Backroom Work is What Drives the Real Drug Development Process

Recent high-profile speculation about the post-Brexit location of the European Medicines Agency (EMA) or the personality and program of the new head of the World Health Organization (WHO) naturally distracts attention away from some of the less glamorous work that is done in protecting and maintaining human health. The hands-on effort made day after day by countless scientists, technicians and officials engaged in drug development is a case in point. Down in the engine-room where safe and effective medicines are created and tested and controlled, there may not be the same sweeping views of the policy horizon as are enjoyed by those on the bridge. But without all those unremitting efforts, progress would stall, the vessel-no matter how well piloted-would lose way, and the journey would come to an end.

So alongside the celebrations (and commiserations) over the election of the Ethiopian health minister as director-general of WHO, the World Health Assembly in Geneva in May also took a careful and workmanlike look at some aspects of researching medicines, particularly for the developing world. A new Global Observatory on Health Research and Development is being created “to consolidate, monitor and analyze relevant information on health research and development needs.” 

Six pilot projects will evaluate research into visceral leishmaniasis, open-source collaboration to accelerate drug development, affordable biomarkers, schistosomiasis vaccines, point-of-care tests for acute febrile illness, and the potential of a single-dose malaria cure. An Expert Committee on Health Research and Development will recommend priority areas for research and development of specific health products and technologies-such as an innovative vaccine against pulmonary tuberculosis in adults. And a $100 million a year R&D fund was discussed, with a portfolio of 35–40 projects ranging from repurposing existing medicines to the search for effective new chemical entities.

 In Europe, the EMA has just completed the first year of its experimental program to speed promising medicines to patients, known as PRIME. The scheme engages with medicine developers early on, to improve clinical trial designs and raise the chances that the data generated will support successful marketing-authorization applications for products where there is evident unmet need.

 On the face of it, the experiment might seem to be less than a breakthrough, since crude numbers show that of the 96 requests made to join the scheme, 71 were rejected. But looked at another way, the figures suggest that the scheme is being applied exactly as intended, with a scrupulous process of ensuring that resources are focused on the most appropriate candidates. The rejections were largely because supporting data for the product presented were not sufficiently robust, with insufficient justification of therapeutic advantage the second major reason. Others were rejected because development was simply too advanced for PRIME to have any useful role.

The 20 products that were accepted were the consequence, therefore, of careful selection. They included 12 advanced therapies (of which eight were orphan drugs), two biologics, five chemical entities and one vaccine. In total, one in three of the chosen products targets a condition for which no treatment exists. The results were not achieved by accident.

Getting the right products through the system more quickly is only part of the challenge, and just one part of the job. There is a similarly vital infrastructure aimed at making sure that products, once authorized, continue to deliver safely. Take, for instance, the efforts made to keep a better check on how drugs perform. Years of painstaking work to put in place a functioning European adverse reaction reporting system has just been completed, and as from November, companies and national authorities will be required to submit electronic reports of suspected side effects to the EudraVigilance database. This will provide greater oversight of suspected reactions, permitting faster detection and response, and replacing the obligation for multiple reporting to multiple authorities with a single transmission to a central point.

Setting up the new European system for keeping tabs on clinical trials, to take effect late 2018, is similarly dependent on a laborious and meticulous process of preparation and checking far removed from the high-flown rhetoric that characterized the initial policy debates. A new guideline from the EMA sets out how notifications should be made of serious breaches of clinical trial protocols or other deviations from the rules. Drafted by Europe's inspectors of good clinical practice, it has just been released for public consultation (until late August). Again, the approach is the consequence of a refined and detailed assessment of how to get the best results for everyone involved-even at the price of a lot of complexity.

The guideline puts some flesh on the bones of the regulations, which require sponsors to notify serious breaches of the rules without undue delay. It helpfully defines a “serious breach” as “a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial.” And it spells out that notifications must be made through the new EU CT portal when it is up and running. While the application for CT authorization is under evaluation in the EU, serious breaches elsewhere that could impact the accuracy or robustness of data in the application should lead to the sponsor withdrawing the application.

The guidance also clarifies who should notify-in essence, the sponsor-and expands on when the notification should be made: within seven calendar days of the sponsor (or a contractual agent) becoming aware of the breach. Sponsors and CROs will need to ensure that there is a documented process in place for timely communication on serious breaches between the parties so that reporting meets the seven-day deadline, it says. Processes also need to be in place so that if a principal investigator is aware of the occurrence of a serious breach, the information can be promptly reported to the sponsor. And where there are reasonable grounds to believe that a serious breach has occurred, the sponsor should not only report, but investigate and take action, without awaiting all details. 

There is a recognition that many deviations from clinical trial protocols and GCP are merely technical deviations that result in no harm to trial subjects or significantly affect the value of the results. "Not every deviation from the protocol needs to be reported to the EU CT system as a serious breach." For instance, if a subject took an investigational product that had expired two days earlier, but the product was stable and there were no adverse events or likely impact on the data credibility of the trial, this would not be a serious breach. Instead, it is enough to document them (in the trial case report form, the trial master file, or the clinical study report) and to take appropriate corrective action. The judgement depends on factors such as the design of the trial, the extent of the data affected, or the overall contribution of the affected data to key analysis parameters.

But some cases are clear-cut: if an overdose occurred due to a miscalculation, this would be a serious breach regardless of whether or not adverse reactions ensued. And all confirmed instances of clinical trial fraud qualify as serious breaches. So, too, does persistent or systematic non-compliance with GCP or the protocol

The level of detail is necessary for the efficient functioning of any of these subsystems to the development and monitoring of medicines-whether in research labs or regulatory affairs or among official bodies, and it is possible only because of the unsung heroes who work in the background. 

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium