# Presentation: 660449

## HDEs, Humanitarian Use Designations (HUDs), and the Office of Orphan Products

**HDEs, Humanitarian Use Designations (HUDs), and the Office of Orphan Products**

**Elisa D. Harvey, D.V.M., Ph.D.**
**Director, IDE and HDE Programs**
**Office of Device Evaluation (ODE)**
**Center for Devices and Radiological Health (CDRH)**
**Food and Drug Administration **
**AdvaMed**
**15****th**** Annual Device Submissions Workshop**
**May 25, 2005**

## Objectives

- Office of Orphan Products (OOPD) Overview
- OOPD connection to CDRH
- OOPD Development Grants Program and medical devices
- HUD designation/HDE approval

- AdvaMed Device Submissions Workshop May 25, 2005

## What is an Orphan Product?

- 	Drug, biologic, device, or medical food used in the diagnosis and/or treatment of patients with _rare diseases_.

- AdvaMed Device Submissions Workshop May 25, 2005

## What is a Rare Disease?

- Fewer than 200,000 in the U.S. (prevalence)
- “Orphans” because pharma/device industries may have little or no interest in developing therapies

- AdvaMed Device Submissions Workshop May 25, 2005

## 
50% Pediatric
85% Life-threatening or serious
No effective treatment available
Hetereogeneous
10-20 million Americans suffer from one of the approximately 5,000 identified rare diseases
Approximately 25-30 million Europeans affected by rare diseases

- 50% Pediatric
- 85% Life-threatening or serious
- No effective treatment available
- Hetereogeneous
- 10-20 million Americans suffer from one of the approximately 5,000 identified rare diseases
- Approximately 25-30 million Europeans affected by rare diseases

- Characteristics of an Orphan Disease

- AdvaMed Device Submissions Workshop May 25, 2005

## Why “orphans” exist

- Economic
- Poor market return on investment
- Regulatory
- Obstacles in clinical trials
- Trials don’t fit the “gold standard”
- Small patient population spread out over large geographic area
- Heterogeneity of disease

- AdvaMed Device Submissions Workshop May 25, 2005

## Why “orphans” exist

- Regulatory (continued)
- Obstacles in clinical trials
- Few clinical experts
- Product (drug) problems:
- Acquiring drug
- Manufacturing consistency, etc.
- Sponsor may be a smaller firm (e.g., device companies)
- Limited resources
- Limited experience with regulatory processes

- AdvaMed Device Submissions Workshop May 25, 2005

## Where does OOPD fit in?

**FDA Centers and Offices**
- Center for Biologics Evaluation and Research (CBER)
- Center for Devices and Radiological Health (CDRH)
- Center for Drug Evaluation and Research (CDER)
- Center for Food Safety and Applied Nutrition (CFSAN)
- Center for Veterinary Medicine (CVM)
- National Center for Toxicological Research (NCTR)
**Office of the Commissioner (OC)**
- Office of Regulatory Affairs (ORA)

- AdvaMed Device Submissions Workshop May 25, 2005

## Where does OOPD fit in?

**Office of the Commissioner**
- _[Ethics Program](http://www.fda.gov/opacom/ethics/)_
- _[Good Clinical Practice Program](http://www.fda.gov/oc/gcp/)_
- _[History Office](http://www.fda.gov/oc/history/)_
- _[Office of Combination Products](http://www.fda.gov/oc/combination/)_
- _[Office of Crisis Management](http://www.fda.gov/oc/ocm/default.htm)_
- _[Office of Financial Management](http://www.fda.gov/oc/oms/ofm/internet_default.htm)__ _
- _[Office of International Programs](http://www.fda.gov/oia/homepage.htm)_

