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Posted 16 May 2018 | By Gloria HallRandolph Fillmore 

Global Opportunities and Requirements for Expedited Pathways

3566 This interview features insight from two leading industry executives, Bridget Heelan and Bhardwaj (Bob) Desai, on the complexities of expedited pathways in the major markets of the US, EU and Japan and highlights expedited pathways with regard to significant benefit, clinical trials design and data, surrogate end points, orphan drugs, reimbursement and potential drawbacks to expedited pathways.


Because of increased research and drug development in niche indications or subgroups of patients, expedited pathways, aimed at getting drugs to patients sooner, are being used more frequently. These “express lanes” are open to products providing both significant benefit over available therapies and filling an unmet need.

What do readers need to know about expedited pathways in the US?

The US Food and Drug Administration (FDA) has developed four distinct approaches (Priority Review, Breakthrough Therapy, Accelerated Approval and Fast-Track) for making drugs available via accelerated regulatory review pathways, which will be discussed. One benefit will be the ability to discuss with FDA the potential for the rolling review of the marketing authorization dossier.

A Priority Review designation directs overall attention and resources of FDA to evaluate applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications. This designation changes the expected review timeline from 10 months to six months for a regular review process. Significant improvement may be in evidence of increased effectiveness in treatment, prevention or diagnosis of condition; elimination or substantial reduction of a treatment-limiting adverse drug reaction; documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes or evidence of improved clinical safety and effectiveness in a new subpopulation.

What affect did the 2012 passage of the Food and Drug Administration Safety Innovations Act (FDASIA) have on expedited pathways?

FDASIA Section 902 amends the Federal Food, Drug, and Cosmetic Act (FD&C Act){1,2} to allow FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate clinical endpoint (a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of direct patient benefit) or an intermediate clinical endpoint (a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality). Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived.

FDASIA Section 902 provides for a new designation: Breakthrough Therapy Designation (BTD). A breakthrough therapy is a drug intended alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Can you explain the significant endpoints in more detail?

For purposes of BTD, a clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality or on symptoms that represent serious consequences of the disease. A clinically significant endpoint also can refer to findings suggesting an effect on survival, irreversible morbidity or serious symptoms, including an effect on an established surrogate endpoint. An effect on a surrogate endpoint or intermediate clinical endpoint is considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard); an effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease and a significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy.

A drug that receives BTD is eligible for all the advantages available with fast track designation, including intensive guidance on an efficient drug development program and in addition to specific advantage of BTD beginning as early as Phase 1 and organizational commitment involving senior managers. For BTD, clinical data showing potential for significant superior benefit is required. Not all drugs receiving BTD are guaranteed to get approval for marketing authorization.

What is the purpose behind fast track?

Fast track is designed to facilitate the development and expedite the review of drugs to treat serious conditions (i.e., diseases which can impact survival or daily functioning) as well as fill an unmet medical need. Fast track designation can be based on non-clinical or clinical data and may be available with relevant, non-clinical data prior to clinical benefit signal in human clinical studies.

Are there similar pathways in the EU?

There are three main expedited pathways available in the EU. And, in addition, there is the Priority Medicines (PRIME) scheme.{3-5}

First, Accelerated Assessment (AA) is awarded for medicinal products of major interest from the public health point of view and in particular, from the viewpoint of therapeutic innovation. The time for assessment by the regulators is reduced from the 210-day maximum to a 150-day maximum. Second is Conditional Marketing Authorization (CMA). It is granted to a medicinal product fulfilling an unmet medical need when the benefits to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required. It is a “temporary authorization” based on less complete clinical data than is normally the case and subject to specific obligations. The MAH provides more data post-licensing in a pre-agreed timeframe and then converts to a full marketing authorization. Third, Authorization under Exceptional Circumstances (AEC) is awarded with even less data than CMA in very rare diseases and is not expected to ever convert to a full marketing authorization.

The PRIME scheme, introduced in 2016 by the European Medicines Agency (EMA), is awarded in early clinical development stages for medicinal products that are of major interest from the point of view of public health and therapeutic innovation. PRIME results in multiple scientific advice meetings with EMA and sometimes parallel advice with EMA/Health Technology Assessment (HTA) bodies. While PRIME is not a separate regulatory pathway itself and is built on the existing regulatory framework, it is included here as it was introduced to help drug developers with innovative products and to help ensure the final data package is suitable for accelerated assessment.

What about similar expedited pathways in Japan?

In Japan, expedited pathway options include priority review, conditional early approval systems and Sakigake Designation.{6} Priority Review—which takes six to eight months—is available for treatments where the drug is expected to contribute to improving the quality of healthcare and targeting serious disease. Conditional Early Approval Systems have been introduced to put highly useful and effective drugs for treating serious diseases into practical use as soon as possible. Sakigake Designation is for innovative medical products aimed at treating serious diseases where prominent effectiveness is expected based on non-clinical and early phase clinical studies. This designation results in prioritized consultation and review.

What is considered a “significant benefit” and what clinical data will be required to achieve that?

