drug reviews new products zelnorm returning to us … · fusion-dependent β-thalassemia (tdt)....

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SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 14 April 8, 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

BIOSIMILARS

Insulin Applications Intended For Biosimilar Pathway May Already Be At US FDA, p. 13

DRUG REVIEWS

Wanted: Orphan Drugs, Antivirals Dominate China’s Latest Fast Track List, p. 5

NEW PRODUCTS

Zelnorm Returning To US Market With Broad IBS-C Indication, p. 8

EU Hat Trick For Bluebird’s Beta-Thalassemia Gene Therapy NEENA BRIZMOHUN [email protected]

b luebird bio has scored a series of firsts with its life-changing beta-thalassemia gene therapy, Zynte-

glo, after the European Medicines Agency today recommended that the product should be marketed in the EU.

Zynteglo, formerly referred to as Len-tiGlobin, is the first gene therapy recom-mended for approval in the EU for trans-fusion-dependent β-thalassemia (TDT). According to the EMA, it underwent the fastest ever review for an advanced thera-py medicinal product (ATMP) at the agen-cy – taking 150 days of active review time under the EU’s accelerated assessment pathway. Finally, this is the first gene thera-py that the small US biotech company has

submitted for regulatory approval.The EMA’s human medicines committee,

the CHMP, adopted a positive opinion for a conditional marketing authorization for Zynteglo at its March meeting, which took place this week. The marketing authoriza-tion application for bluebird’s gene thera-py – the company’s lead product – was the only MAA up for an opinion at the meet-ing. (Also see “LentiGlobin Hogs The Lime-light At CHMP’s First Amsterdam Meeting” - Pink Sheet, 25 Mar, 2019.)

bluebird CEO Nick Leschly said the com-pany was “beyond impressed” with the EMA and its staff and the process it had run.

The committee’s verdict on Zynteglo came as no surprise. Bluebird’s thunder

was well and truly stolen when the UK Thalassaemia Society and the Italian As-sociazione Veneta Lotta alla Talassemia put out a joint statement late on March 25 say-ing the product had been approved. The move forced bluebird to issue a statement stressing that “no opinion had yet been issued by the CHMP.” (Also see “Bluebird’s Gene Therapy LentiGlobin Coming Into Land In The EU?” - Scrip, 26 Mar, 2019.)

Also at the meeting, the CHMP’s first in Amsterdam after moving from London earlier this month, there were three posi-tive opinions on therapeutic indication extension requests. They relate to two Celgene products used in the treatment of myeloma – Revlimid (lenalidomide) and Imnovid (pomalidomide) – and Genzyme’s stem-cell mobiliser, Mozobil (plerixafor).

The CHMP recommendations will now be sent to the European Commission, which has 67 days to take a legally binding decision valid throughout the EU.

LIFE-CHANGING TREATMENT FOR TDTZynteglo (autologous CD34+ cells encod-ing βA-T87Q-globin gene) is a one-time gene therapy that is expected to dramatically change the course of TDT and the health and quality of lives of patients with the disease. The goal of the treatment is to en-able patients with TDT to produce hemo-globin at sufficient levels to allow lifelong independence from blood transfusion.

The present management of TDT, in-cluding regular blood transfusions every

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exclusive online contentCO V E R EU Hat Trick For Bluebird’s Beta-Thalassemia

Gene Therapy

D R U G R E V I E W S 5 Wanted: Orphan Drugs, Antivirals Dominate China’s

Latest Fast Track List

D R U G S A F E T Y 6 Korea Suspends First Approved Gene Therapy Pending

Component Discrepancy Probe

N E W P R O D U C T S 8 Zelnorm Returning To US Market With

Broad IBS-C Indication

G E N E R I C D R U G S 9 US FDA’s ‘Great’ Generic Approval Engine Can Be Better,

New OGD Director Says

11 House Committee Clears Bills To Prevent Pay-For-Delay Deals, Assure Generic Access To Samples

B I O S I M I L A R S 13 Insulin Applications Intended For Biosimilar Pathway

May Already Be At US FDA

15 EU Countries Examine Reasons For Wide Differences In Biosimilar Usage

M A N U FAC T U R I N G Q UA L I T Y 17 The Quality Lowdown: No Excuses For Homeopathic,

CMO, OTC Quality Failures

C L I N I C A L T R I A L S 19 India’s New Trial Rules Tick Right Boxes, Shed Interim

Compensation Clause

B R E X I T 20 Scottish Govt Explains Approach To No-Deal Brexit Drug

Shortages

A D V I S O RY CO M M I T T E E S 22 Recent And Upcoming FDA Advisory Committee Meetings

inside: 17 5 6

New International Signal Detection Initiative To ‘Influence Industry Practice’https://pink.pharmaintelligence.informa.com/PS125052

Drug companies, regulators and academia have joined together under a three-year international project to explore what new methodologies should be developed to make the most of the opportunities provided by big data and artificial intelligence in detecting adverse effects of authorized medicines.

US And EU Regulators Eye Co-operation In Expedited Pathwayshttps://pink.pharmaintelligence.informa.com/PS125051

US and EU regulatory experts could soon be strengthening ties. They’re considering a pilot program to discuss the scientific advice they provide to companies in the field of oncology under two expedited pathways programs, breakthrough therapy in the US and PRIME in the EU.

Gottlieb Unleashed: Focus on Drug Pricing To Intensify As He Rejoins AEIhttps://pink.pharmaintelligence.informa.com/PS125054

Without constraints of being FDA commissioner, Gottlieb will have podium to push for changes to drug pricing and competition.

Express Scripts Insulin Program Lowers Cost Sharing With Supplemental Manufacturer Discountshttps://pink.pharmaintelligence.informa.com/PS125045

New wrinkle on lowering out-of-pocket spending differs from point-of-sale rebates and manufacturer copay assistance cards, the PBM says, and is not expected to increase plan costs.

Oncology Center Of Excellence Comes Of Age at US FDAhttps://pink.pharmaintelligence.informa.com/PS125027

Our infographic details organizational structure and management of FDA’s first inter-center institute; five of 11 associate director positions are being filled on an acting basis.

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N E W P R O D U C T S

two to four weeks and daily iron chelation therapy, can have many psychological and social consequences. Also, in many pa-tients TDT-related morbidities can lead to a shortened life span.

Zynteglo adds functional copies of a modified β-globin gene into a patient’s own stem cells, thereby addressing the un-derlying genetic cause of the disease. The CHMP’s positive opinion covers the prod-uct’s use in adult and adolescent patients 12 years and older who do not have a β0/β0 genotype and who need regular blood transfusions to manage their disease and have no matching donor for a stem cell transplant.

SPEED OF REVIEWThe speed at which the CHMP reviewed the MAA for Zynteglo is largely thanks to blue-bird having secured a place on the EMA’s Priority Medicines (PRIME) scheme in 2016. Under PRIME, developers of drugs for un-met needs are offered enhanced scientific and regulatory support from the EMA and the likelihood of having their product re-viewed under the accelerated assessment procedure. The fast-track mechanism can cut the time it takes the EMA to evaluate an MAA from up to 210 days to up to 150 days (not counting clock stops when appli-cants have to provide additional informa-tion). The company filed its MAA in early October 2018.

As for the EMA, it said its interactions with the company under the scheme “led to a more robust application package to demonstrate the medicine’s benefits and risks, which allowed accelerated assess-ment of Zynteglo in 150 days, the fast-est advanced-therapy medicinal product (ATMP) review time to date.”

The average review time for ATMPs “is normally close to 210 days active review time,” excluding the time taken by the ap-plicant to respond to the questions from the CHMP, the EMA told the Pink Sheet. The CHMP’s next fastest review for an ATMP was for Novartis’s CAR T-cell thera-py, Kymriah (tisagenlecleucel), which was reviewed in 172 days (active review time, not including clock stops).* There are cur-rently 15 investigational ATMPs in the

PRIME scheme.Zynteglo had also been accepted onto

another program the EMA has been test-ing to improve timely access for patients to new medicines, adaptive pathways.

The review process was “incredibly ef-ficient”, bluebird’s Leschly told the Pink Sheet. “[The EMA had] great questions, actually really informative questions, very reasonable questions. I wouldn’t say it was enjoyable because this is always very hard work and very taxing and stressful and it’s nerve-wracking but at the end of the day we certainly feel a lot stronger for it and I have to say very impressed with EMA and look forward to continuing to work with them on our subsequent products.”

MORE DATA STILL NEEDEDThe positive CHMP opinion was support-ed by efficacy, safety and durability data from bluebird’s Phase 1/2 HGB-205 study and the completed Phase 1/2 Northstar (HGB-204) study as well as available data from the ongoing Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies, and the long-term follow-up

study LTF-303.Conditional marketing authorizations

(CMAs) are granted for products with less complete data than normally expected, in cases where the benefit of a medicine being made immediately available to pa-tients outweighs the risk inherent in the fact that not all the data are yet available. CMA holders are required to complete specific obligations (ongoing or new studies, and in some cases additional activities) with a view to providing com-prehensive data confirming that the ben-efit-risk balance is positive. Once compre-hensive data on the product have been obtained, the CMA may be converted into a standard MA.

US FILING AND MANUFACTURINGWhereas bluebird’s US filing will be based on data from the company’s all-new manu-facturing process, the EMA looked at data from the old manufacturing process as well as the new.

Leschly said. “That’s what’s actually been great about the European agency’s willing-ness to say, ‘hey we know the lion’s share of the data came out of your two original studies’ but in parallel we have been run-ning the study with the new manufactur-ing process and they were very gracious in saying ‘listen, get as much data as you have on that to show that it is indeed working in the way we hope that it is’.”

“Nobody wants a drug out there if it’s not the best drug for patients,” the blue-bird CEO continued. “The EMA saw that early data as part of the review process and so this is approval of the new manu-facturing process. That’s a lot easier from our perspective because you don’t want two separate supply chains. This is all good news and certainly will also be considered as the US filing starts to kick into gear.”

