Regulatory experts offer top tips for working with regulators.
Regulatory agencies recognize that patients with serious or rare conditions can derive clinical benefit by gaining access to potentially transformative therapies as soon as possible. In addition, public health emergencies such as the COVID-19 pandemic require expedited action to bring therapies and vaccines to market quickly and safely. Regulatory authorities across the globe have developed expedited pathways to facilitate the development of new drugs or products for such conditions, and sponsors may pursue more than one of these expedited pathways in parallel. As the criteria for these designations overlap within and across regions, many sponsors seek to harmonize applications for expedited regulatory pathways and streamline the often intense required workload.
To provide an in-depth look at how to craft a harmonized strategy for expedited regulatory approval across regions, Applied Clinical Trials (ACT) hosted a roundtable discussion, sponsored by Parexel Biotech. Parexel regulatory experts from the United States, Europe, and China shared their experience as former regulators for selecting the right expedited regulatory pathway for a harmonized global program. They shared top tips for overcoming the specific challenges associated with different regions, working strategically with regulators, and identifying the right evidence for marketing approval.
Participants in the ACT panel discussion were:
SUITABILITY FOR EXPEDITED REGULATORY PATHWAYS
LISA: What types of clinical development plans are suitable for expedited regulatory pathways?
Lucas: Within the United States, expedited programs are intended for drugs developed to treat serious, life-threatening disorders with unmet medical needs. Some conditions that the U.S. Food and Drug Administration (FDA) considers to be serious include AIDS, Alzheimer’s disease, heart failure, cancer, epilepsy, major depressive disorder, and diabetes. Suitable drugs would affect survival, day-to-day functioning, or disease progression for such conditions.
To meet the criteria of unmet medical need, a new drug or product should provide a therapy where none exists or be potentially better than current standard-of-care. A better therapy must do one or more of the following: show superior effectiveness, have fewer side effects, have a lower discontinuation rate, or result in earlier diagnosis for a condition in which early diagnosis affects patient outcomes.
The FDA also uses expedited programs to prioritize and focus on drugs or products that need to get to market quickly during public health emergencies, such as the COVID-19 pandemic. Finally, the Orphan Drug Designation is used to efficiently bring new therapies to market for rare diseases, which are defined as those that affect fewer than 200,000 people within the U.S. population.
Yajie: The situation is similar in China. Expedited regulatory pathways are in place for drugs or products that treat life-threatening diseases, rare diseases, and diseases that constitute a public health emergency. What is unique to China is that there is no dedicated pathway specifically for rare diseases, such as the U.S. or E.U. Orphan Drug Designation. In addition, unlike in the U.S. or E.U., special emphasis and priority are given to pediatric drugs and products in China.
Bridget: The principles in the E.U. are similar to those in the U.S. in that suitable drugs or products must address an unmet medical need and target a seriously debilitating or life-threatening disease or a rare disease, or they must be intended for use in emergency situations in response to a public health threat.
HARMONIZING APPLICATIONS ACROSS REGIONS
LISA: Can a company harmonize applications to similar expedited pathways across different regions?
Bridget: First, it is important to fully understand the similarities and differences among pathways available in various regions. For example, the Priority Medicine (PRIME) designation in the E.U. shares objectives with the U.S. Breakthrough Therapy Designation, both are suitable for drugs or products that have the potential to address an unmet medical need (Figure 1). There are key differences, however. PRIME is intended to help sponsors at an early stage with a promising drug. PRIME sponsors present proof-of-concept data and/or early clinical data, and the European Medicines Agency (EMA) will actively assist during drug development. The U.S. Breakthrough Therapy Designation request requires clinical data, and the breakthrough therapy application can be submitted later in development than PRIME.
Another example of pathways with nuanced similarities and differences is orphan drug designation (Figure 2). Although the programs share the same name in the U.S. and E.U., the requirements are more stringent in the E.U. because the rare disease itself needs to be life-threatening or chronically debilitating. This is not the case in the United States.
