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Pharma intelligenceinforma

SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 19 May 13, 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

REGULATORY UPDATE

Orphan Products: US FDA Working On ‘Sameness’ Policy For Cell And Gene Therapies, p. 15

REGULATORY UPDATE

Real-World Evidence Should Be Flagged In US Drug And Biologic Applications, p. 9

BREXIT

EMA Chief Says Brexit Has Impaired Ability To Support R&D, p. 5

DTC Ad Final Rule Means Reliance On PhRMA Program Risks Enforcement Action – AzarCATHY KELLY [email protected]

P harmaceutical companies risk en-forcement action under the Trump Administration’s final rule on list price

disclosures in direct-to-consumer TV ads if they think it is enough to observe the Phar-maceutical Research and Manufacturers of America’s voluntary disclosure program, ac-cording to HHS Secretary Alex Azar.

The final rule requiring DTC TV ads to dis-close list prices was released by the Centers for Medicare and Medicaid Services 8 May with few changes compared to the pro-posed rule. (Also see “Trump Administration’s Rx-Price-Disclosure Reg Sets Up Legal Fight With PhRMA” - Pink Sheet, 15 Oct, 2018.) The final rule is scheduled to be published 10 May and become effective 60 days later.

PhRMA announced its voluntary program as an apparent alternative to mandatory disclosure on the same day the proposed DTC rule was released.

Under the trade group’s program, which became effective 15 April, TV ads can refer viewers to a company website with infor-mation about drug costs, including cost sharing, as well as manufacturing assistance programs. (Also see “PhRMA’s Defensive Move On DTC Ads: Putting Drug List Prices ‘In Con-text’” - Pink Sheet, 15 Oct, 2018.)

However, “a link to pricing information would not be compliant with this rule,”

Azar maintained in a call with reporters. “I have said before that if they simply do the PhRMA proposal that is not acceptable.”

The final rule provides additional color on the Administration’s position.“It is our view that the absence of a drug’s WAC would make a DTC television advertise-ment potentially misleading because consumers appear to dramatically under-estimate their [out-of-pocket] costs for expensive drugs, but once they learn the WAC they become far better able to ap-proximate their OOP costs,” it says.

As to compliance with the PhRMA prin-

ciples, the rule points out “they are not binding on PhRMA members, let alone non-members, and there is nothing to prevent PhRMA from revising its prin-ciples at any time, a fact which is under-scored by the timing of the issuance of the guideline to coincide with the issu-ance of the proposed rule.”

Moreover, “including directions to where price information can be found will not have the same impact as including the information in the advertisement itself,” CMS argued. “One-third of adults surveyed

“ We believe that relatively few viewers will make use of the approach advocated by the PhRMA proposal, even assuming that members implement” it.

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exclusive online contentCO V E R DTC Ad Final Rule Means Reliance On PhRMA

Program Risks Enforcement Action – Azar

B R E X I T

5 EMA Chief Says Brexit Has Impaired Ability To Support R&D

7 Brexit Halts Work On 119 EMA Guidelines

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

8 EMA Discusses Pivotal Role Of RWE For Six Drugs

9 Real-World Evidence Should Be Flagged In US Drug And Biologic Applications

11 A Guide To US FDA’s Drug-To-Biologic Transition Process

13 UK NICE To Pharma Firms: Up Your Game In Horizon Scanning

15 Orphan Products: US FDA Working On ‘Sameness’ Policy For Cell And Gene Therapies

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

14 Gene Therapy: Industry Seeks Greater Clarity In Final FDA CMC Guidance On INDs

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

18 Recent And Upcoming FDA Advisory Committee Meetings

inside: 13 5 9

France OKs Early Access To Tecentriq For SCLC Pending EU Approvalhttps://pink.pharmaintelligence.informa.com/PS125257

Tecentriq has become the second authorized medicine to be made available for an unapproved indication under modifications to France’s early access program. Patients with small cell lung cancer can now be given the product pending EU approval of its use in this condition.

China Alarms Excipient Suppliers With Proposed Requirement To Share Proprietary Informationhttps://pink.pharmaintelligence.informa.com/PS125260

China’s Food and Drug Administration has proposed a regulation that would require excipient suppliers to disclose information that is above and beyond what is needed to demonstrate safety of pharmaceutical ingredients and that poses considerable IP risk to excipient suppliers, industry official says.

Pregnancy Registries Are Insufficient To Assess Drug Safety, US FDA Sayshttps://pink.pharmaintelligence.informa.com/PS125253

Draft guidance recommends complementary studies to evaluate effects of drug use during pregnancy; FDA may require lactation studies more frequently.

Bronchitol Gets Narrow Approval Vote From Advisory Cmte., Leaving US FDA Host Of Issues To Considerhttps://pink.pharmaintelligence.informa.com/PS125255

Pulmonary-Allergy Drugs Advisory Committee votes 9-7 that the benefits of Pharmaxis’ cystic fibrosis drug outweigh its risks, leaving the FDA with a muddled verdict.

ICER Chief Scientific Officer Bradt Brings Pharma Perspectivehttps://pink.pharmaintelligence.informa.com/PS125188

Pamela Brandt joins health technology assessment group after stints at Aegerion, Astellas and Abbott Labs.

European Cross-Country Pricing Collaborations Gather More Steamhttps://pink.pharmaintelligence.informa.com/PS125239

Iceland has joined the Denmark-Norway pricing alliance while Denmark could soon join the BeNeLuxAI collaboration.

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4 | Pink Sheet | May 13, 2019 © Informa UK Ltd 2019

stated they do not frequently use the inter-net, making the PhRMA proposal relatively meaningless to that cohort.”

For the other two-thirds, the PhRMA pro-posal “would require them to immediately open their browser, navigate to the URL flashed on the television screen, and then click through the find the pricing informa-tion. We believe that relatively few viewers will make use of the approach advocated by the PhRMA proposal, even assuming that members implement” it.

Manufacturers “put $4bn a year into television advertising because the televi-sion ad is where people are getting their information” so “the transparent pricing information should be at the place and location where [manufacturers] are also pitching the patient to go talk to their doctor,” Azar pointed out.

The final rule also states that “given the popularity of TV among potential pur-chasers of a manufacturer’s drugs … we have no basis to conclude that manufac-turers would stop advertising on TV in fa-vor of other media.”

In response to the final rule, PhRMA expressed its ongoing concern that the requirement will prove confusing to pa-tients and “may discourage them from seeking needed care.”

The trade group also announced a new web platform for patients called the Medicine Assistance Tool, which links to the company websites referenced in DTC ads so patients can obtain pricing infor-mation and connect with financial assis-tance programs.

INDUSTRY WOULD ENFORCE THE RULE ITSELF Given industry skepticism about the rule, the HHS decision to have firms themselves enforce it is surprising. The rule continues to rely on manufacturers to self-police competitors and anticipates that compa-nies would bring suits charging deceptive trade practices under the Lanham Act if they find non-compliance.

“There are very large legal practices that have been built on pharma companies suing each other for violations of the de-ceptive trade practices provisions of the

Lanham Act so this will be a quite effective method of enforcement,” Azar said.

However, Rachel Sachs, associate profes-sor of law at Washington University in St. Louis, argued on Twitter that “Lanham Act suits can only be brought by competitors (as the rule notes), and by definition many of these drugs won’t have competitors.”