Significant benefit refers to a clinical improvement over and above available best standards of care that have a clinically meaningful impact on the patient’s disease, whether this is a prolongation of survival or a reduction in severe morbidity. The significant benefit must be clinically meaningful and better than outcomes afforded to patients by available therapies. To demonstrate significant benefit, clinical trial data is required. The nature of the trial, the comparator used and the endpoints should all be agreed upon with regulators in advance of conducting the trial.

What differences are there in terms of data submitted, trial design and speed of assessment for successful conditional approvals compared with products receiving a full Marketing Authorization Application (MAA) approval in oncology?

The majority of drugs approved on the basis of conditional marketing approval have demonstrated clinical benefit on a limited dataset. Despite needing confirmatory studies, these drugs become available to patients much earlier than drugs developed and licensed via traditional pathways and therefore, enable earlier access to medicines to patients with few or no alternative therapy options.

The number of subjects enrolled in trials applying for conditional approval pathway are smaller than the numbers typically enrolled in trials submitted under a standard MAA. The trial design is rarely the standard double-blind-randomized controlled design. Surrogate endpoints, such as Objective Response Rate (ORR), rather than overall survival, are used more frequently as endpoints in trials where expedited pathways for approval are sought, though duration of ORR does play an important role in this decision making by the regulatory authorities. In addition, the complexity of the assessment is revealed by the increased number of advisory group meetings requested by the EMA for dossiers undergoing review under CMA as opposed to those under review for a full MAA. A useful comparison of the differences in aspects of the trials and the procedures performed for drugs licensed by the EMA in oncology, either through a standard or CMA procedure, was reported by Hoekman, et al.{7}

Which surrogate end points have been used for accelerated approvals in the US?

FDA uses several surrogate endpoints for accelerated approvals, which are known to have an effect on causative mechanism of disease and are likely to correlate with the overall clinical outcomes. These include prolonged suppression of viral load for the anti-viral agents, clearance of bacteria from the blood stream, outcome of the six-month follow up treatment for the pulmonary tuberculosis, decrease in iron storage for the drug for iron chelation in the Thalassemia patients, changes in the validated disease clinical activity related biomarker such as Prostate-Specific Antigen (PSA) and tumor shrinkage rate or ORR for oncology indications.
Also, multiple drugs have been approved based on priority review of randomized studies with surrogate endpoints, such as progression free survival in the oncology. The most recent approval under priority review was of apalutamide, with the primary endpoint of metastasis-free survival in prostate cancer. This suggests FDA is open to clinically meaningful novel surrogate endpoints for drug approval.

The recent approvals of the check-point inhibitor (targeting PD-1 and PDL-1) agents in oncology were approved in the later stage of metastatic disease setting with ORR of 15% to 30%; however, with durable response, which is likely to be more than historically expected survival of these patients.{8-10} This suggests a potential for accelerated approval based on single arm studies if the agent demonstrates clinically robust activity based on a durable and much higher than expected tumor regression or disease remission in acute leukaemia. This has been demonstrated with Chimeric Antigen Receptor (CAR) T Cell treatments as compared to available therapies among patients with a poor prognosis and may have a chance of getting accelerated approval. The interest for the drug developer is that FDA is looking now not just at ORR, but duration of response and confidence interval, rather than just point estimates.

Hokeman, et al, also examined the characteristics of oncology medicines receiving full or conditional marketing authorization in Europe between the years 2006 and 2013.{11} They found that whereas overall survival as a primary endpoint was used in 61% of full MAAs, no product licensed under CMA used this endpoint. By contrast, response rate was used in 64% of CMAs, but only 13% of full MAAs. Time to progression was used more often in CMA (9%) compared with full MAAs (1%) and PFS was used in a similar percentage of trials for both CMA (27%) and full MAAs (23%).

Where does orphan designation fit into expedited pathways?

In Japan, orphan designation results in priority review. Orphan designations are not an expedited pathway in the EU or US. However, in view of the often-small numbers of patients in the clinical data package, many orphan designated drugs—particularly in cases where there is a serious unmet need—also utilize expedited pathways (such as AEC or AA).

Are there potential drawbacks to expedited pathways?

For PRIME in the EU and BTD in the US, the main drawback is the frequency of regulatory interactions. This requires repeated documentation preparation during the drug development process. For AA in the EU, there is little time to address regulatory questions, in contrast to a standard procedure. This means that the company needs to have a high-quality dossier, as well as the bandwidth to address all questions quickly in order to maintain the shortened assessment time.

Are there commercial implications for reimbursement for products authorized under expediated pathways in the EU?

This need for reimbursement and the challenges of providing a data package acceptable to the payers in the EU is a challenge, especially where data gaps are larger than those seen for standard authorizations. For this reason, parallel consultations with regulators and Health Technology Assessment (HTA) bodies are encouraged early in development, as well as before the pivotal trial design is finalized, in order to accommodate the differing requirements of the payers and regulators. These meetings also can be informative in planning future pharmacovigilance activities.

How many BTD and PRIME designations have been achieved so far?

