By Deborah Borfitz

May 18, 2021 | The pandemic has put the spotlight on agencies around the world overseeing the conduct of clinical trials as well as advanced efforts to harmonize their separate sets of regulations, according to Aman Khera, global head of regulatory strategy at Worldwide Clinical Trials, a contract research organization (CRO) based in Research Triangle, North Carolina. There has never been a better time to develop a regulatory strategy that factors in all the new moving parts and engages agencies early and often to stay on track.

Regulatory agencies, historically viewed as “the ‘no’ people,” have proven themselves to be compassionate collaborators looking to help rather than hinder the development of medicines with data-gathering obstacles, including limited patient population size, Khera says. They can be surprisingly supportive resources for sponsors and researchers.

It is easy to get out of step with current realities, says Khera, a 24-year industry veteran nicknamed the Rebel Regulator for her dogged determination to have the regulatory voice be heard. Continuous monitoring of the regulatory landscape is the only way to stay up to date given the breakneck pace of change over the past year. At one point, a policy change was being made about every few days somewhere in the world.

Sponsor companies appear uncertain about which interim stances of regulators will stick over the long term, she says, and some still mistakenly believe an Emergency Use Authorization (EUA) is a pathway to product launch rather than a measured response to a public health emergency. CROs are particularly well positioned to see the regulatory forest for the trees because of their work with regulators across different regions and therapeutic areas.

“CROs typically have to be quite reactive but during COVID-19 we have shown industry and sponsor companies how strategic we can be,” says Khera. Among the regulatory intelligence coming from Worldwide Clinical Trials was a tally of the differences and commonalities from one agency to the next.

At the height of COVID-19, when even the websites of regulators were periodically out of date, the International Coalition of Medicines Regulatory Authorities (ICMRA) became an invaluable source of up-to-the-minute information, Khera says. Established in 2012, ICMRA brings together senior executives at regulatory agencies in 34 nations to support enhanced communication, information sharing, and crisis response as well as address regulatory science issues. The group had been meeting face to face twice annually but since last spring has been holding strategic meetings virtually every two weeks to discuss international alignment on COVID-19 policies.

Holistic Thinking

As a regulatory strategist, Khera routinely shares the “tone and tenor” of various regulatory agencies with sponsor companies, she says. She also makes it her business to understand how best to navigate agencies based on product type and indication.

Sponsors are of course anxious to get clinical trials up and running, but she encourages them to invest a little extra time engaging regulatory agencies on the front end for the downstream benefits. Not only are regulations at the “center of everything we do as an industry,” Khera says. Regulators are also more collaboratively minded today than ever before.

Ideally, regulatory strategies look holistically across multiple regions of the world rather than in silos, she adds. She suggests that companies engage regulatory bodies in parallel and be transparent about it, to unearth any untapped opportunities to harmonize the drug development process.

Sponsors developing gene therapy products will sometimes needlessly avoid placing trials in Europe due to perceptions that regulatory requirements there are more rigid than in the U.S., says Khera. After the Food and Drug Administration (FDA) has weighed in with its requirements, her suggestion would be to seek the advice of national scientific advisors with an agency in a country such as Germany or France or perhaps with the European Medicines Agency (EMA). The guidance companies receive is far more valuable than what they could glean from static documents posted on agency websites, she adds.

In the U.K., the Medicines and Healthcare products Regulatory Agency (MHRA) is reestablishing itself as a “powerhouse” regulatory agency, Khera notes. MHRA earlier this year launched a new accelerated drug approval pathway involving an “Innovation Passport” sponsor companies fill out to explain how their candidate drug treats a life-threatening condition or meets a significant public health need. A team of experts is available to help companies build a target development profile roadmap for their drug.

“I highly recommend that sponsor companies consider this or even seek advice from the MHRA Innovation Office that provides free and confidential expert regulatory information, advice, and guidance because… it is a chance to get another voice from regulatory agencies,” Khera continues. Taking either the Innovation Passport or Innovation Office advice route may delay the start of clinical trials by a few months, but the feedback sponsors receive will be “priceless.”

