Vol 1 No 2 une 10 2019 - Pink Sheet

CONTINUED ON PAGE 4

FOR THE LATEST INSIGHT ON BIOPHARMA REGULATION AND POLICY VISIT: PINK.PHARMAINTELLIGENCE.INFORMA.COM

Vol. 81 / No. 23 June 10, 2019

REGULATORY UPDATE

Navigating The Regulatory Maze In Emerging Markets – It’s An Art Too, p. 16

R&D

Overhaul Call For Outdated EU Innovation Incentives, p. 8

LEGISLATION

US House Appropriators Tip-Toe Into Biologics Transition Controversy, p. 11

tem may need to evolve to accommodate the large number of novel but expensive therapies that have shown impressive clini-cal results in recent years.”

SIGNATURE ACHIEVEMENTS That’s not to say there weren’t signature achievements. The POLO study showed a dramatic effect in a subset of patients with a notoriously difficult cancer – in pancreat-ic cancer patients with germline BRCA mu-tations, AstraZeneca PLC/Merck & Co. Inc.’s PARP inhibitor Lynparza (olaparib) yielded median progression-free survival (PFS) of 7.4 months compared to 3.8 months for placebo, with more than twice as many pa-tients remaining progression-free at both one year (34% vs. 15%) and two years (22% vs. 10%). (Also see “AZ/Merck & Co’s Lynparza POLO Study ‘Practice Changing’ For Pancre-atic Cancer Subgroup “ - Scrip, 3 Jun, 2019.)

Astellas Pharma Inc./Pfizer Inc. got con-firmation that enzalutamide has a role when added to testosterone in first-line treatment of hormone-sensitive prostate cancer from ENZAMET, with longer overall survival but also some increased toxicity.

But progress doesn’t always come with great leaps forward; sometimes it’s a mat-ter of incremental advance. Going fast can miss things – the checkpoint inhibitors rightly made a big splash and have come to dominate many cancers (and billboards around the city of Chicago).

But the first few years were filled with questions about how to identify the right patients, better information on dosing and appreciating differences between the PD-x drugs (remember when it was thought

ASCO REVIEW: Progress Is Where You Find ItMARY JO LAFFLER [email protected]

W ithout a definitive new drug ready to change practice, many observ-ers rejected this year’s American

Society of Clinical Oncology as slow. But coming out of the meeting, the

trends highlighted show a remarkable amount of progress and the tremendous efforts underway to realize the full poten-tial of genomic research to identify new therapies, find the best treatment settings and combinations and match them to the right patients.

True, none of the plenary abstracts fea-tured a new molecular entity (and one was on a drug already withdrawn for lack of ef-

fect). But that allowed ASCO to put a spot-light on other areas of progress.

As Credit Suisse analysts put it going into the 31 May-4 June conference in Chicago, “the intense scrutiny on detailed data points from numerous pivotal trials from our large cap companies (most notably Merck and Bristol-Myers) has been replaced by what we expect to be some still-important data presentations, but also with a focus now on bigger picture themes as we think about the emerging oncology landscape,” includ-ing “how patients/physicians are manag-ing the costs/side effects related to various therapies, as well as how our healthcare sys-

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CO V E R ASCO Review: Progress Is Where You Find It

D R U G P R I C I N G 6 US Affordable Care Act Impact On Cancer Care

Quantified At ASCO

R & D 8 Overhaul Call For Outdated EU Innovation

Incentives

G E N E R I C D R U G S 10 Heritage Is First To Settle DOJ Generic Drug Price

Fixing Probe; Will Others Follow?

13 GDUFA III May Rely Less On PDUFA As A Role Model

L E G I S L AT I O N 11 US House Appropriators Tip-Toe Into Biologics

Transition Controversy

R E G U L ATO RY U P D AT E 14 Cannabis Products: FDA Asks Dosing, Research

Incentive Questions

16 Navigating The Regulatory Maze In Emerging Markets – It’s An Art Too

M A N U FAC T U R I N G Q UA L I T Y 17 UK MHRA Consults On Applying Quality By Design

Principles To Monographs

N E W P R O D U C T S 18 Fifth PD-1, Zavicefta, Novel Psoriasis Ointment

Among Latest China Approvals

A D V I S O RY CO M M I T T E E S 19 Recent And Upcoming FDA Advisory Committees

inside: 13 6

11

UK Buyers Club To Get Lower Cost Versions Of Vertex’s CF Drugshttps://pink.pharmaintelligence.informa.com/PS125424

A UK buyers club in is planning to import generic versions of Vertex’s cystic fibrosis drugs that are unavailable on the NHS. Some commentators think such clubs may become more common.

What Is A Drug Shortage? First EU Definition Due This Monthhttps://pink.pharmaintelligence.informa.com/PS125422

Efforts to harmonize the notification and communication requirements for drug shortages in the EU will take a step forward this month when regulators adopt a common definition of a shortage together with a number of guidance documents. The situation with regard to drug shortages has been called a public health emergency.

Insys Must Divest Subsys, Buprenorphine Candidate Products As Part Of Corporate Integrity Agreementhttps://pink.pharmaintelligence.informa.com/PS125425

Settlement with US government also includes $225m payment to resolve criminal and civil cases related to illegal marketing of the sublingual fentanyl spray Subsys.

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• BIO 2019 Notebook: Merck On Finding The Right Balance, NORD On Patient Engagement, Sandoz On The Next Wave Of Biosimilars https://bit.ly/2QV6u3s

• BIO 2019 Notebook: Lartruvo Lookback, M&A Soars, BIO Vs. ASCO https://bit.ly/2WjUrh7

BIO 2019 NotebookOur editors provided wide-ranging coverage of BIO’s annual convention in Philadelphia in four daily notebooks.

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Keytruda (pembrolizumab) and Opdivo (nivolumab) might be interchangeable?) – the sort of thing that isn’t fleshed out when moving on a fast track.

In recent years, there’s been a lot of fill-ing in around the edges as more informa-tion rolled in. Researchers have clarified differences between the drugs in terms of efficacy and tolerability, better dos-ing regimens have been established in some cases, and the utility of the PD-L1 biomarker has been debated. This year there was a notable focus on emerging biomarkers for IO as well as understand-ing resistance patterns.

And Merck presented five-year sur-vival data from the KEYNOTE-001 study with Keytruda in non-small cell lung can-cer – a landmark analysis that codifies the impact IO is having on the cancer landscape.

Whereas traditionally lung cancer has had a five-year survival rate of 5% or less, Merck Research Labs’ chief medical officer Roy Baynes noted, the five-year overall survival (OS) rate was 23.2% in treatment-naïve patients and 15.5% in previously treated patients. In patients with high levels of PD-L1, five-year OS was 29.6% in treatment-naïve patients and 25.0% in previously treated patients.

The trial also supports longer-term use. In patients who had been on ther-apy for two or more years, the five-year OS rate was 78.6% in treatment-naïve patients and 15.5% in previously treated patients. “The data also bodes well for Merck’s ability to gain traction with pay-ers, including those outside of the US who may look for more longer-term data to fully support a product,” Credit Suisse analyst Vamil Divan said in a 2 June note.

Landmark data were also presented for Roche/Genentech Inc.’s Perjeta (per-tuzumab) in combination with Herceptin (trastuzumab) and docetaxel in patients with previously untreated HER2-positive metastatic breast cancer, with an “un-precedented” effects seen at an end-of-study analysis.

After eight years of follow up, patients on the Roche regimen had a 16.3 month improvement in survival over patients

on the comparator – a statistically signifi-cant 31% reduction in the risk of death.

PRICING REMAINS A PAIN POINT Long-term use does raise financial is-sues, however, and cost concerns came up again and again in scientific pre-sentations, especially regarding com-bination therapy. ASCO 2019 featured more than a handful of talks on value assessment, including a town hall on drug pricing and a specific session on oncology reimbursement reform that reviewed lessons learned from the on-cology care model.

In addition, health services/quality of care research took prominence with the presentation of research in the plenary session showing how Medicaid expan-sion under the Affordable Care Act al-most eradicated racial disparity in can-cer care compared to states that did not expand Medicaid.

It was one of several abstracts show-ing almost 10 years into Obamacare that access to care and better insurance are connected to better survival. (Also see “US Affordable Care Act Impact On Cancer Care Quantified At ASCO,” p. 6.)

FINDING A WAY WITH BIG DATA There was a dedicated education session on big data, and the role of artificial in-telligence and data analytics to process vast amounts of information – and the potential to better harness real-world ev-idence – came up in multiple tracks. The exhibit hall also reflected a shift toward more incorporation of a wide spectrum of technology into drug development and clinical practice, with splashy booths for sequencing and AI companies. And the plenary abstract on racial dispari-ties was conducted using Flatiron Health claims data.

