ARTICLE

UNDERSTANDING REGULATORY REQUIREMENTS IN TODAY’S ACCELERATED APPROVAL ENVIRONMENT Accelerated regulatory pathways for the development of new drugs in the U.S., Europe, and Japan – intended to bring important new treatments to patients more quickly – have multiplied in recent years, offering opportunities, benefits, and challenges for developers, patients, regulators, and payers.

By Alberto Grignolo, Ph.D., Corporate Vice President, Global Strategy, and Leslie De Vos, MS, Vice President, Worldwide Head of Integrated Product Development, PAREXEL International

Collectively, these mechanisms speed up the approval process, and apply a degree of flexibility with respect to the evidence requirements for the approval of certain medicines. In almost all cases, medicines that qualify for these pathways must address serious, rare, or difficultto-treat diseases, and offer substantial improvements over available therapies. In the U.S., accelerated pathways (APs) include Fast Track (FT), Breakthrough Therapy Designation (BTD), Accelerated Approval (AA), and Priority Review (PR). And although the Orphan Drug pathway is not an AP per se, orphan drugs typically meet the qualifications for APs, and are awarded similar advantages due to their focus on unmet medical needs. In Europe, APs include Accelerated Assessment (AA), Conditional Marketing Authorization (CMA), Authorization

Date Introduced

Under Exceptional Circumstances (EC), Adaptive Pathways, and the new Priority Medicines (PRIME) scheme. In Japan there’s the Sakigake (or “forerunner”) fast-track development and review system, announced in 2014 and launched in 2015. Worldwide, the product portfolios of companies large and small have shifted to address unmet needs. Today, there are roughly 7,000 medicines in development across the globe, many targeting areas of high unmet need (Pharmaceutical Research and Manufacturers of America, 2015). Nearly half of all novel drugs approved by FDA in 2015 were orphan drugs, setting a new record (U.S. Food and Drug Administration, 2016). Also, scientific advances have led to targeted therapies that zero in on biomarkers, and are efficacious for one genetic slice of a disease population, meaning more companies are launching more

Program Features

Eligibility

UNITED STATES Priority Review (PR)

1992

• FDA takes action within 6 months of BLA/NDA submission (versus 10 for a standard review)

Treat serious or life-threatening condition AND demonstrates significant improvement over existing therapies in efficacy or safety OR labeling change pursuant to pediatric study report OR has QIDP designation OR has PR Voucher

Fast Track (FT)

1997

• More frequent meetings with FDA • Rolling review of BLA/NDA • Possible eligibility for AA and PR

Treat serious or life-threatening condition AND has potential to address unmet medical need OR has Qualified Infectious Disease Product (QIDP) designation

Accelerated Approval (AA)

1992

• Allows use of surrogate or intermediate endpoints to measure clinical benefit (i.e., tumor shrinkage versus overall survival)

Treat serious or life-threatening condition AND provides meaningful benefit over existing therapies (or when there is no current therapy) AND demonstrates activity on a surrogate or intermediate endpoint that is “reasonably likely” to predict clinical benefit

Orphan Drug (OD)

1983

• 7-year marketing exclusivity • Protocol assistance from FDA • Possible research grant aid from FDA • Tax credits of 50% of U.S.-based clinical trial costs (upon approval) • Waiver of PDUFA fees ($2.4 million in 2016

Disease affects fewer than 200,000 people in the U.S. (if prevalence greater than 200,000, no “reasonable expectation” that R&D costs for indication can be recovered by sales) AND “scientific rationale” that drug will have activity in disease (evidence can be clinical, animal or in vitro data)

Breakthrough Therapy Designation (BTD)

2012

• Intensive FDA guidance on efficient development plan, starting as early as Phase I • FDA commits senior managers and experienced review staff to application • FDA assigns cross-disciplinary project lead to review team to facilitate agency interactions • Rolling review of BLA/NDA • Possible eligibility for PR

Treat serious or life-threatening condition AND preliminary clinical evidence indicates potential for “substantial” improvement over existing therapies on one or more clinically significant endpoints

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Date Introduced

Program Features

Eligibility

EUROPE Accelerated Assessment (AA)

2005

• CHMP reviews MAA in 150 days (versus 210 for non-accelerated products)

Of “major interest” in terms of public health and in particular of therapeutic innovation

Conditional Marketing Authorization (CMA)

2006

• Market authorization granted early on basis of less complete clinical data

Fulfils unmet medical need AND addresses seriously debilitating or life-threatening disease, rare disease or is for public health emergencies AND benefit-risk balance is positive (benefits of immediate public access outweigh risks of incomplete data) AND it is likely the sponsor will be able to provide comprehensive data at some point in future

Exceptional Circumstances (EC)

2005

• Market authorization granted on basis of incomplete clinical data

Not possible to collect data needed for complete MAA (reasons include extreme rarity of condition, data collection impossible with present state of scientific knowledge or it would be unethical to collect data)

Adaptive Pathways (AP)

2014

• Life-cycle approach to evaluation and licensing

Primarily for conditions with high medical need AND suitable for an iterative development pathway (e.g., CMA product or gradual expansion of target population)