- AdvaMed Device Submissions Workshop May 25, 2005

## Where does OOPD fit in?

**Office of the Commissioner**
- _[Office of the Ombudsman](http://www.fda.gov/oc/ombudsman/homepage.htm)_
- _[Office of Orphan Products Development](http://www.fda.gov/orphan/index.htm)_
- _[Office of Pediatric Therapeutics](http://www.fda.gov/oc/opt/default.htm)_
- _[Office of Planning](http://www.fda.gov/ope/opehome.html)_
- _[Office of Policy](http://www.fda.gov/oc/op/default.htm)_
- _[Office of Public Affairs](http://www.fda.gov/opacom/moremedia.html)__ _
- _[Office of Special Health Issues](http://www.fda.gov/oashi/home.html)_
- _[Office of Women's Health](http://www.fda.gov/womens/default.htm)__ _
- _[Small Business Program](http://www.fda.gov/oc/ofacs/fdasbo/default.html)__ _

- AdvaMed Device Submissions Workshop May 25, 2005

##  Mission of the Office of Orphan Products Development (OOPD)

- To assist and encourage the identification, development, and availability of safe and effective products for people with rare diseases/disorders**  **

## How does OOPD achieve mission?

- Implementing Orphan Drug Act
- Orphan Drug Designations
- Orphan Products Development Grants Program
- Humanitarian Use Device Designations

- AdvaMed Device Submissions Workshop May 25, 2005

## How is OOPD’s mission relevant to CDRH?

- Grants Program
- Humanitarian Use Device (HUD) Designation Program
- LINK = DEVICE DEVELOPMENT
- Note: OOPD is organizationally independent from the review divisions

- AdvaMed Device Submissions Workshop May 25, 2005

## The Orphan Drug Act (1983) 

-    Established public policy that Federal Government could/would assist in development of treatment for rare diseases

- AdvaMed Device Submissions Workshop May 25, 2005

## Grey Days Prior to Orphan Drug Act

- Fewer than 15 drugs approved for rare diseases
- Patients had limited pharmacotherapeutic options
- Limited clinical data for most drugs
- Drugs that were available prescribed “off-label”

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Drug Designation Incentives

- Primary:  Seven year marketing exclusivity to first sponsor obtaining FDA approval of a designated drug
- Other:
- Tax credit equal to 50% clinical investigation costs
- Marketing application filing fee waivers
- Assistance in drug development process
- Orphan products grant funding

- AdvaMed Device Submissions Workshop May 25, 2005

**Notes:**
PDUFA is Prescription Drug User Fee Act
Application fees for FY 2005: 
$672,000 if application requires clinical data
$336,000 for applications not requiring clinical data
Also eligible for waiver of:
Establishment fees: $262,200/year
Product fees: $41,710/year

## Orphan Drug Designation Program

- Determines eligibility for incentives of the Orphan Drug Act
- Two criteria applied:
- 		- Prevalence < 200,000 in U.S.
- 		- Rationale for use of the drug to treat 		  the disease or condition

- AdvaMed Device Submissions Workshop May 25, 2005

## Note:

- Orphan drugs:
- Must be _just as safe and effective_ as other drugs approved by FDA
- Subject to _same review standards_ as non-orphan drugs
- Devices not included

- AdvaMed Device Submissions Workshop May 25, 2005

## Market Impact of Orphan Drug Act Incentives

**Reduced fixed development costs**
**Increased effective market size**
**Increased motivation for firms to develop drugs for small populations **

- AdvaMed Device Submissions Workshop May 25, 2005

## Market Impact of Orphan Drug Act Since 1983

- >1414 designated orphan products
- 265 approved orphan products
- 209 drugs
- 56 biologics
- 38 devices (since 1996)

- AdvaMed Device Submissions Workshop May 25, 2005

**Notes:**
Nearly 50% of all biological products approved since 1982 are orphan products

## Market Impact of Orphan Drug Act Incentives

- Development of “Orphan Industry”
- Many Small-to-Medium Sized Pharmaceutical Companies have been established to develop rare disease therapies
- Orphan Medical
- Major pharmaceutical organizations have subsidiaries devoted to the development of orphan drugs
- Genentech, Amgen, and Genzyme

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Development Grants:   Program Objectives

- Fund _clinical_ research that will accelerate or assist in the approval of products which demonstrate promise for rare diseases/disorders
- Fund studies leading to publications in peer-reviewed journals

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Development Grants:  Program Overview