Big pharma continues to explore ways to exploit data analytics. Roche has fully embraced it, making it a centerpiece of its oncology strategy with its early alliances (and later acquisitions) of Flatiron Health and Foundation Medicine. (Also see “Next-Generation Roche: How Data Analytics Will Keep It In The Lead In Oncology” - Scrip, 8 Jun, 2018.)

Lilly announced a deal with AI special-ist Atomwise during ASCO. (Also see “Time For AI To Deliver In Drug Discovery, Says At-omwise CEO” - Scrip, 4 Jun, 2019.)

While using non-traditional data sources like electronic health records and claims databases “are not designed with clinical evidence generation in mind, and analyses of these databases are retrospec-tive rather than prospective, they can yield important insights into real-world practice and include many more patients than is typical for an oncology trial,” In-forma Pharma Intelligence analyst Dan Chancellor told Scrip. “This is particularly useful for studying niche populations, such as those with rare tumors or unique molecular/genetic signatures.”

Data analytics companies are eager to ex-pand the role of real world evidence (RWE). Private AI play ConcertoHealthAI, which had a fairly large booth in the exhibit hall, has come up with a model for prospective research and is working with Pfizer, Bristol-Myers Squibb Co., Astellas and other undis-closed partners, including payers.

President Jeff Elton talked about how encouraging the US FDA has been in embracing RWE and modernizing data collection and analysis in an interview at

CONTINUED FROM PAGE 1

R & D

Even the exhibit

hall reflected a

shift toward more

incorporation of a

wide spectrum of

technology into drug

development and

clinical practice, with

splashy booths for

sequencing and

AI companies.


ASCO. “FDA has been spectacular leader-ship in this,” he said. “They are ready for in-novation and want to see protocols.”

Big data is generating big buzz, Merck’s Baynes agreed, as companies look to sys-tematize datasets for pattern recognition and clues – but it’s early days yet.

“You’re only as good as the algorithms you employ,” he commented. “There’s tre-mendous enthusiasm around [data analyt-ics] and it’s important to pursue, but at the end of the day you need to recognize that the findings are hypothesis-generating.”

CHECKING IN ON NEW CHECKPOINTS Analysts and physicians alike are keenly tracking the emergence of new check-point inhibitors beyond the PD-1/L1 fam-ily, and ASCO featured early data on a few hotly watched targets.

The data on Aduro Biotech Inc./Novar-tis AG’s ADU-S100, a stimulator of inter-feron genes (STING) activator, were from a dose escalation study, but they showed an encouraging 100% disease control rate among the eight patients with triple-neg-ative breast cancer evaluable for response, “strengthening the value of STING activa-tion as a novel immunotherapy approach for solid tumors. There is now preliminary efficacy across TNBC, melanoma, adding to previous data for Merck’s MK-1454 in head and neck cancer and thyroid carcinoma,” according to Biomedtracker analysts.

Both ADU-S100 and MK-1454 are deliv-ered intra-tumorally. Merck’s Baynes noted that there was “no question of local effect” for STING and that Merck is in the process of expanding its trials. Aduro noted that enrollment in a study of ADU-S100 and ipi-limumab in relapsed/refractory melanoma is ongoing and it anticipates initiating a trial with pembrolizumab in first-line head and neck cancer in the second half of 2019.

There were also early data on LAG-3, an-other next wave checkpoint inhibitor. But no monotherapy patients responded to Regeneron Pharmaceuticals Inc./Sanofi’s REGN3767 and only 5% of patients re-ceiving it with the anti-PD-1 cemiplimab achieved a partial response. Patients who converted to PD-1 monotherapy after re-ceiving the LAG-3 drug did the best.

“It suggests that LAG-3 may be best used as a sequential agent and it does sensitize tumors to PD-1 inhibition, but the effect in this trial was weak (16% PR). This was a dose escalation study and not designed to determine efficacy, but you can’t ignore the low overall response rates,” Chancellor told Scrip.

WHAT CAN WE LEARN FROM FAILURE? ASCO threw the interesting twist of high-lighting a trial failure for one of the four plenary spots, which served as a post-mortem on the accelerated approval and subsequent withdrawal of Eli Lilly & Co.’s Lartruvo (olaratumab) and an examina-tion of what it was about soft tissue sar-coma (STS) that contributed to the failure.

It played out like a mystery – here was a drug that had a significant survival bene-fit in a large randomized Phase II trial, but then missed the survival endpoint in the Phase III study.

The principal investigator William Tap, Memorial Sloan Kettering Cancer Center, walked through the Phase II evidence, the sound decision for accelerated ap-proval and the rigor and quality of the Phase III study. Both he and the discus-sant on the trial, Erasmus University’s Jaap Verweij, identified issues about

the heterogeneity of the STS classifica-tion and the likelihood of differential re-sponses in subgroups.

The public debate of the findings seem to put to rest any concerns about the ac-celerated/conditional approval mecha-nisms – this is an example of a “success-ful failure” and a confirmation that these programs that push for new advances on early evidence must necessarily have some that don’t work out.

Failure is of course an all too common part of the drug development process. Focusing on the olaratumab experience showed how much can be learned out of failure, and how it can inform future development.

When Merck comes up with a failed trial, it rallies a team to pull it apart – look at the setting, the degree that it missed the endpoint, if there were crossover ef-fects or there might be a subgroup that is responding, Baynes explained in an inter-view at ASCO.

Even a positive trial is picked apart to glean intelligence about subgroups and response patterns, Baynes said, “but if a study fails, we spend a lot of time trying to [understand what happened].“

Failed trials are tremendous learning opportunities. As Genentech oncology product development leader Alan Sandler told Scrip, “the only mistake in clinical de-velopment is if you think you know more than you do.”

NOT ACTUALLY SO QUIET?It may have been a year that investors and analysts found quiet – although according to Baynes, ASCO was “anything but quiet.” Of course Merck now has the leading IO franchise in Keytruda and the leading PARP inhibitor in Lynparza, and presented some of the biggest results of the conference.

But the different areas of focus at ASCO 2019 drive home the changing landscape in oncology, as IO falls into place as an established pillar of oncology, political and commercial pressure tightens on re-imbursement and pricing, and new tech-nologies raise new possibilities for R&D.

It sets the stage for what to look out for in 2020.

Published online 5 June 2019

R & D

Analysts and

physicians alike are

keenly tracking the

emergence of new

checkpoint inhibitors

beyond the PD-1/L1

family, and ASCO

featured early data

on a few hotly

watched targets.



US Affordable Care Act Impact On Cancer Care Quantified At ASCO

MARY JO LAFFLER [email protected]

N ine years after its implemen-tation, the impact of the Af-fordable Care Act and the

optional expansion of Medicaid that followed is being demonstrated with dra-

matic improvements in access to cancer care and reductions in disparities.

The issue was given a high-profile focus at the Amer-ican Society of Clinical Oncology annual meeting plenary session 2 June. While health services and policy research is a regular track at ASCO, it is rare for it to reach the plenary session, where the top four abstracts of the 5,600 accepted are highlighted.

ASCO also embraced policy issues with a town hall on drug pricing, which focused on the Trump administration’s proposal to experiment with using and international pricing index to set payment rates for Medicare Part B physician-administered drugs and reform of the 340B federal program to discount drugs pro-vided to vulnerable patient groups. (Also see “Turning Question Marks Into Check Marks: HHS Blueprint One Year Later” - Pink Sheet, 10 May, 2019.)

During that morning’s press briefing, ASCO leadership pre-sented the plenary abstract showing “previous racial disparities in timely cancer treatment between African American and white patients practically disappeared in states where Medicaid access was expanded under the Affordable Care Act (ACA),” as well as abstracts on ovarian cancer diagnosis and an analysis of the im-pact of insurance type on outcomes in multiple myeloma, which is treated with costly drugs.

In addition to creating private insurance marketplaces, the ACA, also known as Obamacare, allowed states to expand Med-icaid coverage starting in 2014 to adults falling under 138% of federal poverty guidelines. As of January 2019, 33 states and the District of Columbia had done so.

It is hard to find a control for this sort of policy research, Wil-liam Dale, City of Hope, told the press briefing, but the optional expansion of Medicaid created a group of states that had broad-ened enrollment and some that had not – although demographic criteria needed to be taken into account.

EARLY DETECTION OF OVARIAN CANCER“Under the Affordable Care Act, women with ovarian cancer were more likely to be diagnosed at an early stage and receive treatment within 30 days of diagnosis,” Anna Jo Smith, Johns Hopkins Univer-sity, et al. concluded. “As stage and treatment are major determi-nants of survival, these gains under the ACA may have long-term impacts on women with ovarian cancer.”

