Unmet Need in ABDD Project

Jamie Roberts, MA, CCRP, MPH[c]

Senior Clinical Project Manager, CTTI

March 1, 2016

Meeting Objectives

Present perspectives from patients, caregivers and physicians on antibacterial drugs developed using streamlined approaches

Identify focus group themes and discuss topics which should be further explored or where draft recommendations could be made

Obtain feedback to improve labeling, risk communication, public understanding and stewardship

Change

Build consensus

Gather evidence

Formulate recommendations

Identify solutions

Target problem areas in

clinical trials

Better, Streamlined,

Fit for Purpose

Clinical Trials

Unmet Need

Project

Unmet Need

Project

The Issue

Many economic and regulatory disincentives to the development of new antibacterials exist

Process is long and costly

Trials are difficult to enroll, complete & analyze

ROI is low (not blockbusters, low & infrequent use)

Yet the need to develop more treatment options for patients with unmet need is urgent

What We Need to Know

The perspective of patients and providers regarding the use of newly approved drugs for which there might be

greater uncertainty and

lower levels of precision

E.G., when developed using streamlined approaches

Objectives & Methods

Objectives:

Characterize patient and provider opinions regarding the tradeoffs between precision and uncertainty in the context of non-traditional pathways to antibiotic development

Identify the specific needs for patient and provider education and clarifications to improve patient understanding of the need to expedite the availability of antibiotics to a limited patient population without full knowledge of the risk (safety information).

Methods:

Conduct focus groups to solicit patient views

Conduct SSIs and FGs to solicit provider views

Identify specific need for education/clarifications

Anticipated Impact

Increased tolerance among patients and providers of the tradeoffs between precision and uncertainty in the use of antibacterials developed using streamlined approaches

Increased awareness among patients and providers of the need for expedited development processes

Improved uptake and appropriate use of antibacterials developed using streamlined approaches

Terms

Streamlined development approaches

Refers to approaches to antibacterial drug development for serious bacterial infections that a sponsor may consider using

Unmet medical need

A condition for which treatment or diagnosis is not adequately addressed by available therapies

Serious conditions

A disease or condition associated with morbidity that has substantial impact on day to day functioning

Antimicrobial Stewardship

Programs that promote the appropriate use of antimicrobials, improve patient outcomes, reduce microbial resistance, and decrease the spread of infections caused by multidrug-resistant organisms

CONNECT WITH CTTI www.ctti-clinicaltrials.org

Thank you.

Jamie RobertsJamie.Roberts@Duke.edu

Session I: Current Landscape of

Antibacterial Drug Development for

Serious & Unmet Medical NeedFacilitator: Deborah Collyar, PAIR

March 1, 2016

The Current Landscape and Pipeline of Antibacterial

Products

Vance Fowler, MD

Disclaimer

The views and opinions expressed in this presentation are those of the individual presenter and do not necessarily reflect the views of the Clinical Trials Transformation Initiative.

Vance Fowler is an Employee of Duke University and reports the following potential conflicts of interest: Chair of the Scientific Advisory Board for Merck V710; paid consultant for Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy; Grants pending from MedImmune, Actavis/Forest/Cerexa, Pfizer, Merck/Cubist, Advanced Liquid Logics, Theravance, and Novartis; royalties from (UpTo- Date), personal fees for development or presentation of educational presentations (Green Cross, Cubist, Cerexa, Durata, Theravance), outside the submitted work; and patent pending related to sepsis diagnostics.

The Landscape

2 million serious multi-drug resistant infections/year

23,000 deaths

Preventing infections and improving antibiotic prescribing habits could save 37,000 lives from mdr-infections over 5 years

The Power of Antibiotics

Disease

Pre-

Antibiotic

Death Rate

Death With

Antibiotics

Change

in Death

Community

Pneumonia1

35% 10% -25%

Hospital Pneumonia2 60% 30% -30%

Heart Infection3 100% 25% -75%

Brain Infection4 >80% <20% -60%

Skin Infection5 11% <0.5% -10%

By comparison…treatment of heart attacks with

aspirin or clot busting drugs6-3%

15

1IDSA Position Paper ’08 Clin Infect Dis 47(S3):S249-65; 2IDSA/ACCP/ATS/SCCM Position Paper ’10 Clin Infect Dis In Press; 3Kerr AJ. Subacute Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4;04Lancet ’38 231:733-4 & Waring et al. ’48 Am J Med 5:402-18;

5Spellberg et al. ’09 Clin Infect Dis 49:383-91 & Madsen ’73 Infection 1:76-81; 6’88 Lancet 2:349-60

16

Science and

regulatory barriers

directly impact

economics by

increasing cost of

development and

affecting return on

investment

Science Economics

Regulatory

No New Abx

*Spellberg, CTTI presentation 2012

Antibiotic Market Failure: Causes

1. Science: low hanging fruit plucked

2. Economics: not a good investment

3. Regulatory: R&D too risky/expensive

Economics: Investment Options

Therapy

AreaeNPV*

Cost to

Develop

Time to

DevelopPrice Use Patient pop

Musculo-

skeletal$1,150m $$$$ Chronic Large

Neurology $720m$$$$

Chronic Large

Oncology $300m$$$

Acute/

ChronicMedium

Anti-

infectives$-50m $$$ Acute Small

*Projan 2003; Sharma & Towse ’11Slide courtesy of David Payne, GSK

eNPV: expected Net Present Value

Novel Drug Approvals 2011-2016

12

1

62

0

29

36

26

35

43

1

0

5

10

15

20

25

30

35

40

45

2011 2012 2013 2014** 2015*** 2016^

Anti-infectives* All other drugs

*Includes anti-fungals;