Lucas: Let us consider the various conditional approval pathways as well (Figure 3). Companies frequently equate the Accelerated Approval pathway in the U.S. with the Conditional Marketing Authorization in the E.U. or the Conditional Approval pathway in China because all three pathways involve surrogate endpoints to predict the benefits of a drug or product. It is critical to understand that a surrogate endpoint that is considered acceptable by the EMA may not be considered acceptable by the FDA or the National Medical Product Administration’s (NMPA) Center for Drug Evaluation (CDE). Close collaboration across the regions is required to avoid performing multiple different studies to satisfy different agencies.
I encourage companies to leverage cluster meetings whenever possible. These regular meetings are held by phone or videoconference between regulatory agencies. The agencies share information about applications for marketing authorization, extensions of indications, clinical trial design (including surrogate endpoints), risk management plans, and evaluation of safety signals.
Yajie: One caveat that companies may not be aware of when applying for expedited pathways in China is a specific requirement for Chinese data. A company cannot use foreign data in the application unless there are also data from studies performed in mainland China. The one situation where this may not be as stringently enforced is in an application for pediatric and/or rare disease drugs or products, which may be permitted to rely on foreign data.
China also has an extremely rapid priority review pathway called Special Review Procedure that does not have a direct equivalent in other countries’ priority review pathways (Figure 4). This pathway is specific to drugs and products treating diseases that constitute public health emergencies, such as COVID-19 or H1N1 influenza. This pathway has a first-round technical review duration of only 15 calendar days, not working days. The sponsor will be expected to provide a daily report of updates to the agency. This requires a very nimble and dedicated team.
ADDRESSING REGION-SPECIFIC CHALLENGES
LISA: What are some of the challenges specific to expedited pathways in different regions?
Yajie: In recent years, Western companies have become interested in marketing in China, given that the Chinese pharmaceutical market is the second largest in the world. These companies would like to be able to leverage Western or foreign clinical data to support applications for marketing approval in China. However, as I mentioned already, the CDE has stringent requirements for the inclusion of data from studies conducted in China. If a company has no plan to capture Chinese data in their clinical trials, it will be difficult to gain approval in China. The minimum requirement is that, in general, at least 15–20% of the total study population of a pivotal clinical trial should be recruited from mainland China. In addition, the results from included Chinese patients must demonstrate consistency with the results seen in the overall study population. The only exceptions the CDE might consider would be for rare diseases or pediatric indications.
Lucas: In the United States, innovative rare disease programs tend to rely heavily on expedited pathways. When designing a rare disease clinical trial, companies try to get the most information out of the fewest number of patients because of difficulties with recruitment. Many of the resulting trial designs can present regulatory challenges. For example, a company might perform an open-label trial where the control cohort is drawn from a real-world natural history study. Those data may not be transferable from one region to another because of inherent issues that generate bias, such as differences in the standard-of-care or use of concomitant medications in different regions. Many of these issues can be overcome with careful trial design and statistical planning.
Another common challenge is patient privacy protection when moving biological samples from one country to another. Medical privacy rules in the United States may preclude a company’s ability to use these data freely in a global context.
Bridget: I agree that any clinical trial design must consider the standard-of-care and available treatments across different regions and consider the relevance of the comparator cohort, if one is used. Difficulties in clinical trial design can be offset by careful planning and by taking advantage of any scientific advice procedures available through the regulatory agencies themselves. Companies must ensure there are no late surprises by talking with regulators early and often.
EVIDENCE REQUIREMENTS ACROSS REGIONS
LISA: What type of evidence will be required in the different regions to best achieve marketing approval?
Bridget: Assessors must be able to say the benefit outweighs the risk, so the data must support that. But typically, with conditional marketing authorization, the full set of clinically relevant endpoints will not be available at the time of submission for marketing authorization. Therefore, there is a big emphasis in Europe on post-marketing activities, and these need to be planned and strategized carefully in advance if they are suitable for more than one region.
Lucas: Particularly for Accelerated Approval in the U.S., the FDA will want to ensure that the company is already planning trials with clinically meaningful endpoints when considering accelerated approval using existing surrogate endpoint data.
Yajie: Unlike in the U.S., one well-designed study can support full drug or product approval in China. In the U.S., only the Orphan Drug Designation pathway allows a single-study approval, while other pathways require at least two studies. Thus, careful study design is of the utmost importance, and as I mentioned before, the study must include patients from mainland China with the exception of some rare situations.
