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SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 17 April 29, 2019

F R O M T H E E D I TO R S O F S C R I P R E G U L ATO RY A F FA I R S , T H E R P M R E P O RT , G O L D S H E E T , P I N K S H E E T DA I LY A N D P I N K S H E E T

DRUG REVIEW PROFILE

Onpattro, Tegsedi Cardiac Imaging And Serum Biomarker Data Failed To Impress US FDA, p. 6

REGULATORY UPDATE

First US FDA RMAT Designation Of 2019 Goes To ExCellThera’s ECT-001, p. 5

R&D

Landmark Malaria Vaccine Pilot Launches In Malawi, p. 15

ICH To Partner For Training Of Regulators, Industry On Key GuidelinesBOWMAN COX bowman.cox@informa.com

T o help accelerate global implemen-tation of its guidelines, the Interna-tional Council on Harmonization

has issued a call for expressions of interest from accredited non-profit organizations that would like to provide training.

Global pharmaceutical manufacturers and major industrialized nations formed ICH in 1990 to harmonize regulatory ap-proaches around the world, and now less-developed nations are working to catch up with harmonized approaches of their own. But they will need training.

The council is looking to contract with one or more organizations for a year, with an option to renew, to help it address the training needs of its regulatory and indus-try members and observers.

Contracted activities could include de-veloping online training materials and a library of case studies, delivering in-person training courses and providing ICH with consulting services.

ICH expects respondents to say which activities they’d want to perform and to provide information on the potential cost. ICH wants interested firms to email com-pleted response forms to training@ich.org by May 3. Anyone with questions should email them to training@ich.org by April 26.

TRAINING SOUGHT ON TOP TIER GUIDELINESAn April 5 “terms of reference” document provides details about the call for expres-sions of interest, which comes in the wake

of a successful pilot training program ICH launched in 2017.

The document says ICH wants help to provide free in-person training as well as online training materials and case studies in English on tier 1 and 2 guidelines, except M1, and priority tier 3 guidelines. M1 is a dictionary of standardized medical termi-nology for regulatory activities called Med-DRA that ICH gives to regulatory authori-ties and sells to industry.

The council also wants ad hoc input and advice for its training subcommittee, sec-retariat and work groups.

A FOCUS ON NEW AND PROSPECTIVE MEMBERSSince it changed from a conference to a Swiss association in 2015, ICH has been adding regulatory and industry members as well as observers who hope to become members.

The original regulatory members – the EU, the US and Japan – are generally up to date on implementing the ICH stan-dards they’ve been helping to develop for nearly 30 years. But many of the new and would-be regulatory members welcomed into the association have a long way to go. (Also see “ICH Reforming in Ways that Could Strengthen Harmonization Process” - Pink Sheet, 20 Nov, 2014.)

The council has made regulatory mem-bership contingent on demonstrating progress in implementing its more than 60 guidelines, which it has divided into three tiers.

Since it changed from a conference to a Swiss association in 2015, ICH has been adding regulatory and industry members as well as observers who hope to become members.

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pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 3

exclusive online contentCO V E R ICH To Partner For Training Of Regulators,

Industry On Key Guidelines

R E G U L ATO RY U P D AT E

4 Dual Approval For Verzenio Under International Review Scheme

5 First US FDA RMAT Designation Of 2019 Goes To ExCellThera’s ECT-001

13 Overplay Of Big Data Benefits Worries French Medical Experts

17 Overhaul In Store For Cambodia’s ‘Fragmented’ Drug Rules

D R U G R E V I E W P R O F I L E

6 Onpattro, Tegsedi Cardiac Imaging And Serum Biomarker Data Failed To Impress US FDA

D R U G P R I C I N G

11 Rx Importation: Califf’s Switch Means US FDA Commissioners No Longer Uniformly Opposed

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

13 Research-Based Pharma Urges Redress From Negative Impact Of EU SPC Waiver

R & D

15 Landmark Malaria Vaccine Pilot Launches In Malawi

M A N U FAC T U R I N G Q UA L I T Y

16 UK Agency Tests Remote Inspections Program To Identify At-Risk GDP Sites

A D V I S O RY CO M M I T T E E S

18 Recent & Upcoming FDA Advisory Committees

inside:

Regularly updated information about new submissions, pending applications and FDA actions, online-only interactive content at your fingertips 24/7 at pink.pharmaintelligence.informa.com/product-reviews-and-approvals/fda-performance-tracker

FDA performance tracker

ONLINE ONLY!

15 11 13

A Successful Failure? Lartruvo’s Speedy Withdrawal Sets New Bar For Accelerated Approval Drugshttps://pink.pharmaintelligence.informa.com/PS125180

Lilly withdraws soft tissue sarcoma drug for failure to confirm clinical benefit two and a half years after US FDA awarded accelerated approval, becoming the fastest withdrawal yet under the regulatory pathway.

Medicare Weighing Higher Add-On Payments For New Drugs, Including CAR-Thttps://pink.pharmaintelligence.informa.com/PS125174

Change would increase maximum new technology add-on payments from 50% to 65% of costs.

AZ, Pfizer, Lilly Novel Anticancers Head For India Debuthttps://pink.pharmaintelligence.informa.com/PS125153

AstraZeneca’s Calquence, Pfizer’s Lorbrena and Lilly’s Verzenio, which all address unmet medical needs, have been endorsed by an expert panel in India, paving the way for their potential introduction on the market. But all eyes will be on pricing to ensure access in this largely self-pay market.

Rounding Up And Down: Assessing FDA FY 2019 and FY 2020 Workload Estimateshttps://pink.pharmaintelligence.informa.com/PS125147

US FDA provides a few hints about upcoming industry application filing volume and the agency’s assessment pace in FY 2020 budget documents.

exclusive online content

4 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

M A N U FA C T U R I N G Q U A L I T Y

Under the rules of procedure developed by the council’s assembly, ICH won’t admit regulatory authorities for membership until they have demonstrated implemen-tation of the three tier 1 guidelines – Q1, Q7 and E6. (See below for explanations of several of the guidelines.)

ICH gives authorities it admits five years to implement the tier 2 guidelines: E2A, E2B, E2D, M4 and M1.

The council is establishing processes for gauging their progress.

THE NEED FOR TRAININGWhen the council formed, there was a recognition that the new members would require training to implement the guidelines.

At the time, ICH saw a need to de-velop a training program because it was receiving numerous requests for ICH training and outside, unaffiliated organizations were filling the void with training that wasn’t accurate, Michelle Limoli, who chairs a training subcom-mittee that ICH formed in 2016, told a recent conference.

The council started by conducting a needs assessment survey, said Limoli, who works in FDA’s Center for Biological Evaluation and Research.

The council then conducted a yearlong pilot in 2017 with trusted training providers.

SURVEY IDENTIFIES TOP TRAINING NEEDSThe survey showed which guidelines most urgently required training, Limoli told a meeting in September of the Association for Accessible Medicines.

It also showed that while training ma-terials were developed for the newest guidelines when they were approved, they had never been developed for older guide-lines, Limoli told the meeting in Baltimore.

Other findings:

• Both regulators and industry need training.

• As expected, implementation challenges were concentrated outside of the three original ICH regions (the US, the EU and Japan).

THE TRAINING PILOTICH partnered with seven organizations for the pilot, which focused primarily on devel-oping training materials for the Q1, Q7, E6, M4 and E2 tier 1 and 2 priority guidelines.