The first European sales are likely to be in Germany by the end of the year. (Also see “Bluebird Bio’s Zynteglo Flies Through Its CHMP Review “ - Scrip, 29 Mar, 2019.)

Published online March 29, 2019

Additional reporting from Alexandra Shimmings.

CONTINUED FROM COVER

EMA said its interactions with

the company under the PRIME scheme

“led to a more robust application package

... which allowed accelerated assessment

of Zynteglo in 150 days, the fastest advanced-

therapy medicinal product (ATMP) review

time to date.”


WANTED: Orphan Drugs, Antivirals Dominate China’s Latest Fast Track ListBRIAN YANG [email protected]

U nlike previous rounds of fast track approval review designa-tions in China, in which oncology

drugs took the lead, this time orphan drugs are shining.

The latest list of selected products re-leased March 28 by China’s National Medi-cal Products Administration (NMPA) ap-pears to have a clear message for pharma companies around the world– bring your approved orphan drugs to China, the sooner the better.

The agency’s new drug review subsidiary, the Center for Drug Evaluation, noted that the newly fast track-listed drugs are those with the largest unmet needs in China.

Among the total of 30 products, rare dis-eases treatments accounted for half. These included not only more established drugs but also new therapies such as Kyowa Hakko Kirin Co. Ltd.’s Crysvita (burosum-ab), which was approved last February by the European Medicines Agency for X-linked hypophosphatemia.

Other notables include Novo Nordisk AS’s insulin preparation Levemir (insu-lin detemir) for Noonan syndrome and Prader-Willi syndrome. Several enzyme replacement therapies are also listed in-cluding BioMarin Pharmaceutical Inc.’s Aldurazyme (laronidase) for MPS I, Shire PLC’s Elaprase (indursulfase) for MPS II and Genzyme Corp.’s Fabrazyme (agalsi-dase beta) for Fabry’s disease.

In effect, three drugs will be listed for Fabry’s disease in China, the other two be-ing Shire’s Replagal (agalsidase alfa) and Amicus’s Galafold (migalastat).

Similarly, three pulmonary artery hy-pertension drugs are now set for priority reviews in China: Janssen-Cilag GMBH’s Tracleer (bosentan),

Pfizer Inc.’s Revatio (sildenafil) and Toray Industries Inc.’s Careload (bera-prost sodium).

Other orphan drugs designated for pri-ority review were Bioverativ Inc.’s Alpro-

lix (coagulation Factor IX) for hemophilia B, Ruconest (recombinant human C1-in-hibitor) from Pharming Group NV for hereditary angioedema, Sanofi’s Lem-trada (alemtuzumab) for multiple sclero-sis, Radicava (edaravone) from Mitsubishi Tanabe Pharma Corp. for amyotrophic lateral sclerosis.

Out of the orphan drug companies, Sanofi/Genzyme and Takeda/Shire each scored two drugs in the new listing, and both have showed their intention of strengthening their rare disease prod-uct portfolios in China, an increasingly important market for such products. The most recent list is also another indication that the government is willing to intro-duce more and newer treatments to the market.

During the International Pharmaceuti-cal Innovation Forum held March 26 in Beijing, Sanofi CEO Olivier Brandicourt told the audience that the French drug maker stands ready to help improve the treatment and diagnosis of rare condi-tions in China.

OTHER FOCUS AREASOrphan drugs aside, antivirals are also emerging as a major area of unmet need in China, underscored by the new listing of four new therapies for fast track review.

Included were Gilead Sciences Inc.’s Bik-tarvy (bictegravir, emtricitabine and te-nofovir alafenamide) for HIV, which was approved in February in the US, Shionogi & Co. Ltd.’s Xofluza (baloxavir marboxil) for seasonal flu A and B, Daiichi Sankyo Co. Ltd.’s Inavir (laninamivir octanoate hy-drate) to treat or prevent flu, and AbbVie Inc.’s Maviret (glecaprevir/pibrentasvir) for hepatitis C viral infections.

Meanwhile, pediatric drugs are another area of focus in the listing, which includ-ed Increlex (mecasermin) for children with growth deficiency, and Santen Pharma-ceutical Co. Ltd.’s Verkazia (ciclosporin) for children’s eye infections, and Aucta Phar-ma’s Vigadrone (vigabatrin) was selected in combination use to treat partial seizures in infants, young children and adults.

Published online April 2, 2019

D R U G R E V I E W S



Korea Suspends First Approved Gene Therapy Pending Component Discrepancy ProbeJUNG WON SHIN [email protected]

S outh Korea’s ministry of food and drug safety (MFDS) has asked Kolon Life Science Inc. to suspend the manufactur-ing and sale of Invossa (TG-C), the country’s first approved

gene therapy, after determining that one of its two main active components may be different to that in the data submitted at the time of approval, apparently due to evolving production and testing technology.

A temporary halt has also been placed on a US Phase III devel-opment program by the company as a precautionary measure.

Kolon Life said it had voluntarily suspended on April 1 all sales and distribution of the product in South Korea, where it was approved in July 2017 as the world’s first allogeneic cell-mediated gene therapy for degenerative osteoarthritis (OA). (Also see “First Approval For Ko-lon’s Invossa But No Disease-Modifying Status” - Scrip, 14 Jul, 2017.) The near-term intention is to get re-verification from the MFDS about the consistency of the cell line used in South Korea.

TG-C is a combination of an allogeneic (donor) cell and gene ther-apy that involves the administration of primary human chondro-cytes (cartilage cells) and chondrocytes transduced to express the therapeutic growth factor TGF-ß1 (transforming growth factor- ß1). The therapy is delivered via single, direct intra-articular injection.

The Invossa product approved in South Korea consists of a vial each of Solution No. 1 (human chondrocyte, or HC) and No. 2 (transduced human chondrocyte, or TC), and was approved spe-cifically for the treatment of moderate knee osteoarthritis (Kellgren & Lawrence Grade 3) with symptoms such as pain that persist de-spite three or more months of conservative treatment.

At present, the product is supplied to 443 hospitals and clinics in the country, and the ministry has asked these to prescribe alterna-tive treatments until the results of an official probe. Based on the

results of this analysis, expected in mid-April, the ministry said it will impose administrative measures including a potential Invossa sales halt on the company if any violations are found, in line with the provisions of the national Pharmaceutical Affairs Act.

In the worst case scenario, the ministry could completely cancel the marketing license for the therapy and the company might have to re-file for approval, according to Kiwoom Securities.

PRODUCT IN US TRIALS DIFFERENT?The issues stem from a finding by Kolon Life during an ongoing Phase III program in the US. (Also see “Disease Modifying Status Tar-geted As Kolon’s Novel OA Therapy Enters US Phase III “ - Scrip, 10 Jul, 2018.) Through its US subsidiary Kolon TissueGene Inc., formerly known as TissueGene Inc., Kolon found that the cell used in solu-tion No. 2 in the US trials was different to that stated in the data submitted in support of the Korean approval, the ministry said.

Given the possibility that the actual cell being used in commer-cial sales in South Korea could be the same as that in the US, the ministry decided to halt sales while it investigates the exact cause of the possible variation.

The product being used for the US clinical trials is manufac-tured at BioReliance Corp., while that sold in South Korea is manufactured at the Chinese contract services group WuXi Ap-pTec Inc., according to the ministry, which claims it uses GP2-293 (human embryonic kidney 293 cell) to manufacture TGF-B1, which is inserted into cartilage cells during the manufacturing process for Solution No. 2.

The TGF-B1 gene is separated and refined to be inserted into cartilage cells, but during this process the company estimates that part of the human embryonic kidney cells may have been inserted

D R U G S A F E T Y


due to incomplete separation and refining.Based on the data obtained so far, the MFDS’ view is that there

are no major concerns over product safety as there haven’t been any reports of side effects that since clinical trials began 11 years ago. During manufacturing, Solution No. 2 (TC) is irradiated and af-ter injection to help growth of cartilage cells in Solution No. 1, and ceases to exist in the body after two weeks.

In addition, at the time of product approval in Korea, there weren’t any particular issues with the toxicity test results submit-ted to the ministry. Since the product was launched in that market, there had been a total of 102 reported cases of adverse effects by this March 30, but these relate mainly to issues such as injection site pain and swelling, the ministry noted.

US PHASE III HALTED, IN TALKS WITH FDAAccording to a corporate disclosure to the Seoul stock market, Ko-lon TissueGene in the US has confirmed that the TC active ingre-dient (transduced human chondrocyte) has actually derived from the 293 cell, and not from human chondrocytes. It has notified this finding to the US FDA in relation to the US trials, and the two sides have begun to discuss the matter. The company has temporarily halted recruitment for the Phase III trial in the interim.

Kolon also said that it believes the variation will not affect the product’s safety and efficacy, as it had been using the 293 cell as the transduced human chondrocyte in its preclinical, Phase I and Phase II trials.

It claimed its perception that TC was derived from human chon-drocytes was based on an analysis of TC characteristics in 2004, although Kolon TissueGene had recently informed Kolon Life that TC had been confirmed to have actually derived from the 293 cell.

The two entities are using the same cell line and the 293 cell is

used to produce various retroviral vectors for gene therapies. Ko-lon Life said it had been consistently using the 293 cell from clini-cal samples through to commercialized products, and so remained confident on safety and efficacy, but now plans to reconfirm the consistency of the cell used in South Korea through analysis by an external institution.

“We apologize for raising concerns from patients. As soon as we get reconfirmation of the safety of Invossa, we will try to meet ex-pectations of patients through prompt resumption of supply,” the company stressed.

During a briefing with local reporters in Seoul, Kolon Life report-edly further explained that the reason for the apparent variation in

the active ingredient is due to a difference in technology between 2004 and now, which affected the analytical results. During the 2004 analysis, the ingredient was determined as human chondro-cytes, but using the latest technology (STR test) it was confirmed as the 293-derived cell. In effect, only the name has changed, accord-ing to some local media.

The STR test wasn’t required by the US FDA, but was a neces-sary step given that a contract producer was manufacturing the therapy for US clinical trials, noted Kolon Life, reportedly adding that in Korea, Invossa was manufactured at its Chung Ju plant at the time of the MFDS approval.

