally, whereas the prediction obtained when midazolam was administered intravenously was satisfactory. For the reference drug, all predictions could be considered satisfactory. For the WB-PBPK approach, all predictions were satisfactory, regardless of the substrate, route of administration, dose and coadministered inhibitor. DDI risk predictions are performed throughout the research and development processes and are now fully integrated into decision-making processes. The regulatory approach is useful to provide alerts, even at a very early stage of drug development. The 'steady state' approach in Simcyp(R) improves the prediction by using physiological knowledge and mechanistic assumptions. The DDI predictions are very useful, as they provide a range of AUC ratios that include individuals at the extremes of the population, in addition to the 'average tendency'. Finally, the WB-PBPK approach improves the predictions by simulating the concentration-time profiles and calculating the related pharmacokinetic parameters, taking into account the time of administration of each drug - but it requires a good understanding of the absorption, distribution, metabolism and excretion properties of the compound.

Leveraging Prior Quantitative Knowledge to Guide Drug Development Decisions and Regulatory Science Recommendations: Impact of FDA Pharmacometrics During 2004–2006

The End-of-Phase 2A meetings are proposed to identify opportunities to make innovative medical products available sooner and to increase the quality of drug applications through early meetings between sponsors and the FDA. This article summarizes the overall experience across 11 pilot End-of-Phase 2A meetings since 2004. Four case studies are presented in more detail to demonstrate the various issues and methods encountered at these meetings. Overall, industry and FDA scientists ranked these meetings to be "very helpful" (average score of 4 on a scale of 1 to 5). In almost all the instances the sponsors changed their drug development plans subsequent to these extensive quantitative analyses-based meetings. A draft Guidance is being developed to be issued in 2008, and we hope this initiative will be resourced by then.

Untying the Gordian Knot

To the Editor: In their editorial that accompanied four articles on dexmedetomidine use in children, Drs. Tobin, Shafer, and Davis (1) assessed the broad impact of the pharmaceutical industry's lack of interest in conducting appropriate drug development studies for children. Yet the solution to “untying the Gordian knot” extends beyond the Food and Drug Administration (FDA) and industry. A critical factor largely absent from the discussion is training clinical investigators to meet the needs of pediatric drug development. We take issue with the contention that investigator-initiated studies cannot meet “… the FDA's definition for adequate and well controlled studies, …” because adequately trained investigators can certainly undertake such studies when given adequate support. Our recent experience with dexmedetomidine shows how this can be done. From October 2003 to December 2005, we repeatedly attempted to engage various members of Abbott Pharmaceuticals to initiate appropriate pediatric studies. These efforts failed. However, we garnered limited support from the National Institute of Child Health and Human Development's Pediatric Pharmacology Research Unit (PPRU), allowing us to implement a pediatric, drug development plan for dexmedetomidine. The PPRU comprises 13 academic sites that develop and perform clinical pharmacologic research in the pediatric population, often in collaboration with industry partners. The network includes experts in quantitative drug analysis, pharmacokinetic/pharmacodynamic (PK/PD) modeling, pediatric clinical trial design, and a wide range of pediatric subspecialties. Our initial trial is a PK/PD study of dexmedetomidine administered as a continuous infusion in infants after open-heart surgery. This dose-escalation study evaluates both the PK profile in this population and concentration-response relationships with respect to hemodynamic variables, tracheal extubation readiness, quality of sedation, and overall safety. The trial is nearly complete, and has produced a preliminary model of dexmedetomidine PK in infants. This model will enable us to design the next stage of investigations. As described in the accompanying editorial (2), our investigator-initiated study is being performed under an Investigational New Drug application, and our interaction with the FDA has been productive. There is a paucity of funding and an insufficient number of programs available to train experts in pediatric drug development. Although there are more than 250 children's hospitals in the United States, only a few train pediatric subspecialists in clinical pharmacology. Future efforts to assure appropriate design of clinical pharmacologic studies in children must include a comprehensive effort to train young investigators. These investigators are desperately needed in academia, industry, and the FDA. The solution to this Gordian knot is perhaps not that complex. Society, academia, government, and industry must simply decide that it is important enough to untie. Felice Su, MD Athena F. Zuppa, MD, MSCE Department of Pediatrics Division of Clinical Pharmacology and Therapeutics Department of Anesthesia and Critical Care Medicine Division of Critical Care Medicine The Children's Hospital of Philadelphia Peter C. Adamson, MD Department of Pediatrics Division of Clinical Pharmacology and Therapeutics Philadelphia, PA [email protected]