The goal was to develop at least one in-

troductory online training session and one in-depth session by 2021 for each guide-line as follows:

• Q1, Northeastern University;

• Q7, the Parenteral Drug Association and the Pharmaceutical Inspection Cooperation Scheme;

• E6(R2), The Multi-Regional Clinical Trials Center of Brigham & Women’s Hospital and Harvard University;

• The E2 suite of pharmacovigilance guidelines, Asia-Pacific Economic Cooperation’s APEC Harmonization Center.

• M4, the common technical document, the Regulatory Affairs Professional Society.

TOP TRAINING REQUIREMENTSThe top training needs identified in the survey were concentrated in the tier 1 guidelines, mastery of which is a condition of ICH membership.

Several of the Q1 suite of stability guidelines shot to the top of the survey’s priority list of training needs for ICH mem-bers and observers.

Q1A (R2), stability testing of new drug substances and products, published in 1994 and revised in August 2001 and in February 2003, explains how stability test-ing protocols should vary by trial dura-tion and climatic zone. Originally focused on the temperate and subtropical zones prevalent in the developed world, it was later expanded to hot dry and hot humid zones more common in lesser-developed

equatorial countries.Q1D, bracketing and matrixing designs

for stability testing of new drug substances and products, which went final in February 2002, provides for reduced stability testing.

Q1E, evaluation of stability data, issued

in February 2003, explains when extrapola-tion of retest periods and shelf lives beyond real-time data may be appropriate, and dis-cusses various statistical approaches.

Q1c and Q1D were much less urgent, though they still ranked 10th and 12th in the survey results.

Training on three other guidelines was nearly as urgent for survey respondents as the top three Q1 guidelines.

E6(R2), the guideline on good clini-cal practices, was finalized and revised in 1996, then revised again two decades later with an addendum integrated throughout the document in November 2016 to reflect advances in electronic data reporting and recording.

Q7, a good manufacturing practice guide for active pharmaceutical ingredients, was finalized in November 2000.

A related guideline, the Q7 Questions and Answers document, was finalized in June 2015. It reflects experience gained with Q7, removing various ambiguities and uncertainties and harmonizing expec-tations for inspections of small-molecule and biotech APIs.

Published online April 19, 2019

CONTINUED FROM COVER

Several of the Q1 suite of stability guidelinesshot to the top of the survey’s priority list of training needs for ICH members and observers.

@PharmaPinksheet

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 5

R E G U L AT O R Y U P D AT E

Dual Approval For Verzenio Under International Review SchemeNEENA BRIZMOHUN neena.brizmohun@informa.com

E li Lilly’s metastatic breast cancer drug, Verzenio (abemaciclib), has been approved in Australia and

Canada, making it the second medicine to be reviewed under an international work-sharing program for new chemical entities (NCEs) that was set up last year.

Australia’s Therapeutic Goods Admin-istration and Health Canada carried out a joint review of Verzenio under the Austra-lia-Canada-Singapore-Switzerland (ACSS) Consortium. The program was estab-lished in April 2018, and in July, Janssen Pharmaceutical’s prostate cancer treat-ment, Erlyand (apalutamide), became the first drug to be approved. Australia and Canada were again the regulators in-volved in that review. (Also see “Janssen’s Apalutamide First To Gain Approval Under International Work Sharing Program” - Pink Sheet, 9 Jul, 2018.)

Partnerships like the ACSS Consortium decrease the time it takes to get new

treatments to patients and reduce the cost of the drug review process, Health Canada said in a statement announcing Verzenio’s approval this month.

They “bring together countries with smaller markets to create a larger popu-lation base, which may make it more at-tractive for a drug company to file a sub-mission to sell its drug in Canada,” the government department said.

The TGA commented that “efficien-cies were achieved through the work-sharing of the evaluation” between both regulators, “with each regulator taking a lead in the evaluation of different parts of the regulatory submission dossier.” The agency clarified that each regulator made independent decisions regarding Verzenio’s approval.

Health Canada also noted that it had partnered with the Canadian Agency for Drugs and Technologies in Health to align the department’s and the agency’s

reviews of Verzenio. “This partnership reduced the time between Health Can-ada’s approval of the drug and CADTH’s recommendation on whether Verzenio should be funded by provincial and ter-ritorial governments, resulting in faster access to this new treatment option for Canadians,” it said.

Verzenio is already approved in the EU (where it is called Verzenios) and the US.

The ACSS NCE working group invites applicants interested in participating in the work-sharing program to contact their regional regulatory authority: the TGA, Health Canada, Singapore’s Health Sciences Authority or Swissmedic. The working group last year said it would focus on common submissions between Health Canada and the TGA, while it built confidence and experience in the program.

Published online April 18, 2019

First US FDA RMAT Designation Of 2019 Goes To ExCellThera’s ECT-001BRIDGET SILVERMAN bridget.silverman@informa.com

C anadian biotech ExCellThera broke a five-month dry spell in announce-ments of new Regenerative Medi-

cine Advanced Therapy (RMAT) designa-tions when it reported on April 23, 2019 that its lead product, ECT-001, had received the expedited review designation from The US FDA’s Center for Biologics Evaluation and Research (CBER).

The RMAT designation, established in December 2016 by the 21st Century Cures Act, had been awarded to 33 products as of March 31, 2019, according to FDA. With ECT-001, the Pink Sheet has identified 27.

ECT-001 received the RMAT for treat-ment of hematologic malignancies, “based on strong data from Phase I/II clinical trials using ECT-001 to expand stem and immune cells for the treatment of blood cancers,” ExCellThera said. ECT-001 combines a small molecule, UM171, and an “optimized culture system” for ex-pansion of stem and immune cells from cord blood. ExCellThera touts the speed of the ECT-001 system, which is “capable of expanding the number of stem and immune cells exponentially in as little as seven days.”

SAFER, EASIER BONE MARROW TRANSPLANTATION The company has said that “ECT-001 ex-panded single cord transplants combine the advantages of conventional grafts using bone marrow (low chronic GvHD), peripheral blood (low treatment-related mortality) and cord blood (accessibility, low relapse and chronic GvHD) in a single, low cost, easy to produce 7-day culture product, which could lead to a paradigm shift in bone marrow transplantation.”

ExCellThera completed a Phase I/II trial of ECT-001 for allogeneic stem cell trans-

6 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

R E G U L AT O R Y U P D AT E

plant in 2018 that enrolled 21 patients with high-risk hematologic malignancies and multiple comorbidities, who were engrafted with blood cells expanded with ECT-001.

“A seven-day ECT 001 expanded single cord blood unit provided substantial clini-cal benefits, including faster engraftment, fewer infectious complications, better HLA matching and very low treatment-related mortality, all the while saving production and hospitalization time and costs,” the company announced Dec. 4, 2018.

“With a median follow up of 14 months, there has been no moderate-severe chronic GvHD, and despite a median comorbidity index of 2 and some very high-risk patients, there has been only one treatment-related

mortality and only three cases of relapse,” ExCellThera continued. “At 12 months, overall survival, progression-free survival and GRFS were excellent at 95%, 77% and 67%, respectively. Immunosuppres-sive therapy was discontinued at 12 months in 76% of patients.”

IND FOR LEUKEMIA Recently, on March 25, ExCellThera an-nounced FDA’s clearance of its IND for ECT-001 to treat patients with high-risk leukemia and myelodysplasia. Health Canada also approved a clinical trial ap-plication, paving the way for two com-plementary 20-patient Phase I/II studies, one in the US and one in Canada. Pri-

mary endpoints for the studies include relapse-free survival and incidence of transplant-related mortality; secondary endpoints will measure graft-versus-host disease and other infectious com-plications.