**Zerbaxa; ***Avycaz ; ^as of 2/19/2016

Adapted from FDA Drug Innovation at

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

DrugInnovation/default.htm

Follow the Money

Anti-

Infectives

(including

anti-fungals)

All

others

# of Pharma/Biotech

IPOs in 2015*

2 60

*Flanagan M. 2015 in Review: Initial public offerings – is the well finally starting to run dry?

12/23/15 http://www.firstwordpharma.com/node/1341308?tsid=33#axzz40YojLdci

**Analyst: Current Crop of Biotech IPOs a Mixed Bag of Low Market Caps, Little Data. 12/3/14.

http://www.biospace.com/News/analyst-current-crop-of-biotech-ipos-a-mixed-bag/356890

The Pipeline

September 2015 Pipeline

By characteristic

Phase

1 2 3

# companies with antibiotics in development by

phase8 16 10

# new antibiotics with the potential to treat

serious bacterial infections in clinical

development

10 17 12

# new antibiotics with expected activity against

gram negative ESKAPE pathogens2+ 4 5+

# new antibiotics with expected activity against

CDC urgent threat pathogen5+ 6+ 7+

ESKAPE: Enterobacter species,Klebsiella pneumoniae, Acinetobacter baumanii, or Pseudomonas aeruginosa

Adapted from the Pew Charitable Trust Tracking the Pipeline of Antibiotics in Development Issue Brief. Dec 2015.

Accessed online at http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-

development Accessed 2/12/2015.

The Pipeline (cont’)September 2015 Pipeline

By indication and phase

Phase

1 2 3

C.Diff 2 2 2

ABSSI 1 10 5

HAPB and/or VABP 1 0 7

CLABSI 0 0 1

cUTI and/or Acute Pyelo 0 2 6

cIAI 0 0 5

CABP 0 4 3

Bacteremia 1 0 1

GC (uncomplicated) and/or urethritis 0 2 1

Osteo and/or prosthetic joint infection 0 1 2

Respiratory tract infections and/or bronchiectasis 0 2 0Adapted from the Pew Charitable Trust Tracking the Pipeline of Antibiotics in Development Issue Brief. Dec 2015.

Accessed online at http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-

development Accessed 2/12/2015.

In Summary

The antibacterial pipeline remains precarious

Limited number of agents overall

Gaps for Acinetobacter, Metallo-beta-lactamase-producers, & Oral

Very limited diversity of mechanism

… we need a culture of cooperation between stakeholders; one that

recognizes that there must be a balance between public health/clinical needs and the commercial realities of drug discovery

and development.

Steven J Projan. Why is big Pharma getting out of antibacterial drug

discovery? Current Opinion in Microbiology 2003, 6:427–430

CONNECT WITH CTTI www.ctti-clinicaltrials.org

Thank you.

Unmet Medical Need in Antibacterial Drug Development

Expert Multi-Stakeholder Meeting

March 1, 2016

Joseph G. Toerner, MD, MPH

Deputy Director for Safety

Division of Anti-Infective Products

CDER/FDA

25

Current Situation

• Resistance continues to create areas of unmet need; patients with few or no appropriate therapeutic options– Multi-drug resistant Gram-negative rods

– Multi-drug resistant Neisseria gonorrhoeae

• Need to keep pace with development of new mechanisms of resistance

• Development of a new drug can take 5-10 years– Difficult to react in a timely fashion once resistance has occurred

– Some development programs not successful

– Ideally have options to choose from in advance of the need

26

Unmet Need

• Draft guidance issued 2013

27

http://www.fda.gov/downloads/Drugs/GuidanceCom

plianceRegulatory

Information/Guidances/UCM359184.pdf

Unmet Need: General Considerations

• Smaller data package; greater uncertainty about risks/benefits– One adequate and well-controlled trial with supportive evidence

– Infections at different body sites can be pooled for certain trial designs

• Greater uncertainty could be acceptable for patient populations with serious disease that do not have other treatment options (21 CFR 312.80, subpart E)

• Healthcare community should be aware of greater uncertainty about risks and benefits in such development programs

• Risks and benefits communicated appropriately in labeling

28

Unmet Need: Statutory Standards• Drugs approved on the basis of a streamlined

development program must still meet the statutory standards for effectiveness of the FD&C Act – Substantial evidence as “evidence consisting of adequate and well-

controlled investigations, including clinical investigations,…”

– Section 115(a) of the Modernization Act: allowed for data from one adequate and well controlled clinical investigation and confirmatory evidence to establish effectiveness

– 21 CFR 314.126(b): Adequate and well-controlled studies

• Guidance on Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products, describes FDA’s flexibility within these statutory requirements.

