The risk-based approach to ATMP development - generally accepted by regulators but infrequently used by companies.

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, "Do companies use a risk-based approach for the non-clinical development of ATMPs?" and, secondly, "Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?" Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.

The cost-effectiveness of periodic safety update reports for biologicals in Europe.

We analyzed the cost-effectiveness of all Periodic Safety Update Reports (PSURs) submitted for biologicals in Europe from 1995 to 2009 by comparing two regulatory scenarios: full regulation (PSUR reporting) and limited regulation (no PSUR reporting, but all other parts of the pharmacovigilance framework remain in place). During this period, PSUR reporting resulted in the detection of 2 out of a total of 24 urgent safety issues for biologicals: (i) distant spread of botulinum toxin and (ii) edema/fluid collection associated with off-label use of dibotermin-alfa. We used Markov-chain life tables to calculate costs and health effects of PSURs. The incremental cost-effectiveness ratio (ICER) of full regulation (PSUR reporting) vs. limited regulation (no PSUR reporting) for the base-case scenario was \[euro]342,110 per quality-adjusted life year (QALY) gained. It is possible to assess the cost-effectiveness of regulatory requirements using the same methods as those used in assessing the cost-effectiveness of medical interventions.

The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies.

We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~€2.4 million per sudden cardiac death prevented and ~€187,000 per quality-adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost-effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures.

The sponsored pandemic of the Mexican flu?

The first reports of the New Influenza A (H1N1) spoke of a markedly increased morbidity and mortality. Later it turned out that this flu was a very mild flu. Gradually the role of the WHO was questioned. The definition of a pandemic flu had been changed and there rose doubts about the independency of the experts advising the WHO. It showed that some of these experts had a conflict of interest with the pharmaceutical industry, especially with those producing vaccines and neuraminidase inhibitors. As of june 2010 the WHO declared the outbreak to be a pandemic. This provided the momentum to produce vaccines. At the outbreak of the pandemic in the northern hemisphere, there was sufficient evidence that the pandemic would not be so serious, that a single vaccination was sufficient, that there were strong doubts about the efficacy of oseltamivir and that the drug, although rarely, could have serious side effects. With the stockpiling of neuraminidase inhibitors and with the recommendation of the vaccination political decisions were involved. These decisions should be driven and supported by independent scientific advisory bodies with no room for even the semblance of conflicts of interest. Stronger measures to limit the impact of experts with conflicts of interest on the development of, among others, guidelines are necessary.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.