INTERACTING WITH DIFFERENT REGULATORY AGENCIES
LISA: How can sponsors best leverage their interactions with regulatory agencies?
Lucas: Early advice is best. I encourage sponsors to seek out every opportunity to gather as much regulatory feedback as possible on their clinical development programs, especially if surrogate endpoints or non-clinical data will be used to support an application. It may require more work and more requests for information upfront, but it will result in a much higher likelihood of approval later.
Yajie: The situation is similar in China. If sponsors would like to discuss their clinical development plans with the CDE, a meeting request should be submitted. The CDE will decide whether to provide a written response to questions, a teleconference, or a face-to-face meeting. A sponsor is more likely to be granted a face-to-face meeting if a breakthrough designation is obtained or when the product or drug is for an illness causing a public health emergency, such as COVID-19.
Bridget: Early meetings are also vitally important for expedited pathway success in the E.U. For example, the PRIME (priority medicine) designation requires the sponsor to first submit a written proposal. If the decision from the EMA is positive, then the PRIME pathway involves multiple meetings with the EMA as the sponsor progresses through the clinical development plan. Another example is the Orphan Drug Designation in the E.U., which also allows a sponsor to arrange for a meeting before any submissions are made. Meetings may be via teleconference or in person, and sponsors should take advantage of any opportunities for meetings.
MANAGING WORKLOAD EXPECTATIONS
LISA: What should sponsors expect for their staffing workload when using expedited pathways?
Yajie: Certain pathways will have a higher workflow requirement than others. The Conditional Approval pathway will involve a great deal of work because the CDE asks many detailed questions about unmet medical needs, study design, and clinical data. As I discussed previously, the Special Review Procedure creates a very intense workload with the expectation that the sponsor’s staff will forgo holidays and weekends during the review duration.
Lucas: In the United States, sponsors should expect frequent interactions and many information requests from the FDA, especially if the application for an expedited pathway involves innovative trial designs or complicated data packages. Information requests can go up into the hundreds over a six-month review period. Sponsors should be staffed accordingly. Have the publications team, the medical writing team, the clinical staff, and the statisticians all under the direction of a particularly good program manager who can interact seamlessly with the agency’s program manager. Failing to respond quickly and clearly may result in a major amendment if the package at filling is deemed insufficient upon review and the timelines are extended.
Bridget: Companies can face challenges if they do not have the bandwidth to manage the workloads required for a marketing authorization application using expedited pathways. For example, if responses are not provided quickly during an Accelerated Assessment, the advantage of this pathway (in terms of shortened assessment time by the agency) is lost. Also, for an Accelerated Assessment, the data and dossier must be of high quality because if a major objection is raised, the timelines will immediately revert back to the standard timeline. If multiple applications are happening across regions at the same time, the sponsor will need extremely good project management and can expect a heavy workload for their team.
Expedited programs can be a key part of a sponsor’s global strategy to quickly bring drugs to market for rare diseases, serious disorders with unmet medical needs, or diseases that constitute a public health emergency. Drugs that are suitable for expedited pathways are those that affect survival, day-to-day functioning, or disease progression and provide a therapy where none exists or one that is potentially better than currently available therapy. It is important to fully understand the similarities and differences among expedited pathways when harmonizing applications across regions.
Early and frequent consultation with regulatory agency advisors and close collaboration across the regions is required if sponsors wish to avoid performing multiple different clinical studies to satisfy different agencies. Sponsors must keep in mind region-specific requirements for clinical studies to support their applications, such as the minimum requirement by the CDE that, in general, at least 15–20% of the total study population of pivotal trials must be recruited from mainland China. Sponsors must also account for differences in the standard-of-care and available treatments across different regions and consider the regional relevance of comparator cohorts, if used. Difficulties in clinical trial design can be offset by careful planning in partnership with regulatory agencies and experienced project managers. Sponsors must also be prepared for the intense staffing workload requirements inherent to expedited pathways when launching global drug development programs.
For more information, watch the on-demand discussion (www.appliedclinicaltrialsonline.com/act_w/pathways) or download our Early Planning and Development eBook (www.parexel.com/bioteching/roadmap-early-planning-and-development).