US TRIAL DESIGN In November last year, Kolon TissueGene dosed its first patient in the pivotal US Phase III clinical trial for knee osteoarthritis. The study will enroll close to 1,020 patients in about 60 sites across the US, and will assess pain and function endpoints as well as MRI, X-ray and liquid biomarkers.

In addition to demonstrating significant improvements in pain relief and function, the trials are designed to show structural ben-efits, including a delay in disease progression. If successful, Invossa could achieve a disease-modifying osteoarthritis drug, or DMOAD, label claim from the FDA, which would be a first for any osteoar-thritis drug approved in the US.

The pivotal Phase III program consists of two planned trials: TGC12301, a double-blind, placebo-controlled study to determine the efficacy of TG-C in subjects with Kellgren and Lawrence Grade 2 or 3 OA of the knee; and TGC15302, a double-blind, placebo-con-trolled study to determine the efficacy and effectiveness of TG-C in subjects with Kellgren and Lawrence Grade 2 or 3 OA of the knee.

BLOW TO KOLON’S REPUTATION, KOREAN BIOTECH? Although any action against Invossa is yet to be determined by the MFDS, the news still came as a blow to the company’s reputation as a leading Korean gene therapy developer, as well as to the coun-try’s broader biotech/pharma sector, which is increasingly pursu-ing the development of innovative medicines.

Kolon has high hopes for the commercial success of Invossa giv-en that its prescriptions have been rising sharply, and gene and cell therapies in general are one of the main focus areas the biotech sector in the country is aiming to nurture.

Shares in Kolon Life and Kolon TissueGene, which are both traded on Korea’s Kosdaq market, fell by their daily limit on April 1 following the news, which hurt investor sentiment in the broader biotech and pharma sector.

The issue also highlights the manufacturing challenges being faced by developers of gene therapies, which are expected to in-crease as companies progress more and more complex such prod-ucts through clinical trials and commercialization. (Also see “Gene Therapy Manufacturing Make-Or-Buy Options Weighed” - Pink Sheet, 22 Mar, 2019.)


The STR test wasn’t required by the US FDA, but was a necessary step given that a contract producer was manufacturing the therapy for US clinical trials, Kolon Life said.

D R U G S A F E T Y




Zelnorm Returning To US Market With Broad IBS-C IndicationMICHAEL CIPRIANO [email protected]

T he US FDA has given Zelnorm (tegaserod maleate) the green light to return to the US market with a broad indica-tion for the treatment of adult women less than 65 years of

age with irritable bowel syndrome with constipation (IBS-C) who are at low cardiovascular (CV) risk.

The new label for Zelnorm, a serotonin-4 (5-HT4) receptor ago-nist now owned by US WorldMeds LLC, contains a contraindica-tion for patients with a history of myocardial infarction, stroke, transient ischemic attack or angina, but it does not restrict the drug to patients who are severely symptomatic for IBS-C.

Zelnorm was initially pulled from the market in 2007 by its then-sponsor Novartis AG after a retrospective analysis of pooled clini-cal trial data revealed an imbalance in CV ischemic adverse events. (Also see “Door Open For Zelnorm Return Despite Marketing “Sus-pension,” Novartis Says” - Pink Sheet, 2 Apr, 2007.)

US WorldMeds subsidiary Sloan Pharma submitted a supple-mental new drug application (sNDA) in February 2018 to reintro-duce the drug in the US with a revised indication, but FDA was torn about the most appropriate subpopulation for which the benefits outweigh the risks, and convened its Gastrointestinal Drugs Ad-visory Committee (GIDAC) to weigh in. (Also see “US FDA Seems Ready For Return Of Zelnorm, But Seeks Advice On Best Subpopula-tion” - Pink Sheet, 16 Oct, 2018.)

A majority of the panelists supported a broader indication for the treatment of IBS-C females at low CV risk. The panel’s two cardiology experts, however, both voted for a narrower approval for IBS-C females at low CV risk and who are severely symptom-atic. Overall, there was general agreement that there was a small but real signal for CV risk, but those who voted for the broader indication felt that restricting the indication by symptom sever-ity would be operationally difficult and contended that the risk/benefit assessment should be left up to the patients and their prescribers. These panelists also urged FDA to consider the un-met need for treatment for IBS-C. (Also see “Zelnorm’s Return: US FDA Panel Hands Down Split Decision On Constipation Drug’s Target Population” - Pink Sheet, 17 Oct, 2018.)

In addition to the contraindication for patients with a history of CV disease, labeling also includes a standard warning for cardiovascular ischemic events, including major adverse cardiovascular events.

“The potential risks of treatment must be balanced with expec-tations in improvements in symptoms of IBS-C,” labeling states. “Discontinue Zelnorm treatment in patients who experience a myocardial infarction, stroke, transient ischemic attack or angina. Evaluate the risks and benefits of continued treatment in patients who develop clinical or other evidence of cardiovascular ischemic heart disease and/or experience changes in health status that could increase cardiovascular risk during treatment.”

FDA HEEDS PANEL’S ADVICE FDA agreed that it would be reasonable to narrow the initially ap-proved indication of females with IBS-C to females with IBS-C who are at low CV risk, defined as those below 65 years of age and with-out cardiovascular ischemic (CVI) disease history.

“The review of index cases suggests that ischemic events occurred mostly in patients with a history of CV disease and/or with CV risk factors,” FDA’s multidisciplinary review states.

The agency ultimately heeded the advisory committee’s advice by not restricting use of Zelnorm to patients who are severely symp-tomatic. In a separate vote at the October advisory committee meet-ing, GIDAC voted 12-0 that that the drug’s therapeutic gain is gen-erally similar in magnitude between the severely symptomatic and originally approved population of all female IBS-C patients.

The review notes that “given the lack of established guidelines used in clinical practice for ‘severe’ symptoms, restricting the in-dication by symptom severity poses an operational difficulty in adequately defining such a population in labeling. In addition, the GIDAC noted that the cardiovascular signal was deemed to be weak, if present at all. For these reasons, this ‘severely symptomatic’ subpopulation was not pursued as an indication in labeling.”

FDA also agreed that Zelnorm fills an unmet need. There have been three drugs approved by the agency for IBS-C since Zelnorm was withdrawn from the market in 2007: Sucampo Pharmaceuti-cals Inc.’s Amitiza (lubiprostone), Allergan PLC’s Linzess (linaclotide) and Synergy Pharmaceuticals Inc. ‘s Trulance (plecanatide). Ardelyx Inc. has a novel drug candidate, tenapanor, undergoing a standard review at FDA for the treatment of IBS-C, with a user fee date of Sept. 13, 2019 or earlier. (Also see “Keeping Track: AstraZeneca Wins Approval For Lumoxiti, AbbVie Expands Label For Venclexta With MRD Data, and FDA Delays Acorda’s Inbrijia NDA” - Pink Sheet, 16 Sep, 2018.)

“The available treatment options do not completely meet the needs of patients with IBS-C; the available approved products have a modest treatment benefit over placebo, and over-the-counter and nondrug therapies are not specifically approved for IBS-C,” the



review states. “If reintroduced to the United States market, te-gaserod would join several products that are approved in the United States for IBS-C, and its unique mechanism of action as a 5-HT4 agonist would present a product with a different mecha-nism of action for this disease from those already available. Not all available treatments are effective in all patients, and some may have limited tolerability.”

STANDARD WARNING FOR SUICIDAL IDEATION US WorldMeds scored another victory in Zelnorm’s label with just a standard warning for suicidal ideation and behavior (SI/B).

“Monitor patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment,” labeling states. “Instruct patients to immediately discontinue Zelnorm and contact their healthcare provider if their depression is per-sistently worse or they are experiencing emergent suicidal thoughts or behaviors.”

SI/B became an issue for Zelnorm in 2005 after a review of adverse events found an imbalance of SI/B events in patients on Zelnorm in clinical trials compared with placebo patients. FDA recommended that Novartis include language in the warnings and precautions section of the label describing the risk, although the update never took place, as Novartis had suspended marketing over the CV concerns.

Advisory committee members discussed the SI/B risk at the October meeting, generally agreeing that there was a small but real risk of SI/B associated with Zelnorm. One panelist, Udho Thadani, a professor at Oklahoma University and one of the two cardiologists on the panel, called for a black box warning for SI/B, as well as for the CV risk. Thadani was the one mem-ber to vote “no” on the question of whether the reintroduction of Zelnorm to the US market supported by the available safety data, although he noted he would be willing to change his vote if there was a black box warning for the two issues.

FDA evidently felt a black box was not necessary, noting that in its multidisciplinary review that, “It was determined that al-though a causal association between treatment with tegaserod and increased risk of SI/B has not been established, a signal could not be ruled out. Therefore, although presence of this sig-nal would not preclude approval, prescribers should be aware of this risk, especially given that psychiatric disorders are often a comorbid condition in patients with IBS.”

POSTMARKETING REQUIREMENTS US WorldMeds’ only non-pediatric postmarketing requirement is to conduct a lactation trial “in lactating women who have re-ceived therapeutic doses of Zelnorm using a validated assay to assess concentrations of tegaserod in breast milk,” the approval letter states.

The trial is scheduled for completion by January 2021, with the final report submission due by November 2021.


US FDA’s ‘Great’ Generic Approval Engine Can Be Better, New OGD Director SaysDERRICK GINGERY [email protected]

T he new director of US FDA’s Office of Generic Drugs believes a few tweaks may be needed to increase assess-

ment process efficiency but does not envi-sion any major changes.

Sally Choe, who took over following Kathleen ‘Cook’ Uhl’s March 1 retirement, said during an in-terview with the Pink Sheet in her office at FDA head-quarters that OGD already is running well, but potentially could use some assessment process adjustments or new tools to improve it.

“There are definitely areas that I think we can do better than what we’ve been doing, but I won’t call them problems,” Choe said. “Whether it’s going to be in the review process or whether it’s going to be the tools, we’re looking into a lot of areas right now.”