Using the National Cancer Database, which captures data on

approximately 70% of all new ovarian cancer cases, according to ASCO, researchers collected data on women diagnosed and treat-ed between 2004-2009 (pre-ACA; 35,842 patients) and 2011-2014 (post-ACA; 37,145 patients). Data were assessed based on stage at ovarian cancer diagnosis and time to treatment, comparing simi-larly sized groups of women ages 21-64 and 65 and older, which served as the control as they had access to Medicare “and hence had a much lower risk of being uninsured either pre-or post-ACA.”

The datasets were adjusted for race, rural demographics, neigh-borhood household income, education level, distance traveled for care, Census region, practice setting where they received care and a co-morbidity score that predicts risk of death. The type of insur-ance women had was also taken into consideration.

Based on a “difference in differences” approach to compare changes over time between the two groups, compared to the 65 and older group “there was a relative gain of 1.7% in early-stage diagnosis (defined as stage 1 or 2) of ovarian cancer,” the research-ers concluded. “There was also a relative improvement of 1.6% in women being treated within 30 days of diagnosis for those age 21 to 64 as compared with women 65 and older.” The p-value for the trend was less than 0.001 for each.

While a 1.7% difference in early diagnosis “may not sound very large,” Smith pointed out for the 22,000 women diagnosed with ovarian cancer in the US annually, “it means that close to 400 more women could be diagnosed at an early, treatable stage and have a good chance of living a longer life.”

Women who received public insurance post-ACA saw the great-est benefits, with relative gains of 2.5% in early-stage diagnosis and timely treatment, which were consistent “regardless of race, income or educational level.”

Research is continuing to look at years beyond 2014 and to con-sider other gynecologic cancers.

INSURANCE STATUS AND SURVIVAL IN MULTIPLE MYELOMAAnother study used the National Cancer Database to analyze demographic statistics for patients with multiple myeloma and found that socio-economic factors including private insurance, living in a higher-income area and receiving treatment in certain practice settings were associated with longer survival.

“With the continuously increasing cost of health care, it is im-portant to highlight the presence of a survival disadvantage for people who cannot afford their treatment costs,” lead author Ka-mal Chamoun, University Hospitals Seidman Cancer Center, told the ASCO press briefing. “Prices of oral cancer drugs have been rapidly escalating, especially for patients and survivors of multi-ple myeloma, and we need to take action to limit and reverse the

D R U G P R I C I N G



disparity for those who cannot afford private insurance or have lower incomes.”

Chamoun cited earlier studies by other researchers that multi-ple myeloma is the top cancer treated with oral medications and that the proportion of treatment cost due to medications nearly tripled between 2000 and 2014.

Bristol-Myers Squibb Co./Celgene Corp.’s Revlimid (lenalido-mide) and Takeda Pharmaceutical Co. Ltd.’s Velcade (bortezo-mib) has dramatically improved myeloma survival rates. Drugs are moving into earlier lines of treatment lines and as patients live longer with longer treatment durations, costs are escalating. (Also see “Multiple Myeloma: Pricing And Reimbursement Challeng-es Escalate Even As Blockbusters Go Generic” - Scrip, 6 May, 2019.)

“With patients often treated with triple regimens, and many quadruple combinations of newer market entrants making up the late-stage pipeline, payers express concern surrounding the increasing usage of combination regimens within multiple my-eloma,” Datamonitor Healthcare states in its recent Multiple My-eloma Pricing, Reimbursement And Access report.

Chamoun and his colleagues reviewed data from 117,926 pa-tients living with multiple myeloma between 2005 and 2014. They found that:

• Patients receiving treatment in an academic institution had a 49% greater probability of survival;

• Patients living in an area with a median income of $46,000 or more had a 16% greater chance of survival compared to patients with a median regional income of less than $46,000;

• A lower percentage of people receiving Medicare or Medicaid traveled more than 120 miles to a treatment facility compared with people with private insurance;

• Neither race (black or white) nor gender had an impact on survival rates.

The impact of insurance type was the most notable finding. Across the dataset, 52% of the population was on Medicare, 35% had private insurance and 5% were on Medicaid. Chamoun re-ported that out-of-pocket costs were significantly higher for pa-tients with Medicare than other types of insurance.

“People with private insurance had a 59% greater probability of survival than those who were insured through Medicaid,” the researchers found. “Similarly, people with private insurance had a 62% greater probability of survival than those who had no insur-ance. For people age 65 and older, those who had private insur-ance also lived longer than those who had Medicare,” although the latter was not statistically significant.

Chamoun noted that since oral medications fall under Medi-care Part D plans, patients can have a harder time affording long-term use – and limited access to expensive drugs could explain the study findings. Medicare patients can face significant spend-ing on drugs both in the program’s coverage gap and if they reach the catastrophic costs threshold. (Also see “Capping Off The Rebate Debate: Will 2019 Price Push End With Co-Pay Cap?” - Pink Sheet, 1 May, 2019.)

MEDICAID EXPANSION IMPACT ON RACIAL DISPARITIESRacial disparities have been well established across the spectrum of cancer care, from screening to treatment and outcomes, Ad-amson told the ASCO briefing, and timely treatment is essential to positive outcomes.

Adamson and colleagues tested the hypothesis that “Medicaid expansion reduced disparity in timely treatment of black patients compared to white patients with advanced cancer,” using elec-tronic health records from Flatiron Health and linked to data from the Kaiser Family Foundation on expansion status. Flatiron Health also funded the study.

The analysis included adults 18-64 years with advanced or met-astatic cancer from January 2011-January 2019. They looked for timely treatment defined as systemic treatment initiated within 30 days of diagnosis.

Of the 30,386 records included in the patient population, 11,708 fell into the expanded Medicaid cohort and 18,678 in the not expanded group. The racial breakdown was not even, but it was demographically consistent for the states: the not-expanded state group was 73.3% white and 14.6% black, and the expanded group was 70.3% white and 8.7% black. The breakdown of can-cer types was consistent with the national averages, with lung, colorectal and breast cancers predominant.

The adjusted rate of timely treatment was 48.3% for white pa-tients and 43.5% for black patients in the not expanded arm, a dif-ference of 4.8 percentage points. (p<0.001). It was not significant in the expanded arm, at 50.3% for white patients and 49.6% for black patients, a difference of 0.8 points (p=0.63).

“Implementation of Medicaid expansions as part of the ACA differentially improved African American cancer patients’ receipt of timely treatment, reducing racial disparities in access to care,” the abstract concludes.

“Under expansion, the difference almost disappeared com-pletely,” Adamson told the ASCO briefing. The reduction in dis-parity went down 4.0 points from 4.8 points (p=0.042).

“Medicaid expansion was most beneficial for African Ameri-cans when it came to timely treatment, with a 6.1 percentage point improvement as compared with a small and statistically in-significant 2.1 percentage point increase among white patients,” ASCO noted.

The investigators are currently developing models to predict what treatment outcomes would be if there was no Medicaid ex-pansion as compared with expansion in all states.

Responding to the racial disparity abstract during the plenary, Yousuf Zafar, Duke Cancer Institute, pointed out that the con-clusions lack the definitiveness of a randomized controlled trial – but the study “takes a leap forward” in shifting the paradigm to safely and fairly use patient-level data to inform policy. “It’s a proof-of-concept that health systems can indeed share their data to not only inform health policy but also improve outcomes and decrease disparities.”


D R U G P R I C I N G



Overhaul Call For Outdated EU Innovation IncentivesFRANCESCA BRUCE [email protected]

R eplacing data exclusivity with data compensation and rethinking the prevalence threshold for determin-

ing whether a medicine is an orphan prod-uct are two of several recommendations aimed overhauling the EU system for in-centivizing innovation.

Such measures could counter “cata-strophically” high medicines prices, ac-cording to a new briefing paper from Med-icines Law & Policy, an organization that provides analysis to about the availability of safe, effective and affordable medicines.

The briefing paper, entitled European Union Review of Pharmaceutical Incen-tives: Suggestions for Change, comes as an EU review on the incentives available for pharmaceutical innovation is drawing to a close. The Council of the European Union first announced the review in 2016 when it “noted with concern an increasing number of examples of market failure in a number of Member States, where patients access to effective and affordable essen-tial medicines is endangered by very high and unsustainable price levels.” (Also see “’Skyrocketing’ Drug Prices, Access And Avail-ability In Line For EU Scrutiny” - Pink Sheet, 20 Jun, 2016.)

