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Trends In US Expedited Review Programs

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Swift Pace Of Accelerated Approval Submissions Suggests Strong Constituency For US FDA Program

Executive SummaryFDA may be evaluating the future of accelerated approval, but data from the Pink Sheet’s Performance Tracker shows growth in the submissions and approvals over the past five years.

More than 25 years after the US Food and Drug Administration established accelerated approval, the pathway is more popular than ever, with 2020 starting off at a potentially record-setting pace.

Of the new drug and biologic applications and efficacy supplements approved by FDA this year,

more than 14% received accelerated approval, well ahead of the 7.8% in 2019 and 8% in 2018. The AA share in 2020 is even outpacing 2017, one of the best years ever for accelerated approvals, when 11.4% of approvals used the AA pathway, according to an analysis using data from the Pink Sheet’s FDA Performance Tracker.

The numbers reflect the recently surging popularity of the pathway. The Center for Drug Evaluation reports 208 total approvals based on surrogate endpoints in the life of the AA program through year-end 2019. One-quarter of those approvals took place in just the three years from 2017-2019.

Accelerated Approval: Still Popular After All These YearsAccelerated approval accounts for a relatively small but solid share of FDA approvals of new drug applications, biologics license applications, and efficacy supplements.

Source: Pink Sheet FDA Performance Tracker and FDA data


A similar pattern can be seen with just novel agents. Looking back at the full decade from 2010 to the end of 2019, the Center for Drug Evaluation and Research approved 49 NMEs and novel biologics with AA, and the Center for Biologics Evaluation and Research cleared five novel agents. (Also see “Accelerated Approval: Avastin, Makena Bookend A Watershed Decade For US FDA’s Expedited Pathway” - Pink Sheet, 28 Apr, 2020.)

Those novel approvals were backloaded onto the years 2015-2019, which produced 36 novel CDER AA approvals and one from CBER. The current year, 2020, has seen one CBER and six novel CDER approvals, with the most recent going to Jazz Pharmaceuticals PLC and PharmaMar SA’s Zepzelca (lurbinectedin) for second-line and later small cell lung cancer on 15 June.

Uncertain FutureThe accelerated approval program, initiated in 1992 in response to the HIV epidemic and codified by Congress in the 2012 FDA Administration Safety Innovations Act, allows for approval of drugs that address unmet medical needs for serious conditions to be approved on the basis of a validated surrogate endpoint that predicts clinical benefit.

Sponsors must complete confirmatory trials to demonstrate clinical benefit in post-marketing. However, the rate of completion of confirmatory trials has long been a focus of criticism of the pathway. (Also see “JAMA Study Continues Wave Of Accelerated Approval Criticism Amid Expansion Of Pathway” - Pink Sheet, 28 Aug, 2017.)

Now FDA may be rethinking accelerated approval. In a recent podcast interview with the Pink Sheet, Oncology Center of Excellence director Richard Pazdur called for re-examination of the pathway, and FDA’s other expedited review programs, in the ramp-up to upcoming user fee reauthorization and an expected “Cures 2.0” legislative package. (Also see “Cures II Wish List: Reconsidering Accelerated Approval?” - Pink Sheet, 17 Jun, 2020.)

“It might be an interesting discussion to take a look at all of these programs and come up with more unified programs,” Pazdur said. “Looking at our collective experience with accelerated approval would be an important dialogue to have, because of the length of experience.”

Oncologic DominationCancer therapies still overwhelm other types of drugs seeking accelerated approval, despite FDASIA’s directive for use outside oncology. More than three-quarters of the NDA, BLA and efficacy supplements submitted for AA 2015 through June 2020 are for cancer indications.

The next largest group are infectious disease therapies, accounting for 10% of submissions.

Just as cancer indications dominate accelerated approvals, accelerated approvals have an outsized presence in cancer approvals. Of 35 cancer approvals in 2020 to date, 29% received accelerated approval. The impact is even greater looking only at new molecular entities and novel biologics: 11 novel oncology therapies have been approved in 2020, and six of them 55% – used AA.


A Pathway Finds Its Place: Cancer & Accelerated ApprovalOncology's Impact On Accelerated ApprovalCancer therapies make up an outsize proportion of NDA, BLA and efficacy supplements submitted for accelerated approval...

Accelerated Approval’s Impact On Oncology...And accelerated approvals make up a healthy proportion of all oncology approvals of NDAs, BLAs and efficacy supplements

Source: Data from the Pink Sheet FDA Performance Tracker and FDA


Supplemental Approvals Driven By Immuno-OncologyJust one category of oncologic – the PD-1/L1 inhibitors – account for half of the cancer accelerated approvals since 2015. The lengthy indication lists of Bristol-Myers Squibb Co.’s Opdivo (nivolumab) and Merck & Co. Inc.’s Keytruda (pembrolizumab) have especially benefited from the program: in the past five years, Keytruda has notched 13 supplemental accelerated approval indications and Opdivo has received 10.

The FDA’s accelerated approvals in the same timeframe (2015 to the present) were almost evenly split between non-novel approvals (new indications or NDAs or BLAs containing a previously approved active ingredient) and new

molecular entities and novel biologics.

The current pipeline of pending applications that are known to be seeking an accelerated approval is small – four applications – but weighted towards NMEs, with three novel agents and one new use of an approved drug (Intercept Pharmaceuticals Inc.’s obeticholic acid).

The pending NMEs for accelerated approval represent an unusually large range of indications, including a product for chronic kidney disease patients (Tricida Inc.’s veverimer), Fabry disease (Chiesi Farmaceutici SPA and Protalix BioTherapeutics Inc.’s pegunigalsidase alfa) and localized prostate cancer (Steba Oncology’s photodynamic Tookad, which failed to receive an advisory committee endorsement in February).


Accelerated Approval: Avastin, Makena Bookend A Watershed Decade For US FDA’s Expedited Pathway

Executive SummaryPink Sheet interactive timeline looks at key regulatory, policy and legislative developments impacting the accelerated approval pathway over the last 10 years.

When it comes to the US Food and Drug Administration’s accelerated approval program, the most recent decade ended much the way it started – with the agency weighing whether to withdraw an approval under the expedited pathway.

In 2010, the FDA sought withdrawal of the breast cancer indication for Genentech Inc.’s Avastin (bevacizumab) for failure to confirm clinical benefit. (Also see “Genentech May Not Get A Chance To Appeal FDA’s Decision To Withdraw Avastin’s Breast Cancer Approval” - Pink Sheet, 20 Dec, 2010.) In 2020, the decision facing the agency is whether to withdraw accelerated approval of AMAG Pharmaceuticals Inc.’s preterm birth prevention drug Makena (hydroxyprogesterone caproate injection), which failed a confirmatory trial that took nine years to complete. (Also see “Makena Withdrawal Dilemma: Advisory Cmte. Split Offers No Clear Direction For US FDA” - Pink Sheet, 29 Oct, 2019.)

The months that have passed since Makena’s October 2019 advisory committee with no agency action suggest a decision of sorts by the FDA, but the product’s fate has yet to be formally announced.