RULE APPLIES TO DRUGS WITH WACS OVER $35 PER MONTHThe final rule requires that companies dis-close in DTC TV ads the list price or whole-sale acquisition costs for all drugs priced at equal to or greater than $35 for a month’s supply or the usual course of therapy, with prices updated quarterly.

“If you do not have pricing information in your television ad, you are implicitly suggesting that your drug costs less than $35 because the rule requires that you post that information if your drug costs

more than $35 and a competitor would sue you,” Azar said.

Following the price disclosure, ads must include the statement: “If you have health insurance that covers drugs, your cost may be different,” which CMS believe will add appropriate “context” to the pric-ing information. The rule also allows man-

ufacturers to include the list price of com-peting products in their ads as a means for comparison.

The $35 threshold was chosen because it approximates the average patient copay for a preferred brand drug, the rule explains.

However, it is well below the monthly WAC prices for the top 20 drugs in terms of DTC advertising, which range from $189 for Pfizer Inc.’s pneumococcal pneumonia vac-cine Prevnar-13 to $16,938 for Pfizer’s breast cancer treatment, Ibrance (palbociclib), ac-cording to the final rule (see table).

CONTINUED FROM COVER

Heavily Advertised Drugs With Highest List PricesDRUG MONTHLY WAC

Pfizer’s Ibrance (palbociclib) $16,938

Lilly’s Verzenio (abemaciclib) $12,087

AbbVie’s Humira (adalimumab) $5,174

Lilly’s Taltz (ixekizumab) $5,162

Merck’s Keytruda (pembrolizumab) $4,719

Pfizer’s Xeljanz (tofacitinib) $4,481

Celgene’s Otezla (apremilast) $3,398

Novo Nordisk’s Victoza (liraglutide) $922

Lilly’s Trulicity (dulaglutide) $730

Source: CMS final rule.

D R U G P R I C I N G

“ There are very large legal practices that have been built on pharma companies suing each other for violations of the deceptive trade practices provisions of the Lanham Act so this will be a quite effective method of enforcement,” Azar argued.


The only change of substance in the final rule is that it clarifies it super-sedes state requirements. “No state or political subdivision of any state may establish or continue in effect any re-quirement concerning the disclosure in a television advertisement of the pric-ing of a prescription drug or biological product which is different from, or in addition to, any requirement imposed by this subpart,” it says.

WAC AS FIRST AMENDMENT DEFENSE In response to stakeholder arguments that the rule represents a violation of the First Amendment because it compels speech, the final rule argues: “The speech here at issue does not implicate First Amendment interests. Manufacturers already disclose the very same information at issue, their products’ WAC, to purchasers as well as publishers of various pricing data-bases and other compendia.”

It is “well established that the gov-ernment may, consistent with the First Amendment, require the disclosure of factual information in marketing com-mercial products where the disclosure is justified by a government interest and does not unduly burden protect-ed speech.”

Nevertheless, many industry watch-ers anticipate a legal challenge to the final rule based on First Amendment and statutory concerns. (Also see “ DTC Ad Proposal: Biopharma, Advertisers Marshall Legal Arguments In Opposi-tion” - Pink Sheet, 19 Dec, 2018.) And despite arguments by the Administra-tion in support its position, some legal experts feel the rule will not survive a First Amendment challenge. (Also see “Trump Administration’s Rx Drug Price Disclosure Reg Seen As Unworkable” - Pink Sheet, 21 Oct, 2018.)

Published online 8 May 2019

D R U G P R I C I N G B R E X I T

@PharmaPinksheet

EMA Chief Says Brexit Has Impaired Ability To Support R&D IAN SCHOFIELD [email protected]

T he European Medicines Agency’s forced relocation from London to Amsterdam following the Brexit

vote has led to sharp cuts in the agency’s activities, including a “severe” reduction in the development and revision of key guidelines, a slowdown in the proactive release of clinical data, and delays to IT in-frastructure upgrades.

In its annual report for 2018, the agen-cy says that while these cuts have mainly focused on those areas that will not im-mediately impact public health, there could be a longer lasting effect if the necessary resources are not reinvested in these areas in future.

Summing up the impact of this regula-tory slowdown, EMA executive director Guido Rasi, says: “There is no escaping that these cutbacks have hampered, at least in the short term, the ability of this Agency to keep abreast of scientific and regulatory developments and to support research and development of medicines in Europe.”

Reacting to what he described as Rasi’s “worrying” statement, Steve Bates, CEO of the UK BioIndustry Association, said: “This is the key message that we need to land with the Brexit negotiators on both sides of the channel” – that divergence and separate regulatory systems would hit the ability of EU countries and the UK to “foster

medicines development in Europe.”In his introduction to the annual report,

Rasi says that the agency’s phased busi-ness continuity plan (BCP) has allowed it to protect all activities relating directly to the evaluation and supervision of medicines, as well as its core public health activities.

“However, we had to make cuts else-where. And while these cuts have focused mainly on suspending or postponing ac-tivities that will not have an immediate impact on public health, we cannot rule out a longer-term impact on this Agency unless the commitment is made to invest the necessary resources again in future.”

“We cannot rule out a longer-term impact on this Agency unless the commitment is made

to invest the necessary resources again in

future.” – Guido Rasi, EMA executive director




One key area affected is the develop-ment and revision of guidelines, “which we had to severely reduce” by the end of 2018, Rasi says. “Guidelines are one of EMA’s key instruments for increasing the efficiency of medicines development in Europe. If their development or update starts to stut-ter, the whole system may suffer.” All in all, work on a total of 119 guidelines and other guidance documents has had to be put on hold. (Also see “Brexit Halts Work On 119 EMA Guidelines” - Pink Sheet, 8 May, 2019.)

The EMA has also had to suspend its proactive publication of clinical data “just as our landmark policy started to yield the benefits we were expecting from it: enabling reassessment of data, facilitat-ing research collaboration and increasing stakeholders’ trust in the medicine evalu-ation process,” Rasi observed. The agency has said, however, that it plans later this year to look at whether it can revive the policy. (Also see “EMA To Discuss Reactivat-ing Landmark Clinical Trials Transparency Policy” - Pink Sheet, 12 Oct, 2018.)

Another area hit by the cutbacks is the agency’s IT systems, where resources have already been stretched over many years by the implementation of large EU telematics projects, including the clinical trials information system and the Eudra-Vigilance drug safety database.

“Brexit and preparation for our reloca-tion now further delay much needed up-grades to our existing IT infrastructure, which is the backbone of our coopera-tion at the European level,” Rasi declares. Resources normally used for innovative IT projects were channeled towards a num-ber of critical projects, including the relo-cation of the EMA data center outside the UK and the introduction of a new offshore IT application maintenance model.

Also because of resource constraints, work could begin on only one of the six actions contained in the EMA’s action plan to improve product information: the ePI (electronic product information) for medicines across the EU. Work on the other areas, aimed at improving content and user-testing of drug information, will begin “once resources are made available,” the report comments.

“All in all, 2018 was challenging for all of

us,” Rasi says. “We had to prepare our de-parture from the UK, a country that was a gracious host to EMA for twenty-four years and whose experts have made a sig-nificant contribution to the regulation of medicines.”