29

Unmet Need: Trial DesignsAdequate and Well Controlled

• Noninferiority

• Superiority

– Active control

– External controls

– Add on: Test drug + SOC vs. SOC + Placebo

• Nested noninferiority-superiority

30

Generating Antibiotic Incentives Now(GAIN)

• Title VIII of the Food and Drug Administration Safety and Innovation Act (FDASIA)

• Enacted on July 9, 2012

• Provides incentives for the development of certain antibacterial and antifungal drug products designated as Qualifying Infectious Disease Products (QIDP)

• QIDP refers to an antibacterial or antifungal human drug that is intended to treat serious or life-threatening infections

31

http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf

GAIN - Incentives

• Additional 5 years marketing exclusivity granted at the time of approval for products that have been granted a QIDP designation

• Priority review for marketing applications for products that have a QIDP designation

• Products that have been granted a QIDP designation are eligible for fast track designation

– Request for fast track should be made when QIDP requested; can only be requested with an active IND

32

http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf

33

Expedited Programs

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

• Final guidance issued May 2014

Expedited Programs

• Fast Track (FDAMA 1997): serious condition; potential to address unmet medical need; opportunities for frequent interactions with review team

• Priority Review (PDUFA 1992): serious condition; improvement in safety or effectiveness; 6-month

• Breakthrough Therapy (FDASIA 2012): serious condition; prelim clinical evidence indicate potential improvement over existing therapies; actions to expedite the review

• Accelerated Approval

34

Unmet Need

21 CFR 312.80

“The Food and Drug Administration (FDA) has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from drugs that treat life-threatening and severely-debilitating illnesses, than they would accept from drugs that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated.”

35

The Use of Antibacterial Drugs Developed

Via Streamlined Approaches:

Perspectives of Patients, Caregivers and Healthy People

Diane Bloom, MPH, Ph.D., InFocus Research

March 1, 2016

Disclaimer

The views and opinions expressed in this presentation are those of the individual presenter and do not necessarily reflect the views of the Clinical Trials Transformation Initiative.

Focus Groups: April 2014 – February 2015

Total of 11 focus groups (N=62)

3 Groups: Healthy participants

2 Groups: Recovered from serious infections

2 Groups: At-risk for hospitalizations and infections

4 Groups: Caregivers of recovered and at-risk patients

Research Goals

Understand the public’s perceptions and beliefs about infections, antibiotics.

Assess reactions to an FDA streamlined development approach to bringing new antibiotics to market sooner.

Gain insight into their comfort level for taking antibiotics developed through a streamlined approach.

Mindset about Prescription Medications

Most preferred not to take them unless necessary

Biggest fear = associated side effects

• Approved drugs pulled from the market due to serious side effects

• DTC TV

• TV ads for class action suits for people harmed by medications

Mindset about Prescription Medications

But all agreed that if they were very ill and needed a medication, they would be grateful to have it.

“I think medication is a necessary evil. But there is always

a catch. Whether it’s an antibiotic or cold medication, you

are taking a chance, because there can be side effects.”

[caregiver of recovered patient]

Patients at-risk for recurrent infections were more positive about medications.

Theoretically, they preferred non-medication approaches but recognized the lifesaving role prescription medications have played in their lives.

Feared dying of infection not chronic illness

“For me, a cold can turn life-threatening, and

medication has helped me tremendously! I’d rather

not spend the money or put those things in my

body, but I realize that ‘better living through

chemistry’ is working.” [recovered & at-risk patient]

Perceptions of Antibiotics

“Wonder drugs” or “miracle drugs” = words to describe antibiotics that cure infections that once were deadly

Antibiotics viewed as safer than many other prescription drugs:

Short-term nature of most antibiotic regimens

Positive experiences using antibiotics

– Infections resolved

– Few to no serious side effects

More Beliefs about Antibiotics

Newer ≠ better

Newer = not fully tested yet

“When my doctor needs to prescribe a

medication for me, I ask for the oldest one

which will work.” [recovered patient]

Beliefs about Antibiotic Resistance

Doctors have been too quick to give antibiotics historically

Excessive use of antibiotics in humans and livestock has contributed to the proliferation of superbugs

When overused, antibiotics can become ineffective in treating infections they once cured

Antibiotic resistance is a very serious problem, especially in hospitals, where these infections can run rampant

Only a few understood the mechanism of antibiotic resistance; most did not.

Most held the mistaken assumption that individuals who take too much of a particular antibiotic will build up a tolerance to it, rendering that drug ineffective for them personally

Even after reading an informational piece on antibiotic resistance, most were still confused

Potential Repercussion of this Misperception

At-risk patients may hold off taking life-saving antibiotics, thinking they will preserve their future options

“You have to be careful about taking too many antibiotics because you

don’t want to build up resistance to them. If you take too many, then

they might not work for you when you need them.” [at-risk patient]

“I don’t mean to be morbid, but even though I have a blood cancer, I

will probably die from a bacterial infection rather than my initial

disease. I’ve had so many infections, and I realize that the effects of

antibiotics could wear out for me with recurring use — and my

condition is a lifelong thing. I don’t want to get to the last antibiotic that

works when I am still in my early 50s. So I try not to take antibiotics.”

