The Future of Drug Development
This article was originally published in SRA
Executive Summary
Advances in drug discovery and development will force sponsors and regulators to reassess the way in which they are approved, according to a new report. Peter Charlish investigates.
Advances in drug discovery and development will force sponsors and regulators to reassess the way in which they are approved, according to a new report. Peter Charlish investigates.
Peter Charlish is a contributing editor to The Regulatory Affairs Journals.
The traditional four-phase model of clinical development will become redundant if current trends in the way medicines are discovered continue. Instead, companies will be allowed to market new products much earlier, although on a very restricted basis, and subsequently be allowed to launch to a wider audience as clinical experience increases. That at least is the view expressed in a new report from management consultants PricewaterhouseCoopers (PwC)1.
The report comes amid concern that clinical trials as currently carried out are overly large and provide information only about the likely effect of a drug in large populations with the same or similar conditions. Unnecessarily large trials increase the cost of drug development and expose patients to unneeded or ineffective medications2. Furthermore, critics argue, physicians do not treat large populations, they treat individual patients.
However, at present the ability of doctors to treat patients individually is limited by a lack of suitable diagnostic tools to identify which patients are most likely to respond to a particular therapy. This is because, in the absence of an adequate understanding of the multifactorial causes of a particular disease, the development of techniques for distinguishing between patients with different disease subtypes is not possible. But that may be about to change as the number of clinical biomarkers being discovered continues to grow. The availability of such biomarkers will enable pharmaceutical companies to identify patients with otherwise indistinguishable variants of a particular disease and to develop specific treatments targeted at specific patient subpopulations. It will thus be possible to test new drugs only in those patients expected to benefit from it, meaning smaller and less expensive clinical trials and fewer unexpected side effects.
But why would anyone want to develop a drug to treat a restricted number of patients? The conventional wisdom is that, in order to maximise returns for the developer, a pharmaceutical product must be targeted at as large a patient population as possible. However, it is argued, targeted products will be able to command a premium price in recognition of their clinical superiority over conventional medicines. In addition, the PwC report suggests, biomarkers themselves will provide additional opportunities for creating value, and using biomarkers to monitor patients' progress can improve long-term compliance.
Emerging technologies
In parallel with the development of biomarkers, other technologies will emerge. Predictive biosimulation and other computer techniques will accelerate the identification and validation of drug targets and selection of candidates at one end of the R'D pipeline, while the use of wireless devices to monitor patients in real time, wherever they are, will broaden the scope of clinical trials at the other.
However, for all these novel technologies to be successfully exploited, a new approach to the development process, and a readiness on the part of regulators to adapt to the new paradigm, will be required. According to the PwC vision, a company would begin the development of a new medicine by determining the minimum amount and kind of information that it would need to be permitted to carry out “in-life” testing. It would then carry out a series of small but highly-targeted clinical studies to ensure that it understood the efficacy and safety of the product, before submitting the data to the regulatory agency.
Provided the regulator accepted the evidence, it would issue a “live licence”, which would authorise the company to market the product, but on a severely restricted basis. However, it could then begin to carry out in-life testing of the product in a small number of patients. As more data about the product's efficacy and safety accrued, the regulator would gradually extend the licence to cover a larger number of patients, a different patient population or additional indications. This approach would effectively render the traditional four-stage approach to clinical development obsolete.
Such a strategy would have a number of advantages, the PwC report claims. It would not only reduce clinical development costs overall but it would also enable companies to recover at least some of their costs earlier, which would allow them to charge lower prices for new products. It would make testing for polypharmacy in wider populations much simpler, and it would help to close the gap between the laboratory bench and the patient's bedside. It could even lead to the complete integration of clinical trials and clinical practice, as is already starting to happen in some areas.
Although these changes will require a considerable amount of goodwill on the part of regulators, PwC believes there are signs that this is already happening. Both the European Commission and the US Food and Drug Administration (FDA) have indicated that they are prepared to grant conditional marketing approvals under certain circumstances: Commission Regulation EC 507/2006 sets out the circumstances under which a conditional marketing authorisation may be granted for products for treating seriously debilitating or life-threatening conditions, products used in emergencies and orphan products3, while the FDA introduced the concept of the continuous marketing application as part of its five-year plan under the Prescription Drug User Fee Amendments of 2002 (PDUFA III)4.