- Clinical (not basic) research in rare diseases
- Total budget: $14.3 million FY 2006
- Award 10-15 new grants per year
- Manage 60-70 active grants
- Up to three years
- $200,000 Phase I (safety)
- $350,000 Phase II & III (safety and efficacy)
- 39 approved products funded by OOPD grants

- AdvaMed Device Submissions Workshop May 25, 2005

## Drugs			~ 80%
Biologics		~ 14%
Devices			~ 5%*
Medical Foods	< 1%

*Device grants not funded at lower rate;
  few applications

- Biologics		~ 14%
- Devices			~ 5%*
- Medical Foods	< 1%
- *Device grants not funded at lower rate;
-   _few applications_

- Distribution of OOPD Grants

- AdvaMed Device Submissions Workshop May 25, 2005

## Devices that have received OOPD Grants (Public Information)

- Neuroprosthesis for Restoration                    of Hand-Arm Function
- Auditory Brainstem Implant for Neurofibromatosis
- Enzyme-Reactors for Management               of Phenylketonuria
- Programmable Implantable Insulin Pump in Unstable Diabetes

- AdvaMed Device Submissions Workshop May 25, 2005

## Devices that have received OOPD Grants

- Collection of Sickle Erythrocytes by Apheresis
- Treatment of Corneal Perforations              with Butyl Cyanoacrylate
- Transcutaneous, Transvesical              Bonding Cystostomy
- Cultured Skin Substitutes for Closure            of Burn Wounds
- Treatment of Rib Anomalies by Titanium Ribs

- AdvaMed Device Submissions Workshop May 25, 2005

## Devices that have received OOPD Grants

- Treating Palatal Insufficiency by Teflon
- Treatment of AV Malformations with n-Butyl Cyanoacrylate
- Efficacy of Injectable Collagen to Correct Glottal Insufficiency
- Peritoneovenous Shunt for Treatment of Ascites
- Spinal Cord Stimulation for Artificial Respiration in Humans

- AdvaMed Device Submissions Workshop May 25, 2005

## Devices that have received OOPD Grants

- Spinal Cord Stimulation for Artificial Respiration in Humans
- UV Device (Fenwal 4R4440) for Transfusion
- Mechanical Exsufflation for                        Non-Trached Ventilator Users
- Clinical Trial of Pulmonary Angioscopy
- Coagglutinin and von Willebrand Disease

- AdvaMed Device Submissions Workshop May 25, 2005

## Application Process

- Annual *Federal Register* notice
- Administrative review
- Convene ad hoc panel of outside experts for scientific review
- Prepare summary statements
- Present to Advisory Council
- Advise - Fund - Monitor

- AdvaMed Device Submissions Workshop May 25, 2005

## Application Process

- 60-100 applications annually
- 20-25% approved
- 9-12 month review
- OUS applications eligible

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Grants Program

- Study is a clinical trial
- Prevalence < 200,000 U.S. patients
- Study must be performed under an   approved IND/IDE (except medical foods)
- Budget is within limits
- Availability of sufficient product

**Program Review Criteria:**

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Grants Program

- Note:
- Study may qualify for OOPD Grant EVEN if not qualified for HUD
- OOPD Grant Award does not confer/imply HUD designation or HDE approval
- Study of approved product for unapproved indication eligible for OOPD grant

**Program Review Criteria:**

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Grant Program

- Soundness of the rationale
- Appropriateness of study design
- Statistical justification for proposed enrollment - POWER
- Potential for patient accrual
- Investigator/support staff qualifications

**Scientific and Technical Merit Criteria:**

- AdvaMed Device Submissions Workshop May 25, 2005

## Orphan Products Grant Program

- Adequacy of resources and environment
- Budget Justification
- Informed consent documents and     IRB approval
- Potential for completion of study    within stated time and budget

**Scientific and Technical Merit Criteria:**

- AdvaMed Device Submissions Workshop May 25, 2005

## Management of Funded Grants

- Assignment to Project Officer
- Liaison between grantee and FDA review division
- Enrollment goals/achievement
- Quarterly progress updates
- Site visits to assure grant compliance
- Sponsor acquisition
- Continuation funding dependent on progress

- AdvaMed Device Submissions Workshop May 25, 2005

## Grants Program Accomplishments

**39** approved orphan products got orphan grant funding
- Hundreds of publications, abstracts, and presentations have been produced as a result of orphan product grant studies

- AdvaMed Device Submissions Workshop May 25, 2005

## The Humanitarian Use Device Designation Program

- Manufacturers seeking premarket approval for new medical devices ordinarily must show that products are safe and _effective_.
- To encourage development of medical devices for rare diseases, FDA will approve such devices if  manufacturers demonstrate the safety and _probable benefit_ to patients.