However, he says that the agency did manage to move forward in some key ar-eas: for example, the priority medicines (PRIME) scheme “started to deliver for pa-tients” with the CAR-T immunotherapies receiving a positive opinion from the EMA’s drug evaluation committee, the CHMP. In addition, the EMA conducted an “extensive review” of cases of sartan contamination, and held its second public hearing, this time on the side-effects of quinolones and fluoroquinolones.

2018 “was also the year which has prov-en the robustness and flexibility of an EU network that concentrated on its ‘raison d’être’ which is to protect and advance public health at any time,” Rasi says.

LOSS OF MHRA, STAFF RETENTIONAnother major worry is that the UK Medi-cines and Healthcare products Regulatory Agency will no longer play an active part in the EU regulatory network after Brexit. The EMA’s deputy executive director, Noel Wa-thion, says the MHRA has been “one of the major contributors to the activities of the network and to the activities of the Agency and the gap they leave will have to be filled. This has never been undertaken before so we needed to find ways to ensure that the loss of expertise can be replaced – both in qualitative and quantitative terms.”

This has involved passing some of the MHRA’s work on to other EU member states, depending on their capacity to absorb it. “We wanted to avoid a scenario where one or two member states take on the full burden,” Wathion says. “Prioritising training is a pivotal factor and our pro-gramme with the EU NTC [Network Train-ing Centre] supports this. That’s why it’s important that member states invest in those resources. We have started well and now we have to see whether this can be sustained over a longer period of time.”

Looking at the question of staff losses due to the relocation to Amsterdam, Wathi-

on, who has led operational and relocation preparedness activities since the referen-dum in June 2016, says that staff retention was always “one of the greatest concerns” but that “so far, this is quite manageable.”

He says that overall staff annual turnover is “still comparable to what we have seen in previous years but the number of resig-nations in that figure is now greater than before. However, the biggest staff losses will be seen in the first half of 2019. We remain optimistic, though, that we will be able to fill any vacancies quickly as recent recruitment efforts have shown that a lot of qualified people are interested in com-ing to Amsterdam and working for EMA.”

According to the report, the need to focus on providing training to ensure the transfer of knowledge to deal with staff losses meant that other courses have had to be suspended, “limiting the agen-cy’s ability to keep its staff at the cutting edge of science.”

BREXIT TALKS STALLED AGAIN?Meanwhile, the Brexit process appears to have stalled again, with talks between the government and the opposition Labour party on a withdrawal deal seemingly hav-ing failed to reach any sort of compromise. The government has now conceded that it is now too late to finalize any deal before 23 May, and that the UK will therefore have to take part in the European elections on that day.

Still, the life sciences industry can at least rest assured that while a no-deal Brexit re-mains the default option if a deal cannot be reached, that prospect is off the table until at least the end of October.

In a update for life science CEOs at the end of April, Bates said: “Last week we re-ceived a letter from the Office of Life Sci-ences which stated that the Cabinet Office has now confirmed that the next date for a possible no-deal Brexit will be the 31 Octo-ber. While this confirms that a no-deal cliff edge Brexit is still a possibility, this clarity from government is welcome and should provide some respite to companies and the wider sector that a no-deal scenario is months, not days or weeks away.”)


B R E X I T


Brexit Halts Work On 119 EMA GuidelinesVIBHA SHARMA [email protected]

T he European Medicines Agency’s capacity to develop and revise sci-entific and regulatory guidelines

has been severely affected by Brexit, with work on 119 guidance documents cur-rently on hold, the agency states in its 2018 annual report.

As of last November, the EMA has had to restrict the development of new and revision of existing guidelines to those that address an urgent public health need or are necessary to support and facilitate preparations for Brexit. The scaling back of activities became necessary for the EMA to be able to cope with the addition-al workload and to ensure that its core activities in the authorization and super-vision of medicines could continue.

However, guidelines play a key role in increasing the efficiency of medicines development, and the EMA’s executive director Guido Rasi is worried that “if their development or update starts to stutter, the whole system may suffer.” A case in point, he explained, is the delay to the update of EMA’s guideline on the devel-opment of novel therapies (ie, gene thera-pies) to treat hemophilia A and B.

“There are exciting new developments based on novel therapies underway. However, we had to temporarily stop the revision of the current guideline to be able to concentrate on Brexit and reloca-tion,” Rasi says in the annual report, which explains in detail the steps taken by the agency to prepare for Brexit and its long-term impacts. (Also see “EMA Chief Says Brexit Has Impaired Ability To Support R&D “ - Pink Sheet, 8 May, 2019.)

Work is also on hold in relation to:

• Development of the good pharma-covigilance practice (GVP) guideline specific to elderly patients. This guide-line is expected to be an important tool to monitor the benefit-risk profile of medicines in the elderly population, which represents a large number of patients but is under-represented in

clinical trials and “exhibits a variability that is best addressed by real-world data collection.”

• Guideline on comparability for ad-vanced therapy medicinal products (ATMPs). This guideline is expected to address a recurrent issue for almost all ATMP developments where manufac-turing changes take place during the product development.

As the development and revision of guidelines is important for the EU to re-main at the cutting edge of scientific re-search, the EMA states in its report that it will resume this work as soon as Brexit-related business continuity arrangements are no longer necessary.

In spite of the scaling back of activities, the EMA updated some key guidance doc-uments in 2018, such as:

• Guidelines on the studies needed to support marketing authorization applications for certain hemophilia medicines. The updated guidelines aim to optimize and facilitate the use of patient registries (rather than small clinical trials) for the investiga-tion of recombinant and human plasma-derived factor VIII and factor IX

hemophilia medicines. (Also see “EMA Reduces Trial Requirements For Hemo-philia Drugs” - Pink Sheet, 3 Dec, 2018.)

• Guideline on clinical studies for Alzheimer’s disease medicines. The revised guidance is expected to “facilitate the investigation and development of medicines for early and even asymptomatic stages of the disease.” (Also see “EMA Addresses Early, Asymptomatic Alzheimer’s In ‘Hugely Important’ Clinical Study Guidance “ - Pink Sheet, 28 Feb, 2018.)

• Guideline on the environmental risk assessment of medicinal products for human use. The revision builds on the experience gained since the original guideline was introduced in 2006. The updated guideline introduces new testing methods, together with an optimization of the tiered testing strategy. It also addresses specific requirements for endocrine active substances. (Also see “EMA Draws On 12 Years’ Experience To Revise Environmen-tal Risk Assessment Guide” - Pink Sheet, 17 Dec, 2018.)


B R E X I T




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

EMA Discusses Pivotal Role Of RWE For Six DrugsVIBHA SHARMA [email protected]

W hile debate continues over the acceptability of real-world evidence for regulatory decision making, espe-cially for demonstrating efficacy, there have been at

least six cases in the recent past where RWE has played a “pivotal” role in decisions by the European Medicines Agency.

The EMA has accepted real-world data “where available evi-dence of efficacy required contextualization” or where uncertain-ties existed around “long-term safety and efficacy,” three senior officials from the EMA wrote in an article in one of the journals of the American Society for Clinical Pharmacology and Therapeutics.

RWE played a critical role in terms of supporting the initial regu-latory decision or postmarketing obligations, according to the au-thors, Alison Cave, Xavier Kurz and Peter Arlett, who work at the agency’s Pharmacovigilance and Epidemiology Department.