With Avastin and Makena as bookends, the decade proved to be a pivotal one for accelerated approval, which saw the first FDA-ordered

withdrawal under the program. (Also see “Avastin Loses Its Breast Cancer Claim; FDA’s Hamburg Opts For Withdrawal Over Restrictions” - Pink Sheet, 21 Nov, 2011.)

Some might say it came out stronger on the other side, with the agency generally insisting on earlier initiation of confirmatory trials, highlighting the conditional nature of approvals, and extracting public commitments from sponsors to withdraw a drug or indication if confirmatory trials fail to verify clinical benefit. (Also see “Accelerated Approval: US FDA Labeling Guidance Calls Out Surrogate Endpoints Needing ‘Additional Context’” - Pink Sheet, 23 Jan, 2019.) (Also see “AstraZeneca Takes “Anti-Avastin” Pledge On Accelerated Approval Withdrawal” - Pink Sheet, 30 Jun, 2014.)

In 2019, the noncontroversial accelerated approval withdrawal of Eli Lilly & Co.’s sarcoma drug Lartruvo (olaratumab) was viewed by some as a textbook example of how the expedited program should work when a drug’s initial promise is not borne out in later studies. (Also see “A Successful Failure? Lartruvo’s Speedy Withdrawal Sets New Bar For Accelerated Approval Drugs” - Pink Sheet, 25 Apr, 2019.)

Through the 2012 FDA Safety and Innovation Act, Congress made clear its desire to expand the use of accelerated approval beyond the cancer setting. (Also see “PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements” - Pink Sheet, 17 Sep, 2012.) As a result, the agency took steps to clarify the pathway’s criteria and expanded work on the development and qualification of surrogate endpoints, biomarkers and other drug development tools.


Over the course of the decade, 49 new molecular entities and novel biologics regulated by the Center for Drug Evaluation and Research, and five regulated by the Center for Biologics Evaluation and Research, came to market under the pathway.

To be sure, the accelerated approval program will continue face criticism from academics, public health advocates and others who assert it allows drugs to reach market on the basis of surrogate or intermediate clinical endpoints of questionable value, and with safety datasets that are too small. Critics also highlight the often lengthy duration of confirmatory trials, which can allow

a drug to remain on the market for years before there is evidence it provides any, or no, clinical benefit. (Also see “JAMA Study Continues Wave Of Accelerated Approval Criticism Amid Expansion Of Pathway” - Pink Sheet, 28 Aug, 2017.)

The agency also may not have helped its case with some of its more controversial approvals under the program, with Sarepta Therapeutics Inc.’s Duchenne muscular dystrophy drug Exondys 51 (eteplirsen) top of mind. (Also see “With Sarepta’s Vyondys, US FDA Staff Saw Opportunity To Right Perceived Wrongs With Exondys” - Pink Sheet, 27 Jan, 2020.)

A Decade Of Accelerated ApprovalsFor CDER, A Story Of Steady FluctuationOver the past decade the number of novel product accelerated approvals by CDER has remained relatively steady, but what variation there was - combined with the swings in CDER's approval of novel drugs - meant that the share of approvals that were accelerated has swung from a low of none in 2010 to a high of 27% in 2016.

Note: There were no new molecular entities or novel biologics approved under accelerated approval by CDER in 2010.


For CBER, A Less Impactful Review PathwayWith far fewer novel approvals than the drugs center, the Center for Biologics Evaluation and Research has relied less on accelerated approval, with no new product approvals under the expedited pathway in six of the last 10 years.

Note: There were no novel biologics approved under accelerated approval by CBER in 2010, 2012, 2013, 2016, 2017 and 2019.


Timeline of key regulatory, policy and legislative developments related to the accelerated approval pathway during the decade.


Tazverik Accelerated Approval: Disease Rarity And Unmet Need Won Out Over Efficacy Concerns

Executive SummaryUS FDA reviewers recommended against accelerated approval of Epizyme’s tazemetostat for epithelioid sarcoma, finding the modest overall response rates were not substantial evidence of an improvement over available therapies; they were overruled by senior oncology review staff, who cited a unanimous ODAC endorsement and the regulatory flexibility encouraged for rare diseases.

The US Food and Drug Administration’s regulatory nod for Epizyme Inc.’s epithelioid sarcoma drug Tazverik (tazemetostat) reflects the careful balancing act agency staff perform each time a drug comes through the accelerated approval pathway – deciding whether it should be made available for a desperate patient population in the face of limited trial data, and at the risk the sponsor will never be able to definitively confirm clinical benefit.

In the case of tazemetostat, reviewers’ doubts about the magnitude of the efficacy benefit were overridden by the agency’s emphasis on flexibility under the expedited pathway, particularly for rare diseases with a high unmet need.

The new drug application’s clinical reviewer and cross-disciplinary team leader recommended against accelerated approval of the methyltransferase inhibitor, finding the modest overall response rates in the uncontrolled clinical trial cohorts did not provide substantial evidence of a clinically meaningful improvement over available therapies for treatment of metastatic or locally advanced epithelioid sarcoma, according to review documents.

However, they were overruled by higher level staff in the Division of Oncology 3 and Office of Oncologic Diseases, who were swayed by the unanimous endorsement of the Oncologic Drugs Advisory Committee, the rarity and life-threatening nature of the disease, the lack of effective treatment options, and the flexibility afforded – and indeed, encouraged – under the accelerated approval pathway.

“Based on the statistical and clinical considerations of this application as described in the review, there is uncertainty surrounding the magnitude of [overall response rate] and [duration of response] of tazemetostat in patients with epithelioid sarcoma as well as the relationship of these treatment effects to ultimate clinical benefit,” Marc Theoret, acting deputy director of OOD, said in his review.

“Greater uncertainty of the magnitude of treatment effects of tazemetostat, in the context of the known safety profile, is acceptable based on the rarity and nature of metastatic epithelioid sarcoma as a serious and life-threatening disease with no effective treatment options,” Theoret said.

Steven Lemery, acting director of the Division of Oncology 3, supported accelerated approval but did so with reservations about tazemetostat’s benefits, and he questioned whether the confirmatory trial would be completed.

While Lemery said he hoped patients would benefit from accelerated approval, he worried about the “opportunity cost” of such a regulatory action, specifically that fewer patients initially would seek out clinical trials due to the availability of tazemetostat. “Such an opportunity cost could, in theory, delay discovery or study of other


therapies for patients with ES,” he said.

‘Marginal’ Treatment EffectOn 23 January, the FDA granted tazemetostat accelerated approval for the treatment of adults and pediatric patients ages 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. (Also see “Keeping Track: Approvals For Tazverik And Tepezza, Priority Reviews For Belantamab Mafodotin And Lynparza” - Pink Sheet, 25 Jan, 2020.)

Epethelioid sarcoma is a rare, malignant, soft tissue sarcoma that accounts for less than 1% of all STS. There are approximately 125 new cases diagnosed in the US each year, and patients with metastatic disease have a five-year reported survival of 0%

Although prior to tazemetostat there were no therapies approved specifically for patients with ES, doxorubicin and pazopanib are both approved for the broader population of patients with STS and are used to treat ES. However, these therapies confer low response rates and significant toxicity.