According to the paper, patents and oth-er exclusive rights like data and market ex-clusivity incentivize companies to innovate through offering them “temporary monop-olies” for their innovations. However, these incentives can lead to monopoly pricing, which can have catastrophic consequences if access is denied or stalled until lower cost versions come to market, it says.

The balance between rewarding innova-tion and ensuring that it is available to pa-tients has “tipped hugely” towards private companies and away from public benefit, it says. The paper argues that market exclusivi-ties are never rolled back and are based on assumptions, for example about profitability of a disease market, rather than hard data.

“The pharmaceutical industry now bene-fits from a web of protections in the EU that together delay market competition for long

periods and allow companies to set profit-maximizing prices that are unaffordable for many,” said Ellen ‘t Hoen of Medicines Law & Policy, one of the paper’s authors. “Com-panies obtain those rights without needing to demonstrate that their turnover is insuffi-cient to recoup investments and make new ones,” she added.

Medicines Law & Policy is therefore offer-ing recommendations designed to ensure that while adequate incentives for pharma-ceutical innovation are available, they do not risk access to these innovations.

The paper focuses on three areas of leg-islation concerning supplementary protec-tion certificates (SPCs), data exclusivity and orphan medicinal products, all of which, it says, “warrant particular readjustment.” All recommendations are based on certain principles, for example, that there is a need

for a clearer link between risk and reward. According to the paper, the pharmaceutical industry relies on “inflated impressions” of the cost of drug development to overstate the exclusive marketing time needed to re-coup investment and become profitable.

SPCSThe paper includes a number of recom-mendations on SPCs. It suggests that their granting should be linked to wheth-er applicants provide evidence that the term of protection provided through the patent is insufficient to cover research investments. Patent offices should be provided with data on past and future development costs, though excluding public funding, as well as expected rev-enues, says the paper. And when an SPC is granted, data on return on investment

R & D

“ The pharmaceutical industry now benefits

from a web of protections in the EU that together

delay market competition for long periods and

allow companies to set profit-maximizing prices

that are unaffordable for many,”

– Ellen ‘t Hoen, Medicines Law & Policy



should be submitted before the SPC en-ters into force to confirm, based on actual reported profits, whether indeed the SPC is necessary. The SPC could be cancelled if research investments had been covered during the patent protection period, the paper suggests.

Another recommendation on overhaul-ing the SPC system involves giving third parties the chance to put forward “ob-servations” to the patent office to block an SPC entering into force. This would be based on evidence from reported profits showing that the patent protection peri-od was enough to cover investments, the paper says.

Meanwhile SPCs entering into force could also be tied to the price of the prod-uct. Companies could win extra protec-tion for their products if they could show that there is a need for the extra protec-tion and that the product is affordable while it is protected.

In addition, procedures that allow an SPC to be revoked could be made avail-able in all EU countries. These would be modeled on patent opposition proce-dures. Many countries in the EU currently lack such mechanisms, the paper notes.

DATA EXCLUSIVITYThe data exclusivity regime could be re-placed with a data compensation regime, argues the paper. The latter would ac-knowledge that investments are required to generate data, but would not allow investors to stop other parties using the data. “Under a data compensation re-gime, the registration of a generic medi-cine or biosimilar medicine is considered fair commercial use and thus not ham-pered by the data protection.” The paper adds that the originator company behind

the investment would receive “adequate remuneration” for the use of the data but would be unable to prevent it being used, for example, by medicines agencies to perform public health duties like register-ing generic medicines.

Waivers to data and marketing exclu-sivity could be introduced to allow gov-ernments to use patents in the public interest, compulsory licensing and other measures for public health reasons. “This would bring coherence to EU law and as-sist member states that are seeking ways to ensure the availability of new medi-cines without undue burden on their health budgets.”

The paper also calls for data exclusiv-ity requirements to be dropped from trade negotiations with other countries. Instead, agreements should focus on ad-dressing medical R&D needs and mecha-nisms to help share the benefits and bur-dens of R&D.

ORPHAN MEDICINESMedicines Law & Policy also says that “the possibility for excessive or abusive ex-ploitation” of incentives set out in Regu-lation 141/2000 on orphan medicinal products should be reduced. This could be achieved by increasing transparency in the orphan product regime to make it easier to “match commercial reward with development risks and cost.”

For example, the paper argues that the line between sufficient and excessive profitability, and therefore between suf-ficient and insufficient return on invest-ment, should be defined in Article 8(2) of Regulation 141/2000. This article reduces the period of market exclusivity from 10 to six years if the product can be shown to be sufficiently profitable.

The prevalence threshold for determin-ing whether or not a drug is an orphan product, as set out in the in Article 3(1)(a) of the same regulation, also comes under scrutiny. This threshold is based on assumptions about the profitability of the disease market in question and is currently set at an EU patient population of no more than five in ten thousand. Ac-cording to the paper, this threshold is too generous and has allowed companies to access incentives without showing evi-dence of insufficient profitability.

The “unprecedentedly high prices charged for orphan medicinal products by some pharmaceutical firms have meant that orphan disease markets with < 10,000 patients can be made to produce ‘blockbuster’ profits,” the paper declares.

Medicines Law & Policy also calls for a rethink of the granting of marketing authorization and orphan exclusivity for versions of products that have previously been used off-label or which have been compounded by pharmacists. The bulk of data required for such awards is already in the public domain, and organizations, for example, hospitals, which previously produced their own versions should be permitted to make the same product as they did before, says the paper. In addi-tion, the commercial reward for sponsors should be linked to their relatively small development costs and risks.

Clawback mechanisms could also be considered to allow the European Medi-cines Agency to reclaim any financial or other “costed support” incentives if the product turns out to be profitable be-yond a predetermined threshold, it adds.


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G E N E R I C D R U G S

Heritage Is First To Settle DOJ Generic Drug Price Fixing Probe; Will Others Follow? BRENDA SANDBURG [email protected]

H eritage Pharmaceuticals Inc. is pay-ing a relatively small sum to be free of the US Department of Justice’s

industry wide probe of generic price fixing. It remains to be seen if other generic manu-facturers will enter similar settlements and how great their liability might be.

Heritage agreed to pay $7.1m to resolve allegations under the False Claims Act that it engaged in a price-fixing conspiracy. It also entered into a deferred prosecution agree-ment resolving a one-count felony charge, under which it will pay a $225,000 criminal penalty and cooperate with the DOJ’s on-going criminal investigation of other ge-neric drug manufacturers.

The government agreed to defer pros-ecuting Heritage for three years to allow the company to comply with the agreement’s terms. Heritage obtained the deferment in part due to its cooperation in DOJ’s investi-gation of other companies.

In a 31 May release announcing the agreement, DOJ said the company’s “sub-stantial and ongoing cooperation with the investigation” has allowed it to advance its investigation into criminal antitrust conspir-acies among other generic manufacturers.

While Heritage escaped the DOJ investi-gation, it is still mired in litigation brought by state attorneys general.

“Our litigation against Heritage is ongo-

ing, and our investigation into the generic drug industry is ongoing and expanding,” Connecticut Attorney General William Tong said in a statement. “The guilty plea [with DOJ] pertains to one drug for a limited period of time and is based off the federal sentencing guidelines. We, the state of Con-necticut, believe that the civil exposure in our litigation and the liability for Heritage is much greater than that and we will con-tinue to prosecute our case aggressively.”

THREE FELONY CHARGES TO DATEThe DOJ’s felony charge, included in an In-formation filing, states that from April 2014 until at least December 2015, Heritage and co-conspirators “knowingly entered into and engaged in a combination and conspiracy with other persons and entities engaged in the production and sale of ge-neric pharmaceutical products, including glyburide, a purpose of which was to allo-cate customers and fix and maintain prices of glyburide in the United States.”

The Information cites meetings, con-versations and communications between Heritage and co-conspirators to allocate customers; price proposals and price an-nouncements; and the sale of glyburide at collusive and noncompetitive prices. The filing says this combination and conspiracy was an unreasonable restraint of interstate trade and commerce in violation of Sec-tion 1 of the Sherman Act.

The felony charge is the third the DOJ has issued in the industry-wide probe. The previous charges were filed against two for-mer Heritage executives in December 2016. (Also see “Generic Price Fixing Probe: First Charges Unsealed, More May Come Before Inauguration Day” - Pink Sheet, 14 Dec, 2016.)

Heritage said it was pleased to put these issues behind it.

“These resolutions fully resolve Heri-tage’s potential exposure in connection with the DOJ’s ongoing investigation into

the generics pharmaceutical industry,” Her-itage said in a release. “The conduct under-lying the company’s resolutions with DOJ involved two former Heritage executives, both of whom pleaded guilty in January 2017 to felony antitrust violations; they are now awaiting sentencing, which is cur-rently scheduled for September 26, 2019.”