Orphan Drug (OD)

2000

• 10-year marketing exclusivity • Possible research grant aid from EMA • Reduced MAA fees (fees fully waived for small to medium size enterprises)

Life-threatening or chronically debilitating condition AND prevalence of less than 5 out of 10,000 people in the EU (if prevalence greater than that, it has to be “unlikely” that the medicine would generate sufficient returns to justify investment) AND there must be no existing treatment for condition (or the new treatment must show “significant benefit” over existing ones)

Priority Medicines (PRIME)

2016

Early dialogue to reinforce scientific/regulatory advice, optimize development and enable AA:

New therapeutic option for condition with no current treatment options OR major therapeutic advantage over existing treatments AND preliminary clinical evidence indicating potential to produce significant benefits for patients with unmet medical needs and hence be of “major interest” from a public health and therapeutic innovation perspective

• CHMP Rapporteur appointed for products at proof of concept stage • K ick-off meeting with multidisciplinary input from Rapporteur and EU network members/ experts to discuss development plan and regulatory strategy • Iterative scientific advice at major milestones • Fee reductions/incentives on Scientific Advice requests for small to medium size companies (and academic sector) throughout development • Advice on MAA preparation and submission • Use of AA procedure to speed CHMP review

JAPAN “Strategy of SAKIGAKE”

2015

• “Prioritized consultation” – wait time for clinical trial consult is 30 days (versus 60) • Substantial pre-application consultation (will accept materials in English) • Prioritized review of 6 months (versus 12 standard), may accept pivotal trial results after submission on case-by-case basis

Demonstrates “radical improvement” compared to existing therapies (based on preclinical and Phase I/II trials) AND novel mechanism of action AND commercially scalable AND submitted for approval in Japan ahead of, or in parallel to the rest of the world

• PMDA assigns manager to serve as application “concierge” YOUR JOURNEY. OUR MISSION.®

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products more frequently for smaller patient populations. And many of them are utilizing accelerated pathways. PAREXEL advises clients that use accelerated pathways on how to ensure their products are developed with minimum risk and maximum value. For example, one risk of utilizing APs is that an approved product may face serious reimbursement hurdles if the clinical evidence is limited. In our view, accelerated drug development demands: 1. Early internal alignment of clinical, regulatory, and market/patient access functions; 2. Early external engagement with regulators, payers, and patients; and 3. Hypervigilant management of the evidence generation strategy.

EARLY INTERNAL ALIGNMENT OF CLINICAL, REGULATORY AND MARKET/PATIENT ACCESS FUNCTIONS Despite efforts at international harmonization, drug developers still must navigate a relatively fragmented global regulatory and reimbursement environment. This challenge is exacerbated by internal industry fragmentation. Clinical, regulatory, and market/patient access teams frequently don’t talk with each other or, if they do, the conversation occurs too late and may even be adversarial. For example, if health technology assessment (HTA) requirements are not integrated into clinical development and market access planning, the product value story could be compromised. And there are few activities more expensive or uncertain than trying to rewrite a botched value story, or reclaim credibility once lost.

TODAY MORE THAN 7,000 MEDICINES ARE IN DEVELOPMENT AROUND THE WORLD TARGETING AREAS OF HIGH UNMET NEED Medicines in Development Worldwide 2,000

1,813

1,500

1,329

1,256

1,120

1,000 599

511

475

500

159 0

Cancers

Neurological Disorders

Infectious Diseases

Immunological Cardiovascular Mental Health Disorders Disorders Disorders

Biopharmaceutical companies are focusing on areas of high unmet need

Diabetes

Biopharmaceutical companies have made significant gains in key disease areas

Note: Defined as single products which are counted exactly once regardless of the number of indications pursued. Source:Health Advances analysis; Adis R&D Insight Database

HIV/AIDS

HIV/AIDS is now a manageable, chronic disease, thanks to prior advances in biopharmaceutical research

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A product value story needs to be outlined when an AP is selected. The chosen AP will inform core evidence requirements, allowing gaps that cannot be filled by randomized clinical trials to be identified and addressed, perhaps by Real World Evidence (RWE). Remember, the product value story told in a regulatory filing should be consistent with that told to HTAs, payers and patients. Doing so requires a high level of coordination and communication. Quality decision making, including early, data-driven, and strategic go-no go decisions can only be produced by cross-disciplinary teams. It takes that kind of team to assess the regulatory landscape (especially new or looming requirements), the clinical treatment setting, product differentiation, and market dynamics. This will help developers understand what evidence will matter and when, which can then guide the choice of primary or secondary data, observational studies, and studies with unique designs (i.e., adaptive, interventional, pragmatic, or hybrid).