“I’m not expecting there is going to be huge changes from what Cook has been doing, but I hope that there is room that we can actually do better.”

Those plans have yet to be defined, as Choe works to fully un-derstand the functions and operations of the generics program. She occupies Uhl’s former office at the White Oak campus, which has just enough room for a desk, bookshelf and table for meet-ings with visitors.

Choe has worked at FDA for several years, most recently as deputy director of the Office of Study Integrity and Surveillance in the Cen-ter for Drug Evaluation and Research’s Office of Translational Sciences (OTS). She never worked in OGD previously, although has supported generic drug assessments. (Also see “US FDA Again Looks Outside Ge-neric Drugs Office For New Director” - Pink Sheet, 12 Feb, 2019.)

Choe said OGD could do better at encouraging more first-cycle approvals, as well as improve its assessment of complex generics. She said there is a “great engine … that is working,” but could be more efficient.

“We have gained a lot of experience in the past [complex product] approvals and we’re trying to see is there anything that we could have done better in terms of the process, the communication,” she said.

“When you have a lot more elements to work with, there is a pro-cess improvement that one can always implement and therefore, yes, it is an area that I’m looking into. At this stage if you say do you have an answer for it? No, I don’t have it yet.”

Indeed, both issues Choe identified are well-known points of con-tention with the generic industry that FDA is working to resolve. The agency is allowing some flexibility to help complex generics reach the market. OGD approved the first generic of GlaxoSmithKline PLC’s Advair Diskus (fluticasone propionate/salmeterol), Mylan NV’s Wixela Inhub, with instructions for use that were different than its reference

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

Sally Choe




product. (Also see “Generic Advair’s Labeling Variation Stems From Per-missible Design Differences, US FDA Says” - Pink Sheet, 11 Feb, 2019.)

Industry also has called for more first-cycle ANDA approvals, amid a median time to approval that remains more than two years. About 18% of the ANDAs approved in fiscal year 2018 came after one review cycle, which although low, was an improvement from previous years. (Also see “Lack Of Priority? No ANDAs Approved Using Expedited Path-

way In FY 2018” - Pink Sheet, 5 Nov, 2018.)FDA still acknowledges that multiple review cycles will be needed

for most applications. (Also see “Let’s Get Real – ANDA Approval Likely Takes More Than Two Years, US FDA Says” - Pink Sheet, 15 Apr, 2018.)

APPROVAL VOLUME GOALS UNNECESSARY A number FDA likes to tout is its ANDA approval total, which has grown nearly every year since the generic drug user fee program launched in October 2012.

Choe does not seem focused on pushing that figure higher, however. When asked whether she has a goal for approval volume, Choe said the existing numbers look great and that setting a goal may not be productive.

“I’m not so sure whether defining a number, whether that means anything,” she said. “I’m not so sure how much that actually adds to the value of what we’re doing.”

Choe added she is not expecting substantial differences in workload or productivity going forward. “When you look at the number of approvals that we have made for the last two years, [it] has been pretty steady at around 1,000 each year,” she said. “Now I don’t expect that that’s going to be dramatically different from year to year, however also our productivity, or the approv-als if we say that as a productivity, that also largely depends on what’s coming and I think there is a certain steady flow also of ANDAs that can come in.”

FDA broke its record for full ANDA approvals in FY 2018 with 781. When combined with 190 tentative approvals, the total creeped closer to 1,000, after a combined approval total of 937 in FY 2017. The agency is predicting the combined number will reach 1,000 in FY 2020, according to its budget request congres-sional justification.

The agency trumpeted the recent approval totals as evidence its efforts to lower drug prices were showing results. But indus-try argued more attention should be paid to the number of ap-proved generics that launch, which is lower. FDA does not have a role in those decisions, however. (Also see “US FDA Sets Generic Approval Record, But Generic Sponsors Aren’t Celebrating” - Pink Sheet, 12 Oct, 2018.)

Generics are one of the pillars of President Trump’s plan to low-er drug costs as increased competition is intended to help push prices down.

Choe said that when she arrived for her first stint at FDA, which ran from 2006-2011, she was trained that pricing was not some-thing FDA could impact. But since arriving at OGD, she better un-derstands FDA’s role in the effort.

“Wherever that there is an opportunity for us to contribute I think we are actually working toward that,” she said.

Choe was not ready to offer an opinion on whether 180-day ex-clusivity rules should be adjusted, as has been proposed by Trump and now is being debated in Congress, to help lower drug prices.

The White House wants to change the start of the exclusivity clock to prevent so-called exclusivity parking, which can delay ge-nerics from reaching the market. The House Energy and Commerce Committee also is considering a bill that would enact the idea. (Also see “CREATES Act Has a Penalty Problem” - Pink Sheet, 27 Mar, 2019.)

EXTERNAL COMMUNICATION EFFORT BEGINS SOON While an FDA and industry veteran, Choe still must get to know the stakeholders that so far have had little interaction with her.

Choe already seems to understand the public side of her new role. She said Uhl stressed before her departure that running OGD is about being the face of the generic drug world and working with outside stakeholders, as well as ensuring operations within the of-fice run smoothly.

Much of Choe’s first month was spent meeting staff and learn-ing the OGD assessment and other systems. While she is familiar with the technical aspects of the operation, the learning curve has been steeper for other issues, including the agency’s policy and legal work.

Choe worked with some generics companies while consulting at Parexel International Corp. and inspected bioequivalence trials during her tenure at OTS, but still came to OGD largely unknown. (Also see “Generic Industry Once Again Must Get To Know New US FDA Office Director” - Pink Sheet, 13 Feb, 2019.)

No meetings with outside stakeholders have taken place yet. The industry’s primary trade group, the Association for Accessible Medicines, said April 1 that it decided to give Choe time to settle into the new role and plans a meeting in the coming weeks.

Choe will jump-start her public relations activities this week. She will give her first speech to an industry audience April 3 during FDA’s Generic Drug Forum, an event hosted by CDER’s Small Busi-ness and Industry Assistance group.

Choe said she wants to stress communication and encourage sponsors to use the information that OGD produces.

“I feel that the external stakeholders have not gotten, I guess, the full grasp of what we are actually offering,” she said. “I’m hoping that we’ll do even more and better communication and make sure that they are available and people really do take advantage of all the information that we put out there because at the end that’s go-ing to result in the quality applications.”


When asked whether she has a goal for approval volume, Choe said the existing numbers look great and that setting a goal may not be productive.



House Committee Clears Bills To Prevent Pay-For-Delay Deals, Assure Generic Access To SamplesBRENDA SANDBURG [email protected]

T he House Energy & Commerce Committee approved six bills, referred to as the “generic package,” that are intended to remove barriers to the marketing of generic drugs.

One of the most high-profile bills, Creating and Restoring Equal Access to Equivalent Samples (CREATES), H.R. 965, was amended to prevent frivolous litigation against brand name manufacturers who provide requested samples of their products.

The bill is intended to prevent brand drug companies from using Risk Evaluation and Mitigation Strategies (REMS) or restricted distri-bution systems to avoid selling samples to generic companies for testing. The measure would allow generic manufacturers to pursue a civil action against brand companies for failure to provide quanti-ties of their product and allow courts to provide monetary penalties.

Committee Chair Frank Pallone Jr., D-NJ, offered a manager’s amendment as a substitute, which was adopted by the commit-tee. He noted that during the Health Subcommittee’s March 27 markup of the bill, there was debate about the potential for bad behavior that could occur during the sample transfer process. He said Republican members expressed concern about possible frivo-lous litigation while Democratic members raised concerns about gaming by the brand, including sending offers to sham mailboxes or email addresses.

Pallone said his amendment addresses this by “providing brand companies with an additional affirmative defense in cases where they have made an offer of sufficient samples under commercially reasonable market-based terms.” He said the amendment would

require a written record of a request offer and acceptance of sam-ples to protect against potential gaming.

Rep. Bill Flores, R-Texas, withdrew an amendment that would have required generic manufacturers to choose one option to challenge a brand’s patents, either litigation in courts or an inter partes review proceeding. Flores is sponsor of the Hatch-Waxman Integrity Act, H.R. 990, which would impose this requirement.

An amendment proposed during markup would have changed the penalty for failure to provide samples to profits or damages rather than the company’s revenue over a specific time. But that amendment was rejected. (Also see “CREATES Act Has a Penalty Problem” - Pink Sheet, 27 Mar, 2019.)

The committee voted 51-0 to move the bill as amended to the House. The other five bills were approved by voice vote. (See chart of the bills on p. 12.)

PAY-FOR-DELAY BILL WILL NOT BE RETROACTIVEThe committee also adopted an amendment to another key bill, Protecting Consumer Access to Generic Drugs Act of 2019, H.R. 1499. The measure would prohibit brand name drug companies from compensating generic drug manufacturers to delay the entry of a generic drug and biologic manufacturers from com-pensating biosimilar makers to delay entry of biosimilar and in-terchangeable products.

Rep. Bobby Rush, D-Ill., sponsor of the bill, introduced a manager’s amendment to remove a retroactive provision so the measure will only be prospective. He noted that concerns had been raised about this during subcommittee markup.

Rush said the Federal Trade Commission will have the authority to exempt certain agreements between brand and generic companies.

Ranking member Greg Walden, R-Ore., withdrew his amend-ment to establish a process for parties to go to the FTC to seek an advisory opinion as to whether their agreement would violate the law. It specified that if the Commission decided the agreement would not violate the law, it would be foreclosed from taking ac-tion against the parties. Walden said he would work with Rush and Pallone on the language, adding that it would help the measure gain strong bipartisan support in the House.

Another measure approved by the committee, the BLOCKING Act of 2019, H.R. 938, is intended to remove a barrier to generic approval posed by 180-day exclusivity given to a first generic ap-plicant that has not yet received final approval.

Bill sponsor Rep. Kurt Schrader, D-Ore., said that on average, a generic manufacturer’s “parking” of 180-day exclusivity occurs five times a year.





Pharma Bills Clear House CommitteeSix bills seeking to remove barriers to lower-cost drugs were marked up by the House Energy & Commerce Committee’s Health Subcommittee on March 27 and cleared the full committee April 3.