ECT-001 appears to bring RMAT count for fiscal 2019, which started

Oct. 1, 2018, to five. FDA’s data shows that four RMATs had been awarded in fiscal year 2019, as of the end of March. Lovance, Axo-Gen Inc., Rocket Pharmaceuticals Inc., and Poseida Therapeutics Inc. all announced RMATs in October and November, which are detailed in the table.

Published online April 24, 2019

D R U G R E V I E W P R O F I L E / An inside look at key lessons learned from recent FDA approvals.

Onpattro, Tegsedi Cardiac Imaging And Serum Biomarker Data Failed To Impress US FDASUE SUTTER sue.sutter@informa.com

Imaging and serum marker data were not enough to persuade the US Food and Drug Administration about the purported car-diac benefits of the first two drugs approved for the treatment

of hereditary transthyretin-mediated amyloidosis (hATTR) patients.The agency did not put much stock in the exploratory data on

cardiac benefits provided by Alnylam Pharmaceuticals Inc. for Onpattro (patisiran) and Ionis Pharmaceuticals Inc. for Tegsedi (inotersen), which were approved two months apart in 2018.

The FDA’s decisions to narrow Anylam’s requested indica-tion for patisiran and exclude cardiac benefit data from label-ing were driven by concerns about the exploratory nature and robustness of serum and biomarker measure improvements in the pivotal trial, as well as an imbalance in some cardiac-related adverse events.

Similarly, the agency concluded the inotersen pivotal study was not designed to adequately evaluate any potential cardiac benefits, and there was little effect on the cardiac biomarkers that were assessed.

In both cases, reviewers recommended limiting the drugs’ use to hATTR patients with polyneuropathy, rather than opening up the labeled indication to patients with the cardiomyopathy form of disease.

Nevertheless, the FDA’s skepticism about the cardiac imaging and serum data spurred Alnylam to design a new patisiran trial

focused on hATTR amyloidosis patients with cardiomyopathy. The study’s endpoints will include a mix of functional and bio-marker outcomes, the company said.

The agency’s doubts about the reliability of surrogate end-points in this setting may be to Pfizer Inc.’s advantage.

The company’s tafamidis meglimune, which is under priority review for transthyretin amyloid cardiomyopathy with a July user fee goal date, has Phase III data demonstrating significant-ly lower rates of all-cause mortality and cardiovascular-related hospitalization – the type of hard CV endpoints the FDA gener-ally prefers. (Also see “Keeping Track: FDA’s Review Actions Carry On During Shutdown” - Pink Sheet, 20 Jan, 2019.)

ANALYZEVisit our website for a table on US FDA RMAT Designations available

only online.https://bit.ly/2GHyJz3

For both Onpattro and Tegsedi, reviewers recommended limiting the indications to hATTR patients with polyneuropathy, rather than opening up them up to patients with the cardiomyopathy form of disease.

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 7

D R U G R E V I E W P R O F I L E

POLYNEUROPATHY POPULATIONS STUDIEDHereditary ATTR is a rare, life-threatening autosomal dominant dis-order caused by mutations in the transthyretin (TTR) gene. These mutations result in protein misfolding, aggregation and deposi-tion in the peripheral and central nervous system, heart, kidneys, eyes, bone and gastrointestinal tract.

Symptom onset typically occurs between 20 and 70 years of age, with death occurring within five to 12 years, most commonly from cardiac dysfunction, infection, or cachexia.

Although hATTR amyloidosis is often viewed as one disease, three forms of the disease have been described, and patients often experience more than one form clinically:

• Neuropathic (hATTR-PN), defined by the presence of peripheral neuropathy and autonomic dysfunction;

• Leptomeningeal, defined by the presence of stroke, intracranial hemorrhage, hydrocephalus, ataxia, spastic paralysis, seizures, dementia, psychosis and vision impairment; and

• Cardiac (hATTR-CM), defined by the presence of arrhythmia, cardiomegaly, heart failure and death.

EXPLORATORY CARDIAC ENDPOINTSPatisiran was the first small interfering ribonucleic acid (siRNA) treatment to be approved by the FDA, receiving the agency nod Aug. 10 following a priority review. Patisiran is administered by intravenous infusion every three weeks. (Also see “Alnylam’s On-pattro Carries Narrower hATTR Indication Without Cardiac Data” - Pink Sheet, 13 Aug, 2018.)

Inotersen, an antisense oligonucleotide, was approved Oct. 5 following a priority review that was extended three months due to a major amendment. Inotersen is dosed subcutaneously once a week. Due to the risks of thrombocytopenia and glomerulone-phritis, the drug is available only through a restricted distribu-tion program under a Risk Evaluation and Mitigation Strategy. (Also see “US FDA Marches Toward Record Novel Approvals With Ionis’ Tegsedi, Leadiant’s Revcovi” - Pink Sheet, 8 Oct, 2018.)

The pivotal trials for both drugs were carried out in hATTR patients with polyneuropathy. Labeling reflects statistically sig-nificant changes from baseline in the modified Neuropathy Im-pairment Scale+7 (mNIS+7) composite score, an objective as-sessment of neuropathy, and the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score, a patient-reported assessment.

Despite limiting its Phase III APOLLO trial enrollment to pa-tients with polyneuropathy, Alnylam sought approval for a broader population encompassing patients with the cardiac form of the disease on the basis that hATTR is a single disease with multi-system involvement.

“Alnylam sought approval for the treatment of hATTR amyloi-dosis based on the results of the APOLLO study, which evaluated both the polyneuropathy (as primary and secondary) [and] cardiac (exploratory) manifestations of this disease,” the company told the Pink Sheet. “However, the FDA ultimately did not agree that the exploratory cardiac endpoints were sufficient to support the pro-posed indication.”

APOLLO did not enroll patients with significant cardiac dis-ease at baseline. However, there was a cardiac subpopulation of 126 patients with baseline left ventricular (LV) wall thickness of >1.3 cm by echocardiograph in the absence of aortic stenosis or hypertension.

Patisiran’s effects on several exploratory cardiac endpoints and biomarkers were explored in this subgroup, including:

• Various echocardiographic parameters (LV wall thickness, LV mass, LV ejection fraction (LVEF), LV longitudinal strain);

Alnylam sought approval for the treatment of hATTR amyloidosis based on the results of the APOLLO study, which evaluated both the polyneuropathy (as primary and secondary) and cardiac (exploratory) manifestations of the disease.

ONPATTRO REVIEWERS

US FDA staff who participated in the review and approval of Alnylam’s patisiran for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Medical Rainer Paine

Chemistry Monica Cooper (drug substance); Charles Jewell (drug substance); Mariappan Chelliah (drug product); Wendy Wilson-Lee (drug product); Erin Kim (process); Nallaperumal Chidambaram (process); Christina Capacci-Daniel (facility); Derek Smith (facility); Banu Zolnik (biopharmaceutics); Ta-Chen Wu (biopharmaceutics)

Clinical Pharmacology Venkateswaran Chithambarampillai; Venkatesh Atul Bhattaram; Hobart Rogers; Theingi Thway; Christian Grimstein; Kevin Krudys; Sreedharan Sabarinath

Immunogenicity Susan Kirshner

Microbiology Denise Miller; Bryan Riley

Pharmacology/ Toxicology

David Carbone; Lois Freed

Statistics Xiang Ling; Kun Jin; Jim Hung; Eiji Ishida (carcinogenicity); Karl Lin (carcinogenicity)

Cross-Discipline Team Leader

Nick Kozauer

Regulatory Project Manager

Annie Nguyen

8 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

D R U G R E V I E W P R O F I L E

• N-terminal pro b-type natriuretic peptide (NT-proBNP), a cardiac stress biomarker; and

• Troponin I.