EARLY EXTERNAL ENGAGEMENT WITH REGULATORS, PAYERS, AND PATIENTS In the AP environment, companies cannot afford two development plans, one for regulators and one for payers. Companies must reach consensus – internally and with external stakeholders – on the basic science, clinical endpoints, and patient populations that will work for both registration and reimbursement. Meanwhile, patients can provide a wealth of information about how new drugs impact their lives. If external stakeholders can come together early on a new product, they can: • Align expectations. Health care financing authorities can help persuade regulators of what is possible at a reasonable cost, and what is not. • Build trust. Unfortunately, there is still a lack of trust among industry, regulators, governments, payers, and patients. • Manage risks. For instance, the UK’s HTA, the National Institute for Health and Care Excellence (NICE), has provided developers early scientific advice since 2009 to reduce uncertainty in the value proposition. • Validate patient-centered outcomes. Endpoints used in randomized clinical trials don’t always reflect measures that matter to patients, and, therefore, by extension to regulators and payers.

HYPERVIGILANT MANAGEMENT OF THE EVIDENCE GENERATION STRATEGY APs confer advantages and impose constraints. When products gain approval, or marketing authorization, with smaller clinical evidence sets, that can create hurdles for gaining HTA approval for reimbursement. And if European national HTAs (there are 28, and hundreds of subnational, regional HTAs – all slightly different) decline to grant reimbursement for a new drug (or restrict its use in the label), the value of winning an AP designation is much diminished. For example, in 2015 the UK’s National Institute for Health Care and Excellence (NICE) issued a preliminary recommendation against reimbursement of Bristol-Myers Squibb’s Opdivo® (nivolumab) for the treatment of advanced squamous non-small cell lung cancer (NSCLC) in patients who have failed chemotherapy. The NICE appraisal concluded that Opdivo® was not “a cost-effective use of National Health Service resources” (NICE, 2015). Yet Opdivo® had previously received FDA approval in the NSCLC indication under BTD designation and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) had labelled it a “Promising Innovative Medicine” (the first step in the UK’s Early Access to Medicines Scheme) (MHRA, 2015). The sequence of events was a reminder both of the influence of HTAs in Europe, and how regulatory bodies and HTAs may view new products differently. The similarities among APs in the U.S., Europe, and Japan also come with important differences in what evidence they require. That, combined with varied pre-approval data requirements for different AP pathways in different geographic jurisdictions, and a growing number of stakeholders, can add additional complexity to an already tortuous road to market for new drugs. For example, sponsors seeking the Sakigake designation in Japan must apply for marketing approval there first, or within days of applying anywhere else. However, the designation of Merck’s Keytruda® as Sakigake for unresectable, advanced, or recurrent gastric cancer (for which it is not approved in the U.S.; the indications of Keytruda® approved in the U.S. are melanoma and metastatic NSCLC) shows that Sakigake designation can be indication-specific. In practice, the Sakigake program requires sponsors to design their development strategies and timelines well in advance if they intend to reap the benefits of the designation.

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IN CONCLUSION… A company that receives a coveted AP designation for a product does not automatically reduce risk. In June 2016, the EMA announced that Biogen’s aducanumab, a promising monoclonal antibody for Alzheimer’s disease (AD), qualified for the PRIME scheme (European Medicines Agency, 2016). Consequently, Biogen will have access to enhanced support from EMA. It will receive advice on how to im¬prove its development plans, and a potentially accelerated assessment of its marketing authorization application (MAA). But the fact remains that any AD drug faces long odds: 99.6 percent of those tested in clinical trials between 2002 and 2012 failed to show efficacy (Cummings, Morstorf and Zhong, 2014). However, even for drugs that may never reach market, APs can help companies deploy resources more efficiently, and those that follow best practices for accelerated development – including seeking expert advice from regulators, payers, and patients, and amassing region- and country-specific data about evidence requirements for both approval and access – will certainly make better, more timely, and cost-effective go-no decisions.

REFERENCES Cummings, J., Morstorf, T. and Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther, 6(4), p.37.

European Medicines Agency. (2016). Recommendations on eligibility to PRIME scheme. [online] Available at: http:// www.ema.europa.eu/docs/en_GB/document_library/ Annex_to_CHMP_highlights/2016/06/WC500207736.pdf [Accessed 15 Sep. 2016]. Medicines and Healthcare products Regulatory Agency. (2015). Early Access to Medicines Scientific Opinion – Public Assessment Report: Nivolumab. [online] Available at: https://www.gov.uk/government/publications/earlyaccess-to-medicines-scheme-expired-scientific-opinions/ expired-early-access-to-medicines-scheme-scientificopinions#nivolumab-for-lung-cancer [Accessed 20 Sep. 2016]. National Institute for Health Care and Excellence. (2015). Appraisal consultation document: Nivolumab for previously treated locally advanced or metastatic squamous non-small cell lung cancer. [online] Available at: https://www.nice.org. uk/guidance/GID-TAG506/documents/appraisalconsultation-document [Accessed 20 Sep. 2016]. Pharmaceutical Research and Manufacturers of America. (2015). 2015 Biopharmaceutical Research Industry Profile. [online] Available at: http://www.phrma.org/sites/default/ files/pdf/2015_phrma_profile.pdf [Accessed 15 Sep. 2016]. U.S. Food and Drug Administration, (2016). Novel Drugs 2015 Summary. Rockville, MD: U.S. Food and Drug Administration. Available at: http://www.fda.gov/ downloads/drugs/developmentapprovalprocess/ druginnovation/ucm481709.pdf [Accesssed 15 Sep. 2016].

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