BILL PROVISION SUBCOMMITTEE ACTION FULL COMMITTEE ACTION

Creating and Restoring Equal Access to Equivalent Samples (CREATES) (H.R. 965)

Would prevent brand drug companies from using Risk Evaluation and Mitiga-tion Strategies to avoid selling samples to generic manufacturers for testing.

Adopted amendment that incor-porates technical feedback from FDA, including clarifying language regarding products that are subject to a shortage and clarifies the ability of generic manufacturers to share separate REMS.

Adopted manager’s amendment providing brand name drug manufacturers an affirmative defense if they provide samples.l

Protecting Consumer Access to Generic Drugs Act of 2019 (H.R. 1499)

Would make it illegal for brand-name and generic drug manufacturers to enter into agreements in which the brand-name drug maker pays the generic manufacturer to keep a generic off the market.

Adopted amendment that incorpo-rates technical feedback from FDA, including ensuring reverse pay-ment settlements among any type of manufacturer, including two ge-nerics, are unlawful, and extending the scope of unlawful agreements to include a generic foregoing development of their own product in lieu of marketing or selling a brand’s authorized generic.

Adopted manager’s amendment removing retro-spective provision so the bill is only prospective; gives FTC authority to exempt certain agreements.l

Bringing Low-Cost Options and Competition while Keeping Incentives for New Generics (BLOCK-ING) Act of 2019 (H.R. 938)

Would discourage parking of 180-day exclusivity by a first generic applicant that is blocking the approval of other generics.

Forwarded without amendment to the full committee.

Reported to House with no amendment.

Purple Book Continuity Act of 2019 (H.R.1520)

Would codify publication of the patents of approved biologics in FDA’s Purple Book, specify that it be published elec-tronically on FDA’s website and updated routinely, and direct FDA to consider the types of patents that should be listed in the Purple Book.

Adopted amendment that incorpo-rates technical feedback from FDA and clarifies that the Purple Book should be published in a search-able electronic format and that exclusivities for biological products should be listed.

Adopted manager’s amendment clarifying patent information to be reported in Purple Book. Requires publi-cation of patents of approved biologic, including biologic’s official and proprietary name, date of licensing and the type of bioequivalence studies required. Secifies that HHS is to make recommendations on what information should be added.

Orange Book Transparency Act of 2019 (H.R. 1503)

Would require exclusivity periods be included for each drug in FDA’s Orange Book. Would require patents found to be invalid through a court decision or decision by the Patent Trial and Appeal Board to be removed from the book.

Adopted amendment that incor-porates technical feedback from FDA and clarifies that removal of patents found to be invalid through a decision by the PTAB only occurs after no appeal has been or can be taken.

Adopted manager’s amend-ment to strike requirement that drug delivery device patents be removed from the Orange Book and replaced with requirement for govern-ment accountability study on the effect of listing such patents in the Orange Book.

Payment Commission Act of 2019 (H.R. 1781)

Provides the Medicare Payment Advi-sory Commission (MedPAC) and the Medicaid and CHIP Payment and Access Commission (MACPAC) with access to drug pricing and rebate data in order for them to help Congress better under-stand the true costs of prescription drugs to consumers and taxpayers.

Forwarded without amendment to the full committee.

Adopted amendment to include rebate data for review.


B I O S I M I L A R S

Insulin Applications Intended For Biosimilar Pathway May Already Be At US FDADERRICK GINGERY [email protected]

O utgoing US FDA Commissioner Scott Gottlieb implied that ap-plications for follow-on insulins

already may be arriving at the agency as part of a flurry of activity in anticipation of the opening of the biosimilar pathway to the products.

Insulin is among the products currently regulated as a drug that on March 23, 2020 will be deemed a biologic, which will open the biosimilars pathway for fol-low-on products.

When asked about the process during a March 28 Senate Appropriations sub-committee hearing on the FDA fiscal year 2020 budget request, Gottlieb said that there already is robust interest from spon-sors and suggested the agency may have some applications intended to move as part of the transition.

“We believe under the biosimilars path-way we are going to see much more vigor-ous competition from truly interchangeable insulin products, and we already have a lot of applications in-house, a lot of activity, for products looking to come through that pathway,” Gottlieb said.

“We’ve seen companies make accommo-dations for the change in the market posi-tion of these,” he added. “And so companies have filed applications or are seeking to file applications under the biosimilars pathway anticipating this change.”

When asked to clarify Gottlieb’s state-ments on applications already arriving, the agency said it is working on how it will handle applications pending when the transition occurs.

“We are carefully considering steps for pending applications if they’re pending before March [23], 2020 to minimize dis-ruption to development programs,” the agency said in an email. “At this time, the agency anticipates that it will impact few, if any, applications.”

Pre-transition applications could be NDAs or 505(b)2 applications, depending

on whether they reference an already ap-proved product. When either are submit-ted and would be subject to the transition, sponsors are counseled appropriately, the agency said.

FDA released several guidances on its plans for the deemed-to-be-biologics tran-sition in December as part of its Biosimilars Action Plan. (Also see “When Drugs Become Biologics: US FDA Guidances Explain ‘Transi-tion Provisions’” - Pink Sheet, 11 Dec, 2018.) The agency also determined that there will be no additional exclusivity awarded for existing products affected by the change. (Also see “US FDA’s Gottlieb Shuts The Door On Exclusivity For ‘Transition’ Biologics” - Pink Sheet, 11 Dec, 2018.)

Attention to the potential for biosimi-

lar insulin increased amid outrage over price increases for the brand products. The House Energy and Commerce Com-mittee’s Oversight and Investigations Sub-committee conducted its first hearing on insulin prices April 2, the same day FDA announced a May 13 public hearing on de-velopment of biosimilar and interchange-able insulin.

GOTTLIEB SUGGESTS PRODUCT DELAYS WILL BE MINIMALThe transition of insulin and other bio-logic NDAs to BLAs was mandated by the Affordable Care Act, the law that created the biosimilars pathway.

Stakeholders are worried when the transition date approaches, FDA will not transition pending applications referenc-ing the affected products. As a result, sponsors may hold back insulin applica-tions if they would not complete the re-view in time, to avoid having to restart their programs as biosimilars.

The resulting “dead zone” could further delay biosimilar insulins from reaching the market. Several senators already told FDA to automatically switch existing ap-plications that reference a transitioning product along with the actual product. (Also see “Senators Press US FDA For Faster Approval Of Generic Insulin” - Pink Sheet, 5 Mar, 2019.)

During the hearing, Gottlieb suggested that a few applications may be delayed because of the transition, but did not expect a widespread problem, in part because industry has been aware of the move for several years.

“Could there be one or two sponsors that sort of get caught trying to slip in un-der the old pathway before the data con-version? It’s possible,” he said. “There was always going to be the potential for a few outliers, but by and large we’re seeing very vigorous activity under this new proposed framework.”

The transition of insulin and other biologic NDAs to

BLAs was mandated by the Affordable Care Act, the law that created the

biosimilars pathway.




Gottlieb also reminded Senators at the hearing that the biosimilar pathway would be eliminated if the ACA was invalidated, although he hoped Congress would quick-ly act to restore it. (Also see “Biosimilar Pathway Would Disappear If ACA Repealed, Gottlieb Says” - Pink Sheet, 28 Mar, 2019.)

BSUFA DEVELOPMENT MEETINGS AVAILABLE PRE-TRANSITIONFDA also is working with sponsors in devel-opment phases to facilitate development of biosimilar and interchangeable alternatives.

The agency said that even though the biosimilar pathway will not open for insulins for another year, sponsors still may request product development meetings through the biosimilar user fee program to receive product-specific advice.

“FDA has been holding these meetings well in advance of the March 23, 2020, tran-sition date to facilitate submission of appli-cations for these products,” the agency said.

The agency said it could not provide specific information about BsUFA develop-ment-stage formal meetings with sponsors.

Biosimilar sponsors have five options for formal meetings with FDA staff ranging from early stage, to pre-submission interac-tions. Meeting can include discussions of specific issues or include a data review. (Also see “Biosimilar Development Meetings At US FDA Not Just For Talking Similarity” - Pink Sheet, 31 Oct, 2017.)

If sponsors request any formal meet-ing other than a biosimilar initial advisory meeting, they must pay the initial bio-similar product development fee, which is $185,409 in FY 2019, and make annual fee payments until the application is submitted.

In January, 70 biosimilars were enrolled in the biosimilar product development program, up from 59 in December 2017, in-

spiring optimism about the product pipe-line. (Also see “US Biosimilars: FDA Seeks To Build On Record Number Of Approvals, But Shutdown May Blunt Progress” - Pink Sheet, 22 Jan, 2019.) There are now 73 products in the program, suggests the growth has been sustained.

SPONSORS INTERESTED, BUT REMAINING QUIETSome companies already have suggested they may develop follow-on insulins, al-though it is unclear whether they want to use the biosimilar pathway.

Most contacted by the Pink Sheet re-fused to comment or did not respond to questions asking whether they were meet-ing with FDA or had applications pending.

Sanofi, which markets Lantus (insulin glargine), said it continues to discuss the transition regulatory process with FDA, but would not discuss the matter further until

all details of the plan are finalized.Eli Lilly & Co., a maker of insulin lis-

pro products Humalog and Humulin, has asked for clarification from the agency on whether following the transition the company could still seek approval of bio-similars of its own products, similar to an authorized generic approach. (Also see “Insulin Maker Lilly Seeks US FDA Assuranc-es On ‘Authorized Biologics’” - Pink Sheet, 20 Feb, 2019.)

Lilly also recently launched an autho-rized generic of the short-acting insulin Humalog with a 50% price discount to help patients struggling with the prod-uct’s rising cost. (Also see “Same Drug, Two Versions And Prices, This Time For Lilly’s Humalog” - Scrip, 4 Mar, 2019.) It’s follow-on insulin glargine Basaglar also is near-ing blockbuster status and among its fastest-growing brands globally. (Also see “Basaglar Follow-On Insulin Booms For Eli Lilly” - Generics Bulletin, 11 Feb, 2019.)