The article, published last month, discuses the operational, tech-nical and methodological challenges posed by the heterogeneous nature of real-world data in the EU and offers potential solutions.

It said that the EMA had accepted RWE where either there was a need to enable “safe and early access to promising medicines for patients with limited treatment options” or where “uncertainties around the medicines remained.”

The article noted that agency accepted RWE in relation to:

• Kite Pharma Inc.’s CAR-T therapy Yescarta (axicabtagene ciloleucel).

• Novartis AG’s CAR-T therapy, Kymriah (tisagenlecleucel).

• MolMed SPA’s somatic cell therapy product Zalmoxis.

• Biogen Inc.’s antisense oligonucleotide Spinraza (nusinersen).

• Alexion Pharmaceuticals Inc.’s monoclonal antibody Soliris (eculizumab).

• Orchard Therapeutics Ltd.’s stem cell gene therapy Strimvelis (autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence).

Where available evidence of efficacy required contextualization, the authors explained that RWE:

• Helped provide an external control arm, as was the case for Zalmoxis. Specifically, the European Bone Marrow Transplanta-tion (EBMT) patient registry was used to compile an appropriate control group selected on the same criteria as the control arm of the on-going Phase III trial and a specific set of matching parameters. However, as uncertainties remained (eg, the impact of differences in baseline characteristics), a non-interventional post-authorization safety study was additionally required to determine long-term safety and efficacy. This study was also expected to collect data about disease status and outcome for all treated patients by using the EBMT registry

• Was used to confirm a response rate in a single-arm trial, as was the case for Yescarta and Kymirah. For Yescarta, RWE was used for a retrospective patient-level pooled analysis of two Phase III randomized control trials (RTCs), and two observational studies were developed as a companion study to contextual-ize the results of an open-label, single arm study (ZUMA 1). For Kymirah, efficacy results were compared against three external data sets to contextualize the results of a single arm trial.

• Provided data to extend an indication, as was the case for Soliris, where an RCT was unfeasible. For this, a global paroxys-mal nocturnal hemoglobinuria (PNH) registry was established for a prospective, observational, noninterventional study. The regis-try was established to support Soliris’ authorization to evaluate safety data specific to the use of the drug and to characterize the progression of PNH as well as clinical outcomes, and morbidities and mortality in Soliris and non-Soliris treated patients.

In cases where efficacy was well-established, but uncertainties existed around long-term safety and efficacy, RWE was used for post-authorization evidence generation coupled with adequate pharmacovigilance activities to quickly address uncertainties, as was the case for Strimvelis and Spinraza.

The article’s authors acknowledged that there is a lower accept-ability of RWD where the outcome of interest is efficacy/effective-ness. “Great caution is generally exercised where positive regula-tory decisions result in patients being exposed to a new medical product, and hence an estimate of efficacy free from the biases of observational data is required,” they add.

While the authors believe that RCTs will remain the best avail-able standard and will be required in many circumstances, they expect that that the acceptance of RWE is likely to increase with advancements in personalized medicine.

The article further discuses the challenges posed in using RWD from a European perspective. A recent analysis, the authors said, revealed that the number of European databases that meet mini-mum regulatory requirements across a broad range of regulatory use cases and which are readily accessible is “disappointingly low and geographically skewed to Western and Northern Europe.”

This, they said, poses problems when results from multiple da-tasets must be pooled to deliver evidence representative of the wider European population or when larger numbers are needed to explore rare diseases, events, or outcome. While issues with using RWD are well-recognized, the EMA experts believe that “compli-ance with the best methodological standards, a detailed descrip-tion of study design and data collected, and full transparency on the protocol and study report (with registration in a publicly avail-able database) would do much to build confidence in results and avoid the confusion created by disparate results.”





Real-World Evidence Should Be Flagged In US Drug And Biologic ApplicationsSUE SUTTER [email protected]

N ew drug or biologic application sponsors should specify the pur-pose of any real-world evidence

submitted with their filing, as well as the real-word data sources used to generate that evidence, the US Food and Drug Ad-ministration said in a draft guidance docu-ment released 8 May.

The agency’s drugs and biologics cen-ters will use this information to track cer-tain types of real-world evidence (RWE) submissions under an investigational new drug application, new drug application, or biologics license application.

The draft guidance, “Submitting Docu-ments Using Real-World Data and Real-World Evidence To FDA for Drugs and Bio-logics,” offers practical advice to sponsors on how to identify inclusion of RWE as an element of an IND, NDA, or BLA for agency-tracking purposes.

However, the document does not ad-dress industry questions on how best to interact with the agency on the develop-ment and suitability of RWE to support regulatory decisions.

BUILDING AN RWE PROGRAMThe draft guidance is another stepping stone in the agency’s development of

a RWE program under the 21st Century Cures Act. The statute directed the FDA to explore how RWE can be used to support approval of new indications for existing drugs and to satisfy postapproval study requirements.

Draft guidance on the use of RWE for regulatory decision-making is due by De-cember 2021 under the Cures Act. That document will be informed, in part, by agency-sponsored demonstration proj-ects and pilot programs required under the FDA Reauthorization Act of 2017.

In December, the agency released a framework that described the scope of the RWE program under Cures and listed guid-ance documents the agency expects to is-sue, or is considering, going forward. (Also see “Real-World Evidence: US FDA Frame-work Emphasizes Data Fitness And Study Quality” - Pink Sheet, 9 Dec, 2018.)

Although the new draft guidance on RWE submissions was not listed in the framework’s mention of upcoming guid-ance documents, it was included in the Center for Drug Evaluation and Research’s 2019 guidance agenda released in March. (Also see “Clinical Trial Reform Is A Focus For CDER’s 2019 Guidance Agenda” - Pink Sheet, 14 Mar, 2019.)

“Today’s draft guidance is a part of an expanding body at work at FDA focused on broadening clinical evidence genera-tion so that study results are maximally applicable to real-world populations,” FDA Principal Deputy Commissioner Amy Ab-ernethy said in a statement accompanying the document’s release.

WHAT THE AGENCY WANTS TO KNOW …Sponsors should identify a submission as containing RWE in the cover letter that ac-companies the filing, by either highlight-ing this information in the letter or includ-ing it as a table. The guidance includes a sample table for use with cover letters (see graphic, p. 10).

This approach will allow CDER and the Center for Biologics Evaluation and Re-search to identify and track RWE submis-sions, monitor outcomes, and ensure ap-propriate relevant review expertise. It also will help inform the RWE program under Cures and help the FDA to understand the scope and use of RWE to support regula-tory decisions on product effectiveness and safety, the guidance states.

The agency’s plans to track RWE sub-missions suggests a far more systematic

The guidance applies to RWD/

RWE submissions that are

tied to a specific product and

being used to support a

regulatory decision on safety

or effectiveness.





approach than seen to date for evaluat-ing the utility of such evidence in making product approval decisions, particularly for effectiveness. (Also see “A Baker’s Dozen Of US FDA Efficacy Approvals Using Real World Evidence” - Pink Sheet, 7 Aug, 2018.)

Examples of submissions using RWD and/or RWE that are subject to the guid-ance include new protocols submitted to an existing IND, a final study report sub-mitted to an NDA or BLA supplement, or a meeting package that discusses the use of RWE.

