QIDP: What have we GAINed - Pharma Intelligence | Informa/media/informa...of methicillin-resistant...

QIDP: What have we GAINed

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2 / July 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)

The UK’s Review on Antimicrobial Resistance estimated that global antibiotic resistance is responsible for over 700,000 deaths each year1. If left unchecked, this could rise to over 10 million deaths per year by 2050. As well as the enormous human cost, it is predicted that this level of mortality would result in a reduction of 2–3.5% in gross domestic product, costing the world up to $100tn1.

In order to counter the threat of antibiotic resistance, the GAIN Act was signed into law as part of the US Food and Drug Administration (FDA) Safety and Innovation Act. The Act provides incentives and additional guidance to pharmaceutical companies developing new antibiotic products, and new antibiotics qualifying for the incentives are granted “Qualified Infectious Disease Product” (QIDP) status. Incentives for QIDP status include an additional five years of exclusivity, on top of any other exclusivity periods, as well as fast track and priority review status. QIDP status is defined as an antibacterial

or antifungal drug intended to treat serious or life-threatening infections. Under the Act, the FDA is required to compile a list of qualifying pathogens and provide guidance on developing new antibiotic products.

It is important to note, QIDP status can be obtained as long as the drug is intended to treat serious or life-threatening infections caused by one of the qualifying pathogens. There is no requirement for drugs gaining the status to be a new chemical entity or in a new class. While there is an undoubted value in developing drugs that offer treatment options to patient populations in which there is an unmet need, it does raise questions about whether granting the QIDP status to such drugs can ever really incentivize companies to develop truly novel antibiotics, and whether a new dosage form of an established antibiotic can do anything to combat the threat of antimicrobial resistance. This fact has previously led to some criticism of the way QIDP status designations are granted 2, 3.

Introduction

1. The Review on Antimicrobial Resistance (2014) Antimicrobial resistance: Tackling a crisis for the health and wealth of nations. Available from: http://amr-review.org/sites/default/files/aMr%20review%20Paper%20-%20tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf [Accessed June 2019].2. Theuretzbacher U (2015) Recent FDA Antibiotic Approvals: Good News and Bad News. Available from: http://cddep.org/blog/posts/recent_fda_antibiotic_approvals_good_news_and_bad_news#sthash.SF8IWsTu.lpaJD8PP.dpbs [Accessed June 2019].3. Allphase Pharma Consulting, LLC (2017) QIDP, a Liberal Hand-Out from FDA. Available from:http://allphasepharma.com/dir/2017/03/05/3211/qidp-liberal-hand-out-fda/ [Accessed June 2019].

Jonathan SlaterAnalyst II, Citeline

The Generating Antibiotic Incentives Now (GAIN) Act passed into law on July 9, 2012. Seven years on, we review the drugs that have obtained QIDP status, the companies involved, and the clinical trial landscape.

July 2019 / 3© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)

4. Pharmaprojects®, June 2019.

To date, there are 106 drugs that have received at least one QIDP status designation 4. Figure 1 shows the number of drugs gaining their first QIDP status designation by year since 2012. The number of drugs obtaining the status designation each year has remained fairly constant, peaking in 2014 and 2015 with 20 drugs each year. At the time of writing, only one drug has so far obtained its first QIDP status in 2019. Even with a stronger second half of the year, 2019 is certain to represent a substantial drop from the highs of 2014–15. It remains to be seen if this is a temporary dip, or the start of a downward trend, as other metrics discussed later point towards

increased development activity.

Given the aims of the GAIN Act, what may be surprising to the casual observer is the number of drugs gaining QIDP status that are classified as reformulations. These are reformulations using novel proprietary delivery systems, reprofiled/repurposed drugs for novel indications, and novel fixed-dose combinations. Of all QIDP drugs, 29 out of 106 (27%) fall into this category. QIDP status designations for reformulated drugs peaked in 2017, with half of the 16 drugs being reformulations of one form or another.

The Drugs

Figure 1: Number of drugs receiving their first QIDP status designation by year

Source: Pharmaprojects®, June 2019

Notes: Only the year in which a drug is granted its first QIDP status is counted. Reformulations are drugs using novel proprietary delivery systems, reprofiled/repurposed drugs for novel indications, and novel fixed-dose combinations.

25

20

15

10

5

0

Coun

t of d

rugs

2012 2013 2014 2015 2016 2017 2018 2019

Reformulations Other Drugs

3 2

13

6

14

7

13

3

11

8

8

3

14

1


One such reformulation is Savara’s AeroVanc, currently the subject of an ongoing Phase III clinical trial. AeroVanc is an inhaled form of vancomycin being developed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis and other high-risk patient populations. This drug gained QIDP status in 2013. Vancomycin was first approved by the FDA as an oral capsule in 1958 for penicillin-resistant staphylococcal infections 5. This is a perfect example of a drug which fulfills an unmet need in terms of the target patient population,

but does not address the need for novel classes of antibiotics.