Mylan NV has 505(b)2 applications for Lantus and the disposable injection pen formulation Lantus SoloSTAR pending at FDA that were co-developed with Biocon Ltd.. Mylan recently received a favorable decision from the US Patent and Trade-mark Office for its Lantus follow-on that should clear the way for launch upon ap-proval. (Also see “Mylan Scores IPR Victory, Paving The Way For Follow-On Lantus” - Pink Sheet, 13 Dec, 2018.)

In 2018, Merck & Co. Inc. decided against launching its generic version of Lantus, ap-proved a year earlier through the 505(b)2 pathway. The move was viewed as a set-back for growth of the US biosimilar market. (Also see “Merck Steps Out Of Insulin Glargine Market, But Says It Remains Committed To Biosimilars” - Scrip, 11 Oct, 2018.)


FDA said that even though the biosimilar

pathway will not open for insulins for

another year, sponsors still may request

product development meetings through the

biosimilar user fee program.

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EU Countries Examine Reasons For Wide Differences In Biosimilar UsageIAN SCHOFIELD [email protected]

I t’s no secret that while biosimilar medi-cines are gradually consolidating their presence in the Europe pharmaceutical

market, their use varies widely by mol-ecule and by country, and often within the same country, depending on factors such as doctor incentives, purchasing and reim-bursement policies, and the perceptions of healthcare professionals and patients that are often swayed by misinformation on the safety of biosimilars.

Speakers from several European coun-tries outlined their experiences with bio-similars to date at Medicines For Europe’s 17th biosimilars conference, which this year was held in Amsterdam rather than London, mirroring the relocation of the European Medicines Agency from the UK to the Netherlands as a result of the Brexit vote.

Peter Goliaŝ, director of Slovakia’s In-stitute for Economic and Social Reform, said his institute had estimated that up to €40m, or 4% of total national phar-maceutical spending, could be saved by greater use of biosimilars, thereby mak-ing biological drugs more accessible to more patients. “This helps to sustain healthcare systems and improve health-care outcomes,” he told the conference, which took place on March 28-29.

He said that historically it had taken around 10 years for some biosimilars to take a 60-80% share of the market, but that in recent years usage had risen much more quickly, and “we can assume that in cer-tain markets could w could achieve these shares in just one year.”

However, he stressed that there a “big differences” among countries, with some developing their biosimilar markets more quickly and others lagging behind, “proba-bly due to the different sets of policies that each country has, which shows us there is room for sharing best experience.”

This was echoed by Judit Bidló, deputy director of the Hungarian National Health

Insurance Fund Administration, who said that while uptake of certain biosimilars in her country, like epoetin and G-CSF, was almost 100%, in other cases like insulin, us-age remained low – around 5% of the mar-ket for biosimilar insulin products.

In fact, she said, epoetin and G-CSF had reached almost 100% biosimilar usage. However, in the case of infliximab there was a “very interesting situation”: there was a government tender, and all inflix-imab manufacturers took part, but the tender was won by the originator (Jans-sen Pharmaceutical Cos.’s Remicade), “so I don’t know how we can define it in this case,” Bidló observed.

Bidló said that in Hungary there is an obligatory 30% price discount on bio-similars versus the originator, and in some cases biosimilar usage quotas are used, which was the case for growth hormone. “But there is no punishment” if the quotas

aren’t reached, “only some recommenda-tions for doctors to use, and to be honest it is not very efficient.”

Biosimilar tenders are obligatory where new patients are to be treated, but not where existing patients are switched from the originator drug, she said. Sometimes a switch is also mandatory, but only in cer-tain cases as with epoetin and infliximab – the product that wins the tender has to be used for all patients.

She noted that there are also issues of doctor and patient resistance to be over-come: “to convince them we have to high-light issues” such as the savings on the medicines bill and the potential benefits for domestic manufacturing if biosimilars are more widely prescribed. Perceptions about side-effects and immunogenicity also had to be addressed. “So there is a lot to do… lots of negotiations and discus-sions with doctors and sometimes with patient associations.”

By contrast, the Netherlands has a policy of promoting not biosimilar up-take specifically but rather competition among the different alternative biologic treatments, said Flora Mulder, senior pol-icy advisor to the Dutch health ministry.

Nonetheless, “we do have actions on biosimilars,” she said, such as the BOM project – a three-year educational pro-gram looking at the various aspects of biosimilars and obstacles to their use in hospitals, which is run by Biosimilars Ned-erland and the Institute of Responsible Medicines Use and subsidized by the health ministry. The ministry is also talk-ing with stakeholders on how to boost the use of biosimilar insulin products as the current system “is not getting results,” Mulder added.

REGIONAL INITIATIVESThe conference also heard some inter-esting examples of regional, as opposed to national, biosimilar policies. Gustav

The Stockholm regional council has

emphasized increasing physician acceptance

of biosimilars, including through gainsharing

agreements.




Befrits, administrator and health econo-mist at the Stockholm County Council in Sweden, said his authority had begun thinking about how to promote biosimi-lar usage since biosimilar infliximab was launched in its first northern European market, Norway, in 2014.

“We chose a few activities to focus on when introducing biosimilars,” Be-frits told the conference. On the supply side, the Stockholm region uses tenders involving confidential discount agree-ments. “We would prefer straight lower list prices, but that is not the way for-ward, I’m afraid, so we have been work-ing on confidential agreements, which have been quite successful.”

On the demand side, the SCC “decided early on in 2014 that what would benefit us most in the long term was if we got doctors to accept and feel comfortable with the concept of biosimilars, if we get them along, we will probably have a much easier time.” This turned out to be a good investment in terms of time and re-sources, and “has worked out very much to our benefit.”

It has therefore been working particu-larly on gainsharing agreements, where savings from the greater use of biosimi-lars are fed back to the prescribing doc-tors’ departments, Befrits said, giving the example of a tender for trastuzumab (the originator is Roche’s Herceptin).

The SCC decided that any gains that were made from introducing the biosimi-lar that won the tender – in this case Sam-sung Bioepis Co. Ltd.’ Ontruzant – would be retained by the budget holder, i,e,. the hospital, Befrits said. “So there was quite a high incentive for physicians – and it worked.” The costs of using trastuzumab after the tender came into effect in De-cember “went right down to near the bio-similar level.” In terms of packs dispensed, after only two months there was a “clear indication” that more patients were get-ting access to trastuzumab since Ontru-zant was introduced.

Interestingly Befrits also noted that af-ter the SCC had talked with hospitals, all of them had expressed a willingness or an intent to go back to using more of the intravenous formulation of traztuzumab

so that the biosimilar could be used, rather than the newer subcutaneous form of Herceptin introduced by Roche.

The sc form of trastuzumab is seen as much more convenient to administer than the iv form, and there have been suggestions that doctors would be un-willing to switch from sc Herceptin to iv Ontruzant. But Befrits said that the cost of employing additional nurses to adminis-ter the iv product was “well and truly off-set by using Ontruzant.

He added that the council was also work-ing on biosimilar switching recommenda-tions, and that these have been evolving over the years. “The first recommendation said that using biosimilars should entail no risk either of safety or efficacy compared with the reference products,” he said. The SCC had used biosimilars, primarily inflix-imab, for a couple of years, when the rec-ommendation was for the use of biosimilars only in naïve patients. “Now our recommen-dations don’t actively promote switching, but they do say that in patients with stable disease and who otherwise have no other complications, their use “is not discouraged”.

SPANISH EXAMPLEAnother example of a regional initiative was presented by Marta Pastor Fàbregas, a health economist with the Catalan Health Service in the Spanish region of Cataluña.

The regional health program, Catsalut, offers free healthcare for 7.5 million peo-ple, and the cost of subsidized medicines in 2018 was in the region of €2.5bn out of a total health budget of €9bn. In 2017 the use of biosimilars as a proportion of all bio-logic medicines was 9% across the board, compared with a national average of 15%: “We were at the bottom of the list, with very low uptake, so we decided to take ac-tion to improve the situation.”

Regional clinical guidelines now recom-mend the use of biosimilars in naïve pa-tients, and the region also has a policy of using indicators to monitor biosimilar us-age, with the aim this year of having bio-similars used in hospitals in at least 80% of new patients. Since 2017 these indicators have applied to etanercept, infliximab and filgrastim, and since 2019 to rituximab, adalimumab and trastuzumab, Fàbregas

said. In 2018, about 20% of hospitals met the 80% usage target.

In certain cases, the health service pays hospitals a flat rate for each unit of a bio-logic drug, calculated on the cost of the biosimilar, so if the hospital uses the bio-similar the full cost of treatment is covered.

An update received by the ministry a few weeks ago showed that the regional average of biosimilar use has risen from 9% to 11%. “We are still far away from the national average, but at least these poli-cies have worked… they show a slight im-provement, and there is still a lot of work to do, but I think we are on the right path.”

MISINFORMATIONMisinformation, by all accounts, is still a factor holding back the wider use of bio-similars. Beata Ambroziewicz, president of the Polish Union of Patient Organizations, told the conference that she thought gov-ernment communications on biosimilars in Poland had been “wrong from the start.”

“Now we have very polarized opinions on biosimilars: on the one hand there are those in favor of automatic switching, and those who want no switching at all. Some-how we lost the meaning of the switch from the medical point of view.”

She said that while doctors and patients should be involved in the switching deci-sion, “of course there are patients who don’t want to be involved.” The most important thing, she said, was to “ensure transparent information for every stakeholder as part of the treatment process. Right now we see in Poland and many countries a lack of information on biosimilars.” That, she said, had resulted in “misinformation and a lack of trust in the whole system, which causes great stress and fear among patients.” She said patients were not concerned specifi-cally about the safety of individual drugs, but more about the quality of the informa-tion provided.


@PharmaPinksheet


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

THE QUALITY LOWDOWN: No Excuses For Homeopathic, CMO, OTC Quality FailuresBOWMAN COX [email protected]

T he question of responsibility and who exercises it was a common thread running through a batch of warning letters the US FDA released in recent days.