Relevant submissions may include RWE to support the following types of

study objectives:

• IND submission for randomized clinical trials that use RWE to capture clinical outcomes or safety data, including pragmatic and large simple trials;

• New protocols for single-arm trials that use RWE as an external control;

• Observational studies that generate RWE intended to help support an ef-ficacy supplement; and

• Clinical trials or observational studies using RWE to fulfill a postmarketing requirement to further evaluate safety

or effectiveness and support a regula-tory decision.

Sponsors should list the purpose for using RWE, such as to support effective-ness or safety for a new product, labeling changes for an approved product, or as a postmarketing requirement.

The clinical study design – such as a randomized trial, single-arm trial or ob-servational study – that includes RWE as part of a submission also should be listed. In addition, the FDA requests the sponsor list all RWD sources used to generate the evidence. These might include electronic health records, medical or claims billing data, disease registry data and data col-lected via mobile technologies.

… AND WHAT’S NOT COVEREDRWD/RWE submissions that are not tied to a specific product or are not being used to support a regulatory decision on safety or effectiveness will not be tracked and are not subject to the guidance’s provisions.

Examples of submissions that sponsors need not identify as containing RWE include:

• Natural history studies for development of a clinical outcome assessment or biomarker;

• Feasibility studies using RWE; and

• Studies using RWD to perform explor-atory analyses and generate hypotheses.

“FDA encourages sponsors and appli-cants to consult the appropriate review division with questions about whether a specific submission should be identified as containing RWE,” the document states.

INDUSTRY SEEKS CLARITY ON MEETING MECHANISMWhile the draft guidance mentions interac-tions with the agency on RWE submissions, it does not go into detail about the appro-priate mechanism or timing for such inter-actions even though the biopharma indus-try has been pressing the FDA for clarity on these points.

In comments on the RWE framework, the Pharmaceutical Research and Manu-facturers of America asked the agency to provide sponsors “with a framework for regulatory interactions to discuss RWE

Sample Template For Real-World Evidence Submissions

Source: FDA draft guidance, “Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics”

Purpose(s) of Using RWE as Part of the Submission (Select all that apply)

To provide evidence in support of effectiveness or safety for a new product approval

To provide evidence in of support labeling changes for an approved drug, including:

Add or modify an indication

Change in dose, dose regimen, or route of administration

Use in a new population

Add comparative effectiveness information

Add safety information

Other labeling change Specify:

To be used as part of a postmarketing requirement to support a regulatory decision

Study Design(s) Using RWE (Select all that apply)

Randomized clinical trial

Single arm trial

Observational study

Other study design Specify:

RWD Source(s) Used To Generate RWE (Select all that apply)

Data derived from electronic health records

Medical claims and/or billing data

Product and/or disease registry data

Other data source that can inform on health status Specify:



study design and analytical methodology throughout the study development and review process.”

“The guidance should include best prac-tices for engagement with FDA, and com-munication should be encouraged with the appropriate review staff or other personnel

as RWE studies progress,” PhRMA said. The Biotechnology Innovation Organi-

zation’s comments on the framework simi-larly urged the FDA to address “practical is-sues” concerning RWE-specific interactions and submissions in future guidance. These issues include how the existing meeting

structure applies to RWE, frequency and timing of communications/meetings dur-ing RWE study planning and execution, what documentation should be submitted and when, BIO said.


A Guide To US FDA’s Drug-To-Biologic Transition ProcessSUE SUTTER [email protected]

T he complex process by which doz-ens of protein products will shift from regulation as drugs to biologics

in March 2020 may face renewed scrutiny at an upcoming US Food and Drug Admin-istration hearing on biosimilar and inter-changeable insulins.

Under the Biologics Price Competition and Innovation Act “transition provisions,” insulin, human growth hormone and certain other types of protein products historically regu-lated as drugs under the Food, Drug and Cos-metic Act will be “deemed” biologics under the Public Health Service Act on 23 March 2020.

The FDA has explained its interpretation of the transition provisions, and the process for shifting products from approved new drug applications to deemed biologics license ap-plications, in a final guidance and draft Q&A guidance, both issued in December. (Also see “When Drugs Become Biologics: US FDA Guid-ances Explain ‘Transition Provisions’” - Pink Sheet, 11 Dec, 2018.)

Since the FDA has interpreted the deeming process to apply only to approved NDAs, af-ter 23 March the agency will not approve any application submitted under Section 505 of the FD&C Act for a biological product subject to the transition provisions that is pending or tentatively approved. Such applications will receive a complete response letter and would need to be resubmitted as either standalone 351(a) BLAs or biosimilar/interchangeable ap-plications under 351(k).

Application of the transition provisions is further complicated by the fact that 23 March 2020 falls on a Monday, with FDA setting a Fri-day, 20 March deadline for approval for certain types of NDAs.

Application of the transition provisions is fur-ther complicated by the fact that 23 March falls on a Monday.

Although approved applications subject to transition will be deemed biologics as of 12:00 a.m. EDT that day, the FDA has set a deadline of 11:59 p.m. Friday, 20 March for approval of pending 505(b)(2) applications that rely to any extent on the agency’s safety and effectiveness findings for a transition product.

A 351(k) application that relies on a deemed BLA for its reference product may be submitted only after the latter has transitioned.

This delay in being able to submit applica-tions for biosimilar or interchangeable insulins could be the focus of criticism at the 13 May hearing the FDA is holding to gather input on scientific standards for evaluating applications for biosimilar and interchangeable insulins.

Registered speakers include representa-tives from biosimilar developers Mylan Inc. and Biocon Ltd., as well as the Association for Accessible Medicines. Diabetes patient and health care professional groups also are scheduled to testify.

In addition, Eli Lilly & Co. will make a presen-tation at the hearing. The company recently launched an authorized generic of its own Humalog (insulin lispro) and may be interested in pursuing an interchangeability designation for Basaglar (insulin glargine), its follow-on version to Sanofi’s Lantus that was approved under the 505(b)(2) pathway. (Also see “Insulin Maker Lilly Seeks US FDA Assurances On ‘Autho-rized Biologics’” - Pink Sheet, 20 Feb, 2019.)

On p. 12 is the Pink Sheet’s step-by-step guide to the transition process.


Application of the transition

provisions is further complicated by the fact that 23 March

2020 falls on a Monday, with FDA setting a Friday, 20 March deadline for approval for certain

types of NDAs.





Is there an approved NDA under 505(b)(1) or 505(b)(2) for a product subject to transition?

FDA will send a letter on March 23, 2020 stating the approved NDA was deemed a

351(a) BLA as of 12:00 a.m. EDT

FDA will assign the same application number used for the approved NDA to the deemed BLA; agency will remove

the product from the Orange Book, and any unexpired 5-year or 3-year exclu-

sivity will cease to have effect

Sponsor will receive a complete response letter; for applications

withdrawn and submitted as 351(a) or 351(k) BLAs after the

transition date, FDA will consider any previously

conducted scientific review

Is there is a pending supplement to the approved NDA?

FDA will administratively convert the supplement to a pending supplement to

the deemed BLA; converted supple-ments will be reviewed under BLA

standards, and FDA intends to maintain the same goal date, where applicable.

YES NO

YES NO

The NDA will be deemed a BLA immediately after approval

Is there an original 50(b)(1) or 505(b)(2) application that does not rely to any extent on FDA's safety/effectiveness findings

for a transition product, pending as of 11:59 p.m. EDT

on March 23, 2020?