[at-risk patient]

Antibiotic Resistance: Perception of the Magnitude of the Problem

All were surprised that 2 million people in the U.S. each year contract antibiotic-resistant infections

Healthy participants thought these resistant infections could be extremely serious — even deadly

Recovered participants and their caregivers knew firsthand how severe infections can be and how long it can take to recover

“In 2013, I had a dental procedure, and a couple of days after that, I

collapsed. I learned I had a bacterial infection in my spinal column. It took

me about a year and a half to survive that episode and regain my health. I

was in the hospital for two months and then in a rehab center learning to

walk again for another five weeks. And then I was homebound for another

two months. I was in constant pain.” [recovered patient]

Magnitude of the Problem

All believed new antibiotics are needed ASAP to combat the growing problem of antibiotic resistance

"We're losing the battle. We're not producing [antibiotics]

as much as we used to, and there's more and more

bacteria resistant to the ones we have.” [healthy patient]

Perceptions of the FDA Drug Review & Approval Process

All knew that the FDA drug review process is long, but were surprised at HOW LONG

Length of time in review didn’t translate into more confidence in a drug’s safety

“The FDA review process does not inspire confidence, because we see so

many drugs pulled from the market because of unforeseen side effects. So,

although the process is long and cumbersome, it does not necessarily

result in the safest drugs coming to market.” [recovered patient]

“They study drugs for a long time, and they do the best they can, but just

because it goes through all these steps doesn’t guarantee that it’s going to

work for you. Your body is different from everybody else’s body, so you

never know before you take it if it’s going to work for you or if you’ll react to

it.” [caregiver, recovered patient]

Streamlined Approach to Drug Development

All participants reacted positively to a description of a streamlined development program.

Advantages

Getting new antibiotics to critically ill patients more quickly

Saving lives

Disadvantages

Limited data on serious side effects, especially in very ill patients

“The problem is dire, and such a program could

bring new antibiotics to market more quickly.”

[healthy patient]

All thought advantages outweigh disadvantages — especially in life-or-death situations.

“We've got so many organisms that are becoming drug resistant. This is a program to confront that. It gets the drugs to the people who really need them, and it restricts them from the general population, where they could become resistant.” [healthy patient]

Biggest Concern about a Streamlined Development Approach

Overuse/abuse by “profit-driven pharmaceutical companies” wanting to fast-track other medications

Wanted safeguards to assure the streamlined development process does not become “the new normal” for other drugs

“I’d like to see that not a lot of new drugs are going through this process

and that pharmaceutical companies won’t take advantage of it to make

more profit quicker and put more people at risk because of side effects.”

"Antibiotics are not the only drugs that save lives, so it sets the precedent for

using this process for other drugs. It's risky, making something short this way,

because it sets a precedent.”

Scenario

“What would you do if you had a life-threatening antibiotic-resistant infection and few or no options for treatment?”

All said they would want a new antibiotic that was approved under a streamlined development program, even though it had less data available.

“I would definitely take the drug, because what would I

have to lose? It would be my last resort. … But if I

didn’t have a life-threating infection, I would take my

chances and pray that my immune system would kick

in.” [at-risk & recovered patient]

" It’s like you're at sea, and

someone throws you a life

ring. You are going to grab it!”

[healthy patient] “In that situation I would be

in no shape to collect a lot

of information. I would be

saying, ‘Bring me the pill!’

not ‘Bring me the iPad!’ ”

[healthy patient]

“If it were a life-or-death situation, I would accept more

risk. If I was really sick and going to die from an

infection, I would take the new antibiotic. I wouldn’t

say, ‘Hey, I want one which has had more years of

research.’ ” [healthy patient]

BUT: Patients would not trust such a critical decision to only one doctor —especially one who was not conversant in the new drug.

“If you’re at that stage, you’re taking on that risk, and if you

die, you die. But my question is, who makes that judgment

that you are in that critical situation and that nothing else will

work? Does one doctor agree with other doctors? Because

these situations are never that cut and dry. That’s the

problem. I think … if somebody said, ‘You’re going to die, but

take this, and there’s a chance you’ll live,’ we’d all do that.

The question is who’s saying you’re going to die? And how

many people agree? It’s not the premise of the drug, it’s the

judgment before that that I question!” [healthy patient]

GOAL: Make sure more than one person weighs in on the decision to use a drug developed under a streamlined approach.

Some envisioned a multidisciplinary team (“The A Team”):

Patient advocate

Pharmacist

Patient’s own doctor

Physician expert

ID

Hospitalist

Immunologist

However, participants were not well-versed in the behind-the-scenes workings of the ICU, where time is critical to outcome and where convening a large team may not be feasible.

Information Desired Regarding Drugs Approved through SDP

Who & how many tested? Population

Side effects? Common, SAEs

Drug interactions?

Effectiveness?

What else is known about drug?

How do you know the PATIENT has an antibiotic resistant infection?

Survival odds w/o the new med? What’ll happen w/o it?

Who decides?

Are there any alternatives?

Bottom line:

They want >1 doctor to make determination (multidisciplinary and/or expert)

At-risk patients said it would be nice to have information about drugs developed through a streamlined program when they are healthy so that their doctor knows their wishes before they are in crisis.