Epizyme’s NDA was based on results from two cohorts of ES patients in an open-label, multi-cohort, nonrandomized trial (EZH-202). The results from cohort 5 (62 patients) were intended to serve as the primary evidence of efficacy for accelerated approval. However, the 44-patient cohort 6 also enrolled ES patients using similar eligibility criteria and the same dosing regimens, so the FDA also considered the results from that cohort.

The primary endpoint was overall response rate (ORR), with the FDA having previously informed Epizyme that it did not consider disease control rate to be an appropriate endpoint. (See sidebar further below for timeline.)

In cohorts 5 and 6, the ORR was 15% and 11%,

respectively, with a pooled analysis demonstrating an ORR of 13%. However, the lower bounds of the associated confidence intervals suggested the true ORR may be as low as the single digits. The pooled duration of response ranged from 3.5 months to more than 24 months.

FDA reviewers voiced doubts about the adequacy of the efficacy evidence ahead of an 18 December review by the Oncologic Drugs Advisory Committee. (Also see “Epizyme’s Tazemetostat Faces US FDA Doubts About Efficacy In Epithelioid Sarcoma” - Pink Sheet, 17 Dec, 2019.)

However, ODAC voted 11-0 in favor of approval. The panel’s sarcoma experts said that given the aggressive nature of ES and the disease’s failure to respond to standard therapies used to treat STS, the ORR achieved in EZH-202 was clinically meaningful, as were the duration of response and disease stability achieved by some patients. (Also see “Epizyme’s Tazemetostat Gains US FDA Panel Nod For Accelerated Approval In Epithelioid Sarcoma” - Pink Sheet, 18 Dec, 2019.)

While the views of the sarcoma experts held sway with ODAC, the FDA’s clinical reviewer and cross-disciplinary team leader ultimately recommended against approval.

The reviewers said there is insufficient evidence that tazemetostat provides a meaningful advantage over available therapies, such as doxorubicin and pazopanib, which is a qualifying criteria for accelerated approval.

“An ORR of 13% is a marginal treatment effect and does not provide sufficient evidence of clinical benefit in this patient population,” clinical reviewer Leslie Doros said in a multidisciplinary review and assessment. She also said it is unclear if this response rate would translate into an improvement in overall survival or progression-free survival.


Although the preliminary duration-of-response data appear promising, the small sample size makes it difficult to estimate the true effect, Doros said.

Contextualizing The BenefitThe reviewers said the observed ORR in cohorts 5 and 6 is low compared to most therapies approved by the FDA on the basis of an ORR primary endpoint, particularly when compared to the response rates seen in trials of other targeted therapies.

In a review of all therapies approved since 2013 on the basis of an ORR endpoint, the reviewers identified 45 eligible trials with related ORR point estimates and 95% confidence intervals. The tazemetostat ORR fell at the low end in this analysis.

“FDA has approved other therapies with similarly low ORR. However, we note that this is more common for supplemental applications, in which efficacy information is supplemented by prior efficacy results in other disease areas, including understanding of mechanism of action,” the multidisciplinary review states. “In some instances, a product was approved based on ORR when efficacy information from a randomized trial was available.”

Data also were insufficient to find tazemetostat provides direct benefit based on reduction in tumor burden alone, the reviewers said, citing the absence of patient-reported outcomes data “or other clinically meaningful endpoints.”

Pondering A Second-Line IndicationCross-disciplinary team leader (CDTL) Ashley Ward agreed that the threshold for accelerated approval had not been satisfied.

Tazemetostat was not shown to confer a higher ORR than doxorubicin, “which I consider to be

an available therapy for patients with epithelioid sarcoma,” Ward said.

She acknowledged the tazemetostat ORR in ES patients who have received prior therapies was numerically higher than the ORR observed in the pivotal trial that supported pazopanib’s approval for second-line treatment of STS. Consequently, “an approval of tazemetostat in patients with epithelioid sarcoma who have progressed after at least one prior therapy would thus potentially meet the regulatory requirement for an improvement over available therapies on an intermediate endpoint for the purposes of accelerated approval.”

Epizyme sought accelerated approval without regard to line of therapy. At the ODAC meeting, two panelists suggested accelerated approval may be justified only in the second-line setting so as not to interfere with Epizyme’s planned confirmatory trial in front-line patients.

However, Ward asserted it would be difficult to argue tazemetostat’s approval should be limited to second-line or later. The observed response rate was similar regardless of the number of prior lines of therapy, and there is no biologic rationale to limit the efficacy conclusions to only a portion of the studied population, she said.

‘Judgement Call’Ward agreed with ODAC’s view that the limited data available on duration of response appear to favor tazemetostat over available therapies.

“However, whether the presented data represent substantial evidence of effectiveness, and are sufficient to conclude that tazemetostat provides a durability of response better than available therapy and that this may be reasonably likely to predict clinical benefit of tazemetostat, is a judgement call,” the CDTL said.


At the advisory committee, Epizyme and its experts asserted that periods of stable disease seen in some non-responding patients should be considered in the evaluation of benefit.

However, the agency does not consider stable disease to be a reliable endpoint in a single-arm trial because it is not possible to determine whether a period of stable disease is due to a drug effect or represents the natural history of a patient’s tumor, Ward said.

“Several sarcoma experts who participated in the ODAC meeting asserted that periods of prolonged stable disease are not expected in patients with epithelioid sarcoma treated with current standard of care therapies,” Ward said. “While this was heavily discussed by the ODAC and may have contributed to the favorable recommendation, the applicant did not present any data supporting this conclusion.”

Ward acknowledged that tazemetostat appears to be less toxic than therapies currently used for ES. “However, the FDA has not historically accepted an improvement in safety as a regulatory endpoint to support approval in oncology, particularly in the absence of data confirming that a reduction in toxicity is not associated with a reduction in efficacy/potency.”

Unique Circumstances That Will Not Set PrecedentLemery favored approval despite reservations about the drug’s efficacy. While he shared many of the review team’s concerns regarding tazemetostat’s clinical effects, he did not question the actual data and respected the advisory committee’s vote, Lemery said.

The division acting director said his “approval recommendation (and underlying uncertainties) is only promulgated based on the (many) unique circumstances regarding this specific application

and should not be interpreted that similar results will be sufficient for approval in other applications.”

Describing the ORR in study 202 as a “modest clinical effect,” Lemery noted that response rate is an imperfect marker for clinical benefit in cancer patients because some drugs can have lower response rates that are associated with a PFS or OS benefit, while others can have effects on ORR that do not translate into clinical benefit.

Lemery said he was conflicted as to whether, based on the objective data presented, the observed clinical effect on ORR actually changed the natural history of disease, or whether it would be reasonably likely to effect such a change.

“Ultimately, this topic was presented at the advisory committee which voted unanimously that the drug provided for a favorable risk-benefit profile and that tazemetostat would be beneficial for patients with ES as this is a rare disease that is difficult to treat and does not have many options for treatment,” he said. “In addition to observed responses, durability of response is encouraging; however, there is uncertainty regarding the effect based on the limited number of patients responding.”

