8.3 Barriers to innovation in pharmaceutical research and development
The impetus for this Project arose from the various reports issued between 2000 and 2003 (Appendix 2). Coincidentally, three papers were published in March 2004 by the EMEA and FDA (Appendix 8.3) and by Michael Rawlins in Nature(Appendix 8.3.4). In addition, a paper prepared by individuals working in the pharmaceutical industry was prepared for this Report (Annex 8.3). These papers all maintained that the present costs and time spent in developing new medicines were unsustainable. The authors suggested similar but slightly different solutions to the main barriers with the EMEA, FDA and Rawlins papers focusing on regulatory obstacles, while the industry paper was broader.
In recent years, the cost[1] and duration of medicines development have increased and this has been coupled with low output of innovative medicines from the pharmaceutical pipeline.[2]Recent estimates suggest that it costs nearly US$ 1 billion for each new chemical entity and takes 10 to 15 years on average from discovery to market authorization. While there may be many projects in early development stages, the fact remains that little of this potential innovation is being translated into market approvals. For some diseases, there remains an inadequate understanding of basic science, and potential targets for medicines development have not been identified.
Regulatory barriers
All authors agreed that every aspect of the regulatory process should be re-examined and that the evidence base for regulatory practices should be critically analysed using modern methodologies. In particular, this includes preclinical regulatory "rituals." For clinical research, there is a suggestion from Rawlins that alternatives to randomized controlled trials should be investigated. Under some circumstances, he suggests, historical controls could be utilized and alternative analytical statistical techniques using Bayesian statistics could be used to analyse data. A key recommendation of all the authors is the need to improve communication between industry, physicians and regulators in the regulatory process.
What is particularly striking about the EMEA, Rawlins and FDA papers are two significant omissions. Apart from the industry paper, none of the three regulatory papers mention any role for patients in the regulatory process. They are referred to as beneficiaries of the process but never as contributors to the decision-making. This is surprising as patients have been very influential in the rapid authorization of AIDS medicines and in the orphan drug movement. It is not clear how patients could be most effectively involved in promoting innovation and removing barriers but this is clearly an area for research. The second striking omission is the absence of any discussion of post-marketing surveillance as a critical component of the overall process. The FDA diagram of the stages of the medicine development process omits Phase IV from its description of all of the steps in medicine development(seeFigure 8.3.1 in Background Chapter 8.3).
Medicines development process
Preclinical studies:Most of the tools used for toxicology and human safety testing are decades old and may fail to predict the specific safety problem that ultimately halts development or that requires post authorization withdrawal.Each aspect of preclinical safety studies (pharmacological ‘screening’ for unintended effects; pharmacokinetic investigations in species used for toxicology testing; single- and repeat-dose toxicity testing; and special toxicology testing (such as mutagenicity) has not been rigorously tested by a robust analysis of its predictive power. The FDA has suggested that scientists working within regulatory agencies have a wealth of application data available to undertake such a critical review.
More generally, there are too few analytic tools (e.g., analytical devices, assay systems, surrogate markers and cell culture methods) to assist in providing medicine safety and effectiveness studies more quickly, with more certainty, and at lower cost. Key enabling technologies involving the use of animals and the use of human tissue in biomedical research are subject to complex regulation. Any increase in complexity of regulation or indeed blocking of access to these technologies by public opinion pressures has the potential to seriously disrupt basic and applied biomedical research.
Clinical development: Regulatory authorities are becoming more risk-averse. This lack of flexibility only entrenches the existing regulatory requirements and perceptions, and often results in the need for expanded studies to quantify potential adverse events. Many requirements of medicines regulatory authorities are based on the opinion of experts, rather than on a robust body of evidence to support the continuing inclusion of each measure as a regulatory requirement.Randomized, controlled, blinded, parallel-group clinical trials are not the only possible approach to investigating the safety and efficacy of a new medicine. It may be that new methodological research to critically evaluate alternative approaches, including actual experiments comparing novel and traditional (RCT) designs, will find that medicines development can be made more efficient without sacrificing safety and efficacy. Such alternative approaches have been successfully used for high risk diseases such as cancer or AIDS where accepting results from limited size studies combined with post-authorization monitoring have allowed products to come to market far more quickly than by conventional approaches. The role of patient groups in the AIDS example cannot be underestimated. Indeed, patients and patients’ organizations could be equal stakeholders participating in decision-making processes that occur in all aspects of pharmaceutical innovation including: clinical trials design; regulatory processes; treatment guidelines; marketing and pricing of medications.
There is often poor communication between the industry, physicians, and regulators during medicines development. This results in requests for additional data and regulatory questions following submission, and in turn these requests lead to increasing unpredictability of outcomes and delays in the marketing authorization process.Payers do not interact with the industry at an early enough stage in the development process.
Post-marketing studies: In the four papers mentioned above, none deals with the important role of post-marketing surveillance.In practice, there is relatively scant attention paid to Phase IV post-marketing studies or systems. Computer-based registries of patients and their clinical outcomes do not presently have sufficient data on both incidence of exposure to the medicine and of adverse events in long-term, post-marketing studies of the risks and benefits of medicines. European countries with their national reimbursement systems are in a strong position to develop such integrated systems while preserving patient confidentiality.
Reimbursement mechanisms: A lack of predictability about the timing and level of reimbursement decisions leads to uncertainty among stakeholders. In Europe, each national reimbursement system is primarily responsible for cost containment. This is achieved by setting prices at a level that may not fully reward innovation and sometimes by delaying decisions about reimbursement. These problems lead to companies choosing to launch their products in the USA which, at present, has no such single national system or government-based price control system.
Within its Sixth Framework Programme, the European Commission has recently called for research proposals that include new approaches for accelerated development of new, safe and more effective medicines. Bottlenecks and barriers in the current medicines development process are to be identified and solutions elaborated to overcome them. The project is expected to involve a range of stakeholders, such as academia, clinicians, patient organizations, large and small industry, regulatory and ethics specialists(Appendix8.3.3).
As part of this call for proposals, it is recommended that the EU should create and support a broad research agenda, so that every requirement within the medicines development process,whether clinical or preclinical, is questioned for its regulatory relevance, costing and predictive value. The involvement of the EMEA and the various European national regulatory agencies and their scientists appears to be critical to the success of this key initiative.
[1]DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003;22(2):151-185.
[2]Aspden P, editor. Medical innovation in the changing healthcare marketplace: Conference summary. Washington, D.C.: NationalAcademy Press; 2002. Available from: 2 August 2004).