“I don’t want to make snap decisions after two or three days of

failed treatment, when I’m slipping into a coma. Then it’s up to

my family members to decide whether I’d want this or not. So

I’d want as much information as possible beforehand, because

you’re not just acting out of survival instinct but are making a

more informed decision.” [at-risk patient]

This “advanced directive” is not feasible, according to physicians:

PCPs are not decision-makers once patients are admitted to ICU

It is commonplace to use treatments in the ICU that don’t have a lot of data behind them

ICU physicians don’t tell patients/families that drugs are approved under a streamlined approach

Families/patients are not asked to weigh in on which drug ICU physicians will use

This kind of “advanced directive” is not feasible, according to physicians: (cont’d)

“Families don’t weigh in very often [on the choice of antibiotics],

and when they do, they probably shouldn’t, because these

complicated infections are very hard even for specialists to

understand, let alone a family member. I don’t want them making

a decision about a complicated intra-abdominal medication in the

hospital. But I do want to know if their loved one is allergic to

penicillin, or if they’ve ever had a bad reaction to a sulfa drug.

That’s where the family can really be of help.” [physician]

“The family never weighs in on treatment. It’s rare that a patient

would have any idea about what the spectrum of an antibiotic is or

why we use a certain antibiotic. I may explain that this one treats a

certain bacteria that we think you have. But I would say that most

patients’ knowledge of antibiotics is ‘it’s a strong one,’ or ‘it’s not a

strong one.’ ” [physician]

The Bottom Line - Participants Believed:

Antibiotic-resistant infections represent a growing crisis and that superbugs pose a serious — even deadly — threat.

Because of the overuse of antibiotics In humans and livestock, many are now ineffective.

The fact that there are few or no new antibiotics coming down the pike is more cause for fear.

We need new antibiotics ASAP.

The Bottom Line (cont’d)

All favored the creation of streamlined development programs, given the dire nature of the crisis.

The following new information surprised participants and were compelling reasons to institute streamlined development programs:

Two million people in the U.S. contract antibiotic resistant infections every year

Superbugs can be passed from person to person

It can take as long as 15 years to bring a new drug to market

The Bottom Line (cont’d)

If they were critically ill with a resistant infection, all would take a new drug developed under a streamlined approach. However they want more than one doctor to weigh in on the decision.

They want mechanisms in place to assure that a streamlined development approach does not become “the new normal” for the development of other drugs.

CONNECT WITH CTTI www.ctti-clinicaltrials.org

Thank you.

Diane Bloom, MPH, Ph.D., InFocus Research

Session III:

Perspectives of Providers and

Investigators

Thomas Holland, MD (Duke)

March 1, 2016

Disclaimer

The views and opinions expressed in this presentation are those of the individual presenter and do not necessarily reflect the views of the Clinical Trials Transformation Initiative.

The presenter is an Employee of Duke University.

Background

Main Objective:

Perspectives regarding risk and uncertainty

Perspectives about using antibacterial drugs developed using these approaches

Better understanding of how physicians make treatment decisions for patients with complicated or resistant infections

23 Semi-Structured Interviews with Providers

Academic and Community

Who Was Interviewed

Academic & Community Providers

Internal Medicine

Critical Care

ID

Pulmonology / Critical Care

Hospitalists

P & T Committee members

Some overlap

e.g., Academic P & T and Community Pulmonologist

Total N=23 but appears larger due to overlap

Specialties N=

P & T Committee 9 current +

2 former

members

Hospitalist 3

Infectious Disease 7

Pulmonologist 6

Critical Care/Intensivist 7

IM 5

Community Only 11

Academic Only 9

Both 3

Initial questions

Think back to some of the patients you have seen who were seriously ill with a complicated (and possibly multi-drug resistant or hospital acquired infections). What have you found to be most challenging aspects of treating these patients?

In those kinds of situations, how do you select the appropriate therapy? [Open-ended, then Probe]:

Greatest Challenges in Treating Patients

with Complicated Infections

Choosing appropriate antibiotic treatment before the pathogens are identified through cultures

Treating medically complex and sick patients who require close monitoring, and whose ability to tolerate antibiotics with significant toxicity is unpredictable

Questions: streamlined development

approaches

Participants then given info about the FDA exploring streamlined development approaches, features of which may include:

Used to treat patients with limited or no alternative options

Clinical data more limited than what would be expected in a traditional development program

Reactions: streamlined development

approaches

All of the physicians interviewed believe that there is now a crisis with antibiotic-resistant infections and that it is appropriate to be developing and reviewing new antibiotics through programs such as the streamlined development approaches

Benefits to pharmaceutical companies are reasonable if they incentivize development of new abx that will never be blockbusters

Perceptions: Excited but Cautious

“It’s exciting in that it [streamlined development approaches] would give a pathway to get these drugs to patients who need them. It’s exciting in that we’d have access to life-saving meds earlier than we normally would in the ‘Phase I, II, III’ approach.

But I would want to have as much information as possible about the new drug and its sensitivities and in terms of how well it will work against different pathogens, as well as about its renal toxicity.”

“It would be good thing for FDA to put out information for clinicians to reassure them that prescribing drugs that have come through the streamlined process does not put them at risk for medical/legal problems.”

Plans: Use of abx developed via

streamlined development approaches

None believed that antibiotics developed through this program should be used first line.

A few would rather use known drugs first due to limited available data on safety/efficacy, especially in critically ill

Use only for patients with true unmet need who have run out of viable options.

Rationale: primarily to preserve the new drug so “it won’t become worthless in six months.”