Development of growth inhibitory agents in urological and other malignancies

The first mini‐review is a critique of some of the methods used to assess endpoints for drug studies in oncology. The authors review studies using tumour shrinkage and those assessing time to progression. The next paper is a Pubmed‐based overview of published reports to establish whether antimuscarinic drugs exert their therapeutic action on detrusor overactivity by reducing the ability of the detrusor to contract. The findings are interesting and somewhat unexpected.Authors from several centres in Europe review anaesthesiology considerations and requirements for endoscopic extraperitoneal and laparoscopic transperitoneal radical prostatectomy. Finally, a touch of history; we do not have a history section, but occasionally we accept papers dealing with pioneers in urology. Recently we had an Irish pioneer, so it is highly appropriate to include one on a Scottish urological leader, Dr Henry Wade.In oncology there have been many new putative anticancer drugs based on the improving understanding of oncogenesis and the malignant phenotype. On the basis of their mechanism of action and preclinical data, many of these drugs are expected to inhibit growth. As such, dramatic tumour shrinkage, which has been the classic endpoint for phase II drug studies, might not be a valid or useful measure by which to make decisions as to whether further phase III trials are indicated. Because this is a critical decision point in the overall drug development plan, alternative endpoints and designs need to be considered. More traditional single‐arm phase II designs using tumour shrinkage endpoints are reviewed, and the use of randomized phase II designs assessing time to progression discussed. It is postulated that randomized approaches will decrease the current high failure rate for oncological drugs in phase III trials.

Model-Based Drug Development: The Road to Quantitative Pharmacology

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies.

Critical Considerations in Drug Development in Ethnically Diverse Populations

In recent years, greater attention has been given to the detection of ethnic differences in drug response and the need to take these differences into account in drug development. Epidemiological studies have identified significant ethnic variations in the rate and pattern of certain diseases, such as cardiovascular diseases, and in the response to drug therapy. Racial or ethnic differences may be related to a number of factors, including social, environmental and genetic factors. Differences in genes or polymorphisms are common and represent major determinants of differences in the effects of medicines observed in various populations. Polymorphisms concern mainly drug metabolism enzymes, receptor proteins and hepatic metabolism. They may influence the pharmacokinetics and pharmacodynamics of a given compound. Although specific polymorphisms are not isolated to any particular ethnic group, polymorphism prevalence may vary between ethnic groups for various categories of medicines. Among drug classes that exhibit varying effects in ethnic groups, benzodiazepines, antidepressants, antipsychotics, analgesics, antihypertensives and antidiabetic agents have been studied. However, it remains unclear how to assess the impact of ethnic differences on drug development and registration. In the E5 guidance from the International Conference on Harmonisation, the aim is “to permit the clinical data collected in one region to be used in the registration or approval of a drug or biological product in another region, while allowing for the influence of ethnic factors”. As a rule, approval of a new pharmaceutical product requires the demonstration of efficacy and safety by controlled clinical trials and the selection of an appropriate and safe dosage. The extrapolation of the original data collected in one region to another region depends of the similarity in dose response, efficacy and safety of the drug in both regions with or without dose adjustment. It is the responsibility of the sponsor to decide whether or not the data can be extrapolated or if additional bridging studies are needed. The type of bridging studies depends on the critical properties of the compound, the ethnic differences between the new and original regions and the requirements of the regulatory authority in the new region. Advances have been made in recent years and clinicians should be aware of the insights gained into ethnic differences in order to improve clinical management of certain diseases in ethnic groups. Ethnic differences observed in clinical trials may justify the approval of a specific drug formulation for a specific ethnic group. Drug development plans should be adjusted according to these known differences and adjustments should be anticipated when possible through different forms of collaboration with regulatory authorities.