Lemery said the following factors provided context for his accelerated approval recommendation:• Extremely rare condition;• Poor prognosis of underlying condition;• No known clearly effective drugs for this

condition; and• Reasonably favorable toxicity profile, given the

life-threatening nature of metastatic ES.

Activity In Another Indication HelpfulTazemetostat’s activity in another cancer indication also gave Lemery some confidence the drug ultimately would prove clinically beneficial in ES.


A Phase II trial of tazemetostat monotherapy in follicular lymphoma demonstrated an objective response rate of 69% for patients with EZH2 mutation-positive disease and 35% for patients with wild-type disease. “If confirmed, these data at least show biological effects of tazemetostat occur in a second cancer (noting that biology may differ between ES and follicular lymphoma),” Lemery said.

On 18 December, Epizyme submitted an NDA for tazemetostat in follicular lymphoma, a far larger commercial opportunity than ES. The application received a priority review, and the agency awarded accelerated approval on 18 June. (Also see “Epizyme’s Tazverik Gets To Market In Rare Sarcoma, Paving Way To Bigger Indications” - Scrip, 24 Jan, 2020.)

Marketing ConcernsIn language uncommon for FDA reviews, Lemery cautioned about the need for careful marketing of the ES indication.

“If approved, it will be important for the manufacturer, in advertising or other presentations, to accurately describe the effects of the drug as well as limitations of the data to ensure that patients and their treating oncologists can make the best treatment decision (e.g., whether to take tazemetostat, receive an alternative regimen, or to enroll into a clinical trial),” he said.

“For example, statements regarding effects on OS or disease stabilization should not be made based on cross-study comparisons of non-randomized trial data to data from natural history studies (the validity of such comparisons may be further limited by small sample sizes, differences in when and where patients were identified, missing data, etc.).”

Epizyme had submitted to the FDA results from a

real-world, natural history study that was based on retrospective review of ES patient records. However, the agency concluded the study design was flawed and results inadequate to provide direct or relevant evidence of tazemetostat’s efficacy. (See sidebar for story.)

OOD Deputy Emphasizes FlexibilityOOD’s Theoret agreed with Lemery that tazemetostat met the statutory criteria for accelerated approval, demonstrating a favorable benefit-risk profile “with a clinically meaningful, albeit modest treatment effect on ORR with prolonged durations of response in the context of acceptable safety risks for the indicated population.”

The tazemetostat approval reflects the agency’s long-standing commitment to regulatory flexibility when it comes to the evidence needed to support approval of treatments for serious or life-threatening diseases with limited therapeutic options, Theoret said.

He pointed to the accelerated approval regulations’ emphasis on broad flexibility in the context of serious or life-threatening diseases, and to language in the FDA Safety and Innovation Act of 2012 directing the agency to consider the severity, rarity or prevalence of the condition and the availability of alternative treatments in awarding accelerated approval.

In addition, the FDA’s May 2014 guidance on expedited programs for serious conditions “affirms flexibility concerning the implications of available therapy on granting accelerated approval,” Theoret said. “For example, a meaningful therapeutic advantage may exist in the absence of demonstration of a direct efficacy or safety advantage, such as therapy with a novel mechanism of action in a setting where available therapy provides modest responses or significant heterogeneity in the responses.”


Cures II Wish List: Reconsidering Accelerated Approval?

Executive SummaryRichard Pazdur wants the oncology community to take a fresh look at US FDA’s expedited review programs. One big question: should there be fewer of them?

It has been nearly three decades since the US Food and Drug Administration instituted the accelerated approval regulations, and Oncology Center of Excellence Director Richard Pazdur thinks it is high time that the pathway – and all FDA’s expedited programs – get a second look.

Pazdur included a re-examination of accelerated approval on a “wish list” of discussion topics for the entire oncology community in the lead-up to any potential “21st Century Cures” 2.0 legislation. As a government official, Pazdur cannot comment directly on legislation, so when asked the question during a podcast interview with the Pink Sheet, he framed his answer as a broader issue for all oncology stakeholders.

“Let me give you a wish list of a dialogue I’d like to have the whole oncology community have, and the whole regulatory community, as well as pharma. Some of these revolve around accelerated approval.”

Noting that accelerated approval is the “granddaddy” of programs (like conditional approval) used by other regulatory agencies, “it would be interesting for us to look at what are the successes, what are the problems, what are the ways to tweak it.”

Pazdur ran through a potential list of discussion topics: “What could we learn from other countries, especially with the confirmatory trials? How we phase the ‘reasonably likely to predict clinical

benefit’ issue? The concept of surrogacy is somewhat problematic,” he said. “Looking at our collective experience with accelerated approval would be an important dialogue to have, because of the length of experience.”

The upcoming user fee reauthorization and expected push for a “Cures 2.0” legislative package will give stakeholders the opportunity to consider changes to the FDA’s most venerable expedited pathway.

The accelerated approval regulations went into effect in 1992, allowing drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. (Also see “Cures 2.0 May Get Fast Tracked Due To COVID-19” - Pink Sheet, 29 Apr, 2020.)

The pathway was then codified by Congress in the Food and Drug Administration Safety Innovations Act of 2012. That same legislation (tied to PDUFA V) also established the breakthrough therapies pathway. (Also see “PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements” - Pink Sheet, 17 Sep, 2012.)

FDASIA also made clear that accelerated approval should be used in conditions outside oncology, and at the time, rare disease advocates were optimistic that the pathway would spur development of orphan drugs.

But the vast majority of accelerated approvals still occur in oncology (Pazdur estimated the percentage at 80-90%), leading him to ask: “why hasn’t this been embraced by other therapeutic areas?”

Fewer Pathways?Perhaps part of the problem is that accelerated approval is not fully understood, especially in


the context of all the other expedited programs offered by FDA: fast track, priority review, breakthrough and the newer Regenerative Medicine Advanced Therapy designation. But accelerated approval is especially confusing: few truly understand surrogate endpoints and what constitutes “reasonably likely to predict clinical benefit.”

“There has been a proliferation of these expedited programs … and nobody really understands these unless you are in drug development,” Pazdur said.

The solution, he said, might be to simplify all FDA expedited programs into fewer pathways. “It might be an interesting discussion to take a look at all of these programs and come up with more unified programs.”

“We have a lot of paperwork going on with all of these individual programs, and I think we have to step back and take a look at what are we trying to achieve,” he suggested. “Can we simplify all of these programs into maybe two: an early clinical program and a late clinical program, rather than have all of these programs floating around that are somewhat duplicitous in nature.”

Getting The Studies DonePazdur himself has expressed frustration with accelerated approval at times, especially when it comes to drug sponsors completing the post-marketing confirmatory trials required under the regulation.

He has used advisory committee meetings to put sponsors (most recently Epizyme Inc.) on notice that issues related to the confirmatory trial should be worked out with FDA well before the approval deadline approaches. (Also see “’The Pazdur Effect’: A Tale Of Three US FDA Oncology Advisory Committee Meetings” - Pink Sheet, 19 Dec, 2019.)