So by 2020, PwC believes, all medicines will be approved on a real-time basis. As a condition for being awarded a live licence, a manufacturer would have to carry out trials in specific patient populations and follow a predetermined schedule for reviewing each set of results. Only if the safety and effectiveness of the medicine was demonstrated would the sponsor be granted an extended licence or permission to use the product in specific populations. This, PwC believes, will provide an incentive for further studies to be carried out and would lead to every medicine having a prearranged, automatic pathway throughout its life cycle, and the development process would in effect become a continuous process, instead of ending when approval is given.
Sponsor-regulator collaboration
Of course, such a model would require much greater collaboration between sponsors and regulatory agencies. Regulators would demand to be consulted regularly by sponsors and starting at a much earlier stage in the development process than currently. Here again, PwC believes, regulators' thinking is already moving in this direction. The FDA's Critical Path Initiative, which has the development of a new generation of tools for predicting drug efficacy and safety as one of its goals, has already demonstrated the agency's intention to become much more involved in the development process, it says. In the same way, one of the specific actions planned as part of the European Medicine Agency's (EMEA) Road Map to 2010 is to “stimulate research and innovation in the EU's pharmaceutical, biotechnology and healthcare industries, leading to the development of an adequate product development toolkit, able to address the bottlenecks during the development of innovative medicines”5.
Another example of this change already happening is the creation of the Innovative Medicines Initiative (IMI), a proposed partnership between the European Commission and the European Federation of Pharmaceutical Industry and Associations (Efpia). The IMI would fund research projects to tackle bottlenecks that slow down the development of innovative medicines.
As a quid pro quo for this streamlined approval process, regulators would increasingly demand evidence that new products are not just safe and effective, but also superior to comparable existing therapies (where they exist). In a background paper for its 12 April 2007 Arthritis Advisory Committee meeting, convened to discuss Merck & Co's Arcoxia (etoricoxib), the FDA said that “a new product that appears to have an increased overall risk profile for CV disease, particularly beyond that seen with other drugs in the class, would not be appropriate for marketing approval unless the product fills an unmet need for a particular patient population that has no relatively safer approved products available to them, and provides a reasonable risk to benefit balance for that patient population.”
Disclosure of study data
Worthy of particular note is PwC's prediction that in the future sponsors of drug trials will be obliged to disclose all data from clinical trials and in-life testing, irrespective of whether or not they are favourable. Companies will be required to submit information electronically, to submit data on adverse events to a website managed by an independent intermediary (to which prescribers will be given access), and be subject to additional scrutiny in the form of third-party auditing of all their activities, it believes.
The report also predicts that data on efficacy and safety will be shared among regulatory agencies to a much greater extent than currently, with a view to creating a better understanding of how individual medicines perform. It is even possible that by 2020 all such data will be managed in a single global database to which all regulatory agencies have access. Again, there are already signs that this is beginning to happen in the form of the EMEA/FDA Parallel Scientific Advice Meetings, which are designed to increase dialogue between the two agencies and sponsors from the beginning of the life cycle of a new product, promote a deeper understanding of the bases of scientific advice and avoid unnecessary testing replication or use of unnecessary diverse testing methodologies. Similar moves are reportedly underway in the Association of Southeast Asian Nations (ASEAN) region.
Taken to its logical conclusion, this trend would result in the establishment of a single, global regulatory authority, although this is probably very unlikely (especially given the recent problems in establishing a trans-Tasman regulatory authority). However, the PwC report suggests that by 2020 there could be one global regulatory system administered at national or regional level. Although such a system would be expensive to set up, in the long term it could “help to reduce the spiralling costs of regulatory compliance”.
References
1. PricewaterhouseCoopers, Pharma 2020: The vision - Which path will you take?, 2007
2. Gottlieb S, Speech before 2006 Conference on Adaptive Trial Design, Washington, DC, 10 July 2006, www.fda.gov/oc/speeches/2006/trialdesign0710.html
3. Official Journal of the European Union, 30 March 2006, L92/6-9
4. PDUFA III Five Year Plan, 2003, www.fda.gov/oc/pdufa3/2003plan/default.htm#cderplan
5. The European Medicines Agency Road Map to 2010: Preparing the Ground for the Future, 4 March 2005, www.emea.europa.eu/pdfs/general/direct/directory/3416303enexec.pdf