On 1 November 2013, the first breakthrough designation received FDA approval, just one year after BTD was signed into law and after 29 designations were announced.{12} In 2017, FDA approved 46 new drugs.{13} 17 (37%) of these 46 drugs were granted breakthrough therapy designation prior.{14} 28 (61%) of these 46 drugs were approved with priority review.{15} 18 (39%) of the 46 drugs also achieved prior fast-track designation.{16} 6 (13%) of the 46 drugs were approved with accelerated approval.{17} As of 2 May 2018, FDA had approved 93 breakthrough therapy designated products and lists that there have been 603 total requests for the designation with 210 designations granted.

Since the start of PRIME in the EU in 2016, a total of 166 in scope applications have been received by the EMA.{18} Of these, 34 have been granted PRIME status as of March 2018. Of those achieving PRIME status, 16 were from companies designated with Small Medium Enterprise (SME) status. The therapeutic indications under investigation by the products that received PRIME were predominantly oncology and haematology. PRIME and the US BTD share the same objective of timely patient access to innovative medicines. However, they have a different legal basis, hence comparison and harmonization is difficult.

In late 2016, FDA and EMA began regular exchange of information and meetings regarding breakthrough therapy designation and PRIME eligibility requests, comparing general experience and program implementation challenges. When requesting BTD or eligibility to PRIME, sponsors are encouraged to inform the agency whether they have submitted a request for designation or eligibility to the other agency and the outcome of this request. For successful planning of global development, both agencies encourage sponsors to contact FDA and EMA on a dually designated product’s development program and seek joint advice under the Parallel Scientific Advice program.

  1. Food and Drug Administration Safety and Innovation Act (FDASIA). FDA website. Accessed 9 May 2018.
  2. Fact Sheet: Breakthrough Therapies. FDA website. Accessed 9 May 2018.
  3. PRIME Priority Medicines. EMA website. Accessed 9 May 2018.
  4. Accelerated Assessment. EMA website. Accessed 9 May 2018.
  5. Conditional Marketing Authorisation and Authorisation Under Exceptional Circumstances. EMA website. Accessed 9 May 2018.
  6. Strategy of SAKIGAKE. MHLW website. Accessed 9 May 2018.
  7. Hoekman J, Boon W P, Bouvy J C, Ebbers H  C, de Jong JP, De Bruin M L. “Use of the Conditional Marketing Authorization Pathway for Oncology Medicines in Europe.” Clinical Pharmacology and Therapeutics. 2015 Nov 1;98(5):534-41.
  8. Drugs: Durvalumab (Imfinzi). FDA website. Accessed 9 May 2018.
  9. Drugs: FDA Grants Accelerated Approval to Avelumab for Urothelial Carcinoma. FDA website. Accessed 9 May 2018.
  10. FDA Grants Genentech’s TECENTRIQ (Atezolizumab) Accelerated Approval as Initial Treatment for Certain People with Advanced Bladder Cancer. Accessed 9 May 2018.
  11. Op cit 7.
  12. About Breakthrough Therapies. Accessed 9 May 2018.
  13. CDER Advancing Health Through Innovation 2017 New Drug Therapy Approvals. Accessed 9 May 2018.
  14. CDER New Drugs Program: 2017 Update. Patrick Frey. FDA/CMS Summit. December 2017. Accessed 9 May 2018.
  15. Ibid.
  16. Ibid.
  17. Op cit 13.
  18. Op cit 3.

About the Executives
Bridget Heelan worked as a consultant immunologist in the National Health Service (NHS) in the UK before moving to pharmaceutical medicine. At the MHRA, she was a senior clinical assessor and was chair of the Rheumatology Immunology Working Party at the European Medicines Agency. As an MHRA assessor, she was the Rapporteur clinical assessor for multiple orphan products, and assessed many products authorized under conditional or exceptional circumstances, including one under accelerated assessment. Since joining Parexel, she has worked on ODD applications and MAA submissions where one or more expedited pathways were being utilized. She has advised companies on seeking PRIME designation or conditional approval. Currently, Heelan is vice president (technical) at Parexel. She can be reached at

Bhardwaj (Bob) Desai, MD is vice president (technical) at Parexel Consulting. Desai has 22 years of global oncology clinical development experience. He spent 11 years working with the pharmaceutical industry and 15 years working as a principal investigator. Desai has experience in all phases of oncology drug development (pre-clinical development, clinical trial management, designing Phase 1 to Phase 3 clinical trials, post-launch marketing, post-approval studies, regulatory affairs and GCP, broad strategy development for compound). Prior to joining Parexel, Desai was the senior medical director and global medical lead at Astellas Oncology, Pfizer Oncology and Abbvie. Desai completed medical school in Vadodara, India. He can be reached at

About the Interviewers
Randolph Fillmore is a technical writer for Florida Science Communications Inc.
Gloria Hall is senior editor, feature articles, RAPS Regulatory Focus.
Cite as: Fillmore R and Hall G. “Global Opportunities and Requirements for Expedited Pathways.” Regulatory Focus. May 2018. Regulatory Affairs Professionals Society.


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