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At the end of this book, it is the place to draw a number of key conclusions. Information is provided and opinions are expressed in the 11 chapters describing the basic concepts of NBCDs, different NBCD and closely related product families, and analytical toolboxes for NBCDs. Going through the contents one can come up with a number of observations and conclusions. In this epilogue: ‘What did we learn? What can we expect in the future? Concluding remarks and outstanding issues’ we will discuss some of these observations and provide (a beginning of) some answers.

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.

propose a framework and list of indicators for measuring the value of PPPs in the pharmaceutical sector, based on a literature study and two international stakeholder workshops involving over 50 leaders from industry, academia, government and PPPs, in which the proposed indicators were discussed (see Supplementary information S1 (box)). The framework resulting from these discussions, which has four stages and four domains for value creation, is shown in FIG. 1, which also includes examples of measurable indicators. The four stages are: input, process, output and outcome. For the ‘input’ stage, indicators measure the ability of the PPP to bring together the people, funds and knowledge needed to create the network for collaboration. For the ‘process’ stage, indicators measure how the different parties in the partnership work together. The remaining two stages — ‘output’ and ‘outcome’ — assess the short-term and long-term results of (projects in) a PPP, respectively, with the aim of reflecting the complexity and long timelines of pharmaceutical R&D.

The Journal of Clinical PharmacologyVolume 50, Issue S9 p. 9S-19S Pharmacometrics as a Discipline Is Entering the “Industrialization” Phase: Standards, Automation, Knowledge Sharing, and Training Are Critical for Future Success Dr Klaus Romero MD, Corresponding Author Dr Klaus Romero MD Coalition Against Major Diseases, Critical Path Institute, Tucson, AZ Address for correspondence: Klaus Romero, MD, Coalition Against Major Diseases, Critical Path Institute, 1730 East River Road #200, Tucson, AZ 85718; kromero@c-path.org.Search for more papers by this authorDr Brian Corrigan PhD, Dr Brian Corrigan PhD Pfizer, New London, CTSearch for more papers by this authorDr Christoffer W. Tornoe PhD, Dr Christoffer W. Tornoe PhD Division of Pharmacometrics, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Jogarao V. Gobburu PhD, Dr Jogarao V. Gobburu PhD Division of Pharmacometrics, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Meindert Danhof PhD, Dr Meindert Danhof PhD Leiden-Amsterdam Center for Drug Research, Leiden University and Top Institute Pharma (TI Pharma), Leiden, the NetherlandsSearch for more papers by this authorDr William R. Gillespie PhD, Dr William R. Gillespie PhD Metrum Institute, Tariffville, CTSearch for more papers by this authorDr Marc R. Gastonguay PhD, Dr Marc R. Gastonguay PhD Metrum Institute, Tariffville, CTSearch for more papers by this authorDr Bernd Meibohm PhD, Dr Bernd Meibohm PhD University of Tennessee Health Science Center, College of Pharmacy, Memphis, TennesseeSearch for more papers by this authorDr Hartmut Derendorf PhD, Dr Hartmut Derendorf PhD University of Florida, Gainesville, FLSearch for more papers by this author Dr Klaus Romero MD, Corresponding Author Dr Klaus Romero MD Coalition Against Major Diseases, Critical Path Institute, Tucson, AZ Address for correspondence: Klaus Romero, MD, Coalition Against Major Diseases, Critical Path Institute, 1730 East River Road #200, Tucson, AZ 85718; kromero@c-path.org.Search for more papers by this authorDr Brian Corrigan PhD, Dr Brian Corrigan PhD Pfizer, New London, CTSearch for more papers by this authorDr Christoffer W. Tornoe PhD, Dr Christoffer W. Tornoe PhD Division of Pharmacometrics, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Jogarao V. Gobburu PhD, Dr Jogarao V. Gobburu PhD Division of Pharmacometrics, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Meindert Danhof PhD, Dr Meindert Danhof PhD Leiden-Amsterdam Center for Drug Research, Leiden University and Top Institute Pharma (TI Pharma), Leiden, the NetherlandsSearch for more papers by this authorDr William R. Gillespie PhD, Dr William R. Gillespie PhD Metrum Institute, Tariffville, CTSearch for more papers by this authorDr Marc R. Gastonguay PhD, Dr Marc R. Gastonguay PhD Metrum Institute, Tariffville, CTSearch for more papers by this authorDr Bernd Meibohm PhD, Dr Bernd Meibohm PhD University of Tennessee Health Science Center, College of Pharmacy, Memphis, TennesseeSearch for more papers by this authorDr Hartmut Derendorf PhD, Dr Hartmut Derendorf PhD University of Florida, Gainesville, FLSearch for more papers by this author First published: 07 March 2013 https://doi.org/10.1177/0091270010377788Citations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume50, IssueS9Special Issue: The Emerging Scientific Discipline of PharmacometricsSeptember 2010Pages 9S-19S RelatedInformation

Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) interfere with cyclo-oxygenase-mediated synthesis of prostaglandins, resulting in the inhibition of inflammatory immune responses. In contrast, it is known that NSAIDs are able to induce gastrointestinal damage. Our aim was to investigate whether NSAIDs are able to enhance sensitization or abrogate tolerance to food antigens. Mice were exposed to diclofenac and sensitized to peanut using cholera toxin as a mucosal adjuvant. In a tolerance model, oral tolerance was induced via feeding of peanut 3 weeks before sensitization with peanut. Diclofenac was administered before peanut feeding. After 4 weeks, peanut-specific antibodies in the serum and cytokine production in the spleen were measured. Induction of intestinal damage after oral exposure with diclofenac and peanut + cholera toxin was examined microscopically. Diclofenac-exposed animals showed increased levels of peanut-specific IgG1, IgG2a and IgE in the serum compared with vehicle-treated animals. Furthermore, peanut-induced cytokine production in the spleen was elevated upon diclofenac treatment. Importantly, diclofenac did not induce peanut-allergic responses in the absence of the cholera toxin, although exposure to diclofenac and peanut + cholera toxin resulted in intestinal epithelial damage. Reduced peanut-specific antibody production in the case of oral tolerance was not reversed after diclofenac exposure. However, oral tolerance, as measured by inhibition of peanut-specific cytokine responses, was reverted by diclofenac. These data point towards an increased risk for induction of food-allergic responses by diclofenac, when other circumstances are also in favour of induction of allergy.