Speeding Things Up 

Pharmaceutical regulatory bodies worldwide have increasingly encouraged expedited regulatory pathways for the approval of new drugs and this has created opportunities for the industry and its suppliers, though there are many challenges to overcome. Such was the message from a keynote session at the American Association of Pharmaceutical Scientists annual meeting in Denver on 14 November.

In the US, noted Jonathan Jarow, managing director of the FDA’s Center for Drug Evaluation & Research (CDER), there are now four main programs for expedited development and review: Fast Track Designation, Breakthrough Therapy Designation (BTD), Priority Review and Accelerated Approval. Each was brought in between 1992 and 2012 by one or more items of legislation.

They vary but share a few basic common features of addressing serious or life-threatening conditions and meeting unmet medical needs. As Alan Poirier of Pfizer’s US Regulatory Policy & Global Intelligence Unit noted, “Expedited pathways were created for drugs which demonstrate potential to significantly improve lives, where the standard of care is inadequate.”

The industry has already used these pathways extensively. Of 193 CDER approvals of new molecular entity (NME) regular drugs between January 2008 and September, 35% used one or more of the programs. Of the 109 rare disease drugs, 86% did. BTD is becoming particularly common, with 388 requests to date, of which 137 were granted (64% in oncology, anti-virals and haematology) and 52 of these approved; 186 were denied and six rescinded by the sponsor.

With expedited pathways, Poirier noted, different types of regulatory flexibility can be brought into play at different times: greater regulator involvement and guidance with development plans, faster review, approval based on surrogate or intermediate clinical endpoints (although with post-approval commitments), approval on limited data and other tools, such as waivers, incentives and vouchers.

The European Medicines Agency (EMA), Japan’s Pharmaceutical & Medical Devices Agency (PMDA), Swissmedic, Health Canada and Australia’s Therapeutic Goods Administration all have different and sometimes multiple expedited pathway programs. They are generally less comprehensive than the FDA’s but Jarow believes that Europe and Japan are moving towards convergence with the US.

Expedited pathways enable clinical development and review to be accelerated at almost any stage from Phase Ib, Poirier said. Such tools also require more and earlier interactions with the regulator and the benefits depend in large part on the timing. There have been real world examples of early interaction changing sponsors’ thinking.

Where a BTD is sought with pivotal data for future submission to expedite the review process, the agency may suggest a submission strategy or advise a rolling submission, advise on methodologies to bridge the data between multiple studies, or offer flexibility in timing for pre-submission meetings and inspection. Where a BTD is sought with early data for expedited development, the agency can offer design guidance on an efficient development program, influence the study design, database size or endpoint selection or help the sponsor to expedite the manufacturing process.

Jarow agreed that expedited programs raise cross-disciplinary issues. They are largely focused on clinical development. Thus, the traditional phases can be disrupted – for instance, stability testing at Phase III if the drug is approved at Phase I, as many are.

Similarly, quality can be affected by the altered timeline of manufacturing development and the use of investigational lots to bridge gaps. The stability data may be immature or the assay development incomplete when a Biologics Licence Application (BLA) is submitted. There is a risk of inappropriate acceptance criteria being based on a small number of lots, while short expiry periods and high demand can create inventory challenges.

Nonetheless, it is working – for all six main regulatory agencies in every year from 2011 to 2015, approval times were faster for expedited than standard approvals, by anything from two months (PMDA) to six (EMA). Studies suggest that expedited review could save over two years in Phase I-III as well. This, Jarow and Poirier agreed, could yield significant savings to the industry when approval takes 11 to 14 years and, if anything, has got longer in recent years.

“The benefits of expedited pathways are clear,” Poirier said. “They recognise the disease impact on patients, as they are reserved for serious diseases and conditions. They create a shared urgency between agency and sponsor, with aligned incentives, more design advice and more efficient, while still rigorous, trials. And patients get earlier access to new treatments.”

Expedited pathways also pose challenges, however. Early studies may become pivotal and trigger pre-submission discussion, there will be a rapid turnaround requirement on information requests and the review clock may be as little as a few months. At-risk investments may be required to prove that the sponsor can make the product and has addressed non-clinical and other issues and internal governance processes may need to be condensed.

“The benefits are clear but the challenges must be addressed in early planning,” Poirier warned.“ That means the sponsor must build the strategy into the drug program before clinical testing in terms of agreed decision points and resourcing, CMC, toxicology, clinical, regulatory, market access and patient views and preferences.”

Jarow concluded by noting that of the recent BTD designated products that were NMEs or BLAs, 91% have been approved but added that this rate was 93% for those that were not BTD-designated. “The FDA can give priority review to a product even if it is not requested and this figure shows a pretty good track record of anticipation,” he said.