In addition to the U.S. and Europe, clinical development teams need to be eying Asia, says Khera. China has “completely revamped” its clinical trial regulations over the past few years and the reforms include a fast-track approval process that has whittled months off the time it was taking trials to pass regulatory review a few years ago.

Expedited Review

Multiple countries have initiatives designed to improve review timelines, Khera notes. Pre-pandemic, Canada Health was financially penalizing itself for missing performance time goals on clinical trial applications. The policy was paused when COVID-19 hit, but review timeframes of necessity shrank from six months or more to six weeks or less.

Globally, the trend has been to increase the number of submissions being done under expedited review, with the FDA leading the charge, she says. Agencies are also conducting some reviews in parallel, as for example the FDA, Therapeutic Goods Administration (Australia), and Health Canada are doing in the oncology space with Project Orbis and the FDA and EMA are doing for orphan drugs.

Expedited regulatory pathways are now available in the U.S., European Union (EU), Japan, and China, says Khera. Options at the FDA include the breakthrough and fast track therapy designations as well as Accelerated Approval Program that allows the use of a surrogate endpoint. Priority review can also shorten the standard application review period by four months.

Five expedited pathways are available in the EU and tend to occur toward the end of the drug development journey, she continues. These include the EMA’s accelerated assessment for therapeutically innovative products that shortens approval times to within 150 versus 210 days. Others are authorization under exceptional circumstances (for rare diseases), adaptive pathways/licensing (leveraging real-world data), conditional marketing authorization (temporary, one-year approval), and PRIME scheme (a scientific advisory approach “quite advantageous for sponsors in early clinical development stages”).

“Japan’s regulatory landscape aligns somewhat with the EMA and the FDA,” Khera says. The priority review pathway shortens the review period from 12 to nine months for orphan drugs, the conditional early approval system speeds the process for drugs targeting serious conditions affecting small patient populations, and the Sakigake designation aims to shorten the review period from 12 to six months for innovative medical products first developed in Japan.

China’s regulatory environment is less aligned with the EMA and FDA, she says, but China joined the International Council for Harmonisation (ICH) as a full regulatory member in 2017. Approval from the National Medical Products Administration to conduct a clinical trial in the country, which used to take roughly two years, can now be accomplished in 60 working days.

Regulatory Alignment

Industry of course welcomes better alignment of regulations on an international scale, and multiple groups have been working toward that goal for years now, Khera says. Among them are, most notably, the ICH, as well as ICMRA, the International Pharmaceutical Regulators Programme, the Pharmaceutical Inspection Co-operation Scheme, and the Asia-Pacific Economic Cooperation.

Greater regulatory alignment is going to make life easier, Khera says, although companies can expect a few bumps during transition periods between old and new systems. She points specifically to the new Clinical Trial Regulation of the EMA that after years of delays is finally set to go live early next year.

The sweeping new regulation creates consistent rules for conducting clinical trials throughout the region and one entry point for submitting clinical trial information. “Agencies will now have to sit down and talk among themselves before they come back with a decision,” says Khera. “How cool it that?”

Companies will have three years to transition away from the old procedures under the existing EU Clinical Trial Directive, she says. It is the responsibility of sponsor companies to ensure compliance.

Regulatory agencies have been acting more in “real time” during the pandemic, and companies need to be mindful of the framework in which the many new guidances have been written and revised, says Khera. The new normal catalyzed by COVID-19 now must be extrapolated to other therapeutic areas, including rare diseases and oncology, which need the help.

Guidances issued by regulatory agencies may be refined post-pandemic but are unlikely to be reversed entirely, Khera says. As a result, clinical trials are going to become more decentralized and thus more patient-focused and more easily meet their recruitment targets.

Khera frequently must remind sponsors that they cannot develop drugs on an EUA pathway because it does not exist. “You are not going to have a pre-EUA meeting but a pre-IND meeting [with the FDA],” she says. It is up to regulatory agencies if a product gets authorized for emergency use.

EUAs, and similar emergency use authorization procedures in other regions of the world, are not shortcuts in drug development but require additional assessments and reviews, says Khera. Data from real-world experience with the product would ultimately get bolted on to any New Drug Application that gets submitted to the FDA.