No further action

No further action

YES NO

Sponsor will receive a complete response letter; for applications withdrawn and submitted as 351(a) or

351(k) BLAs after the transition date, FDA will consider any previously conducted scientific review

YES NO

YES NO

Is there an original 505(b)(2) applica-tion that relies, at least in part, on the

safety/effectiveness findings for a transition product, pending as of 11:59

p.m. EDT on March 20, 2020?

Is there an original 505(b)(1) or 505(b)(2) application that does not rely to any extent on FDA's safety/effectiveness findings

for a transition product, approved on March 23, 2020?

How A Drug Turns Into A Biologic



UK NICE To Pharma Firms: Up Your Game In Horizon ScanningIAN SCHOFIELD [email protected]

A senior official at the UK’s National Institute for Health and Care Excellence has called on the pharmaceutical industry to play a greater role in topic selection and horizon scan-

ning so that NICE can meet its objective of producing timely health technology assessments of new medicines.

Meindert Boysen, director of NICE’s Centre for Health Technolo-gy, also said because of time and resource constraints the institute cannot immediately look at every single medicine that emerges from company pipelines, neither can it negotiate complex man-aged access deals for all new drugs.

“NICE is well known and highly respected for its willingness and ability to respond to policy demands. But it takes time, bear with us, we can’t just turn the dial and look at all new medicines tomor-row. It is not possible, we have to take the time to get used to do-ing things differently,” Boysen told last month’s Westminster Health Forum workshop on medicines pricing and access in London.

While health technology appraisals are a very high-profile compo-nent of NICE’s work, there is “so much else in the National Health Ser-vice that is also relevant for us,” he said, noting that the institute has to “balance the health policy agenda with the industrial policy agenda.”

HORIZON SCANNING AND TOPIC SELECTIONBoysen told the audience of mainly industry representatives that the institute was “very aware of its responsibility” to deliver on im-proving patient access to medicines but that industry also had to play its role, particularly in the area of horizon scanning – which is underpinned by the government’s PharmaScan database of pipe-line drugs – and topic selection.

“It is really surprising that 40% of pharmaceutical topics we look at have no entry in Pharmascan. Why are people not participating in topic selection or the horizon scanning program? That could de-liver all the things we are criticized for not delivering in terms of timeliness and rapid assessment. It needs you to tell us where you are with your technology. We can’t know what we don’t know.”

He conceded that PharmaScan was “perhaps a bit old fashioned, and not really the fancy digital solution you might expect from a horizon scanning offer, and we do need to work on changing that.”

He said it was “really encouraging” that the UK’s new voluntary pricing and access scheme “put so much emphasis on horizon scanning and topic selection,” but stressed that it would only work if industry was fully engaged in these processes at an early stage. “It is right to talk about horizon scanning and topic selection and early engagement because that is where it has to happen. It can’t hap-pen at our committee – if we haven’t got it sorted before it gets to

the committee, it is too late.” The voluntary scheme superseded the Pharmaceutical Price Regulation Scheme at the beginning of this year. (Also see “ABPI Exec Lauds Innovation And Access Provisions In New UK Voluntary Scheme” - Pink Sheet, 29 Apr, 2019.)

MANAGED ACCESS DEALSTurning to NICE’s capacity for negotiating access agreements for new medicines, Boysen said that NICE was “bringing stakehold-ers together around really difficult decisions” including brokering commercial and managed access solutions. “But we can’t do it for every single company, it is impossible, we can’t have 95 managed access solutions. It can’t be done.”

Therefore, he said, the “80/20” rule still applied, whereby 80% of topics that come before NICE should go through “a standardized, simple, transparent and predictable set of rules and regulations, so you know what you are getting into, you iron out all of the difficul-ties and you get through.”

He said there was no doubt that 20% of products would con-tinue to require “specific handling.” He cited one case where “it has taken almost more than half of my time to liaise with one company” in the area of cystic fibrosis – a reference to NICE’s protracted dis-cussions with Vertex over its drug Orkambi (ivacaftor/lumacaftor). (Also see “NHS England, NICE & Vertex Have ‘Forgotten Patients’ In Orkambi Impasse” - Pink Sheet, 12 Mar, 2019.) In an evident burst of frustration, he said: “I understand you all have to gain something from NICE… but maybe spend less time arguing about the ins and outs of NICE methods and do a deal.”

METHODS REVIEWNICE is in fact in the midst of a review of the methods it uses, focus-ing on the criteria used in its highly specialized technologies (HST) appraisal program, which is reserved for “ultra-orphan” drugs for treating diseases with a prevalence of around one in 100,000 people.

NICE chief executive sir Andrew Dillon told a cross-party parliamen-tary group last month that the institute needed to find the capacity to look at more treatments for orphan and ultra-orphan diseases, while





Boysen said that NICE’s review working party would look at specific topics for review and invite contributions from pharmaceutical com-panies. (Also see “UK NICE Review Will Look At Criteria For Appraising Highly Specialized Products” - Pink Sheet, 8 Apr, 2019.)

At the London workshop, Boysen said the reason the methods review working party was set up was that “we can’t do this alone.” He said it was “not just about medicines and technologies, it is about statements of principle and value. Whatever we do in the methods review in technology evaluation will have an impact on the wider works of NICE.”

The institute, he said, would “of course have to think about the really new stuff – site agnostic tumors, advanced therapy medi-cines, antimicrobials,” although other products might come under the scope of the review. He noted, for example, that NICE had nev-er looked at HIV infection, hemophilia, immunization or vaccina-tion. “I’m not saying we will be doing that, but if we were asked by the department [of health and social care] to look at those things, we will have to think whether our methods apply.”

NICE CONNECTIn response to a question about the often “static” nature of NICE appraisals – they are done at a specific point in time and may not take account of what is coming through the pipeline – Boysen said that this issue was being broached through a new long-term project called “NICE Connect.”

The aim of the project is to take a more holistic approach to NICE’s work, ensuring that its recommendations are up to date and based on the best available evidence, publishing information on the sequencing of new drugs and technologies, integrating recommendations into IT systems, and making access to NICE ad-vice quicker and easier.

NICE Connect will “help us present all the work we do in a way that better informs decision-making,” Boysen said, conceding that NICE appraisals were static by nature: “At market entry we take a snapshot of the value of a technology.” He did say, though, that NICE was “much better” than some other countries in terms of translating “small bits of evidence into massive statements about value. We do it, but at a point in time. We make a decision, but what the dynamics subsequently are, what is the sequence in which you use that drug, what are the combinations in which you would use it, this is something the Connect project might be able to resolve.”

Asked by an industry delegate whether there was a danger that the centralization of technology appraisals ran the risk of stifling some of “the really great innovations,” Boysen said: “I get the ‘sti-fling innovation’ argument – that if everything goes through NICE, the ‘NICE blight’ might become quite significant so that no one will do anything unless we have said something.”

But he pointed out that the NHS “can do whatever it likes”, and “can pay for drugs even if we have said no. The only thing we do is answer a relatively simple question: is this value for money at market entry? We are not pretending to say much more than that, so I hope we are not stifling innovation.”