Alnylam reported positive findings on various cardiac endpoints.“With respect to echocardiographic measures of LV morphology,

LV wall thickness was the most direct measure assessed, thus hav-ing better precision than the other parameters with less propaga-tion of error,” Cross-Discipline Team Leader Nick Kozauer wrote in an Aug. 10 review that noted a reduction in LV wall thickness with patisiran compared to placebo.

“The applicant also found that patisiran was associated with favorable effects in NT-proBNP,” elevated levels of which are associated with heart failure, worsening heart failure and other problems, Kozauer said.

However, “after database lock, the applicant observed that the NT-proBNP distributions were highly skewed,” the cross-disci-pline review states. “They applied a logarithmic transformation to normalize the distributions, and were able to conclude that patisiran had a nominally statistically significant treatment effect on NT-proBNP.”

NO MEASURE OF HOW A PATIENT FEELS, FUNCTIONS OR SURVIVESAlthough Alnylam had hoped to get the cardiac benefit data in la-beling, the FDA thought otherwise, concluding that the imaging and serum endpoints were too exploratory.

The APOLLO study “does not provide any cardiac efficacy data,” Preston Dunnmon, a medical officer in the Division of Cardiovas-cular and Renal Products, said in a March 13, 2018 consult review. “Imaging and serum biomarkers such as global longitudinal strain and NT-proBNP do not measure how a patient feels, functions, or survives, nor are they known to predict how a patient feels, func-tions, or survives and hence do not measure a clinical benefit.”

Dunnmon’s review notes that the point estimate for the placebo-corrected change from baseline in LV wall thickness “is reduced by less than 1 mm with the upper bound of the 95% CI being 1.7 mm.”

In addition, although the LV mass trends downward with pati-siran, it is important to note that LV mass is calculated, in part, from the LV wall thickness and is not independent from the wall thick-

ness assessment, he said.The cardiology reviewer also pointed to a divergence in the

echocardiogram results from what would normally be expected. “Interestingly, longitudinal strain is improved, driven by a more

pronounced deterioration of the placebo subjects,” Dunnmon said. “LVEF was not changed. While the LVEF trend to improvement oc-curred in the first nine months of follow-up, the LV strain improve-ment did not occur until months 9-18, which is not the physiologic pattern of what would be expected from a true response.”

Discussing Alnylam’s post hoc modification of the NT-proBNP data, Dunnmon said: “The differential effect of this exploratory/hypothesis-generating analysis is intriguing in the setting of the trends in the 2-D echo data. It would be interesting to see these analyses performed on a population of ATTR-CM subjects with symptomatic cardiomyopathy.”

Although parts of Dunnmon’s review are redacted, some of his concerns about data robustness and persuasiveness are evident.

“If one is willing to accept the data selection process in study ALN-TTR02-004, the LV thickness changes were small, and the trend toward improvement in LV strain occurred after the apparent trend in improvement of LVEF (since strain is purported to be the more sensitive indicator of trends in LV systolic function, it should have changed first),” he wrote.

The NT-proBNP data “were skewed such that their analysis re-quired modification. While that modification suggested a trend to-ward improvement, there were two open-label extension studies in which echocardiography and NT-proBNP were measured that showed no meaningful differences in these measures with 18 to 24 months of follow-up,” Dunnmon said.

INOTERSEN SHOWS ‘LITTLE EFFECT’ ON CARDIAC BIOMARKERSAkcea Therapeutics Inc., a wholly owned subsidiary of Ionis, said it anticipated inotersen would be labeled for the subpopulation of hATTR patients with polyneuropathy because the pivotal trial, ISIS 420915-CS2, “was not powered to detect outcome or functional endpoints for cardiomyopathy, which the regulators had told us we would need for an even broader label.”

The trial enrolled patients with familial amyloid polyneuropathy, all of whom underwent transthoracic echocardiography at base-line and week 65 (or early withdrawal).

Patients could consent to participate in the ECHO substudy, where an additional echocardiogram would be obtained at week 41 or 47 if they had an LV wall thickness of 13 mm or greater at baseline, the FDA’s Oct. 5 summary memorandum states. The CS2 protocol also defined a cardiomyopathy (CM)-ECHO subgroup that included all of the patients in the ECHO subgroup, as well as any patient who had a diagnosis of TTR-cardiomyopathy at baseline but was not in the ECHO subgroup.

Various echo parameters were assessed along with NT-proBNP.On the global longitudinal strain endpoint, “with 65 weeks of

treatment, the ECHO subgroup that received inotersen had a min-iscule change in the favorable direction that was not significant … while in the randomized and CM-ECHO sets of patients, the result

“ There appears to have been little effect on these cardiac biomarkers but the confidence limits on the effects within each group were large enough to have failed to resolve considerable harm.” – Preston Dunnmon

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 9

D R U G R E V I E W P R O F I L E

at 65 weeks was marginally but not significantly worse than place-bo,” Clinical Reviewer Christopher Breder and Statistical Reviewer Tristan Massie said in an Oct. 4 review. “The applicant attributed these findings to baseline imbalances [in] demographic attributes related to the disease.”

“In an exploratory analysis of other ECHO parameters, no sta-tistically significant differences between treatment groups in the CM-ECHO Set were observed in parameters of left ventricular size and function, including interventricular septum thickness, poste-rior wall thickness, left ventricular ejection fraction, left ventricular mass, left ventricular mass index, left atrial strain, or E/Em lateral ratio,” the review states.

Similar to his criticisms of the APOLLO trial, the cardio-renal divi-sion’s Dunnmon said the CS2 trial did not provide any cardiac effi-cacy data, and imaging and serum biomarkers do not measure, and are not known to predict, how a patient feels, function or survives.

“There appears to have been little effect on these cardiac bio-markers but the confidence limits on the effects within each group were large enough to have failed to resolve considerable harm,” he said in a Feb. 12 consult review.

SAFETY CONCERNSThe agency’s safety review of patisiran highlighted imbalances in cardiac deaths and atrioventricular block that made reviewers un-comfortable with the idea of indicating the novel drug for a popu-

lation with cardiomyopathy.Although there was a higher percentage of total deaths in the

placebo group of APOLLO, there was a higher percentage of cardiac deaths in the patisiran arm – 4.7% (seven deaths) vs. 1.3% (one death).

Alnylam had these cases re-adjudicated by an independent blinded committee to determine if the causes of death were “car-diovascular” or “non-cardiovascular.”

“The results of that re-adjudication suggested that two addition-al placebo deaths could be considered as cardiovascular in nature,” Clinical Reviewer Rainer Paine said in an Aug. 6 review. “However, these deaths were notably caused by strokes and not CHF [conges-tive heart failure] or arrhythmias. All of the patisiran deaths were related to CHF or arrhythmias. Therefore, the deaths due to cardiac causes such as CHF or arrhythmia remain at seven (4.7%) to one (1.3%) in the drug versus placebo comparison.”

Two of the patisiran cardiac deaths were in patients who had a genetic mutation associated with higher mortality, the clinical re-viewer observed.

“Death from ATTR amyloidosis occurs most often because of cardiac dysfunction,” Paine said. “Cardiac deaths occurred more of-ten in the patisiran group, but these deaths included patients with gene mutations associated with a higher mortality. The small num-bers of cardiac deaths, combined with the lower overall incidence of death on treatment, make this finding difficult to interpret.”

The safety review also flagged concerns about heart block.In APOLLO, four patients in the patisiran group (2.7%) had seri-

ous adverse events of atrioventricular block requiring pacemaker support, with zero cases reported in the placebo arm.