The pipeline of QIDP drugs would appear to be relatively healthy, with 23 drugs currently at Phase II and a further 14 at Phase III, as shown in Figure 2. Only three out of 106 QIDP drugs have been formally announced as discontinued, while a further seven have had no recent information released in the public domain, and so we assume are also no longer under commercial development.

Figure 2: Number of drugs with QIDP status by highest phase of development globally


5. Levine DP (2006) Vancomycin: a history, Clin Infect Dis; 42(Suppl 1), S5–12. Available from: 10.1086/491709 [Accessed June 2019].

Precli

nical

Phase I

Phase II

Phase III

Pre-re

gistra

tion

Registere

d

Launch

ed

Discontin

ued

No Deve

lopment

25

20

15

10

5

0

Coun

t of d

rugs


Brand Molecule Originator Company gaining QIDP status

First US approval date

Aemcolo rifamycin Cosmo Pharmaceuticals Cosmo Pharmaceuticals November 19, 2018

Nuzyra omadacycline Paratek Pharmaceuticals Paratek Pharmaceuticals October 2, 2018

Arikayce amikacin Insmed Insmed September 28, 2018

Xerava eravacycline Tetraphase Tetraphase August 27, 2018

Zemdri plazomicin Ionis Pharmaceuticals Ionis Pharmaceuticals June 26, 2018

Solosec secnidazole Symbiomix (now Lupin) Symbiomix (now Lupin) September 17, 2017

Vabomere meropenem + vaborbactam The Medicines Company The Medicines Company August 29, 2017

Baxdela delafl oxacin Wakunaga Melinta Therapeutics June 19, 2017

Cresemba isavuconazonium chloride Pfi zer Astellas and Basilea Pharmaceutica March 6, 2015

Avycaz avibactam + ceftazidime AstraZeneca Forest Laboratories (now Allergan) February 25, 2015

Zerbaxa ceftolozane sulfate + tazobactam Cubist (now Merck & Co.) Cubist (now Merck & Co.) December 19, 2014

Orbactiv oritavancin Eli Lilly The Medicines Company August 6, 2014

Sivextro tedizolid Cubist (now Merck & Co.) Cubist (now Merck & Co.) June 20, 2014

Dalvance dalbavancin Pfi zer Durata Therapeutics (now Allergan) May 23, 2014

In February 2018, the FDA reported to Congress on its progress with the GAIN Act 6. They reported that between July 9, 2012 and September 30, 2017, 147 QIDP designation requests had been granted, and 11 denied. As pointed out in the FDA’s report, “…the QIDP designation applies to a specific drug product from a specific sponsor for a specific indication, more than one designation may be granted for the same active ingredient. For example, one sponsor may receive QIDP designation for multiple dosage forms of the same active ingredient, or for multiple indications...” It is for this reason that the numbers of drugs gaining QIDP

status reported here will differ from the 147 QIDP designations granted.

The same FDA report stated that 12 QIDP drugs had been approved during the same period. However, this again included multiple dosage forms of the same drug (eg tedizolid phosphate tablet and injection), bringing the total down to nine unique drugs. Bringing that statistic up to date, there have been 14 different drugs that have gained QIDP status designation and gone on to gain their first US approval (Table 1).

Table 1: Table of drugs that have gained a first US approval following a QIDP status designation

6. Department of Health and Human Services (2018) Report to Congress on Generating Antibiotic Incentives Now (GAIN). Available from: https://www.fda.gov/files/about%20fda/published/Report-to-Congress-on-Generating-Antibiotic-Incentives-Now-%28GAIN%29.pdf [Accessed June 2019].


Notes: Only the first US approval for a drug is included. Excludes Minocin (minocycline; Melinta Therapeutics), which gained its first US approval prior to gaining QIDP status.


In the seven years prior to the introduction of the GAIN Act, 20 antibacterial, mycobacterial, or fungal drugs (excluding biologics) gained a first approval within the US. In the seven years following the introduction of the Act, there have been a total of 30 drugs, 14 of which had gained QIDP status designation prior to their approval (Figure 3). Over half of the anti-infectives approved since 2014 had

gained QIDP status, which would suggest that the Act has at least had some effect on the number of anti-infectives coming to market. Furthermore, considering the average development timeline for anti-infective drugs with QIDP status – estimated by Pharmapremia to be 10.1 years – the full effect of the GAIN Act may not yet be realized.