Heritage said its board of directors termi-nated the executives in August 2016 after learning of their antitrust conduct and dis-covering they “orchestrated a years-long embezzlement scheme that looted tens of millions of dollars from the company.”

The two former Heritage executives en-tered into settlement agreements with the AGs and are cooperating in that case.

SECOND SUIT BY STATE AGSThe generic industry has been embroiled in the DOJ inquiry and a parallel investigation by state attorneys general for the past five years. In July 2014, the Connecticut attor-ney general issued subpoenas to numerous generic manufacturers seeking information on product pricing. And in November 2014, the DOJ’s antitrust division began issuing grand jury subpoenas to generic firms re-questing information on pricing and com-munications with competitors.

After criminal charges against the Heri-tage execs were unsealed, 20 state AGs, led by Connecticut, filed a civil suit against Heritage and five other companies claim-ing they entered contracts and conspira-cies to maintain prices and reduce compe-tition for two drugs, Doxy DR (doxycycline delayed release) and glyburide.(Also see “Generic Industry Hit With Avalanche Of Price Fixing Suits” - Pink Sheet, 22 Feb, 2017.)

The AGs filed a motion to amend the complaint in October 2017 to increase the number of generic manufacturer de-fendants to 18, and the number of drugs at issue to 15, and to name two individual defendants. (Also see “ Generic Price-Fixing Lawsuit Grows As More Companies, Two Ex-




ecutives Named Defendants” - Pink Sheet, 31 Oct, 2017.) A judge granted the mo-tion in June 2018.

On 10 May, a coalition of 44 states led by Connecticut AG Tong filed a second complaint against Teva Pharmaceuticals USA Inc. and 19 other generic drug man-ufacturers, alleging they conspired to artificially inflate and manipulate prices and reduce competition for more than 100 drugs. The suit also names 15 indi-vidual senior executives as defendants.

The allegations are similar to those in the first complaint, citing emails, text messages, telephone records and meet-ings as evidence of a conspiracy to fix prices and divide market share for ge-nerics. But unlike the previous case, the second one focuses specifically on Teva.

The complaint alleges that during a 19-month period beginning in July 2013 and continuing through January 2015, Teva significantly raised prices on ap-proximately 112 different generic drugs and colluded with “High Quality” com-petitors on at least 86 of them.

The suit says the states have obtained valuable cooperation from a number of individuals during the course of the investigation. It notes that cooperating witnesses include three former execu-tives at Sandoz Inc. and former execu-tives at Rising Pharmaceuticals Inc., Glen-mark Pharmaceuticals Inc. and Heritage.

Evercore ISI analyst Umer Raffat said in a 13 May report that the state AGs ap-pear to be using the litigation to apply more pressure to force settlements.

The first suit is pending in the US Dis-trict Court for the Eastern District of Penn-sylvania and will proceed on a parallel track with the second complaint, which was filed in the US District Court for the District of Connecticut. By filing a new suit rather than further amending the first complaint, the original suit can go for-ward without delay.


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House Appropriators Tip-Toe Into Biologics Transition ControversyDERRICK GINGERY [email protected]

U S House appropriators addressed the so-called regulatory “dead zone” for insulin products about to

switch from regulation as drugs to regula-tion as biologics, although not as forcefully as recently-proposed Senate legislation.

Language in the report accompanying the House fiscal year 2020 Agriculture, Ru-ral Development and US Food and Drug Administration appropriations bill, which was marked up and sent to the floor 4 June, encourages the agency to use specific pro-grams to assess insulin products with user fee goals prior to 23 March 2020, the statu-tory date they would move from drug to biologics regulation.

The committee said in the report that “to ensure patient access to lower-cost insulin,” relevant insulin applications should be as-sessed using the PDUFA V “Program,” the model implemented in 2012 for many NMEs that allows mid- and late-assessment cycle communications. The Program extended assessments by creating a two-month fill-ing period before the review clock starts. (Also see “PDUFA V ‘Program’ First-Cycle Ap-proval Rates Significantly Higher For All Applications” - Pink Sheet, 12 Dec, 2016.)

In addition, the agency was asked in the report to “work to identify and promote ef-ficiencies in the review” of any insulin applications submitted under the Public Health Service Act that were previously submitted under the Food, Drug and Cosmetic Act with goals before 23 March 2020 and were not approved by that date.

The 2009 Biologics Price Competition and Innovation Act mandated that insulin, hu-man growth hormone and some other protein products that are regulated as drugs to be regulated as biologics beginning on 23 March 2020.

Stakeholders and industry raised concerns when the agency said in guidance on the transition that some Food, Drug and Cosmetic Act Section 505 applications submitted for a biologic product subject to the transition that are not approved by 20 March 2020 would receive a complete response letter, forcing them to be re-submitted. (Also see “A Guide To US FDA’s Drug-To-Biologic Transition Process” - Pink Sheet, 8 May, 2019.)

As a result, sponsors are not expected to submit affected applications in the months leading up to the transition because they may be forced to start over as a BLA, creating what has been called an application “dead zone.” (Also see “Insulin Applications Intended For Biosimilar Pathway May Already Be At US FDA” - Pink Sheet, 2 Apr, 2019.)

The House language does not attempt to eliminate the dead zone, but may be an at-tempt to provide some regulatory certainty to sponsors who have insulin applications awaiting an agency approval decision.

The report does not go as far as a recently released Senate drug pricing bill, which

L E G I S L A T I O N

The House language

may be an attempt to

provide some regulatory

certainty to sponsors who

have insulin applications

awaiting an agency

approval decision.




would eliminate the possibility that a CR could be issued in those cases. The Health, Education, Labor and Pensions Committee’s dis-cussion draft would require applications assessed under Food, Drug and Cosmetic Act Section 505 and filed by 23 September to continue to be reviewed, even if the review lasts beyond the transition date. Upon approval (or 23 March 2020, whichever is later), those applica-tions would immediately be deemed BLAs under the Public Health Service Act. (Also see “Biologics Transition ‘Dead Zone’ Could Be Elimi-nated Under US Senate Bill” - Pink Sheet, 28 May, 2019.)

Committee members also urged the agency in the report to “act quickly” in reviewing the feedback and recommendations received during the 13 May public meeting on the future of insulin biosimilars. Among the ideas offered was allowing follow-on insulins to use the interchangeability pathway without first being approved as a bio-similar. (Also see “Best Pathway To Interchangeable Insulins Is In The Eye Of The Beholder” - Pink Sheet, 15 May, 2019.)

LANGUAGE ON GENETIC MODIFICATION OF EMBRYOS RE-INSERTEDDuring the mark-up, committee members decided to include a ban of funding for FDA to receive applications involving inten-tional heritable genetic modification of an embryo, approving the amendment by voice vote.

The provision had been in FDA appropriations bills the last four years, but was left out in the initial version of the FY 2020 bill. (Also see “US FDA Wins Big In Shutdown-Averting Approps Bill” - Pink Sheet, 14 Feb, 2019.)

Members indicated that there are moral and ethical questions involving such gene editing, but some also worried about a blan-ket denial of the practice, which could prevent mitochondrial re-placement therapy from moving forward.

Several committee members agreed that the ban should be re-viewed going forward, in part because many of those questions may be resolved.

Rep. Andy Harris, R-MD, who is a physician, said he supported the amendment “with the caveat that this is going to need to be looked at because the technology is advancing way more rapidly than what this amendment suggests.”

BILL, IF ENACTED, WOULD BOOST FDA FUNDINGThe FDA would receive $5.85bn in the House bill, a 4.7% increase compared to the FY 2019 funding bill, but significantly less than Pres-ident Trump allocated in his budget request.

The Center for Drug Evaluation and Research would receive the largest increase within the agency, $98.7m. (Also see “US FDA Gets Another Appropriations Increase In FY 2020 House Bill” - Pink Sheet, 22 May, 2019.)

While the funding level is another win for the FDA, it was not based on budget numbers that have been agreed to by the Senate and White House, a complaint Republicans made during the mark-up. Until an agreement is reached, enactment likely remains in doubt.

The Senate has not yet released its FY 2020 FDA appropriations bill.


G E N E R I C D R U G SL E G I S L A T I O N

GDUFA III May Rely Less On PDUFA As A Role Model SUE SUTTER [email protected]

O ne and a half years into the second iteration of the generic drug user fee program, industry is question-ing whether some of the processes adapted from the

prescription drug review side are useful in expediting the market availability of generics.