“Atrioventricular block could be a chance finding, but there are data suggesting that patisiran causes remodeling of the intraven-tricular septum, which could predispose to atrioventricular con-duction defects,” Paine said, concluding that the risk is uncertain.

“If it is true that patisiran causes intraventricular septal thinning in patients with cardiac involvement, it is plausible that there is remod-eling and/or inflammation within the septum, in turn affecting atrio-ventricular conduction,” Kozauer said in his cross-discipline review. “Although the number of cases of serious atrioventricular block was low, they are nevertheless concerning, and would be of particular concern if patisiran were indicated for hATTR-cardiomyopathy.”

Kozauer said that atrioventricular block would be mentioned in the Adverse Reactions section of labeling. “Given the small number

TEGSEDI REVIEWERS

US FDA staff who participated in the review and approval of Ionis Pharmaceuticals amyloidosis drug inotersen.

Medical Christopher Breder (efficacy); Evelyn Mentari (safety); Sally Usdin Yasuda (safety)

Chemistry Rohit Tiwari (drug substance); Charles Jewell (drug substance); Rao Kambhampati (drug product); Wendy Wilson-Lee (drug product); Kejun Cheng (process, facility); Nallaperumal Chidambaram (process); Derek Smith (facility)

Clinical Pharmacology Mariam Ahmed; Venkatesh Atul Bhattaram; Theingi Thway; Hobart Rogers; Christian Grimstein; Kevin Krudys; Sreedharan Sabarinath

Immunogenicity Assay Haoheng Yan

Microbiology Peggy Kriger; Erika Pfeiler

Pharmacology/Toxicology David Hawver; Lois Freed

Statistics Tristan Massie; Kun Jun; Feng Zhou (carcinogenicity); Karl Lin (carcinogenicity)

Cross-Discipline Team Leader

Nick Kozauer

Regulatory Project Manager

Fannie (Yuet) Choy

“ Although the number of cases of serious atrioventricular block was low, they are nevertheless concerning, and would be of particular concern if patisiran were indicated for hATTR-cardiomyopathy.” – Nick Kozauer

10 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

D R U G R E V I E W P R O F I L E

of cases, this conduction abnormality does not rise to the level of a Warning/Precaution.”

The FDA reviewers found inotersen to be associated with serious and potentially fatal adverse effects, including thrombocytopenia, glomerulonephritis and renal toxicity, inflammatory and immune adverse reactions, hepatic toxicity and hypersensitivity reactions.

“In the setting of the clearly established effectiveness of inoter-sen for the treatment of a serious disease with only one FDA-ap-proved therapy, the safety profile of inotersen does not preclude approval,” said the summary review by Kozauer, Division of Neurol-ogy Products Director Billy Dunn and Robert Temple, acting depu-ty director of the Office of Drug Evaluation I.

However, the agency determined a REMS with elements to as-sure safe use was needed to address the risks of thrombocytope-nia and glomerulonephritis. The FDA also imposed a REMS registry and required expedited post-approval safety reporting.

ALNYLAM READIES FOR A NEW STUDYAlthough Alnylam did not get the broad indication and cardiac data that it wanted in labeling, it did get a head start on designing a new trial targeting that objective.

The company said that toward the end of the review process when the FDA informed it that no cardiac efficacy data would be included in labeling and the indication would be narrower than hATTR amyloidosis, the agency nevertheless expressed interest in discussing how to potentially expand patisiran’s labeling in the fu-ture based on the APOLLO exploratory data.

“From that point on, we have worked closely with the FDA to define the most efficient path forward to broaden the currently ap-

proved indication,” the company said.Alnylam plans to initiate the APOLLO B Phase

III trial in mid-2019.The study is planned as a randomized, dou-

ble-blind, placebo-controlled trial evaluating patisiran in ATTR amyloidosis patients (either wild-type or hereditary) with cardiomyopathy. It is expected to enroll 300 patients who are TTR stabilizer naïve or TTR stabilizer progres-sors. The primary endpoint will be change in six-minute walk distance at 12 months, with key secondary endpoints expected to include quality of life, outcomes, and cardiac biomark-ers, the company said.

APOLLO B is expected to complete in 2020 or 2021. The company also plans to initiate a Phase III study of another siRNA therapeutic, vutrisiran, in ATTR am-yloidosis patients with cardiomyopathy in late 2019. (Also see “J.P. Morgan Notebook Day 1: Pfizer, Gilead, Alnylam, Novartis, Sarepta, Deal Trends And Cell Therapy Challenges” - Pink Sheet, 8 Jan, 2019.)

Akcea said there is an ongoing investigator-sponsored study of Tegsedi in patients with cardiomyopathy. In addition, “we are de-veloping our next-generation TTR inhibitor, AKCEA-TTR-LRx, for all TTR patients – both wild type cardiomyopathy and patients with hereditary ATTR polyneuropathy or cardiomyopathy.” The investi-gational agent is in Phase I/II, with Phase III expected to begin this year, the company said.

However, both drugs may have some catching up to do with Pfizer.The company’s tafamidis meglumine is under priority review

at the FDA for treatment of TTR amyloid cardiomyopathy (ATTR-CM). In pooled data from two cohorts that received oral tafamidis in the Phase III ATTR-ACT study, tafamidis demonstrated a statisti-cally significant reduction in the combination of all-cause mortal-ity and the frequency of cardiovascular-related hospitalizations after 30 months compared to placebo. (Also see “Pfizer Has Tafami-dis Data In Hand, But Market Development Still A Challenge” - Scrip, 27 Aug, 2018.)

Published online April 18, 2019

The APOLLO B randomized, placebo-controlled trial will evaluate patisiran in ATTR amyloidosis patients (either wild-type or hereditary) with cardiomyopathy.

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pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 11

RX IMPORTATION: Califf’s Switch Means US FDA Commissioners No Longer Uniformly OpposedMICHAEL CIPRIANO michael.cipriano@informa.com

U S Food and Drug Administration commissioners have al-most universally opposed importing drugs from foreign countries as a mechanism to reduce drug prices, but Rob-

ert Califf now looks to have bucked that trend. At least somewhat.Writing in an 23 April Journal of the American Medical Associa-

tion editorial with former Centers for Medicare and Medicaid Ser-vices Acting Administrator Andy Slavitt, the former Obama health officials refer to drug importation as “a workaround born of des-peration,” and lay out several drawbacks of the practice.

However, they express support for a narrow form of importation, writing that “when a distorted market affects access to a specific drug so that public or individual health is at significant risk, the FDA should use its authority to support importation.”

The FDA had been exploring the possibility of drug importa-tion after forming a working group last year, although the effort was moved to the parent Department of Health and Human Ser-vices. (Also see “Drug Importation Can Be Triggered By ‘Excessive’ Price Increases; Now US FDA Has To Decide What That Means “ - Pink Sheet, 19 Jul, 2018.)

Califf and Slavitt cite importation in the editorial as one of four ways that are most effective to addressing Rx pricing, along with re-ducing administrative costs, direct negotiations between manufac-turers and public payers, and creating a value-based health system.

A CHANGE IN TUNE FOR CALIFF The position on importation marks a notable departure from Cal-iff’s previous remarks on the subject, as he, like other former FDA commissioners, has sharply criticized the practice as a solution to lowering drug prices. Califf had a notable exchange with Sen. Bernie Sanders, I-VT, about the subject at his confirmation hearing in 2015, when Califf told the senator that the FDA has “major con-cerns” about importation. (Also see “FDA Can Help On Drug Prices – Except When It Can’t, Califf Says” - Pink Sheet, 17 Nov, 2015.)