Tolerance of uncertainty about risks increases as patients get sicker and have fewer options

Concerns: Use of abx developed via

streamlined development approaches

Most would not have concerns about using a new antibiotic developed through this shortened review process in patients with unmet need, given that the available alternatives have serious and potentially life-altering toxicities, and that many other procedures and treatments used routinely in the ICU are also not well-supported by data.

A minority of the physicians expressed concern over using a drug developed through the streamlined development approach because of a lack of data both for efficacy and for side effects (especially renal effects) when used in critically ill patients such as those in the ICU.

Confidence: Using Drugs Developed via

streamlined development approaches

Confidence would be boosted by the fact that these new antibiotics are FDA approved and would have been scrutinized and vetted by their hospital’s P&T committeebefore being placed on the formulary.

If the new antibiotic contained a drug component the doctors have already used, it would further boost their confidence.

Need: Ongoing Clinical Use Data

Some of the physicians said they would like ongoing updates on the efficacy, side effects and toxicities of the streamlined development drugs as they are being used in real-life clinical settings

Some suggested that the FDA require these data be continually submitted as part of the approval process, and that the FDA partner with a neutral and trusted third party like the Infectious Disease Society of America (IDSA) to inform physicians and establish treatment guidelines for these new antibiotics

Perceptions: Need Real-World Data

“I’m excited about having new products to use, because I face this problem a couple times a month when I have a patient who has a resistant infection, and it comes to having to use toxic medications. But the Phase II trial data [of drugs developed under the streamlined program] doesn’t cover the kinds of patients I see. I want to know how it would do with real-world patients who need this drug — the frail patients who may be on dialysis or on continual dialysis. How will they do?”

Restrictions: Use of ABX Developed via

streamlined development approaches

Currently, most ICU and ID physicians have very few restrictions on their authority to prescribe antibacterials.

All thought that new antibiotics approved under this program should have mandatory ID consults with IDs who are on their hospital’s antibiotic stewardship committee or who are certified experts in MDR infections and the new antibiotics developed to treat them

A few of the physicians said they wanted to make sure that ID consults wouldn’t interfere with critically ill patients getting lifesaving antibiotics in time to have the best outcomes.

Need: Mandatory Bedside ID Consults

Almost all said that new antibiotics developed under the streamlined development approach with limited safety data should have mandatory ID consults every time they are initiated with patients

“Absolutely I would want to do this at my hospital. It’s important to restrict or prevent overuse.”

However…

All of the physicians said that patients’ suggestion about having an “A-Team” review cases to decide whether patients are a good candidate for a newly developed antibiotic was neither necessary or feasible, because the time it would take to convene such a committee would delay life-saving treatment. They said that a mandatory ID consult should suffice

Patient Advanced Directive for SDP-

Approved ABX Use

None of the physicians interviewed thought having patients with chronic conditions necessitating frequent hospitalizations create an “advanced directive” about their wishes concerning drugs developed through a SDP was a good idea.

They said that patients are not savvy when it comes to antibiotics in complicated infections, and the personal community physician never makes decisions for their patient in the ICU.

Providers then given:

a press release announcing February 2015 approval of Avycaz

An informational piece about Avycaz prescribing highlights and microbiology profile

Most had heard of Avycaz and presumably all were familiar with the cephalosporin component

Perceptions of AVYCAZ

The vast majority said that they would be comfortable using a streamlined development drug like AVYCAZ with patients with true unmet need, and with no other viable options.

Would not use AVYCAZ as first line therapy

None would use it if there were alternatives, even after cultures

• Allows preservation of AVYCAZ for true unmet need

– A few indicated discomfort using AVYCAZ in fragile pts due to rapidity of approval and limited data of the effect on the critically ill

Overall Perceptions & Limitations

Crisis in ABDD

Support need for streamlined approaches

Providers more comfortable with current structures for internal review than patients

Indicate they would not use these drugs as 1st line therapy or before culture results are known

Would like real-time clinical use data provided

Limitations: social desirability bias

CONNECT WITH CTTI www.ctti-clinicaltrials.org

Thank you.

Thomas Holland, MD

Thomas.Holland@Duke.edu

Session III: Key Issues & Considerations

Presentation of Focus Group Issues

Stephen Mikita, JD, Patient Advocate, Team Lead

Session Facilitator: Rose Tiernan, FDA

March 1, 2016

Disclaimer: Rosemary Tiernan, MD, MPH

The views and opinions expressed in this presentation are those of the speaker and do not reflect official FDA, HHS or other government opinion or policy. They also do not necessarily reflect the views of the Clinical Trials Transformation Initiative.

I have nothing to disclose.

Disclaimer: Steve Mikita, JD

The views and opinions expressed in this presentation are those of the individual presenter and do not necessarily reflect the views of the Clinical Trials Transformation Initiative.

Session Objectives

Discuss Key Issues from Patient & Provider Focus Groups:

Gaps & Challenges?

Implications for Stakeholders?

Solutions?

Issues

1. Patients/Providers perceive antibacterial drug development crisis

2. Clarifying definition of “unmet need”

3. Limiting overuse/inappropriate use of streamlined development approaches

4. Decision making and medical-legal risk issues

5. Stewardship

6. “Real-time” post-approval data collection, data sharing, and publication of treatment guidelines for use of these products

7. Risk Communication

Key Issue #1: Patients/Providers Perceive Crisis in ABDD

Patients/Providers—Acknowledge the need for streamlined development approaches.