“The biggest predictor to getting the trial done is

having the trial ongoing before the AA is granted,” he reiterated during the podcast interview. Pazdur is watching to ensure that ongoing confirmatory trials are completed, but understands there will be some brief interruptions due to the pandemic. So far, he has not heard of any delays.

“We have not had any strong conversations on missing studies. I’m sure some were put on pause, but we are talking about a pause of three or four months because of COVID,” he said. “What we’re really interested in is the long-term perspective. Will these be done, and usually we’ve seen a commitment from most of the sponsors from getting these done in an expeditious fashion – especially from the major pharmaceutical companies.”

Post-COVID Trial ConsiderationsFDA is also starting to think about how to best enroll patients in oncology clinical trials once they have recovered from an infection with the SARS-CoV-2 virus. The agency is discussing that issue now with sponsors to gather input, and Pazdur wants to hold a public meeting and possibly a National Academies workshop. “I think it’s a very important question.”

“What we are particularly interested in are what are some of the subtle changes that may not be readily picked up but may become problems for a clinical trial? For example, residual lung toxicity that isn’t picked up on a routine chest x-ray, and when a patient is receiving a drug that may cause, or been implicated in, interstitial lung disease, this may become a problem.”

Likewise, he continued, for a drug that may have a thrombotic tendency, will that present a problem in a post-COVID patient, and perhaps cause thrombosis? The characterization of the post-COVID patient also will be important to consider: A patient that presents with a mild infection is much different than a patient who was in an ICU


on a ventilator before they recovered. Those differences should be recorded before patients are enrolled in trials.

Pazdur does not want a COVID-19 infection to discourage patients from enrolling in clinical trials, or deter drug sponsors from including them. “To

send a clear message: we want these patients, if they have recovered from their COVID infections, to be entered in clinical trials.” Given all the energy that has been spent on expanding eligibility criteria, he said, “we certainly don’t want to go backwards.”


Antifungal Drug Sponsors Seek Clearer Regulatory Pathway, Less Burdensome Trials

Executive SummaryCiting difficulties in conducting randomized trials, industry speakers call for a new way of thinking about the US FDA’s substantial evidence standard for antifungal approvals under the LPAD route, as well as revisions to enrollment criteria and study endpoints.

The US Food and Drug Administration should reconsider and clarify the quantum of evidence and types of data it is willing to accept under the limited population approval pathway for new antifungals that address unmet medical needs and rare infections, industry representatives said at a recent agency workshop.

Stakeholders also called for rethinking the enrollment criteria and endpoints currently used in antifungal clinical trials given the difficulty in conducting such studies, and they urged the FDA to be more open to the use of external case controls when randomized trials are not feasible.

The FDA convened the 4 August virtual workshop to discuss unmet medical needs of patients with infections caused by invasive molds and Candida auris, as well as clinical trial design considerations, such as study populations, endpoints and control arms.

Data Package ExpectationsSumathi Nambiar, director of the Division of Anti-Infectives, laid the groundwork for the day-long meeting by reviewing the FDA’s expectations for a data package for antifungal drug development.

Antifungals must demonstrate substantial evidence of efficacy, with at least one adequate

and well-controlled trial per indication, coupled with supportive evidence from nonclinical and in vitro studies or another indication. For products with orphan designation, the statutory standard of substantial evidence still needs to be met.

Nambiar noted the availability of the limited population pathway for antibacterial and antifungal drugs (LPAD), which was created under the 21st Century Cures Act. This pathway applies to drugs that are intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs.

LPAD allows for a more flexible benefit/risk assessment that takes into account the severity, rarity or prevalence of the infection the drug is intended to treat, and the lack of alternatives available for the patient population. However, sponsors seeking approval via this pathway still must demonstrate substantial evidence of efficacy.

To date, the FDA has approved two drugs under LPAD: Insmed Incorporated’s Arikayce (amikacin liposome inhalation suspension) for the treatment of Mycobacterium avium complex lung disease; and the Global Alliance for TB Drug Development’s pretomanid regimen for tuberculosis. (Also see “LPAD As An Afterthought? Insmed’s Arikayce Reaches US Market Thanks To Limited Population Pathway” - Pink Sheet, 3 Oct, 2018.) (Also see “Pretomanid Approval For Resistant TB: With Regulatory Flexibility Comes Usage Restrictions” - Pink Sheet, 15 Aug, 2019.)

The agency recently finalized its LPAD guidance, providing additional clarification about the definition of limited population and availability of the LPAD route for fewer than all indications.


Current Development ChallengesNumerous industry and academic speakers described the significant hurdles they face in trying to satisfy the substantial evidence standard for antifungals for unmet medical needs. These hurdles, coupled with the related financial challenges, are hindering investment and development efforts in this space, they said.

Randomized controlled trials are difficult in the best of circumstances and not feasible for some infections, stakeholders said.

The relatively small number of patients with invasive fungal infections necessitates establishing a large number of clinical study sites, with trial costs of approximately $100,000-$200,000 per patient, said Michael Hodges, chief medical officer at Amplyx Pharmaceuticals.

Phase III trials in invasive candidiasis and invasive aspergillosis historically have required about 300-600 patients, Hodges said. However, recruitment rates per site are very low, with less than two patients per site per year, he noted.

Enrollment speed in antifungal trials also is negatively impacted by delays in diagnosis due to insensitive culture methods and limited availability of rapid, sensitive and specific non-culture-based diagnostics, said Peter Pappas, an infectious disease specialist at the University of Alabama.

Enrollment criteria requiring that potential study subjects be off antifungal treatment for more than 48 hours also limits the patients who can be enrolled, workshop participants said.

Rethink What Constitutes Substantial EvidenceSeveral industry speakers called for a new way of thinking about the substantial evidence standard in the antifungal drug development space.

“We think that invasive fungal infection drug

development would benefit from a new paradigm for demonstrating the statutory requirements of substantial evidence, similar to other orphan rare drugs to treat life-threatening diseases,” Hodges said. “Drugs to treat life-threatening, rare orphan diseases have been approved based on small datasets that support the substantial evidence of effectiveness required for approval of all drugs.”

Although LPAD permits the risk/benefit assessment more flexibility by taking into account severity, rarity and prevalence of the infection, this regulatory pathway does not alter the overall FDA approval standards, Hodges said. With only two LPAD drugs approved to date, “it is unclear how far this flexibility might extend in the approval of new antifungal drugs that address the high unmet medical need of invasive fungal infections.”

David Angulo, chief medical officer of Scynexis, Inc., said candidas infections should qualify for LPAD consideration. “I think this provides an opportunity for the whole community to work together identifying feasible ways to provide substantial evidence of effectiveness for this infection, considering the current unmet needs and limited treatment options.”

Of the substantial evidence standard, Angulo cited the need for a “well-balanced definition of substantial, in light of the unmet medical need,” and consideration of alternative approaches to satisfying the standard.

Discussion is warranted around how much weight preclinical assessments can contribute to evidence of effectiveness, he said.

As for clinical demonstration of efficacy, following only traditional approaches may limit availability of new therapeutics in the future, and the community should be open to discussing how to implement alternatives and more feasible approaches that can provide the substantial


evidence of effectiveness needed, with the acceptance of a greater uncertainty based on risk/benefit assessment, he said.