Notes: Number of antibacterial, mycobacterial, or fungal drugs approved each year in the US. Biologics and vaccines are excluded.

Figure 3: US approvals of anti-infectives by year

10

9

8

7

6

5

4

3

2

1

0

Coun

t of d

rugs

Without QIDP Status With QIDP Status

2005 2006 2007 2008 2009 2010 2011

Introduction of GAIN act

2012 2013 2014 2015 2016 2017 2018

1

4 4

1

5

32

1

3

5

4

2

3

1 1

3

3

4


A total of 72 companies have been the originator of a drug with QIDP status, with 21 of these having more than one product. Merck & Co leads the way with seven, including products gained as part of its 2014 acquisition of the anti-infectives-focused Cubist Pharmaceuticals (Figure 4). Half of the top 20 pharmaceutical companies (as defined by the Scrip 100 January 2019 rankings) have been originators for products that have gained QIDP status. If we expand that to include companies

that have licensed a product with QIDP status, 12 of the top 20 companies are or have been involved. These numbers include drugs that have gone on to be divested or discontinued, for example Johnson & Johnson is the originator of two drugs: acorafloxacin, which was out-licensed to Furiex Pharmaceuticals (now Allergan) in 2009; and cadazolid, which was acquired in Johnson & Johnson’s purchase of Actelion and later discontinued.

The Companies


Notes: Number of drugs originated per company by phase of development. Only shows companies that have originated two or more drugs. A company is considered the originator if it has acquired a company that originated the drug; eg Merck & Co. acquired Cubist Pharmaceuticals and is therefore considered the originator of drugs included in that acquisition.

Figure 4: Number of drugs with QIDP status per company

Matinas BioPharma

Leo

Melinta Therapeutics

Allecra

Evofem Biosciences

AstraZeneca

Tetraphase

VenatoRx Pharmaceuticals

Debiopharm

Johnson & Johnson

MicuRx

Giaconda

Spero Therapeutics

The Medicines Company

Cidara Therapeutics

Viamet

Bayer

Nabriva Therapeutics

Pfizer

Wockhardt

Merck & Co.

0 1 2 3 4 5 6 7

Preclinical

Phase I Clinical Trial

Phase II Clinical Trial

Phase III Clinical Trial

Pre-registration

Registered

Launched

Discontinued

No Development Reported


Looking at the number of industry-sponsored Phase I to Phase III trials of antibiotics and antifungals initiated each year, there has been a general increasing trend from 2005 to 2016 (Figure 5). The trend appears to have continued increasing at roughly the same rate since the introduction of the GAIN Act. It is encouraging that over 2012–16 there were more trials initiated than

in any of the preceding seven years. The drop in the number of trial initiations from 2016 to the present day can, in part, be explained by reporting bias in the public domain. Since we are only considering trials with a known start date, there is a strong likelihood that many trials, while having been announced, will have had no start date yet made publicly available.

The Trials

Figure 5: Trial initiations per year

Source: Trialtrove®, June 2019

Notes: Only industry-sponsored trials with a known start date are included. Phase I to III trials. Disease types included: bacterial skin infection, clostridium difficile infection, intra-abdominal infection, onychomycosis, otitis media, respiratory infections, sepsis, and urinary tract infections. Ongoing or completed trials only; terminated trials have been excluded. Does not include bioequivalence trials. Where a product being developed for multiple indications has received QIDP status in only some of those indications, all trials have been counted as a trial of a QIDP status product, regardless of indication.

100

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30

20

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0

Num

ber

of tr

ials

initi

ated

QIDP Non QIDP

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Introduction of GAIN act

57 57 70 69

84 86 91

29

63

41

58

40

67

47

67

39

60

29

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32

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15

11


If we focus on trials initiated since 2012 (Figure 6), we can see that a significant proportion of the trials initiated each year are later-stage trials;

since 2017, over half of the Phase III trials so far initiated have been for products with QIDP status.

Figure 6: Trial initiations per year by phase

Source: Trialtrove®, June 2019

Notes: Only industry-sponsored trials with a known start date are included. Trials are counted at their highest phase only; Phase I/II counted as Phase II, Phase II/III counted as Phase III. Disease types included: bacterial skin infection, clostridium difficile infection, intra-abdominal infection, onychomycosis, otitis media, respiratory infections, sepsis, and urinary tract infections. Ongoing or completed trials only; terminated trials have been excluded. Does not include bioequivalence trials. Where a product being developed for multiple indications has received QIDP status in only some of those indications, all trials have been counted as a trial of a QIDP status product, regardless of indication.