GENE THERAPY:

Industry Seeks Greater Clarity In Final FDA CMC Guidance On INDs JOANNE S. EGLOVITCH [email protected]

B iopharmaceutical groups say they want greater clarity from the US Food and Drug Administration on the scope of recent draft guidance on chemistry, manufacturing and

controls information for gene therapy investigational new drug applications. Industry said that the level of CMC information out-lined in the draft is very close to the level required for a biologics license application rather than an IND.

They complain that the 54-page draft document tries to do too much, in the process commingling advice on various devel-opment stages, supply chain stages and gene therapy types.

The draft guidance covers human gene therapy products as well as combination products that contain a human gene ther-apy in combination with a drug or device. When finalized, the guidance will replace an April 2008 version. (Also see “FDA’s CMC Guidance For Investigational Gene Therapies Reflects Broader CMC Evolution” - Pink Sheet, 11 Jul, 2018.)

According to the agency’s regulatory agenda, FDA plans to is-sue a final version of the guidance this year.

CTD VERSUS GMP Many of the industry respondents expressed confusion about the scope of the draft guidance document.

For example, the Parenteral Drug Association raised concerns about the way the draft document intermingles guidance on con-forming IND submissions to the electronic Common Technical Doc-ument format with guidance on good manufacturing practices.

“The scope of this document is unclear as it varies between describing the content and format of the material presented for INDs and a discussion of relevant GMP requirements,” PDA said. The association went on to propose that “this document be clarified against the intended scope. We recommend reor-ganizing the information or creating two separate documents to address the two topics. In its current form, the document is confusing and potentially in conflict with other guidance re-garding GMPs for gene therapies and does not provide the ap-propriate focus on the respective topics.”

PDA said that more clarity is also needed to differentiate wheth-er the guidance applies to the drug substance or the drug product.

EX VIVO VERSUS IN VIVOThe two leading trade organizations for research-based biophar-maceuticals said that many of the recommendations in the guid-

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



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

ance may be more applicable to ex vivo gene therapy products than in vivo products.

The Pharmaceutical Research and Manufacturers of America (PhRMA) “encourages FDA to clarify the scope of each recom-mendations throughout the draft guidance … the scope covers gene therapy products, generally. However, many recommenda-tions within the draft guidance may not be broadly applicable to all gene therapy products. Some of the recommendations may be more suitable for ex vivo gene therapy products as opposed to in vivo products.” PhRMA pointed to recommendations on shipping and handling as an example.

The Biotechnology Industry Association (BIO) concurred. The group “finds that the scope of the document is not clear. … Some recommendations, such as those regarding shipping and han-dling, are specific to ex vivo gene therapy and are not appropriate for in vivo gene therapy products.”

IND VERSUS BLA PhRMA also complained that some of the information covered in the draft guidance is unrelated to information to be submitted in the IND.

“Some recommendations in this draft guidance are applica-ble to the initial IND submission, while others may be applicable to different phases of development after the initial IND submis-sions and some are applicable as information to be included at the time of BLA submissions which may have been collected

during the IND stage.” PhRMA suggested that the agency may want to consider issu-

ing phase-specific draft guidance.Gene therapy company bluebird bio Inc. concurred. The com-

pany said that “the level of CMC information required by the draft guidance appears to be close to the level of information that would be required for a BLA rather than for an initial IND application. We recommend FDA clarify what level of CMC information is sufficient relative to product safety, identity, quality and purity and strength (including potency) to enable an IND application to support prod-uct development at each key stage of development.”

BIO also suggested tailoring guidance to stage of manufacture as “the draft guidance recommendations are unclear for which stage of development they would apply to.”

MORE INFORMATION ON MANUFACTURING CHANGES SOUGHT Lonza Group Ltd. said that the guidance lacked information on manufacturing changes.

The firm states that “in several locations throughout the docu-ment, references are made to manufacturing changes. However, no descriptions or examples are provided to guide the designation or of major vs. minor changes.”


ORPHAN PRODUCTS: US FDA Working On ‘Sameness’ Policy For Cell And Gene TherapiesSUE SUTTER [email protected]

T he biotechnology industry wants the US Food and Drug Administration to clarify how it will apply the concept of “sameness” for orphan product exclusivity purposes to cell

and gene therapies.The FDA’s response: We’re working on it.“More to come,” Center for Biologics Evaluation and Research Di-

rector Peter Marks recently told Pink Sheet when asked about the agency’s approach to determining the impact of orphan exclusiv-ity for cell and gene therapies. “We understand the need for clarity on orphan sameness.”

In private conversations and public forums, industry attorneys and company representatives are increasingly raising concerns that the agency’s interpretation of sameness in the context of cell and gene therapies could block new products from coming to market.

On the other side of the coin, however, are worries that exist-ing incentives to develop cell and gene therapies for rare diseases could be undermined if orphan exclusivity is hard to come by for those products that actually make it to market.

R E G U L AT O R Y P O L I C Y

“ We understand the need for clarity on orphan sameness.” – Peter Marks




EXCLUSIVITY BLOCKS SAME PRODUCT FOR SAME INDICATIONIn the US, approval for an orphan-designated indication comes with seven years of marketing exclusivity specific to that drug and use. During that period, the agency cannot approve the same drug for the same disease except under very limited circumstances, such as when the subsequent product is “clinically superior” to the previously approved drug.

How the FDA intends to apply this concept of sameness to cell and gene therapies remains a bit of an unknown. However, it is an important question hanging over the biotechnology industry be-cause companies that are developing such treatments (and their investors) seek assurance either that their path to market will not be blocked by a competitor who got there first, or that they will be able to enjoy an exclusive period of sales without fear of near-term competition.

“There are tremendous incentives to develop drugs for small populations, and by drugs I mean cell therapies, biologics,” David Fox, a partner in the Washington, DC office of Hogan Lovells, said during a recent webinar sponsored by the firm. “But that whole system is premised on the idea that one company’s product blocks another company’s product if those products are considered to be the same. And lining up naturally derived, cell-based products as the same is exceedingly difficult.”

FDA clarity would be beneficial “to make sure that innovation isn’t blocked” by regulations that were intended to incentivize and reward innovation. – Spark’s Paul Savidge

When it comes to the “entirely novel area” of gene therapies, FDA clarity would be beneficial “to make sure that innovation isn’t blocked” by regulations that were intended to incentivize and re-ward innovation, said Paul Savidge, US general counsel of Spark Therapeutics Inc., which makes the retinal gene therapy Luxturna (voretigene neparvovec-rzyl).

Depending on how the FDA applies its orphan drug regulations, it could “actually shut down innovation in gene therapies by using older standards of how to interpret sameness,” Savidge said at the Food and Drug Law Institute’s recent annual meeting.

By their nature, gene therapies for a specific disease are always

going to have something in common, such as the gene that they are replacing or trying to modify or the delivery system, Savidge said. “We’re looking forward to working with the FDA to come to an understanding of the application of these provisions so that we can bring novel important gene therapies that, in fact, may dem-onstrate differences that are important to the public health.”

Industry is not alone in seeking a better understanding of where the FDA stands on the issue. The National Organization for Rare Disorders said additional regulatory clarity on the issue of same-ness for gene therapies is critical.

“FDA’s policy will ideally strike a balance between ensuring that incentives to make meaningful innovation in this space are strong and promoting competition at the appropriate time. That’s a win-win for patients,” said Rachel Sher, vice president of policy and reg-ulatory affairs at the patient advocacy organization.