In responding to questions for the record from Sens. Lamar Alex-ander, R-TN, and Susan Collins, R-ME, about importation, Califf also wrote that, “FDA is concerned that the risks of unapproved prod-ucts from foreign sources outweigh any potential cost savings. We are also concerned that adverse events flowing from importation of such unapproved products could lead to diminished confidence in FDA-approved products.”

Califf echoed this sentiment in a 16 March, 2017 open letter to Congress written with former agency heads Mark McClellan, Mar-garet Hamburg, and Andrew von Eschenbach. The ex-commission-ers wrote that importation “is not the right approach” to improving Rx product affordability.

“Allowing importation of drugs purported to be manufactured overseas in FDA-inspected facilities and drugs purported to be

manufactured domestically for export to other countries and reim-ported from those countries to the United States cannot meet the requirements under the existing closed drug manufacturing and distribution system because the drugs could not be tracked and certified by the manufacturer,” the former commissioners wrote.

“We urge Congress and the many others concerned about the cost of drugs to deal directly with the issues driving the cost of medicines and not to place false hope in measures that will place patients who need treatment at risk and jeopardize public health,” they added.

They also notably argued that any improved access and cost sav-ings resulting from importation “are likely to be minimal.”

Although the letter referred to broad-based importation schemes, the former commissioners made clear that they did not support the practice beyond the limited scope that FDA currently allows, such as for a major shortage of a generic drug for which there is an urgent need.

“Current law permits drug importation if the FDA determines it can be done safely. ... However, none of us, acting in our roles as for-mer FDA Commissioners, were able to conclude that a wider policy of routine importation would increase access to safe and effective drugs for the American public,” according to the letter.

Califf and Slavitt acknowledged several of the drawbacks of im-portation in their JAMA editorial before supporting it in narrow circumstances.

“A substantial proportion of drugs imported via the internet are either fake or only partially potent; many contain impurities, toxic substances, and adulterations,” the editorial states. “An expensive infrastructure would be needed to ensure the quality of imported drugs on large scales; furthermore, importation could exacerbate

D R U G P R I C I N G

12 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

disparities as more savvy individuals and states could benefit dis-proportionately. Drug importation would also burden the FDA, which is shouldering a growing responsibility to protect the public with limited funds and personnel.”

VALUE-BASED PAYMENTS ARE “MOST PROMISING”The former health officials posit that importation, along with direct negotiation and reducing administrative costs “can all im-prove affordability for some populations.” However, they add that these solutions are only “partial remedies” which would “still leave many US residents without access to needed medications, while also failing to send a sufficiently clear signal for innovation.”

Instituting a system of value-based payments for prescription drugs, they argue, “is the most promising path toward a fair sys-tem that rewards innovation.”

Califf and Slavitt concede there are difficulties with imple-menting a value-based system, such as estimating cost and de-fining value.

“However, the underlying concepts are sound, and it would be preferable to have a system in which actual measurements of benefit could supersede estimates derived from the minimal data available at time of approval for marketing,” they say.

Value-based payments have received broad support from both Congress and industry stakeholders. (Also see “ Value-Based Contracting Bill Aims For Bipartisan Political Support” - Pink Sheet, 3 Feb, 2019.) CMS has said it is interested in fostering val-ue-based payments for drugs, although it has only approved a three state Medicaid plans to do so. (Also see “Colorado Medicaid Outcomes-Based Contracting Gets Green Light From CMS” - Pink Sheet, 26 Mar, 2019.) The agency previously decided not to move forward with a value-based payment program for Novartis AG’s gene therapy Kymriah (tisagenlecleucel). (Also see “HHS Message On Value-Based Drug Pricing Complicated But Themes Emerging” - Pink Sheet, 6 Nov, 2018.)

Published online April 24, 2019

D R U G P R I C I N G

Overplay Of Big Data Benefits Worries French Medical ExpertsIAN SCHOFIELD ian.schofield@informa.com

T he French independent drug bulletin, Prescrire, has criti-cized some of the recommendations of the EU task force on the use of big data in medicines regulation, saying that

the debate “should not be used to further weaken the current drug approval process” by placing too much reliance on the pro-vision of real-world data after marketing authorization.

The task force, which was set up jointly by the EU Heads of Medicines Agencies network and the European Medicines Agen-cy, made its recommendations in February in a summary report that was open for consultation until 15 April.

The EU report said that big data would play a key role in regu-latory procedures for developing, evaluating and monitoring the safety and effectiveness of medicines, by providing evi-dence to support decision-making across the whole product life cycle. However, it conceded but that many hurdles remained to be overcome in areas such as data access, transfer, interoper-ability and data quality.

Prescrire acknowledges that there are some areas where big data can be useful, most notably to “enrich the drug’s harm-ben-efit balance assessment” once the product has been authorized for marketing. It notes that “great hope is put in the utility and opportunities of ‘big data’ for the health sector, including greater capacities, cost-efficiency and fast results.”

It is worried, however, that too much emphasis might be placed on its use to the detriment of evidence provided pre-approval,

R E G U L AT O R Y U P D AT E

The current discussion around big data “should not be used to further weaken the current drug

approval process; instead it needs a critical review.” – Prescrire editors

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 13

R E G U L AT O R Y U P D AT E

and says it is important to establish what kind of big data, “if any,” might be helpful in regulatory decision making.

The current discussion around big data “should not be used to further weaken the current drug approval process; instead it needs a critical review,” Prescrire editors say. “We urge European and national regulators not to weaken marketing authorization requirements by shifting the provision of evidence to real world data after marketing authorization.”

Experience shows that once a drug has been approved, “years can go by before studies of sufficient methodological quality are obtained,” and “even once a drug is proven to have severe or even fatal effects, it often takes months, if not years, to with-draw its marketing authorization.”

“We strongly invite EMA and HMA to consider very carefully the source and quality of ‘big data’ and their internal validity and utility for new approaches in the regulatory context,” the bulletin says.

It points out that the current gold standard for granting a marketing authorization is the randomized double-blind clini-cal trial, augmented where appropriate by data from post-mar-keting studies to monitor safety issues. While RCTs are long and costly, “this is the price for their utility for patients and caregiv-ers who rely on these data to make the best possible therapeu-tic decisions.”

WEAKNESSES AND LIMITATIONSBig data has weaknesses and limitations that need to be ad-dressed, according to Prescrire. “We are often faced with multi-ple sources of data of great heterogeneity and fragmentation, sometimes without any quality control.”

It says that research is needed into the clinical effectiveness and related cost efficiencies of the wider use of big data in health products regulation, and that “major methodological challenges of bias in real life data have to be addressed.”

Moreover, transparency “has to be ensured” and any recom-mendations must be based on “robust evidence generated through independent rigorous evaluation free from vested financial conflicts of interests.”

Any research and studies using big data should be placed in a publicly accessible and centralized European registry that complies with data reporting requirements, and there should be “reproducibility, validated statistical analyses and transparency throughout the whole process (from data col-lection to data use).”

It also points out that the task force identified the need for standardization and data quality as “key prerequisites” for data analysis, noting that because of data heterogeneity and the many local and regional data collection initiatives, “standard-ization is already a challenging task.”

As for the make-up of the task force itself, Prescrire says “we are surprised that next to the EMA only 14 of the 28 national compe-tent authorities participate in the joint task force.”

Published online April 24, 2019

Research-Based Pharma Urges Redress From Negative Impact Of EU SPC WaiverVIBHA SHARMA vibha.sharma@informa.com

E urope’s research-based pharmaceu-tical industry has strongly criticized the European Parliament’s vote in fa-

vour of a new regulation that would allow EU-based companies to manufacture a generic or biosimilar version of a medicine while it is still protected by a supplemen-tary protection certificate (SPC).