Angulo noted that clinical evidence from a statistically powered, randomized controlled trial in patients with C. auris infection is unlikely to be feasible due to the small number of patients and high mortality rate, among other factors.

He suggested alternative approaches could include conducting a randomized controlled trial in invasive candidiasis species that is enriched with C. auris patients, or conducting a randomized trial in other candida or other fungal diseases, with a small study in C. auris patients that is either nonnrandomized and compared to external controls, or is randomized but not powered for efficacy.

Other alternative approaches could include multiple smaller studies in different fungal diseases that are relevant to C. auris, he said.

Adjust Exclusion CriteriaTaylor Sandison, chief medical officer of Cidara Therapeutics, Inc., described a “moving target” of substantial effectiveness. “We don’t really know what to aim for in terms of what’s substantial evidence of effectiveness,” he said, suggesting an opportunity for greater reliance on pharmacokinetic/pharmacodynamic data.

“Given the recent advances in PK/PD target attainment, can we put more emphasis on that in lieu of a Phase III clinical trial powered for inferential statistics depending on the unmet needs and the … other categories and things that are part of the assessment of what’s required,” Sandison said.

He also suggested a need for leniency in some of the key exclusion criteria for clinical trials to increase patient experience with investigational

antifungals, for example, eliminating the requirement that subjects be at least 48 hours removed from empiric therapy. Potential concerns about whether prior treatments impacted an investigational drug’s efficacy could be addressed through stratification and analysis, rather than just keeping such patients out of a trial entirely, he said.

Mortality A ‘Blunt’ EndpointIndustry and academic speakers also suggested a need to reconsider the clinical endpoints that traditionally have been used in antifungal trials.

Commonly used endpoints in antifungal trials have been all-cause mortality or a global response endpoint, said Cheryl Dixon, an FDA statistical reviewer. However, global or overall response is not recommended as primary endpoint for noninferiority trials due to the inability to provide a data-driven, justified NI margin in most cases, although it still is recommended as a secondary endpoint in such studies, she said.

John Rex, chief medical officer and director of F2G Ltd, said that while all-cause mortality is a strong endpoint because it is so clear, “it’s also a blunt tool in that it gets entangled with underlying disease.” For example, Rex noted that patients with invasive aspergillosis “are dying of leukemias and other things along the way.” All-cause mortality also is not well-suited for infections that progress “more inexorably and slowly,” he said.

Luis Ostrosky-Zeichner, director of the laboratory of mycology research at McGovern Medical School in Houston, similarly took issue with crude mortality as an endpoint. He noted that people with candida infections are likely to die from numerous other factors, so it is difficult to know if such patients are dying because of candida or merely with candida. He urged a move away from crude mortality in favor of attributable mortality.


Reclassify ‘Stable’ As SuccessRex also raised concerns about a global response endpoint, the success of which requires improvement on all three components – clinical, radiologic and microbiologic. “There is an intermediate space that you see 20%-40% of the time, in which something’s better, something’s worse, and this leads to the categorization of stable,” he said. For example, a patient classified as stable could be clinically better, although their radiology has not improved.

Although stable is considered as a failure on the overall clinical response endpoint, “stable is very definitely the prelude to success. It enables staying alive,” Rex said.

Scoring stable “as failure sends the wrong message to clinicians and payers, and some of these people have very significant improvements in their quality of life,” Rex said of patients. “The label of stable just is not right anymore. We developed these endpoints some years ago before we understood some of the consequences of managing more difficult invasive fungal infections, and it’s something I’d like us to reconsider.”

The FDA said it has heard industry’s concerns about stable disease being classified as a failure for purposes of a global response endpoint.

“We understand that for some, a stable response is considered a positive outcome since it allows the patient to be suitable for continued treatment of their underlying disease,” Dixon said. “We have indicated our willingness to look at additional analyses based on a dichotomy of complete/partial/stable response, versus progression or death, for assessing a global overall response endpoint, and that the best way to describe the results of treatment response in any future labeling would be determined upon review of the final data.”

External ControlsOstrosky-Zeichner said invasive antifungal infections are exactly the type of setting for which the LPAD pathway was designed, and the agency and stakeholders should work together on an approval framework. “I think we need small, open-label trials in high incidence areas, both in the US and ex-US primarily, where we can collect case series of 20-30 very, very well-studied cases and compare them to contemporary controls.”

Workshop participants discussed the potential use of external controls for comparison purposes in nonrandomized trials, as well as the challenges inherent in ensuring that such external data represent a population comparable to that being studied in the trial.

Karen Higgins, an FDA statistical team leader, said there are cases where externally controlled trials can be used, but these are weaker trials than randomized studies because the sponsor is not able to control for many factors. Having a historically controlled trial be supported by a randomized controlled trial “is certainly helpful and we’d love to see that whenever possible, though we do understand there are certain circumstances when that would be difficult to do.”

John Perfect, chief of the division of infectious diseases at Duke University, said an opportunity exists now to systematically collect good data on patients with fungal infections who could serve as contemporary controls for nonrandomized studies.

Academic centers in the US that specialize in treating patients with fungal infections can screen dozens of patients for studies, only one of which might end up on a trial, he said. Efforts should be made to better understand more about the patients who do not go on trials and the types of outcomes they experienced, he said.


Rare Pediatric Priority Review Voucher Program Seems Headed For Short-Term Renewal

Executive SummaryChair of the House Energy and Commerce Committee raises questions about the priority review voucher program’s value, suggesting another limited extension may be upcoming.

Reauthorization of the rare pediatric disease priority review voucher program does not appear threatened by the House Energy and Commerce Committee, but the fact that questions about its value continue to emerge may be telling about its long-term future.

A 29 July legislative hearing on HR 4439, the Creating Hope Reauthorization Act, which would ensure the voucher opportunity remains available in perpetuity, included witnesses not only in support, but also against continuation of the program. And Rep. Frank Pallone, D-NJ, who chairs the Energy and Commerce Committee and would control the fate of the legislation, raised many long-running concerns about it.

The program will sunset 30 September absent congressional renewal. Under the current framework, if the program expires, products with a rare pediatric disease designation still can receive a voucher if approved by 30 September 2022. (Also see “Rare Pediatric Disease Designations May Be Unavailable After July As Program Renewal Remains Uncertain” - Pink Sheet, 17 Jun, 2020.)

Pallone indicated that renewal by the deadline seems assured. However, a permanent reauthorization, which advocates desire, may be less likely. He said that the FDA’s concerns about the vouchers’ effect on its resources also must be

considered before reauthorizing the program.

“While this program has provided value to some pharmaceutical companies who have made investments in rare disease programs, it also places a strain on the Food and Drug Administration,” he said during the virtual Energy and Commerce Committee Subcommittee on Health hearing. “We must keep that in mind and we should think carefully about whether a permanent reauthorization makes sense at this time.”

A priority review voucher allows the holder a priority assessment for any application they choose. Vouchers also may be sold and in some cases are a way for small companies to raise capital.