The generic drug sector’s business model and market dynam-ics are so different from those of the innovator industry that the prescription drug user fee program model for meetings and in-teractions with the agency may not be well suited to the needs of abbreviated new drug applicants, industry representatives said at the recent Food and Drug Law Institute annual meeting.

Speakers from industry and the US Food and Drug Administra-tion agreed that more time and data would be needed to assess the impact of some of the GDUFA II elements aimed at speed-ing generic drug development and first-cycle approvals, such as product development meetings, pre-ANDA meetings and mid-cycle meetings.

However, when it comes time to start negotiations on GDUFA III, there may be less appetite, at least among those in industry, to import features from the more established PDUFA program.

“I’ve been wondering a lot recently about how relevant some of the PDUFA systems or philosophies are to a very, very different kind of development and review mechanism,” said Brian McCormick, VP and chief regulatory counsel at Teva Pharmaceuticals USA Inc.

He said the PDUFA meeting model may not be a good fit for the generic drug industry, which is all about volume, systems and speed. “It’s an extraordinarily complicated set of decisions over the course of years,” to which some of the PDUFA mechanisms may not be well suited, he said.

The generic drug industry is hypercompetitive, with ANDAs filed at a fast pace for new chemical entities and non-NCEs alike, said Chad Landmon, a partner in the Washington, DC and Hartford, CT offices of Axinn, Veltrop and Harkrider.

Although GDUFA II formalized a pre-ANDA submission process and meeting opportunities, “the competitiveness and speed of the industry has maybe made that a little less important or useful, at least as seen by a lot of the clients we work with,” Landmon said.

EARLY VIEWS ON PRE-ANDA PROGRAMAlthough the panel discussion was titled “Incentivizing Generic Drug Competition,” the discussion among industry and FDA representatives served as an early check on the successes and failures of various elements in GDUFA II, which took effect on 1 October 2017 and runs through 30 September 2022.

GDUFA II created a pre-ANDA program for complex products. Elements include controlled correspondence improvements, product-specific guidances and various meeting opportunities




modeled after the PDUFA program, such as product development meetings, presubmission meetings and mid-review cycle meetings.

The goal is to clarify regulatory expectations early in product de-velopment, help applicants develop more complete submissions, promote a more efficient and effective ANDA review process, and reduce the number of review cycles. (Also see “Unhappy With GDU-FA II? Note It For GDUFA III, FDA Says” - Pink Sheet, 28 Nov, 2017.)

However, these new meeting opportunities could be ripe for tweaking under GDUFA III.

The pre-ANDA program has been a mixed success, with “huge benefits overall, but aspects of the program I think clearly have not worked out,” McCormick said. He cited the mid-cycle meetings as “pretty unsuccessful, in my personal view, about adding value.”

The agency has limited experience with mid-cycle ANDA review meetings thus far, but expects volume to increase as the program matures. (Also see “Complex Generic Mid-Cycle Meetings: US FDA Suggests Taking The Date Offered” - Pink Sheet, 7 May, 2019.)

Although product development meetings have been more suc-cessful, these can be difficult from a timeliness perspective be-cause it takes one month for the FDA to grant a meeting request and then four months to schedule it, McCormick said. “That’s an eternity in a hypercompetitive R&D development process.”

INTEGRATING PDUFA ELEMENTS INTO GENERIC DRUG DEVELOPMENTJeffrey Francer, SVP and general counsel at the Association for Acces-sible Medicines, noted pre-ANDA meetings and other elements were imported from PDUFA, a much more established program that has

evolved over the course of six authorizations.“These types of interactions at very specific times of the develop-

ment process I think have been successful in PDUFA,” Francer said. “However, the PDUFA program is much older than the GDUFA pro-gram and has kind of iterated itself every five years.”

Francer said there needs to be a data-driven approach to deter-mining whether the GDUFA II meeting elements result in either more first-cycle approvals or more delays in getting generics to market.

“I think this is a great topic for the negotiation to say, ‘What’s the iterative improvement there?’ but we’re going to have just a small amount of data for things that have really started through the pro-gram and been submitted,” said Robert Lionberger, director of the Of-fice of Generic Drugs’ Office of Research and Standards.

Companies are still trying to figure out how to integrate the GDUFA II meeting elements into their development programs, Lionberger said. (Also see “ANDA Pre-Submission Meetings A ‘Challenge’ To Integrate Into Development Timelines” - Pink Sheet, 23 Feb, 2018.)

He said better advance planning and adoption by industry for these milestone meetings could reduce the impact of the five-month gap between requesting and holding product develop-ment meetings.

However, McCormick suggested some of the meeting elements may not be well-suited to the generic drug manufacturer business model, which is built on volume and speed.

“It’s hundreds of development programs, at least for larger com-panies,” and hundreds of decisions that have to be made years in ad-vance about product selection and regulatory considerations, he said. “What is the market going to look like? How do I develop an ANDA? When do I submit it? When can I expect action? What’s the feedback going to be? What are the approval standards going to be? When can I get on the market, at what time, versus what competitors?”

PRESUBMISSION FACILITY CORRESPONDENCE DAMPENS ENTHUSIASMAnother less-than-successful GDUFA II element so far has been the priority review pathway and the accompanying information sub-mission burdens, industry representatives said.

Under GDUFA II, certain ANDAs may qualify for an eight-month, rather than 10-month, assessment. However, this pathway requires that sponsors submit facility and other information, such as bio-equivalence data, 60 days before ANDA submission. (Also see “New ANDA Review Pathways: Should You Be A Priority Or Expedited?” - Pink Sheet, 13 Nov, 2017.)

“From a generic company’s perspective it’s hard to view the PFC [presubmission facility correspondence] process as a success or as fulfilling the goals that it could, simply because of the extensive data that are required to be included in the PFCs,” McCormick said. “I believe summary bioequivalence data are required to submit a PFC, which seems fairly divorced, from my perspective, from the facilities information, because if a generic company has the sum-mary bioequivalence data developed and assembled it’s going to submit the ANDA, it’s not going to submit the PFC.”

Similarly, Landmon said he has not had many clients interest-ed in the PFC program due, in part, to the extensive amount of

Although GDUFA II formalized a

pre-ANDA submission process

and meeting opportunities, “the

competitiveness and speed of the

industry has maybe made that a little

less important or useful.”

– Axinn Veltrop’s Chad Landmon




information needed.FDA did not approve any priority review ANDAs in fiscal 2018.

(Also see “Lack Of Priority? No ANDAs Approved Using Expedited Pathway In FY 2018” - Pink Sheet, 5 Nov, 2018.)

PRODUCT-SPECIFIC GUIDANCES A SUCCESS BUT LEGALLY PROBLEMATIC?The GDUFA II pre-ANDA program also includes an agency commit-ment to issue product-specific guidance with bioequivalence and other recommendations for 90% of NCEs approved on or after 1 October 2017 at least two years before the earliest lawful ANDA filing date. This goal does not apply to complex products, but the FDA has committed to issue guidance for complex products as soon as scientific recommendations are available.

McCormick described the product-specific guidances as a “vir-tually unqualified success of the GDUFA program and the GDUFA regulatory science program.”

However, the iterative nature of these guidances raises a legal issue, he said.

Although the agency revises the guidances to ensure its recom-mendations are consistent with current regulatory science, sponsors of pending ANDAs suddenly can find themselves subject to the new standards of a revised guidance, rather than the recommendations that were in place at the time the application was submitted.

In contrast to how it treats pending ANDAs, the FDA does not retroactively hold approved ANDAs to the standards laid out in re-

vised product-specific guidances, McCormick said.“I think the PSGs are a huge benefit for industry in terms of the

regulatory science. I think sometimes the way they are imposed upon industry can be legally problematic,” McCormick said, recom-mending that ANDAs be governed by the product-specific guid-ance in effect at the time of submission.

Lionberger said revisions to product-specific guidances often are very beneficial to industry and recognize advances in the sci-ence that may allow for more efficient development pathways. With the recent rollout of the FDA’s new website, the agency has begun listing the new and revised product-specific guidances for complex generics that it plans to issue in the coming year, he said. (Also see “US FDA’s New Website May Facilitate Broader Outside Use Of Data” - Pink Sheet, 30 Apr, 2019.)

“We’ve tried to be as transparent as we can about upcoming re-visions and what might be in them so that companies have more notice, so hopefully that will help a little bit about the uncertainty of a surprise revision,” Lionberger said.

Nevertheless, he acknowledged that such advance notice may only serve to move the point of concern earlier in time for an affected sponsor. “We’ll see how that works out and if that process is helpful.”

The agency’s guidance development efforts also could benefit from modeling approaches that better predict when ANDAs are likely to be submitted for new chemical entities.