The regulation includes a waiver that would allow manu-facturing either for exporting the medicines to third countries where protection has expired or never existed, or for stockpiling during the final six months of an SPC to allow day-one entry of the generic/biosimilar immediately after the SPC expires.

The generics industry understandably welcomed the vote as the new regulation is expected to generate over €1 bn in net ad-ditional sales per year and up to 25,000 new jobs over 10 years. The European Federation of Pharmaceutical Industries and As-sociations, however, said the SPC manufacturing waiver would “hit innovation” and would send a “negative signal to the world that Europe is devaluing its intellectual property framework.”

The new regulation went through Parliament on 17 April with a huge majority – there were 572 votes in favor, 36 votes against, and 22 abstentions. The regulation is now expected to be formally adopted by the European Council within weeks. The waiver is due to come into force in July 2019 and companies will be able to start manufacturing under the waiver from July 2022.

Overall, EFPIA claimed, the regulation would make Europe “less attractive” for research and development, affect jobs and invest-ment, and would ultimately impact the R&D-based industry’s capacity to develop new treatments for patients living with dis-eases like cancer, diabetes and dementia.

Earlier, the European Association for Bioindustries (EuropaBio) had also criticized the commission’s proposal for an SPC manu-facturing waiver, saying it was a “regrettable example of well-meant but, ultimately, counterproductive policy making, with far-reaching negative impacts on EU competitiveness.”

On concerns raised by the R&D industry, patent attorney Mike Snodin explained that different economic studies have shown “wildly different impacts” of the SPC manufacturing waiver upon the innovative pharmaceutical industry. The new regu-lation is based upon the assumption that the 2017 study con-ducted on behalf of the European Commission by Charles River

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

14 | Pink Sheet | April 29, 2019 © Informa UK Ltd 2019

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

Associates is correct, said Snodin, owner and founder of patent law firm Park Grove IP.

The study concluded that the waiver would result in: additional net sales for the EU pharmaceutical industry amounting to €9.5bn; 25,000 additional jobs; €254.3m additional net sales of EU active pharmaceutical ingredients; 2,000 new direct jobs for the EU API industry; and savings in the European healthcare system of €3.1bn. “It remains to be seen whether that assumption is justified,” Snodin told the Pink Sheet.

JUSTIFIED CONCERNSRegardless, Snodin believes “there are justified concerns” regard-ing the provision that allows firms to manufacture medicines for stockpiling purposes in the six-month period prior to SPC expiry. This, he explained, is because it is unclear whether the safeguards included in the legislation would be sufficient to prevent abuse of the stockpiling exception.

Another concern, says Snodin, is that the legislation appears to be rather vague – or even silent – on precisely what is meant by SPC expiry. “This is potentially problematic in the light of variations in patent terms between different EU Member States, as well as a lack of clarity regarding the significance of SPC extension applica-tions that are pending (but not yet granted) at 6 months to expiry of normal SPC term. In the light of such concerns, it appears that litigation, as well as references to the Court of Justice of the EU are likely to be required before the precise scope of the waivers can be determined,” Snodin said.

BACKGROUNDThe regulation represents a targeted revision of pharmaceu-tical-related patent rules and was proposed by the European Commission to help EU-based drug companies tap into the fast-growing global markets. It aims to remove a “major competitive disadvantage” for EU-based manufacturers compared to their non-EU counterparts, the parliament said in a statement.

While the commission had initially proposed that SPC manu-facturing waiver should be for export purposes only, legislators agreed on a compromise text covering generics or biosimilars produced for export to non-EU countries where protection of the original medicine does not exist or has expired, and also for stockpiling purposes.

The parliament claims that the new regulation is a “well-cali-brated adjustment to the current regime” and strikes a balance between ensuring the attractiveness of Europe for innovative pharmaceutical companies and allowing EU-based generics and biosimilar manufacturers to compete on the global market. EFPIA, however, said there was “no doubt” that the SPC manu-facturing waiver would weaken Europe’s research and develop-ment offering in the face of increasing competition from other global regions.

RE-BALANCING NEEDEDIf Europe wants to realize its potential as a leader in medical research and development, “then the next Commission [president] will need

to look for opportunities to redress the balance, supporting research, development and innovation more broadly,” EFPIA said.

This, it suggested, could include measures to improve fast-track-ing of breakthrough therapies and by maintaining and developing incentives and reward mechanisms for research and development to drive the discovery of new treatments in areas of unmet medi-cal need and by supporting a flexible legal framework for public private partnerships in health to foster medical R&D activities and modernized manufacturing.

To this end, EFPIA said it “stands ready to work with policy mak-ers across Europe to see how we can restore international confi-dence in Europe as a research destination and deliver a number of practical initiatives that can once again make Europe a global leader in medical research and development.”

GENERICS SECTOR, HEALTH ADVOCATES WELCOME DECISIONMedicines for Europe, which represents the generics and biosimi-lars industry, said the new regulation would allow EU companies to “compete on a level playing field globally for manufacturing op-portunities in generic and biosimilar medicines which is growing year on year.”

“Europe has everything to gain from fully implementing the waiver to enable more competition on the pharmaceutical market and to improve its own security of medicines supply,” said Medi-cines for Europe director general Adrian van den Hoven.

The new regulation has also been welcomed by advocacy group Health Action International, which said the compromise text ad-opted by the parliament was “more closely aligned with the public health perspective than the merely commercial nature of the Sin-gle Market Strategy that shaped the consultation in the first place.”

HAI policy advisor Jaume Vidal said the revision of IP incentive-related mechanisms and other forms of market exclusivity should not end here. “With increased scrutiny on orphan drugs and the national level examination of SPC, the debate around how to bet-ter guarantee access to medicines in a time of excessive prices and IP protection abuses remains wide open,” Vidal said.

GENERIC COMPANIES FEAR FRIVOLOUS LITIGATIONUnder the new regulation, a generic or a biosimilar firm wanting to benefit from the manufacturing waiver would have to notify its intention to the national patent office that granted the SPC in question, using a standardized form, as well as the SPC holder no later than three months before the intended start of manufacture, explains information services company Wolters Kluwer.

The concerned national patent office, in turn, would have to ensure that the information contained in that notification is made public. Medicines for Europe said it would work with its members to facilitate the practical use of the waiver and “will monitor and act against any potential misuse of the notification system for frivolous litigation.”

Published online April 18, 2019

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 15

R & D

Landmark Malaria Vaccine Pilot Launches In Malawi FRANCESCA BRUCE francesca.bruce@informa.com

G laxoSmithKline PLC’s malaria vaccine, RTS,S/AS01 was launched on 23 April in Malawi as part of a “landmark” pilot that will generate evidence to inform World Health

Organization policy recommendations on the wider use of the vaccine. Launches in Ghana and Kenya are set to follow over the next few weeks.

The Malaria Vaccine Implementation Program is being coor-dinated by the World Health Organization in collaboration with health ministries from the three countries and other partners, in-cluding GSK and the non-profit organization PATH. Unitaid, Gavi, the Vaccine Alliance and the Global Fight to Fund AIDS, Tubercu-losis and Malaria have together provided some $50m for the first phase of the pilots.

GSK is donating up to 10 million doses of the vaccine. Accord-ing to the WHO, it is to be used as “a complementary malaria con-trol tool” alongside other WHO-recommended core prevention measures, such as nets treated with insecticides, and timely test-ing and treatment.

The vaccine will be available to children aged up to two years in selected areas of high transmission in the three countries at facili-ties that provide routine childhood vaccinations. It is expected to reach at least 360,000 children a year across the three countries.