FDA also has not expressed overwhelming support for priority review vouchers, indicating in a Government Accountability Office study that vouchers divert resources to applications that may not warrant such treatment. (Also see “Priority Review Voucher Programs Poised For US Legislative Attention In 2020 “ - Pink Sheet, 18 Feb, 2020.)

In 2016, FDA officials told GAO the rare pediatric disease voucher program should not be renewed. (Also see “Review Voucher Program For Rare Pediatric Diseases Should Not Be Reauthorized, FDA Says” - Pink Sheet, 2 Mar, 2016.)

Rep. Gus Bilirakis, R-FL, said during the hearing that he hoped the bill could be marked-up in September. The program has been extended multiple times, most recently in 2016. (Also see “Pediatric Rare Disease Voucher Program Faces Expiration” - Pink Sheet, 10 Sep, 2016.)


If it were to receive a short-term extension this time around, the voucher program could be coming up for renewal along with the reauthorization of the user fee program in 2020, when, if some polling is accurate, Democrats may have unified control of Congress and the White House. Under that scenario, the program could come under considerably more political pressure.

Vouchers Are Not Free For Taxpayers, Kesselheim ArguesAaron Kesselheim, a Harvard University medical professor and opponent of the voucher program, discussed with Pallone a study he co-authored that found the PRV program did not lead to an increase in rare pediatric disease drugs under development. Kesselheim also argued during the hearing that the program costs taxpayers money, even though the Congressional Budget Office scored it as having no cost.

“It lets run-of-the-mill, non-innovative drugs onto the market sooner so that they can start being charged extremely high prices to Medicare and Medicaid,” he said. “That’s where the voucher gets its value from.”

Kesselheim suggested the program be allowed to expire, but added that if it continues, it should be modified to apply to only first-in-class drugs or those that fill an unmet need. He also said vouchers should not be given to sponsors of drugs cleared using accelerated approval and that any drug receiving a voucher should be marketed to US patients using a value-based price.

Kesselheim’s study, which was published in 2019, indicated that since the voucher became available, the likelihood of a rare pediatric disease drug moving from Phase I to Phase II increased compared to drugs for adult rare diseases. A similar result was not seen for the move from

Phase II to Phase III. (Also see “Rare Pediatric Disease Priority Review Voucher Not Generating New Drug Trials “ - Pink Sheet, 19 Feb, 2019.)

Voucher sale prices also are dropping, which Kesselheim said was diminishing their attractiveness.

The most recent value of a voucher was $100m, announced as part of a buyout between Merck & Co., Inc. and Lumos Pharma, Inc. on 27 July. The sum was a far cry from the peak sales price of more than $300m. (Also see “Merck Warned Of Q2 Slump, But How Far Did Revenue Fall?” - Scrip, 29 Jul, 2020.)

Permanence Will Provide More Certainty, More Drugs, Advocate SaysNancy Goodman, founder and executive director of Kids v Cancer, an advocate for pediatric cancer treatments, spoke in favor of the bill at the hearing. She said a permanent reauthorization would strengthen the incentive’s weakest point, which is when sponsors decide whether to start development.

“Drug developers, at the very beginning of the drug development process, when they’re looking 10 to 15 years out, they don’t have any assurance that the program is going to be there for them,” she said. “If we have a permanent program, we’re going to see many, many more drugs for seriously ill kids.”

Goodman also pointed to the number of pediatric rare disease drug approvals since the program was implemented as emblematic of its success. Since the voucher became available, 22 drugs have been approved for 18 rare pediatric diseases. Rare pediatric disease designations also have increased from three in FY 2013 to more than 60 today.


Priority Review Voucher Eligibility List Gains Three Tropical Diseases

Executive SummaryUS FDA adds brucellosis, opisthorchiasis and paragonimiasis to the list of qualifying diseases but declines to include clonorchiasis and coccidioidomycosis, finding a significant market in developed nations for treatments or vaccines addressing the two conditions.

The US Food and Drug Administration has added three infectious conditions to the list of qualifying tropical diseases under the priority review voucher program but declined to add two others. In final orders published in the Federal Register on 15 July, the agency added brucellosis, opisthorchiasis and paragonimiasis to the list, bringing the total number of qualifying diseases to 27.

However, the agency declined to add clonorchiasis and coccidioidomycosis to the list of qualifying diseases, finding that there was a significant market in developed nations for drugs or vaccines to treat or prevent these conditions.

The tropical disease priority review voucher program was created by the FDA Amendments Act of 2007 to incentivize development of new drugs and biologics for treatment and prevention of certain neglected diseases that affect underserved populations. Sponsors that bring such products through the FDA approval process may be eligible for a priority review voucher, which can be redeemed for a shorter review of another product or monetized through sale to another product sponsor.

To date, the FDA has awarded 11 vouchers under the program. The tropical disease program is

permanent and does not require reauthorization like the pediatric rare disease and medical countermeasures voucher programs.

New To The ListWhile most of the diseases on the list were mandated by statute, the agency has the ability to add other infectious conditions for which there is no significant market in developed nations and that disproportionately affect poor and marginalized populations. (Also see “Neglected Tropical Disease Designation Rejected For First Time By US FDA” - Pink Sheet, 3 Sep, 2018.)

The agency concluded that brucellosis, opisthorchiasis and paragonimiasis meet these criteria.

Brucellosis is a common zoonotic infection that occurs in more than 500,000 individuals worldwide annually through contact with fluids or inhalation of aerosols from infected wild or domestic animals, the agency’s notice states.

There are currently three FDA-approved treatments for brucellosis: doxycycline, streptomycin and tetracycline. A vaccine exists for brucellosis in livestock but there is no FDA-licensed vaccine for human use.

In high-income countries, the direct market for products to prevent brucellosis is small due to the success of strategies to decrease human exposure through control efforts in livestock and food, the FDA said. The agency noted it is unaware of any significant funding for drug development targeting treatment or prophylaxis of the disease by US government sources.

The World Health Organization has identified


brucellosis as a neglected tropical disease, and it remains significant in many parts of the world, including countries in the Mediterranean basin, Africa, Middle East, Asia and Central and South America.

Opisthorchiasis and paragonimiasis are both foodborne trematode infections that are acquired through the consumption of raw or undercooked fish or crustaceans.

There is one FDA-approved treatment for opisthorchiasis – praziquantel – and none for paragonimiasis.

The market for drugs for the two diseases in developed countries would largely consist of immigrants and travelers from endemic regions, which is unlikely to provide sufficient incentive to encourage development of products to treat or prevent the diseases, the FDA notice states.

Failure To Meet Lack Of Market Demand CriterionAlthough clonorchiasis is also a foodborne trematode infection, the FDA concluded this disease does not meet the statutory criteria. Although it disproportionately affects poor and marginalized populations, there is a significant market in developed nations, the agency notice states.

The prevalence of this infection in South Korea is over 2% of the population, which exceeds the agency’s 0.1% population threshold for determining whether a significant market may exist for a treatment.

The prevalence of 1.4 million infected people in South Korea as of 2008 “may offer an incentive to drive development of new drug products to treat or prevent clonorchiasis,” the agency said.