Patients/Providers—Both Providers and Government (regulators) share responsibility in developing programs/approaches to address unmet need.

Patients/Providers—Recognize the need for effective, not just rapid, steps to be taken to reduce the risk of MDR bacterial infections, especially in hospital and long-term carefacilities.

6

Key Issue #2: Patient Understanding of Unmet Need in

Antibacterial Drug Development

Patients need further clarity on the definition of unmet need.

Patient advocacy groups (e.g., oncology) have various understandings of unmet need – limited vs. no options.

7

Key Issue #3: Limit Overuse/Inappropriate Use of

Streamlined Development Approaches

PATIENTS believe these approaches are necessary but desire safeguards to prevent misuse by industry.

PROVIDERS believe these approaches are warranted and also believe:

The process should not be abused & need reassurance that incentives are commensurate with severity of need.

Regulators should maintain adequate oversight of these streamlined development approaches to ensure scientific rigor.

Stewardship should be encouraged.

8

Key Issue #4: Decision-Making and Medical-Legal Risk

PATIENTS desire input and consensus from a multi-disciplinary team

The “A-Team”

Ensures that providers are making the right decisions regarding approved or off-label use.

PROVIDERS are concerned they may be at increased medical/legal risk when using drugs developed through these approaches

Need assurance that using these approved drugs, where the safety database supporting approval may be more limited, does not place them at additional medical-legal risk.

9

Key Issue #5: Stewardship

Limit use of antibacterial drugs developed with streamlined approaches

PROVIDERS: Unless there are extenuating circumstances, reserve use of antibacterial drugs developed using these approaches only following known culture results.

PATIENTS: There may be a need to increase public awareness of how decisions are made regarding unmet need, treatment timeliness, and diagnostic limitations.

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Key issue #6: Require “Real-Time” Data Collection/Sharing

and Publication of Treatment Guidelines

PATIENTS and PROVIDERS

desire ongoing information to be collected and made publicly available regarding antibacterial drugs developed using these approaches.

besides post-marketing studies, one approach to providing this information might be to implement a registry for drugs developed using these approaches.

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Issue #7: Risk Communication

Provide standardized information to prescribing physicians in hospitals

The following information should be readily available to physicians with hospital prescribing privileges:

Is the drug on the hospital formulary?

Are there any restrictions to prescribing the drug (who, when)?

What is the cost of the drug?

What is the known data in the critically ill?

What are the known renal effects? Other known side effects?

12

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Thank you.

Session IV

Facilitator: Jamie Roberts et al.

March 1, 2016

Session Objectives

Breakout 1: Risk communication with the Public & Providers

Facilitators: Deborah Collyar (Patient Advocates in Research) & Amy Corneli (Duke)

Room:

Breakout 2: Real-time Clinical Data Use Collection

Facilitators: Pamela Tenaerts (CTTI) & Jeff Loutit (The Medicines Company)

Room:

Breakout 3: Stewardship Issues

Facilitators: Thomas Holland (Duke) & Diane Bloom (InFocus Research)

Room:

Breakout Session #1

Luke Chen, MD

Duke University

March 1, 2016

BREAKOUT SESSION #1

Post-marketing stewardship

issues for drugs developed using

streamlined approaches

Do antibiotics that are developed through streamlined approaches need or demand a different level of stewardship?

If yes, what would a different level of stewardship look like?

Levels of Stewardship

Stewardship is a common need in all healthcare settings

But only common in high resource healthcare settings

There is not a single, one size fits all approach that is unique to ABX approved through a streamlined pathway

Consensus that there is a need to have the right set of eyes looking at their use at both the hospital and patient level

Does Stewardship Happen Differently for

SDA? Less Data Available?

Formulary decision is different up front

Streamlined ABX would likely to be more restricted on formularies

Probably get better stewardship in these cases

How Does Stewardship Happen in All Settings?

<5% are AMCs

What would be the best way to do this?

Providing some kind of ‘how to’ for ASP

• Ex: wording and guidelines

• Produced by a multidisciplinary committee

Partnership mechanism between high and low resource settings

• Ex: Duke does an outreach program to small, community hospitals

• CMS requirement to do this

• How about using State Health Departments?

What Would Different Levels of

Stewardship Look Like?

Education is key

The more you restrict an ABX, the less physicians are likely to know about it

• Direct to physician education by physician education by drug companies has gone

• Must fill this void

• Who is now responsibility is this?

– IDSA or SHEA?

» Too narrow a reach

A general level of education is required about WHY stewardship is needed to all members of the healthcare team

Particularly challenging for off-label use

Where do you get your data to determine required level of stewardship?

How Granular Does Stewardship get for

Each Individual Patient?

Hospital dependent

Regulatory data helps support institutional decisions

Some institutions will not allow off-label use of ABX

What Triggers a Need for Stewardship?

Current typical standards

• Pathogen Specific

• Disease Specific

• Sub-population Specific

Typically when providers (non-specialists) see a problem, but don’t know how to treat

How should we handle the stewardship of new agents?