Restoring value to stalled Phase II compounds: the case for developing a novel compound for depression using pharmacogenetics

PharmacogenomicsVol. 6, No. 2 EditorialRestoring value to stalled Phase II compounds: the case for developing a novel compound for depression using pharmacogeneticsCarol Reed, , Matthew Kalnik, , Kevin Rakin, Maria Athanasiou & Richard JudsonCarol ReedSearch for more papers by this author, , Matthew KalnikSearch for more papers by this author, , Kevin RakinSearch for more papers by this author, Maria AthanasiouSearch for more papers by this author & Richard JudsonSearch for more papers by this authorPublished Online:24 Nov 2005https://doi.org/10.1517/14622416.6.2.95AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleBibliography1 Coulthard SA, Matheson EC, Hall AG, Hogarth LA: The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. Nucleosides Nucleotides Nucleic Acids23(8-9), 1385–1391 (2004).Crossref, Medline, CAS, Google Scholar2 Murray L: Physicians’ Desk Reference (58th edn). Medical Economics Company, Montvale, NJ, USA (2004).Google Scholar3 Suzuki T, Mitsudomi T, Hida T: The impact of EGFR mutations on gefitinib sensitivity in non-small cell lung cancer. Personalized Med.1, 27–34 (2005).Link, Google Scholar4 Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M: Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry3(6), 508–511 (1998).Crossref, Google Scholar5 Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E: Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J. Clin. Psychopharmacol.20(1), 105–107 (2000).Crossref, Medline, Google Scholar6 Zanardi R, Serretti A, Rossini D et al.: Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry50(5), 323–330 (2001).Crossref, Medline, Google Scholar7 Pollock BG, Ferrell RE, Mulsant BH et al.: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology23(5), 587–590 (2000).Crossref, Medline, CAS, Google Scholar8 Ellison JM, Harney PA: Treatment-resistant depression and the collaborative treatment relationship. J. Psychother. Pract. Res.9(1), 7–17 (2000).Medline, Google Scholar9 Nemeroff CB: Improving antidepressant adherence. J. Clin. Psychiatry64(Suppl. 18), 25–30 (2003).Crossref, Medline, CAS, Google Scholar10 Sanders CE: Molecular genetics of mood disorders. In: Neurobiology of Mental Illness. Charney DS, Nestler EJ (Eds), Oxford University Press, New York (2004).Google Scholar11 Caspi A, Sugden K, Moffitt TE et al.: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science301, 386–389 (2003).Crossref, Medline, Google Scholar12 Vaswani M, Linda FK, Ramesh S: Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog. Neuropsychopharmacol. Biol. Psychiatry27, 85–102 (2003).Crossref, Medline, CAS, Google Scholar13 Mancama D. Kerwin RW: Role of pharmacogenomics in individualising treatment with SSRIs. CNS Drugs17, 143–151 (2003).Crossref, Medline, CAS, Google Scholar14 Rausch JL, Johnson ME, Fei YJ et al.: Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol. Psychiatry51(9), 723–732 (2002).Crossref, Medline, CAS, Google Scholar15 Serretti A, Artioli P: From molecular biology to pharmacogenetics: a review of the literature on antidepressant treatment and suggestions of possible candidate genes. Psychopharmacology174, 490–503 (2004).Medline, CAS, Google Scholar16 Bartoszyk GD, Hegenbart R, Ziegler H: EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322(2–3), 147–153 (1997).Crossref, Medline, CAS, Google Scholar17 Sullivan CG: How personalized medicine is changing the rules of drug life exclusivity. Pharmacogenomics5(4), 429–432 (2004).Link, Google Scholar18 The Hamilton Rating Scale for Depression. J. Operational Psychiatry10, 149–165 (1979).Google ScholarFiguresReferencesRelatedDetailsCited ByPharmacogenomics in Psychiatric DisordersRinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics, Vol. 40, No. 4 Vol. 6, No. 2 Follow us on social media for the latest updates Metrics Downloaded 309 times History Published online 24 November 2005 Published in print March 2005 Information© Future Medicine LtdPDF download

Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to Bedside

Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-gamma and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-gamma and IL-12. Prospective laboratory drug development plan that would produce human clinical trials. Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-gamma and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (-/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-gamma and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-gamma by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer.

Assessing Tumor-Related Signs and Symptoms to Support Cancer Drug Approval#

Cancer causes premature death and significant, often devastating, symptoms. While prolongation of survival is an obvious end point for new cancer drug approval, the US Food and Drug Administration (FDA) has also utilized end points that evaluate patient symptoms. In this article we discuss the end points, evidence, and analyses supporting cancer drug approvals based on evaluations of tumor-related signs and symptoms. With advice from the Oncologic Drug Advisory Committee (ODAC) in the late 1970s and early 1980s, FDA determined that acceptable end points for cancer drug approval were survival or an improvement in the quality of a patient's life, e.g., an improvement in tumor-related symptoms. This article summarizes 15 FDA cancer drug approvals based on patient symptom assessments and/or physical signs (thought to represent symptomatic improvement) as the primary evidence of effectiveness. These include painful bone events (three cases), cosmetic improvement in Kaposi's sarcoma and cutaneous T-cell lymphoma (six cases), the consequences (decreased transfusions, etc.) of long-duration responses in leukemias and lymphomas (two cases), relief of pulmonary or esophageal obstruction (two cases), and one case each of symptom benefit in pancreatic cancer (also associated with survival benefit) and pulmonary symptom benefit in lung cancer. An instructive example of an individual patient benefit end point is discussed, though it did not lead to a drug approval (the cisplatin–epinephrine gel application). Improved trial designs and analysis plans may allow greater reliance on morbidity assessments to support future cancer drug approvals. Drug sponsors are encouraged to include symptom assessments in cancer clinical trials and to perform further research to improve symptom-assessment methods. The FDA routinely meets with sponsors at End of Phase 2 Meetings to discuss drug development plans and the design of phase 3 trials. We encourage sponsors to request special protocol assessments (SPA) after meeting with the FDA to get written confirmation of the adequacy of plans for assessing cancer morbidity and quality of life, including protocols, end points, statistical analysis plans, and draft case report forms.

Accelerated Approval of Oncology Products: A Decade of Experience

We review the regulatory history of the accelerated approval process and summarize the U.S. Food and Drug Administration experience with accelerated approvals in oncology. The accelerated approval regulations, promulgated in 1992, allow approval of drugs for serious or life-threatening diseases on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit, such as survival or symptom benefit, pending completion of studies designed to confirm clinical benefit, referred to as phase 4 commitments, which are required to be conducted with due diligence. From 1992 to 2004, 22 applications involving anticancer drugs or biologics were approved. Of these 22 applications, accelerated approval was granted to 15 on the basis of findings from studies without an active comparator (i.e., single-arm studies or studies comparing two dose levels) and to the remaining seven on the basis of one or more randomized studies. Of the 22 approved applications, six (i.e., applications for dexrazoxane, irinotecan, capecitabine, docetaxel, imatinib mesylate, and oxaliplatin) have had one or more indications converted to regular approval. This review reports information that was presented at an Oncologic Drugs Advisory Committee meeting held in March 2003; it also presents a discussion of accelerated approval study designs, the study populations evaluated in the accelerated approval and confirmatory settings, and the integration of accelerated approval into a comprehensive drug development plan.