The agency also declined to designate

coccidioidomycosis, also known as Valley fever, a systemic fungal infection that is endemic to substantial parts of the southwestern US, including Arizona and California.

From 1990-2011, the incidence of reported cases in the US increased more than eight-fold in areas of endemicity, and the disease is responsible for an estimated 200 deaths each year.

There are two FDA-approved treatments – amphotericin B deoxycholate and ketoconazole – and the potential for development of vaccines has long been a topic of interest among experts.

The FDA said that if there is a significant market for either a treatment or prevention of an infectious disease, then the criterion that there be “no significant market” in developed nations is not met.

Such is the situation case with coccidioidomycosis, the FDA concluded.

”FDA has found that a sizeable direct market may exist for products to prevent coccidioidomycosis (e.g., vaccines) in developed nations, depending upon the specific attributes of the product and the recommended population,” the agency’s notice states. “For this reason, the statutory criterion that there be ‘no significant market for prevention or treatment’ of coccidioidomycosis is not met.”

The agency cites a 2000 report by the Institute of Medicine that estimated an annual target population size for a vaccine in the US to be more than 1 million people.

The agency points to US government grants for coccidioidomycosis drug development, orphan drug designation for potential therapeutics and inclusion of the Coccidioides species on the list of qualifying pathogens under the Generating Antibiotic Incentives Now (GAIN) Act.


Investment Challenges For Valley FeverJohn Galgiani, director of the Valley Fever Center of Excellence at the University of Arizona, is among the stakeholders who had urged the FDA to make coccidioidomycosis a qualifying tropical disease.

“Attracting commercial investment in new therapies for Valley fever has been virtually impossible,” Galgiani said in written comments to the agency in December 2019.

He noted the University of Arizona is the sponsor on an investigational new drug application for nikkomycin Z, a potential cure for Valley fever. With support from government grants and contributions from a foundation, the university activated a previously dormant IND, completed a multi-dose Phase I trial and has held a pre-Phase II meeting with the FDA. However, “it has not been possible to attract private investment despite the promise that this new agent represents to help patients with Valley fever,” he said.

In an interview with the Pink Sheet, he said the IoM paper cited by the agency estimated that $360m would need to be invested to develop a vaccine and that the process likely would take 15 years. Those estimates make it difficult to attract capital to such an endeavor, he said, also adding that the estimated market of 1 million people is not very large.

“There is no market from the point of view [of] can you see an investor willing to take this risk to get there,” he said.

He also cited an Arizona State University paper that estimated the total cost burden borne by Arizona residents who were diagnosed with Valley fever in 2019 is $789m.

Galgiani said he plans to discuss the investment challenges during an FDA workshop on 5 August on the development of antifungal drugs for the treatment of coccidioidomycosis infection.


Keytruda And FDA’s Oncology Center of Excellence: The Regulatory Milestones Keep Coming

Executive SummaryMerck’s anti-PD-1 therapy Keytruda keeps piling up new indications, including three approved by US FDA in just two weeks – all during a pandemic. The remarkable therapy has been a centerpiece for an equally remarkable period of regulatory innovation.

The US Food & Drug Administration’s 29 June approval of another new indication for Merck’s blockbuster anti-PD-1 cancer treatment Keytruda (permbrolizumab) is all too easy to overlook.

Amid the COVID-19 pandemic, the extension of the Keytruda label to yet another cancer type – in this case, patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer – is greeted as a nice bit of good news, but not otherwise remarkable. (Also see “Keeping Track Of US FDA Decisions: COVID-Induced Complete Response Letter For Contepo; Safety Sinks Abicipar Pegol; Approvals For Fintepla and Gimoti” - Pink Sheet, 28 Jun, 2020.)

Which is itself astonishing. Consider:

• The approval is based on an interim analysis of an ongoing study (KEYNOTE-177) that was only conducted in April of 2020. The supplemental application for approval of the indication was filed less than one month before the approval was granted. FDA, however, has now made it almost routine to start reviewing important new data before the application is submitted, under the Real-Time Oncology Review Pilot.

• FDA also undertook the review in collaboration

with global regulators in Australia, Canada and Switzerland under the Project Orbis initiative launched last year. (The international reviews are still ongoing, Merck says.) (Also see “’Project Orbis’ Oncology Pilot Eventually Will Target ‘Major Impact’ Applications” - Pink Sheet, 7 Oct, 2019.)

• The review was also supported by the Assessment Aid tool to help streamline the exchange of information between sponsor and the agency. Thus it might be called a “three project” review, featuring Orbis, RTOR and the Assessment Aid from the Oncology Center of Excellence toolbox.

• Finally, the agency leveraged the “summary level review” mechanism provided by the 21st Century Cures Act. This allows the FDA to conduct a streamlined, focused review using clinical study reports, protocols, summary documents and, if necessary, targeted re-analysis of the datasets for the primary efficacy endpoint to verify data quality. The oncology review divisions have now used this pathway for three supplemental applications and will continue to do so “where the evidence supporting efficacy is based on a well-established endpoint with a statistically persuasive result for a previously approved product that has a large existing safety database,” the FDA told the Pink Sheet.

What makes all of that truly remarkable is that none of it is unprecedented nor even especially unexpected at this point.

The KEYNOTE-177 trial, after all, showed a 40% reduction in disease progression or death and a doubling in progression free survival (to 16.5


months) compared to standard chemotherapy in a treatment setting with a poor prognosis. That is exactly the kind of dramatic benefit that the oncology team at FDA has made a habit of expediting in recent – and for which it has redoubled its commitment during the pandemic. (Also see “US FDA’s Oncology Center In The Lockdown: ‘Business As Usual’” - Pink Sheet, 18 Jun, 2020.)

But then consider: the new colorectal cancer indication was the third new indication for Keytruda approved in just two weeks. On 24 June, FDA approved the drug for use in patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

And on 16 June, FDA approved a tissue-agnostic claim for use in treatment of patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors. (Also see “Merck’s Keytruda Is First Checkpoint Inhibitor To Win US Approval Based On TMB Biomarker” - Scrip, 17 Jun, 2020.)

Neither of those reviews went as quickly. In fact, the cSCC indication took almost a full 10 months

from submission to approval, making it feel more like an outlier. The TMB-H indication took six months and used the Assessment Aid. And it marked the second time that Keytruda has added a “tumor agnostic” indication, three years after the drug made history with the first ever indication tied to a biomarker rather than a traditional cancer diagnosis. (Also see “Biomarker-Led Claim Is Small Step For Merck’s Keytruda, Giant Leap For Cancer Indications” - Pink Sheet, 23 May, 2017.)

For those keeping track, there are now 18 (!) different cancer indications in the Keytruda label – not counting sub-indications included for several different tumor types.

By now, it is well established the Keytruda and other immuno-oncology therapies are transforming cancer treatment. And it is equally well recognized that FDA will be innovative in expediting regulatory approvals when presented with important new data. At this point, an “on time” oncology approval feels slow.

Even amid a pandemic, it is worth pausing to realize how remarkable that state of affairs truly is.

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