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of tr

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initi

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at in

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QID

P dr

ug

Phase I Non QIDP Phase II Non QIDP Phase III Non QIDP Phase I QIDP

2012 2013 2014 2015 2016 2017 2018 2019

Phase II QIDP Phase III QIDP % QIDP


As part of its recommendations to Congress 6, the FDA conceded that “…many products that qualify for QIDP designation are approved drugs being developed with modifications, such as a new dosage form or new indication. While improvements to existing drugs may provide some benefit to patients, the development of innovative, novel drugs is essential to addressing the antimicrobial resistance crisis and ensuring that safe and effective options are available to treat current and future patients...”

The agency goes on to recommend that “…although GAIN has contributed to facilitating the development of new antibacterial drugs, additional efforts are needed. The President’s Advisory Council on CARB (PACCARB) and groups like the Duke/Margolis Center for Health Policy are working on potential solutions to the antimicrobial resistance crisis including a focus on developing appropriate incentives to spur drug, vaccine, and related diagnostic development. Thought-leaders in the United States and Europe have discussed various push and pull incentives, including new business models for antibacterial drug development that delink the sales of these drugs from companies’ return on investments…”

One such group of European thought leaders are DRIVE-AB (Driving reinvestment in R&D and responsible antibiotic use). This is a project composed of 15 public and seven private partners

from 12 countries, funded by the Innovative Medicines Initiative (IMI). In a recent report 7, they discuss various examples of push and pull incentives to drive innovation in the development of new antibiotics, citing the GAIN Act as the only current example of a pull incentive. Tellingly, in a survey of stakeholders comprising academics, representatives of large pharmaceutical companies, and non-profit organizations, zero responders thought that monopoly protections, such as the GAIN Act, had a strong ability to stimulate innovation. One believed it was not able to stimulate innovation at all, while nine and four thought that they could weakly or moderately stimulate innovation, respectively.

Despite some of the negative feedback regarding the GAIN Act, its introduction has coincided with both increased trial activity in the anti-infectives space and an increase in anti-infectives coming to the market. This would suggest that it has had a positive influence on research activity. What is clear, however, is that the GAIN Act can only be a starting point, and a global effort to developing new antibiotics is needed. Push incentives including funding by organizations such as the Biomedical Advanced Research and Development Authority (BARDA) have helped create public-private partnerships for the development of novel antibiotics. Since 2010, BARDA has provided $1.1bn in support 8. More

7. DRIVE-AB (2018) Revitalizing the antibiotic pipeline. Stimulating innovation while driving sustainable use and global access. Available from: http://drive-ab.eu/wp-content/uploads/2018/01/DRIVE-AB-Final-Report-Jan2018.pdf [Accessed June 2019].8. Bright R (2019) Building New Models To Support The Ailing Antibiotics Market. Available from: https://www.forbes.com/sites/thelabbench/2019/05/10/building-new-models-to-support-the-ailing-antibiotics-market/#5bea73122909 [Accessed July 2019].

The Future


recently, CARB-X, a global non-profit partnership of which BARDA is a member along with other international government agencies and charities, has made $550m available for the funding of early-stage development of new antibiotics; vaccines; rapid diagnostics; and other products to prevent, diagnose, and treat life-threatening bacterial infections 9. Although significant, one would assume that far more funding is needed in this area when considering the enormous cost entailed in bringing a single drug to market.

What has been encouraging to see is the number

of organizations and stakeholders actively making policy suggestions. These range from DRIVE-AB, mentioned above, which has made 12 recommendations 7, to the World Health Organization (WHO), which produced a report making 16 recommendations 10. Many of the recommendations being made rely on changes to the economic model for drug development and reimbursement. Implementation of these will take multinational collaboration and considerable investment from national governments. The cost of not acting upon these recommendations could be considerably more.

About the Author

Jonathan SlaterAnalyst II, Citeline

In his current role as a Trialtrove Analyst specializing in infectious, metabolic, and cardiovascular diseases, Jonathan tracks clinical trials in these therapy areas and provides insight and guidance to our clients working in this field. Following the completion of a PhD and post-doctoral fellowship in synthetic chemistry, Jonathan joined Informa in 2009. Since then he has worked across a range of Informa Pharma Intelligence services, and has been involved with both the development of content and the training of clients on the use of Informa’s data and products.

9. CARB-X (2019) About CARB-X. Available from: https://carb-x.org/about/overview/ [Accessed July 2019].10. Renwick MJ, Simpkin V, Mossialos E (2016) Targeting innovation in antibiotic drug discovery and development. Available from: http://www.euro.who.int/__data/assets/pdf_file/0003/315309/Targeting-innovation-antibiotic-drug-d-and-d-2016.pdf [Accessed July 2019].

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