It is hoped that the program should address key questions and inform how the vaccine should be used in real life settings. The pi-lot, for example, will look at the feasibility of administering the four doses that are required, how the vaccine helps reduce childhood deaths and its safety in the context of routine use.

Meanwhile, PATH says it will lead a qualitative study on health-care utilization to better understand the reasons why the vaccine is used or not used. It will also look at the economics of vaccine implementation and the costs of providing the vaccine.

“These pilots will be crucial to determine the part this vaccine could play in reducing the burden this disease continues to place on the world’s poorest countries,” said Seth Berkley, CEO of Gavi.

RTS,S is so far the only vaccine to show a protective effect against malaria in young children in a Phase III trial. The three-year trial involved some 15,000 young children and infants in

seven sub Saharan countries at trial sites. In children who received four doses, the vaccine prevented four

in ten (39%) cases of malaria over four years and three in ten (29%) cases of life-threatening malaria. There were also significant reduc-tions in overall hospital admissions and in admissions owing to se-vere anemia or malaria. In addition, the vaccine cut the need for blood transfusions by 29%.

In 2015, two independent WHO advisory groups, the Strategic Advisory Group of Experts on Immunization and the Malaria Pol-icy Advisory Committee, called for a pilot implementation of the vaccine in three to five sub-Saharan settings. In January 2016, the WHO officially adopted this recommendation. “In doing so, the Organization recognized the public health potential of the RTS,S vaccine while also acknowledging the need for further evaluation before considering wide-scale deployment. There is currently no WHO policy recommendation for the large-scale use of the RTS,S malaria vaccine beyond the pilot programme,” says the WHO.

In July 2015, the European Medicines Agency concluded that the vaccine has an acceptable safety profile.

Published online April 23, 2019

The WHO is coordinating the project in collaboration with national health ministries and other partners, including GSK and non-profit groups.

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M A N U FA C T U R I N G Q U A L I T Y

UK Agency Tests Remote Inspections Program To Identify At-Risk GDP SitesVIBHA SHARMA vibha.sharma@informa.com

T he UK medicines regulator has an-nounced plans to test a new ap-proach to check industry’s com-

pliance with good distribution practices (GDP) by undertaking remote, office-based inspections and risk assessments.

A pilot of the office-based evaluation and risk assessments (OBERA) program is being launched to test the new approach, the Medicines and Healthcare products Regulatory Agency said on 16 April.

The pilot will cover holders of a whole-sale dealer’s license (WDA(H)) that mainly operate from a single head-office location but have several satellite sites performing a very limited range of GDP activity. The MHRA will assess the satellite sites remote-ly using information that that the company has provided in a standardized format.

The agency clarified that the OBERA pro-gram is not intended to replace physical inspections, rather it would complement them. As such, the pilot includes plans for “a number of on-site ‘assurance inspec-tions’ of selected satellite sites” to quality-assure the process, it said.

The MHRA believes that that the remote inspections approach will enable the agen-cy to increase its level of oversight whilst reducing the regulatory burden on those companies that have a large number of sites that perform reduced or limited lev-els of GDP activity. This approach will also

allow the MHRA’s GDP inspectorate to re-direct its resources towards sites deemed to present a greater risk according to the established risk-based inspection model.

GATEWAY INSPECTIONSThe pilot will initially cover companies with over 100 sites on their wholesale dealer’s license. A decision on whether these companies can be included in the pilot will depend on whether the com-pany’s head office passes an on-site “gateway inspection,” which would fol-low the standard GDP inspection format. Depending on the size and complexity of the operation, the gateway inspection may take longer than one day.

The MHRA explained that its on-site gateway inspection is designed in a way that it allows a company to demonstrate to the inspectors that the appointed re-sponsible person for GDP has good con-trol over the activities being performed at the remote satellite sites and that these sites are compliant.

Companies that pass the gateway in-spection will be asked to complete a questionnaire covering approximately 25% of the sites named on the WDA(H). The requested information would have to be submitted within a specific times-cale along with requested photographic evidence and a declaration by the re-

sponsible person for GDP that the data presented for each individual site is accu-rate, the MHRA said.

The questionnaire would then be pro-cessed by the agency’s GDP inspectorate, which may request further information. “Once the assessment is complete, the site will be notified of the outcome, along with the approximate timescale for re-inspection, and be invoiced accordingly,” the MHRA said.

Companies that fail the gateway inspec-tion will be notified through a post in-spection letter that it will not be included in the OBERA pilot and any re-assessment for suitability would be made during the next scheduled head-office inspection.

As for the MHRA conducting assurance inspections at random satellite sites, if such an inspection indicates that a site is not GDP-compliant, then the agency will undertake additional assurance inspec-tions “on other selected sites to ascertain whether this is a systemic failure of con-trol by head office or a single instance of a poorly performing site/member of staff,” the MHRA explained.

Depending on the outcome of the pilot, the MHRA may apply the OBERA process to other companies operating applicable business models.

Published online April 23, 2019

The OBERA program is not intended to replace physical inspections but rather to complement them.

pink.pharmaintelligence.informa.com April 29, 2019 | Pink Sheet | 17

R E G U L AT O R Y U P D AT E

Overhaul In Store For Cambodia’s ‘Fragmented’ Drug RulesIAN SCHOFIELD ian.schofield@informa.com

T he World Health Organization says that Cambodia’s regulatory and leg-islative framework for pharmaceuti-

cals and medical devices is to be brought into line with modern-day international standards because the existing rules are fragmented and enforcement of the legis-lation is “challenging.”

In a tender issued on 22 April, the WHO invited bids from contractors to carry out a comprehensive review of the current framework and to develop new or amend-ed regulations and guidelines to ensure that the manufacture, trade and use of medicines and other medical products are appropriately regulated, and that patients have access to good quality medicines and accurate drug information.

According to the organization, Cambo-dia’s Law on Pharmaceutical Management, which was adopted in 1996 and amended in 2007, regulates products including med-icines, biologicals and biosimilars, medical devices, health supplements, traditional/herbal medicines, and veterinary drugs.

However, the WHO says the law is very brief and is implemented by means of a number of royal decrees, sub-decrees, ministerial orders, decisions, circulars and local regulations.

The aim of the review is to evaluate the pharmaceutical law and its related regulations, and to support the process of developing of a fresh legal framework that will cover a whole range of aspects of pharmaceutical regulation. These include

manufacturing, import and export, dis-tribution and supply, sale and retail, and use of pharmaceuticals and other medical products. Processes and systems will need to be aligned with international standards and good practices.

When updating Cambodia’s regulatory framework, international initiatives such as the Agreement on Trade-Related Aspects of International Property Rights (TRIPS) and regional harmonization projects will need to be considered, the organization says.

The individual or institution that wins the tender will need to produce a comprehen-sive tool for assessing the current regulato-ry and legislative situation and identifying any gaps, organize stakeholder consulta-tions on the review, amend current regu-lations, help to develop comprehensive primary and secondary pharmaceutical

legislation and relevant guidelines, facili-tate a consultation meeting for stakehold-ers, and produce a final report.

The resulting legal framework is ex-pected to ensure that “quality assured, safe and effective products” are made available in Cambodia and that “medi-cines and medical products are regulated appropriately while assuring the balance between regulation of and access to es-sential medicines.”

The review is to be carried out under the direction of the WHO’s Cambodia coun-try office and in close collaboration with the country’s Ministry of Health. Bids for the tender are due in by 30 April, and the length of the contract has been set at sev-en months.

Published online April 23, 2019

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