King Bio’s quality unit should have been able to recall microbio-logically contaminated homeopathic drug products and certainly should have fixed the contamination problems that had plagued the firm’s water supply for years, FDA said in one warning letter.

The agency reprimanded other homeopathic firms for sell-ing products that contained un-checked levels of snake venom, trapped moths or objectionable microorganisms.

After a US contract manufacturer couldn’t convince a client to change its formula, the firm raised questions at FDA by going on to make a second unstable batch of product.

Another US firm just gave up trying to figure out how to manu-facture over-the-counter topicals correctly, receiving a plea from FDA to simply cancel its US registration.

Meanwhile, a facility in Kenya passed a World Health Organiza-tion inspection.

And FDA proceeded with efforts to roll back regulations on drug manufacturers, removing an out-of-date biologics inspection re-quirement and proposing to remove an outdated mycoplasma testing requirement.

Also, a pre-International Council on Harmonization meeting was announced, and two firms were added to FDA’s drug GMP import alert.

FDA HITS KING BIO ON QUALITY As FDA rushes to address more than 4,800 comments and pro-duce a final version of the risk-based enforcement guidance it drafted in December 2017 for drug products labeled as ho-meopathic, the agency April 1 published four more warning letters concerning poor homeopathic drug manufacturing practices as well as a stern news release quoting FDA Commis-sioner Scott Gottlieb.

Gottlieb singled out one of the warning letter recipients, King Bio of Asheville, North Carolina, for a bit of a tongue lash-ing because previous warnings and other FDA actions appear to have gone unheeded, saying the firm “continues to concern us because of the low quality of their operation and the threat their products pose to consumers … despite previous actions we’ve taken.”

The King Bio warning letter resulted from the same July 9-20, 2018, inspection that led the firm, at FDA’s urging, to recall all water-containing products, and that led FDA to warn consum-ers not to use any of the firm’s products. (Also see “The Quality Lowdown: Recalls And Shortages” - Pink Sheet, 29 Aug, 2018.)

The March 20 warning letter, which FDA copied to King Bio’s Chi-cago lawyer, Abhishek Gurnani, provides further details about high levels of Burkholderia multivorans, a strain of the Burkholderia cepa-cia complex, that had contaminated the facility and its products.

FDA criticized the firm’s quality unit for failing to act over the years to extremely high levels of microbiological contamination in test results for water used in its drug products, despite find-ing objectionable microorganisms in retained samples and cus-tomer complaint bottles.

And it criticized the firm for failing to listen when the quality assurance manager recommended a recall due to microbiologi-cal contamination.

“The quality unit must be empowered to make final quality decisions,” stressed the warning letter.

FDA also complained the firm didn’t validate its manufactur-ing process, even though it put poisonous strychnine in one product, Nux vomica.

FDA also raised concerns about the firm’s failure to fix its wa-ter system, despite evidence that it knew about the contami-nation and responded to it by, for example, adding filters and at one point in May 2017 shutting it down and buying purified water for production.

Outgoing FDA Commissioner Gottlieb criticized King Bio because previous warnings and other FDA actions appear to have gone unheeded.




OTHER HOMEOPATHIC FIRMS WARNEDA March 20 warning letter to Red Mountain Inc., Oakland Park, Florida, said the firm lacks a quality unit to oversee its contract manufacturer’s production of drug products that contain poten-tially toxic ingredients like snake venom.

Tec Laboratories Inc., Albany, Oregon, failed to properly investi-gate an out-of-limit result for microbiological deviations in its puri-fied water system, which it attributed to a failed reverse osmosis membrane, by evaluating the impact on topical drug products for use on potentially broken skin such as lice spray and antiseptic gel that were made after Dec. 27, 2017, when the membrane was in-stalled, a March 20 warning letter said.

B. Jain Pharmaceuticals Private Ltd., Biwadi, India, kept using a certain raw material to make homeopathic drug products even af-ter an FDA investigator pointed out during an Aug. 13-29, 2018, inspection that a live moth was floating in it.

The firm could not say whether a cracked holding tank and patched-up piping had allowed entry of microbial contamination, because it had no microbial testing results to show the agency, FDA’s March 21 warning letter added.

FDA put B. Jain on import alert Jan. 9.

THIBIANT WARNED FOR HUMORING UNSTABLE-FORMULA-LOVING CLIENTThibiant International Inc., Newbury Park, California, figured out what was wrong with a batch of over-the-counter drug product it manufactured in August 2015.

The formulation was unstable, the contract manufacturing or-ganization concluded based on its investigation into failures at multiple stability time points over the next two years for pH and viscosity, and at one point for specific gravity.

But after the customer declined proposed changes, Thibiant manufactured a second batch using the same formulation, which also failed for the same reasons.

FDA reviewed these developments in a March 6 warning letter that focused on the shortcomings of the firm’s out-of-specification procedures that allowed it to release failing drug products to the market.

“Even a manufacturer who performs contract manufacturing is responsible for meeting cGMP and cannot distribute substandard, adulterated drugs,” the warning letter stressed.

MARIPOSA WARNING LETTER: PLEASE JUST CANCEL YOUR US REGISTRATIONIf Mariposa Labs LLC followed through on its promise to stop manufacturing and distributing over-the-counter drug products due to quality problems, FDA said in a March 14 warning letter, then the Boise, Idaho, firm should tell the agency why and when it stopped manufacturing each drug product – and then cancel its US registration.

The warning letter focused on three main quality issues: a fail-ure to establish adequate specifications and make sure each batch met them; a failure to adequately document complaints of mold, chemical smell or stinging for creams labeled for use on newborns

and on broken skin; and a failure to establish validated manufac-turing processes.

During the March 2018 inspection that led to the warning letter, Mariposa explained “that it was difficult to determine manufactur-ing parameters” for its drug products. FDA’s investigator found af-ter reviewing production records for two drug products that Mari-posa hadn’t “sufficiently identified critical manufacturing variables, including but not limited to mixing speed and time.”

WHO OK’S KENYA FACILITYThe World Health Organization approved Universal Corp. Ltd.’s fin-ished drug product manufacturing facility in Kikuyu, Kenya, for an-other three years based on a routine Aug. 27-30, 2018, inspection.

WHO noted that the unit of India-based Strides Shasun Ltd. had expanded its manufacturing facilities in 2009-2010 and last year commissioned new granulation, oral rehydration salt, coating, packaging and finished drug product warehouse areas.

WHO noted some issues in its public inspection report, or WHOPIR, with the clarity of instructions for certain manufacturing processes and cleaning procedures.

Notably, the firm did not contract out any manufacturing work.The firm’s quality control laboratory was well equipped but

wasn’t completing sampling and testing in a timely manner, WHO observed. The firm responded by proposing what WHO deemed were appropriate corrective and preventive actions.

DEREGULATION WITHOUT REGULATORY SHORTCUTSThe US FDA April 2 issued a final rule removing an outdated two-year inspection requirement for biologics facilities.

The agency had issued a direct final version of the non-contro-versial rule along with a proposed version of the rule on Jan. 26, 2018, so that if there were no comments, it could proceed immedi-ately with removing the outdated requirement.

However, there were five comments, one on an unrelated topic, and because they had to be addressed, the agency on May 7, 2018, withdrew the direct final rule and considered the comments. (Also see “Removal Of Outdated FDA Inspection Scheduling Rule Blocked By A Few Individuals “ - Pink Sheet, 6 May, 2018.)

Although in the end, the comments didn’t lead to any changes, the fact that FDA considered the comments before acting is another reminder that there are no regulatory shortcuts for deregulation.

STATUS QUO EXPECTED FOR MYCOPLASMA TESTINGFDA says firms won’t switch to quicker, more sensitive mycoplasma detection methods for live and inactivated virus vaccines produced from in-vitro cell cultures – even if a rule FDA proposed April 2 goes final to allow it.

If the proposed rule becomes final, firms would no longer be re-quired to use the outdated mycoplasma detection method specified in Title 21, Part 610.30 of the Code of Federal Regulations.

However, firms would have to keep using the old method until they follow procedures at 21 CFR 601.12( c ) to supplement their bio-



logics license application with a different mycoplasma test.FDA said it believes firms will keep using the old mycoplasma test

and predicts “no quantifiable cost savings” from the proposed rule.The agency is looking to remove the requirement as part of a

deregulatory initiative spelled out in Executive Order 13777, issued Feb. 24, 2017.

FDA, HEALTH CANADA HOLD PRE-ICH MEETINGThe US FDA and Health Canada are taking input April 29 in a meet-ing at FDA headquarters in Silver Spring, Maryland, on activities of the International Council on Harmonization in advance of a June 2-6 ICH meeting in Amsterdam, Netherlands, according to a March 28 Federal Register notice.

The two agencies, which are represented on the ICH manage-

ment committee, are particularly interested in public input on:To attend, register by April 22 online at https://ich_regional_con-

sultation_2019.eventbrite.com.

TWO MORE FIRMS ON IMPORT ALERTThere were two recent additions to FDA’s drug GMP import alert:

• Luen Fook Medicine Sdn. Bhd., Masai, Johor, Malaysia, added March 29; and

• Petra Hygienic Systems International Ltd., Concord, Ontario, Canada, added March 25, for not just drug products but also bath soaps and detergents, and anti-bacterial soaps.


C L I N I C A L T R I A L S

India’s New Trial Rules Tick Right Boxes, Shed Interim Compensation ClauseANJU GHANGURDE [email protected]

I ndia has issued new clinical trial rules that specify time-bound regulatory approvals and provide for local trial exemptions for drugs approved in certain developed countries, subject to spe-

cific conditions. The new rules are also shed certain contentious trial compensa-

tion provisions that were part of a previous draft regulation and had made sponsors nervous.

The New Drugs And Clinical Trials Rules 2019 specify a timeline of 30 working days for the Indian regulator to decide on a clinical trial application for a new or investigational drug discovered in In-dia or for which R&D is being done in the country, and where the drug is also proposed to be manufactured and marketed in India.