• Specifically challenging in low resource settings

Breakout Session #2

Sara Hull

March 1, 2016

BREAKOUT SESSION #2Risk Communication with the

Public & Health Providers

What do the public and providers need to know about the use of drugs developed using streamlined approaches?

REPORT OUT #2

What is needed?

Basic definitions/plain language (What is risk? Explain Unmet Need)

• FDA Drug Snap Shot as possible template

Describe the landscape

• Infections occur in ICU

• Abx resistance exists, therapy limitations do exist

Describe the drug (why, what, how, when)

• What was studied?

• What is unknown?

• What alternatives exist?

REPORT OUT #2

Who to Target?

Patients v. Providers

• But target specific patients (e.g. ICU)

• Similar information to patients and providers, but more freedom to write in more technical terms

– Providers = ID, pharmacists, critical care, hospitalists

– Tiered Information – Access to all types of physicians/providers, but links to more detailed info for physicians/providers more regularly engaged with these issues

Potential Messengers/Outreach Targets

Societies for ID Pharmacists

IDSA

SHEA

CDC

FDA

Society for Critical Care Medicine

American Thoracic Society

Society for Hospital Medicine

Breakout Session #3

Reporter: Jeff Loutit

March 1, 2016

BREAKOUT SESSION #3

Real-Time Clinical Data Use

Registry/Repository: Is it

Necessary & Feasible?

Is a Real-Time Clinical Data Use Registry/Repository for drugs developed via streamlined approaches necessary and feasible?

If yes, what would a clinical data use repository look like?

What exists now?

REMS – If Safety issue exists, FDA can require

MedWatch - The FDA Safety Information and Adverse Event Reporting Program

ARDS Network example

VAERS - Vaccine Adverse Event Reporting System (VAERS)

CDC and FDA

Industry funded post-approval studies

REPORT OUT #3

Is there a need for registry data? YES

In severe diseases where there is an unmet medical need

All antibiotics, not just those approved via streamlined approaches

Needs to be focused on specific organism and/or specific type of infection

“Real-time” not as important as:

Quality data

Quality analysis, in a timely manner

Comparator data

REPORT OUT #3

How?

Network of sites that collects pre-specified data

• Helps to fund research personnel with steady work

Regular data analysis (e.g. every quarter)

Collects data on indications that were not part of streamlined submission

• Not on UTI if pre-approval studies were UTI

• HABP/VABP

Independent Steering Committee

REPORT OUT #3 - Challenges

Who funds???

Not only companies – needs to be independent

• Do not want to discourage development

CDC?

FDA?

BARDA?

Bias if sample not representative

Highlights, Gaps, Challenges & Next

StepsJamie Roberts

Pamela Tenaerts

Rose Tiernan

March 1, 2016

GapsThe key to stewardship is rapid diagnostics to address the inability to detect MDR pathogens early to allow us to do the trials in the people who need it

Need to engage both stewardship and ICU pharmacists in the discussion of use and stewardship

Stewardship philosophy is widely variable

Missing knowledge

Is there a need for more robust data collection systems that capture knowledge (e.g., real-world evidence) we’re missing in registrational clinical trials? (e.g., use in the fragile, critically ill, those with renal failure, etc.)

Knowledge in the ID specialty field about the various different products themselves

Costs vs. benefits

Challenges and Changes Ahead

Risk Communication: Gap in information exists: Need Frame of Reference re: drugs dev’d thru sda’s

• Tailored to Pts (ICU setting) & Providers (tiered forms of info based on specialty), accessible, plain language

• Should be tied to stewardshipConsensus that there’s a need to collect data, diagnosis and/or bug specific ALL abx Independent of drug companies with independent steering cmte Funding? Public-private partnership (CDC, FDA, BARDA, NIH, Pharma)

• Networks? Clarification of what “real-time” means

• Timely, quality data and analysis against comparatorStewardship: Need to fill the void left when pharma stopped being able to educate

providers Need a best-practice or how-to for multidisciplinary stewardship for ASP Partnership between high & low resource settings (AMC community

hospitals)

Next Steps

Face a post-antibiotic era or enhance the social compact protecting antibiotics for future generations

Action, not excuses

Post-meeting electronic survey

Meeting summary and slides

Consider recommendations for the future

Definitely a manuscript

Follow-up with participants for additional feedback as needed

Are there still gaps this team/project should address?

Stewardship

antibiotics are unique because they are the only pharmaceutical agents that have transmissible loss of efficacy over time

…. Antibiotics are a shared community property or trust, and clinicians, health care organizations, patients, and the public are bound

together in the need to protect these drugs from misuse.

Given that antibiotics represent a shared societal trust, the regulatory approval process and national practice treatment guidelines governing use of antibiotics should not be based solely on considerations of efficacy and

safety, as they are for all other drugs. Rather, for antibiotics, the regulatory approval process and national practice guidelines should

incorporate fundamental principles of antibiotic stewardship, in addition to safety and efficacy of the drug, in defining approved

indications and treatment recommendations.

Brad Spellberg, MD; Arjun Srinivasn, MD; Henry F. Chambers, MD. New Societal Approaches to Empowering

Antibiotic Stewardship. JAMA. Published online February 25, 2016. doi:10.1001/jama.2016.1346

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Thank you.