FIVE-YEAR OLD MONOCLONAL ANTIBODY GUIDANCEIn the absence of an explicit FDA policy, industry is trying to glean the regulator’s current thinking from existing guidance documents.

Hogan Lovells’ Fox pointed to an April 2014 guidance on inter-preting sameness of monoclonal antibodies under the orphan drug regulations. “We pore over that document almost every day for clues as to how you would project that analysis onto other types of products,” he said.

The mab guidance explains that antibodies have two functional regions: the variable region, which is responsible for antigen-spe-cific binding; and the constant region, which carries out effector functions. The variable region is divided into complementarity-determining regions (CDRs) and framework regions.

For purposes of determining sameness of unmodified mabs under the Orphan Drug Act and its implementing regulations, the agency consider the CDRs of the heavy and light chain variable re-gions to be the principal molecular structural features.

Two unmodified mab products are considered to be the same if the CDRs’ amino acid sequences are the same or if there are only minor differences between them, the guidance states. “Other po-tentially important amino acid differences outside the CDRs, or dif-ferences due to glycosylation patterns or posttranslational modifi-cations, would not necessarily cause the products to be considered to be different.”

For mab conjugates or fusion proteins, the FDA’s sameness de-termination is based on the mab element and the functional ele-ment of the conjugated molecule, according to the guidance.

“A difference in any one of these elements can result in a deter-mination that the molecules are different,” the guidance states. “Conversely, two monoclonal antibody conjugates or fusion pro-teins would be determined to be the same drug if both the CDR sequences of the antibody and the functional element of the con-jugated molecule were the same.”

“Basically, that guidance says that differences in the variable re-gion would make the monoclonal antibodies different, differences in the constant region would keep them the same,” Fox said. “We’re trying to apply that logic to cell and gene therapies where the


FDA clarity would be beneficial “to make sure that innovation

isn’t blocked” by regulations that were intended to incentivize and

reward innovation. – Spark’s Paul Savidge


question [is] whether differences in the viral vector will render the product different.”

LOOK TO KYMRIAH, YESCARTA CASE STUDIESIndustry also has looked to public remarks by FDA officials for hints as to how the agency might view sameness when there are differ-ences between two therapies in either the transgene or the vector.

At the FDLI meeting, Julie Tierney, CBER’s senior policy advisor for strategic planning and legislation, discussed the agency’s ap-proach to the approval of the first two chimeric antigen receptor T-cell therapies, Novartis AG’s Kymriah (tisagenlecleucel) and Kite Pharma Inc.’s Yescarta (axicabtagene ciloleucel), as indicative of where the agency is headed.

Both products, which the agency classifies as cell-based gene therapies, are CD19-directed genetically modified autologous T-cell immunotherapies.

Kymriah came to the market in August 2017 for patients with refractory/relapsed B-cell precursor acute lymphoblastic leu-kemia. In October 2017, Yescarta won approval for relapsed/refractory large B-cell lymphoma. In May 2018, the agency ex-panded Kymriah’s approval to include relapsed/refractory large B-cell lymphoma. All of the Kymriah and Yescarta indications approved to date carry orphan exclusivity.

“In mid-2018, CBER did make some decisions regarding the scope of orphan exclusivity for CAR-T products, and in doing so we [had] to take a look at our regulations and think about how they apply to these novel products,” Tierney said.

CBER worked closely with the orphan products and chief counsel’s offices in looking at whether Kymriah and Yescarta “were the same product, because there was a supplement for Kymriah for relapsed or refractory diffuse large B-cell lympho-ma, and Yescarta had been approved the year before for that same indication,” she said.

“Part of the exclusivity is not just the decision that you make to give it going forward upon approval, but also who it blocks,” Tier-ney said. “We took a look at the principal molecular structural fea-tures of the two products, which is the standard in our regulation, really focused on the vectors and the CAR proteins of those two products, and determined that they were not the same product for the purposes of exclusivity,” which allowed the FDA to approve Kymriah for B-cell lymphoma.

Although the CAR-T products are ex vivo gene therapies and not directly administered, “I think that can sort of shed some light in the direction the agency is headed,” Tierney said.

She acknowledged that there are a lot of questions on the issue of sameness and the agency is working to develop a policy. “We need to be able to provide more insight to folks moving forward in that space. And there’s a lot of interest there.”

ARE US, EU HEADED IN DIFFERENT DIRECTIONS?CBER’s Marks said the agency is working to issue its regulatory stance in writing soon, but he noted the FDA and European Medi-cines Agency may be going in different directions on the issue.

Nevertheless, the FDA hopes to reach harmonization on this is-sue and expects it will be a topic of conversation at an upcoming meeting of global drug regulators, Marks said.

In June 2018, the European Commission issued an updated definition of “similar medicinal product” within the context of the EU orphan drugs legislation that takes into account the emerging category of advanced therapy medicinal products (ATMPs), which includes cell and gene therapies. (Also see “EU Updates Definition Of ‘Similarity’ For Orphans In View Of Advances In Gene And Cell Therapies” - Pink Sheet, 1 Jun, 2018.)

For ATMPs, similarity between two active substances is assessed on the basis of the biological and functional characteristics, the EU regulation states.

For gene therapies, two products shall not be considered similar “when there are differences in the therapeutic sequence, viral vec-tor, transfer system, regulatory sequences or manufacturing tech-nology that significantly affect the biological characteristics and/or biological activity relevant for the intended therapeutic effect and/or safety attributes of the product.”

Differences in the therapeutic sequence that do not significantly impact the intended therapeutic effect are not enough to support the claim that two gene therapy products are non-similar, the reg-ulation states.


Michael Cipriano contributed to this story.


“We took a look at the principal molecular structural features of the two products, which is the standard in our regulation, really focused on the vectors and the CAR proteins of those two products, and determined that they were not the same product

for the purposes of exclusivity.” – CBER’s Julie Tierney

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Pink SheetLEADERSHIPPhil Jarvis, Mike Ward, Karen Coleman

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ADVERTISINGChristopher Keeling

DESIGNJean Marie Smith

Recent And Upcoming FDA Advisory Committee Meetings TOPICS ADVISORY COMMITTEE DATE

Chiesi USA’s mannitol inhalation powder for management of cystic fibrosis to improve pulmonary function in patients ages 18 years and older in conjunction with standard therapies Pulmonary-Allergy Drugs May 8

Daiichi Sankyo’s pexidartinib for adults with symptomatic tenosynovial giant cell tumor Oncologic Drugs May 14

Daiichi Sankyo’s quizartinib for adults with relapsed/refractory acute myeloid leukemia, which is FLT3-ITD positive as detected by an FDA-approved test Oncologic Drugs May 14

Global Alliance for TB Drug Development’s pretomanid as part of a combination regimen with bedaquiline and linezolid in adults for treatment of pulmonary extensively drug resistant and treatment-intolerant or non-responsive multidrug-resistant tuberculosis

Antimicrobial Drugs June 6

Clinical utility and safety concerns with the higher range of opioid analgesic dosing (higher strength products and higher daily doses) in the outpatient setting

Drug Safety and Risk Management/Anesthetic and Analgesic Drug Products

June 11-12

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

Oncologic Drugs Pediatric Subcommittee June 20

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

Oncologic Drugs Pediatric Subcommittee June 20

A D V I S O R Y C O M M I T T E E S

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