If the Central Licensing Authority fails to communicate within the 30-day timeline, thereafter permission to conduct the clinical trial will be deemed to have been granted, the new rules specify.

In the case of applications for global clinical trials, the new norms set an approval timeline of 90 working days. The Indian Society for Clinical Research (ISCR), whose members include several large multinational firms and clinical research organizations, said that the timelines are “globally competitive” and in line with those in developed countries.

“This will support India’s participation in global drug develop-ment,” the ISCR said.

Among other details, the new regulations also set out the pro-cedure for fee-based pre- and post-submission meetings of appli-cants with the Central Licensing Authority. The rules also define the conditions for providing post-trial access of drugs to patients who require it for the first time.

ISCR president Dr Chirag Trivedi said that the new rules will go a

long way to reassuring local and global stakeholders about India’s commitment to building a robust regulatory and clinical research ecosystem. “The new rules protect the rights, safety and well-being of patients, while ensuring a strong scientific base for the conduct of clinical trials,” he said.

LOCAL TRIAL EXEMPTIONThe new rules also stipulate conditions under which local clinical tri-al data may not be required to be provided as part of an application for permission to import a new drug for sale or distribution in India.

Such a waiver can be granted for new drugs approved and mar-keted in countries specified by the Central Licencing Authority and if “no major unexpected serious adverse events have been re-ported”. It is also applicable in cases where a new drug is approved for marketing in a specified developed nation even as trials for the drug are ongoing in India as part of the global study, which has been approved by the Indian regulator.



In such cases, there should be “no probability or evidence, on the basis of existing knowledge, of difference in Indian population of the enzymes or gene involved in the metabolism of the new drug or any factor affecting pharmacokinetics and pharmacodynamics, safety and efficacy of the new drug”, the new rules specify.

Applicants are also required to provide an undertaking in writing to conduct Phase IV clinical trials to establish safety and effective-ness of such new drug as per a design approved by the regulator.

Suneela Thatte, head of R&D Solutions at IQVIA India, said that while the local trial data waiver was being done more on a case-by-case basis before, it has now been formalized in the new rules. “Sponsors will have to go to via the regulator for marketing authori-zation so the formal waiver will come through via that route,” Thatte told the Pink Sheet.

INTERIM COMPENSATION CLAUSE DROPPEDImportantly, the new rules exclude a contentious interim com-pensation clause that featured in the previous draft trial regula-tions, which had left sponsors jittery.

The 2018 draft rules had stipulated that sponsors would need to pay an interim compensation when “any death or permanent dis-ability” of a trial subject occurs during a clinical trial or bioavailability and bioequivalence study, and the Ethics Committee (EC) after “due analysis” of the case, opines that this is related to the clinical trial.

The sponsor, the draft rules proposed at the time, should pay an interim compensation of “60% of the compensation payable” as per the formula specified to the “legal heir of the trial subject in case of death and to the trial subject in case of permanent disability”, within 15 days from the date of receipt of the EC’s opinion by the sponsor.

A former head of a CRO in India told the Pink Sheet that in view of the concerns about the “competency” of ECs in deciding on com-pensation for serious adverse events, the clause would have led to conflicts between assessments by an EC and sponsor/investigator.

“This means all SAE [serious adverse event] issues would have ultimately landed in CDSCO’s [India’s Central Drugs Standard Control Organization] office. Also, upfront payment of 60% would have raised the budget of trials especially where potential for SAEs is high e.g. anti-cancer chemotherapy,” the official said.

IQVIA’s Thatte said that the interim compensation clause was not in line with international guidelines and practices and would have acted as a “disincentive” to sponsors in placing trials in India

Thatte said that industry was “relieved” that the regulators had decided to continue with the current guidelines in place for com-pensation calculation and pay-outs.“The system has been work-ing well since it was introduced a few years ago and continuing with it is an important step in reassuring sponsors, both Indian and global, about the stability of our regulatory system and pro-cess,” the IQVIA executive explained.

There are no significant changes in the new rules for safety re-porting processes and timelines and in the process and require-ment for compensation payout. (Also see “India notifies tweaked trial compensation rules “ - Scrip, 30 Dec, 2014.)

Published online March 31, 2019

C L I N I C A L T R I A L S

Scottish Govt Explains Approach To No-Deal Brexit Drug ShortagesIAN SCHOFIELD [email protected]

S cottish government officers have written to health profes-sionals explaining the new measures that are being taken to deal with potential medicines supply interruptions in the

event of a no-deal Brexit, saying that while shortages may occur, the National Health Service “will manage the situation and if nec-essary provide suitable alternatives or other treatment while sup-ply is restored to normal levels.”

In a joint letter to prescribers and pharmacists, Scotland’s chief medical officer, Catherine Calderwood, and chief pharmaceuti-cal officer, Rose Marie Parr, say that while drug shortages are not uncommon in normal circumstances, additional steps have been taken to “prepare for the risk that a no deal exit will lead to more shortages than are normally experienced.”

A no-deal Brexit is still the legal default should the UK parliament fail to approve the withdrawal deal negotiated by the EU with prime minister Theresa May. The deal has now been rejected three times, and although members of parliament have voted overwhelmingly against the UK leaving the EU with no deal, on April 1 they once again failed to endorse any alternative options, raising fears that the prospect of a no-deal exit has become more likely.

Drug shortages are expected to be one of the results of such a scenario, and the government asked pharmaceutical companies some time ago to build up an additional six weeks of medicines stockpiles where possible.

In their letter, which was issued a few days before the latest vote in the Westminster parliament, the Scottish health officials say that stockpiling arrangements are being kept under daily review, and that a list has been drawn up of medicines that are already in short supply and so cannot be stockpiled.

“There are plans in place to actively manage each medicine on

B R E X I T


this list,” the letter states. “The proposed actions vary and include seeking further information from the company, seeking an alterna-tive supplier, using an alternative product, directly purchasing the medicine and classifying it as a shortage that is subsequently man-aged on a case-by-case basis.”

The letter also notes that the Scottish government has established a Medicines Shortage Response Group for Scotland, or MSRG (SCO), mirroring the MSRG set up by the UK government, and that the two will be working closely together to identify, assess and respond to shortages, led by the respective chief pharmaceutical officers.

The MSRG (SCO) is “playing a key role in ensuring the NHS in Scotland is positioned to both influence and act on local, regional and national shortages and communicate any associated actions in a timely fashion to enable policy decisions to be made and to ensure implementation at pace,” the letter says.

In primary care, shortages may be identified by various means, including community pharmacies, general practitioners, prescrib-ing advisors and patients, while in secondary care pharmacists should follow their own health board’s policy for managing short-ages, including a risk assessment to evaluate the potential effects, the Scottish officers say.

For low-impact shortages – for example, when an alternative strength, formulation and/or quantity can be used – community pharmacists should be able to amend prescriptions electronically in line with existing guidance on endorsement, which includes dose, strength and brand distribution, rather than having to re-quest a new prescription from the GP. “Community pharmacists should fully utilise this facility,” the letter states.

Where there are national shortages, the MSRGs will produce recommendations for the NHS, and guidance will be given to pre-scribers and pharmacists on the shortages themselves, what steps should be taken, and what information should be passed to health and social care users.

SERIOUS SHORTAGE PROTOCOLSWhere more serious shortages of medicines are concerned, a UK regulation on time-limited “Serious Shortage Protocols” came into force in February, allowing pharmacists to amend a doctor’s pre-scription and dispense a different strength, formulation or even an alternative medicine, within the scope of the SSP.

Further information on how the SSPs will be “operationalized” will follow in due course, the Scottish officers say, although they stress that “we are in a strong place in Scotland to ensure that these protocols can be underpinned with electronic support using the ePharmacy Programme, which includes electronic communica-tions on any amendments between pharmacies and GP practices.”

The SSP regulation ran into some controversy early this year after it was subject to a legal challenge by the not-for-profit organiza-tion, the Good Law Project, which said the secretary of state for health and social care did not have the power to make the regu-lation, and that the new powers had been “rushed out without proper consultation with patient and clinical groups.”

It said a broader range of patient groups should have been con-sulted, and that the five-day consultation exercise that ran in De-

cember 2018 was “grossly inadequate.” A 12-week period would have been the minimum required, given the significance of the policy change, the number of people it would affect, and the po-tential adverse consequences, it added.

Jolyon Maugham QC, director of the GLP, had called on the gov-ernment to “withdraw the prospect of SSPs” until it had “complied with its legal duties and consulted properly on their use.”

However, in a March 29 ruling, the High Court rejected the ap-plication, saying that the government’s regulation had been “law-

fully made.” The judge noted the health secretary’s contention that the 12-week consultation that would normally have been used was not feasible because of “the need to move speedily so that pro-posed changes were in force before the day that the UK was due to leave the EU” (which at that time was still March 29).

The consultation that took place “was, in my view, fair and ad-equate,” the judge concluded.

GOVT WARNING TO COMPANIESOn a more general level, the UK government has issued a warn-ing to the thousands of companies that it says have still not made sufficient preparations for a no-deal Brexit, urging them to do so immediately or risk not being able to trade with the EU.

HM Revenue and Customs says businesses need to take three steps to ensure they can continue to trade in a no-deal situation. Firstly, they should register for an Economic Operator and Regis-tration Identification (EORI) number, without which they will not be able to trade within the EU. HMRC says that so far only 17% of businesses have done so.

Next they should decide how they want to make customs decla-rations, for example by appointing a customs agent. Finally, where businesses importing goods into the UK from the EU use roll-on, roll-off locations (ferries), they can register for new Transitional Simplified Procedures (TSP) allowing them to import without hav-ing to make a full customs declaration at the border and to post-pone payment of any import duties.

“HMRC has identified 145,000 VAT-registered companies that trade with the EU but not the rest of the world, and estimates that a further 95,000 businesses also trade with the EU but are not VAT-registered,” HMRC says. “This means an estimated 240,000 busi-nesses need to take action to continue trading with the EU if no deal is reached.”


B R E X I T

The government’s regulation on serious shortage protocols was

“lawfully made.”– UK High Court



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