CANNABIS PRODUCTS: FDA Asks Dosing, Research Incentive QuestionsDERRICK GINGERY [email protected]

D osing for cannabis products may prove to be one of sev-eral tough questions that the US Food and Drug Adminis-tration must answer in trying to implement some regulatory

control over the industry.The FDA already has clinical evidence for the dose of GW Pharma-

ceuticals PLC’s Epidiolex (cannabidiol), which was approved in 2018 for Lennox-Gastaut syndrome (LGS) and Dravet syndrome, both rare forms of childhood epilepsy.

Alternative cannabis products can be cheaper, but there is no stan-dard dosing regimen for them, which is a concern given the possibil-ity of adverse events.

“They’re making it up as they go along,” Kevin Chapman, a mem-ber of the American Epilepsy Society, said about dosing choices for non-approved treatments during the FDA’s 31 May public hearing on cannabis products.

The agency convened the hearing to obtain scientific data and in-formation about safety, manufacturing, product quality, marketing, labeling and the sale of products containing cannabis and derivatives.

R E G U L A T O R Y U P D A T E




Agency officials also asked about dosing schedules that have been developed for non-approved treatments and whether patients were monitored given the potential for adverse events like liver toxicity, which was seen in the clinical trials for Epidiolex.

Chapman said patient monitoring has been an ongoing problem for several years.

“There’s so much variability within the CBD products and I think that’s one of the biggest concerns that we have,” he said.

Many of the more than 100 speakers at the hearing offered sugges-tions for ensuring dietary supplements and food products with CBD can co-exist with FDA-approved drugs.

Epidiolex was the FDA’s first approval of a drug with purified drug substance derived from marijuana, but the agency was quick to re-mind the public that a broad approval of marijuana had not been issued. (Also see “Gottlieb: Epidiolex Approval Covers One Specific Can-nabidiol Medication, Not Marijuana” - Pink Sheet, 25 Jun, 2018.)

INDUSTRY NEEDS INCENTIVE TO SEEK APPROVAL, EPIDIOLEX SPONSOR SAYS FDA officials also were concerned that its regulatory decisions would not create an incentive to answer its questions about dosing and adverse events. Several speakers were asked whether allowing broad availability of CBD products would take away the incentive to conduct clinical trials.

Jacqueline French, chief medical officer of the Epilepsy Founda-tion, said because CBD has been shown to help control seizures, many patients are using some form of it.

French said epileptics are more afraid of losing access to CBD products than the potential adverse events associated with using unregulated products, where labeling and content sometimes do not match.

“In the best-case scenario, obviously everybody would take the pharmaceutical grade product, but they just don’t have access for it,” she said. “It’s not feasible for everyone so there are many people with epilepsy that are being medicated and often with their physicians’ assistance with CBD oil from various sources.”

French said there will never be an FDA-approved product for all forms of epilepsy, which means the agency likely will have to figure a way for all the products to remain available.

“I’m not saying that this situation is the one I would have picked,” she said. “Many people are taking it and they need to have access to it now because no matter how many other manufacturers get FDA

approval they’ll never get approval for everything.”Alice Mead, VP of US professional relations at GW Pharmaceuticals

subsidiary Greenwich Biosciences, also argued that without better incentives few companies will join GW Pharmaceuticals in using the FDA approval pathway for CBD products.

“The FDA approval process is the only way to answer important questions about a drug, about the disease it seeks to treat and safe-ty considerations that are unique to the patients who will take the drug,” Mead said.

“We recognize that there are patients suffering from serious ail-ments outside Dravet and LGS who feel as though in the absence of an approved cannabis medication, using unapproved cannabis products is their only option. That’s why we support a strong regu-latory framework for cannabis products that encourages robust re-search, maintains the integrity of the FDA approval process for medi-cines, and brings more FDA-approved medicines to patients.”

The FDA also has approved several drugs with synthetic versions of tetrahydrocannabinol (THC), the compound in marijuana that causes many of its psychological effects, including Insys Therapeu-tics Inc.’s Syndros (dronabinol), a treatment for nausea, vomiting and wasting syndrome in AIDS patients and AbbVie Inc.’s Marinol (dronabinol) for appetite stimulation for AIDS patients and as an an-tiemetic and those on chemotherapy. (Also see “Cannabinoid Market Snapshot: GW’s Epilepsy Success Bodes Well” - Scrip, 25 Nov, 2016.)

GMPS SHOULD APPLY, MANY SPEAKERS URGESeveral stakeholders asked FDA to ensure Good Manufacturing Practices are extended to the cannabis space to ensure product quality and labeling accuracy.

Bill Grubb, VP of business development and innovation at Noram-co, a cannabinoid API supplier, also called for tight controls on im-purities, as well as required testing for purity, quality and strength.

“We do believe that regardless of the method of production, the intended use, for drugs, for foods or supplements, that the patients and consumers deserve a CBD that is produced accord-ing to GMP,” he said.

Stephen Mueller, founder and chief technology officer of Mile High Labs, a large-scale hemp extraction and purification com-pany, said existing GMPs should apply to all CBD manufacturers.

Mueller also said the agency must impose laboratory testing standards.

“The level of inconsistency that we’ve seen with some of the con-tract labs and third-party labs is pretty astounding,” he said. “Right now most of the industry uses contract labs who are testing prod-ucts using generic methods that have not been validated for that particular sample matrix.”

The FDA also requested comments at the hearing and for the public docket on manufacturing, processing and holding stan-dards for cannabis and cannabis-derived products, as well as sug-gestions for requirements to evaluate product quality. (Also see “FDA Opens CBD Regulatory Path Docket, Warns Firms On Claims Missteps” - HBW Insight, 2 Apr, 2019.)


Many of the more than 100 speakers

at the hearing offered suggestions for

ensuring dietary supplements and

food products with CBD can co-exist

with FDA-approved drugs.




Navigating The Regulatory Maze In Emerging Markets – It’s An Art TooANJU GHANGURDE [email protected]

Emerging markets are of growing im-portance for pharmaceutical compa-nies, but navigating the regulatory

maze in these markets requires more than just science – it’s also an art, a senior phar-ma industry executive told a conference in Mumbai.

Arun Mishra, executive vice-president, Regulatory Affairs (India Sub Continent) at GlaxoSmithKline Consumer Healthcare, pointed to a range of regulatory contrasts and challenges in emerging markets, but also underscored their growing commer-cial role in pharma’s overall global business palette, despite the complexity.

“The shift we are seeing is that emerg-ing markets have become commercially more important and relevant from the business point of view. Therefore, com-panies are looking at registering products sooner,” Mishra said at the Annual Global Pharma Regulatory Summit organized by UBM in Mumbai, with the disclaimer that he was giving his own views and not those of GSK.

China alone accounted for 15% of the global pharma market in 2017, followed by Brazil, India and Russia (8% together) and other “pharmerging” markets (10%), IMS data presented by Mishra showed.

MOVING TOWARDS SIMULTANEOUS SUBMISSIONS?Mishra also noted how “drug lag” – the de-lay from the first global approval (usually in the US or EU) to a country approval in an emerging market – had come down sharp-ly. In the 1960s, the lag across therapeutic areas was close to 8,000 days, largely because of submission delays (companies often did not submit applica-tions in emerging markets), while the review lag was relatively low.

However, by 2000 the drug lag had fallen sharply to around 700-800 days, and while companies

were making submissions much faster, the bulk of the remaining delay was on ac-count of relatively longer reviews.

Data presented by the executive showed that in 2012, 78% of product ap-plications were filed in emerging markets less than two years from the first approval, while 19% were submitted before the first approval.

“I believe we are moving towards simul-taneous submissions,” Mishra said, adding that in some cases emerging markets had even taken the lead and approved prod-ucts before the US FDA.

Mishra told the Pink Sheet that from com-panies’ point of view “there is an intent” to have parallel submissions and reduce the

drug lag as much as possible, to provide faster access to novel therapies in emerging markets. “The challenge is the regulatory framework and there is room to do more to ensure that the drug lag is reduced,” he said.

Approval timelines in emerg-ing markets have, in general, been unpredictable and vari-

able, though things have begun improv-ing in some markets including India over the past few years. The median approval time from submission to approval for new chemical entities in 2006-10 was about 281 days in Latin America and 390 days in Asia Pacific.

DIVERSITY OF EMERGING MARKETSHowever, the evolving emerging markets regulatory environment also brings with it uncertainties in global drug develop-ment, manufacturing and commercializa-tion.

Underscoring some of the different requirements, Mishra noted that in the area of clinical development, local Phase III data are required for registration in markets like China, South Korea, Taiwan, India, Vietnam and Nigeria. Companies could consider strategic options such as including patients from these regions in global pivotal phase III studies, which may be cost-effective. But then again, sepa-rate studies in emerging markets could “de-risk” the overall global development

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timeline, he noted.Mishra believed that navigating regu-

latory requirements in emerging mar-kets is not just about the science but is also an art. He referred to their diversity, involving over 130 regulatory bodies, more than 76 currencies, 100-plus lan-guages and in excess of 23 time zones.

“It’s very important to understand not only the cultures, communication and science but also how to navigate through the maze. South Korea, for ex-ample is very different from the UK. So as a regulatory strategist who deals with the authorities, you need to understand the culture and the nuances,” Mishra told the Pink Sheet, adding that in emerging markets “every product you register you learn something new.”

“And how you use that in your next project is an art,” he added.

VARIED DOCUMENTATIONThe executive told the Mumbai con-ference that emerging markets have a wide range of documentation require-ments. These may include varied cer-tification requirements for GMP (good manufacturing practice), MA (market authorizations), Price Certificates, COAs (certificate of analysis), and the format and template for certificates is not har-monized across the countries.

Many markets require legalization of documents, which entails time and cost, while some emerging countries need local language, certified translations of certificates. The Price Certificate is a re-quirement in many countries for refer-ence pricing, and is part of the registra-tion process.

Many emerging markets also require sample testing (analytical – full or par-tial) as part of the drug registration pro-cess, Mishra noted. While some such as Algeria, Chile and Kenya may accept COAs if technology is not available, oth-ers like China, Russia, South Korea and Brazil require in-country testing.

The majority of the markets also re-quire special permits to import samples, so planning is critical, Mishra stressed.


UK MHRA Consults On Applying Quality By Design Principles To MonographsVIBHA SHARMA [email protected]

T he UK Medicines and Healthcare products Regulatory Agency is inviting stakeholder feedback on

its proposal to apply analytical quality by design (AQbD) principles to pharma-copoeial standards. The agency believes that the adoption of AQbD principles would offer “clear added benefits” and lead to a “more robust, and clear frame-work than that which currently exists” in the British Pharmacopoeia.

The consultation document – on which comments will be accepted until 31 August – includes a series of examples to illustrate potential Analytical Target Profile (ATP) models for inclusion in the pharmacopoeia.

The consultation document discusses how pharmacopoeial standards “should continue to evolve and adapt to meet public health needs and expectations arising from novel technology and new medicines.” The MHRA explains that the current conventional design and model for monographs and their component analytical procedures have not changed substantially since the initial elaboration of the modern BP monograph.

The MHRA is not the first to experiment with the application of QbD principles to analytical methods. The concept has also been explored by other regulators, indus-try, academia and pharmacopoeias, the agency explains. This work has included defining the method performance re-quirements via an analytical target profile (ATP) and the use of structured, risk-based approaches to method development and evaluation. “However, a lack of an agreed definition has led to a variety of approach-es being proposed,” the agency says.

The MHRA, for its part, undertook a “piv-otal and unique case study” in collabora-tion with industry experts that involved

the development of a pharmacopoeial assay procedure for cholesterol-lowering atorvastatin tablets. The agency explained that because there is a diverse supply chain and large generic market for this drug in the UK, “there is a significant drive for the BP to publish a product specific mono-graph to further ensure high standard in product quality across the large number of manufacturers of Atorvastatin Tablets.” Also, these products have a relatively high percentage content of active substance and standard tabletting processes.

The aim of the project was for the BP to apply and evaluate several AQbD concepts to understand how they could support the development of a pharma-copoeial assay method that was fit for purpose, robust and capable of providing adequate control of the quality attributes of the reportable value for content of ac-tive substance. The case study showed that adopting a structured, risk-based approach to pharmacopoeial method development using AQbD principles can provide clear added benefits.

The MHRA believes that enhanced risk-based approaches and the ATP concept – as outlined in the AQbD principles – can provide a potential platform for ensuring that the pharmacopoeial standard can continue to evolve throughout its lifecycle.


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N E W P R O D U C T S

Fifth PD-1, Zavicefta, Novel Psoriasis Ointment Among Latest China ApprovalsBRIAN YANG [email protected]

F our anti-PD-1 antibodies are already approved in China and the tally keeps going up.

Jiangsu Hengrui Medicine Co. Ltd. has become the latest developer to get ap-proval for its product in the class, Iruituo (camrelizumab, SHR-1210), from the Na-tional Medical Products Administration (NMPA), for recurrent or relapsed typical Hodgkin’s lymphoma patients who have undergone second-line chemotherapy.

Camrelizumab, a humanized anti-PD1 IgG4 monoclonal antibody originated by Hengrui, has been exclusively out-licensed globally to Incyte Corp. in a $795m deal signed in 2015. In becoming the fifth IO approval in China, it is the third granted to a domestic developer.

In 2018, the NMPA granted other IO ap-provals to Bristol-Myers Squibb Co.’s Opdi-vo (nivolumab), Merck & Co. Inc.’s Keytruda (pembrolizumab), Junshi Pharma‘s Tuoyi (toripalimab) and Innovent Biologics Inc.’s Tyvyt (xinlitimab). Meanwhile, BeiGene Ltd.’s anti-PD-1 antibody tislelizumab is pending approval with the NMPA.

DIFFERENTIATION, PRICING Globally, the PD-1 market is estimated at roughly $1.4bn and out of this China so far accounts for only $6.4m, showing large potential for growth. But the battle in this market will be fierce and depen-dent largely on pricing, product differ-entiation and value propositions.

A total of 68 drugs that target PD-1 or PD-L1 are either approved or under de-velopment in China, according to data from Biomedtracker. “There will be few winners coming from the competition and these with differentiation will win,“ noted analysts at Industrial Securities.

To that end, some companies are look-ing at bispecific antibodies rather than just pure PD-1 or PD-L1 inhibitors, not-ed Hardik Patel, director of oncology at Datamonitor. Akeso Bio’s bispecific an-tibody AK104, for instance, targets the checkpoints PD-1 and CTLA-4, and with a US IND will be advanced globally with its first indication in gastric and gastro-esophageal junction cancers.

In China, competing head on with for-

midable global players such as BMS and Merck, domestic players like Junshi are now eager to launch their products to the market and are slashing prices ag-gressively.

Junshi priced its PD-1 inhibitor Tuoyi at nearly one-third the level of Keytruda in China, and is actively seeking local reimbursement. Merck has decided to price its global blockbuster Keytruda lower in China than in the US, Japan and other markets.

GLOBAL FIRST FOR NOVEL PSORIASIS OINTMENTAlso just approved in China and for the first time globally is Guangdong Zhong-hao Pharma subsidiary Wenfeng Tianji Pharma’s benvitimod, a non-steroidal anti-inflammatory drug for moderate to severe psoriasis.

The molecule, an aryl hydrocarbon receptor modulating (TAMA) agent, was licensed in 2016 to GSK subsidiary Sti-efel for $240m. (Also see “How To Make A Global First-In-Class Drug In China” - Scrip, 7 Mar, 2017.) In 2018, Roivant Sciences’ subsidiary Dermavant Sciences Ltd. li-censed ex-greater China rights from GSK for $250m.

Meanwhile, benvitimod is also in Phase III development for atopic derma-titis both inside and outside China and in Phase III for plaque psoriasis as tapinarof.

PFIZER’S ZAVICEFTA Pfizer Inc. has gained an approval from the NMPA for its combination antibacterial Zavicefta (ceftazidime and avibactam), for multidrug resistant infections following a priority review.

Approved by the US FDA under its QIDP (qualified infectious disease product) sys-tem in 2015, the drug was approved in the EU in 2016 and in 40 countries to date..


Anti-PD-1 Agents Approved Or Pending Approval in China

COMPANY PRODUCT INDICATIONS APPROVAL DATE

BMS Opdivo Non-small cell lung cancer (NSCLC)

2018/06

Merck & Co Keytruda Melanoma, NSCLC 2018/07, 2019/04

Junshi Tuoyi melanoma 2018/12

Innovent Bio Tyvyt Hodgkin’s lym-phoma

2018/12

Hengrui Iruituo Hodgkin’s lym-phoma

2019/05

BeiGene tislelizumab pending

Source: Pink Sheet, NMPA



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Antimicrobial Drugs June 6

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Review and discussion of two target classes in the Relevant Pediatric Molecular Target List: targets linked to cell lineage, and targets on normal immune cells and cells in the tumor microenvironment

Oncologic Drugs Pediatric Subcommittee

June 20 (morning)

Potential pediatric development plans for Oncoceutics Inc.’s ONC201 and OncoImmune Inc.’s CD24Fc

Oncologic Drugs Pediatric Subcommittee

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