- AdvaMed Device Submissions Workshop May 25, 2005

## The Humanitarian Use Device Designation Program

- A Humanitarian Device Exemption (HDE) is a provision that exempts sponsors of devices for orphan diseases from the effectiveness requirements of the medical device law, provided the device meets safety conditions and will not expose patients to significant or unreasonable risk.

- AdvaMed Device Submissions Workshop May 25, 2005

## The Humanitarian Use Device Designation Program

- A Humanitarian Use Device (HUD) is a medical device intended to benefit patients in the diagnosis and/or treatment of a disease or condition that affects or is manifested in fewer than 4,000 patients per year in the United States (incidence).

- AdvaMed Device Submissions Workshop May 25, 2005

## The Humanitarian Use Device Designation Program

**Two-step process**:
- HUD designation request submitted to OOPD
- _After_ HUD designation, an HDE application submitted to CDRH             Office of Device Evaluation.

- AdvaMed Device Submissions Workshop May 25, 2005

## HUD Review by OOPD 

- Evaluate rationale and population
- Approve, disapprove, or request    additional information
- Review clock:  45 days

- AdvaMed Device Submissions Workshop May 25, 2005

## HDE review by CDRH

- Ensure HUD designation
- Explanation why device would            not otherwise be available
- Statement that no comparable       device exists
- Amount charged
- Device description
- No user fee

- AdvaMed Device Submissions Workshop May 25, 2005

## HDE review 

- Preclinical testing
- Clinical experience:  data, literature, investigation(s)
- Manufacturing information
- Labeling (physician and patient), including HUD statement

- AdvaMed Device Submissions Workshop May 25, 2005

## HDE review 

- Filing decision
- Administrative – is the application complete?
- 30 days
- Substantive Review
- Office of Compliance (manufacturing)
- Office of Communication, Education, and Radiation (patient labeling)
- 75 days
- Panel review possible (but unusual)

- AdvaMed Device Submissions Workshop May 25, 2005

## Outcome of HDE review

- Minor Deficiency Letter (stops clock)
- Major Deficiency Letter (resets clock to 0)
- Approvable pending (stops clock):
- GMP’s
- Final labeling
- Summary of Safety and Probable Benefit
- Approval
- Not approvable

- AdvaMed Device Submissions Workshop May 25, 2005

## HDE vs. PMA

- Both are marketing approvals
- Approval thresholds differ:
- PMA – safety and effectiveness
- HDE – safety and probable benefit
- IRB approval required for HDE
- Profit not allowed for HDE                       (can recover costs of R&D, manufacturing and handling)

- AdvaMed Device Submissions Workshop May 25, 2005

## Statistics

**Since October 1996:**
- 154 HUD Requests received by OOPD
- 104 devices designated as HUDs by OOPD
- 38 devices approved as HDEs by CDRH*
- *2 HDEs went on to PMA approval,                   so currently 36 approved HDEs

- AdvaMed Device Submissions Workshop May 25, 2005

## Issues for HUD review

- Medically Plausible Subsets
- What it is...
- Examples
- What it is NOT...
- Readily identifiable subset
- Group of patients who meet (or do not meet) inclusion and exclusion criteria for a study
- Patients with an unmet medical need
- Examples

- AdvaMed Device Submissions Workshop May 25, 2005

## Issues for HUD review 

- Estimate of incidence of condition
- Is the condition truly rare?
- Is the HUD/HDE seen as a back door to the market?
- What about “off-label” use?

- AdvaMed Device Submissions Workshop May 25, 2005

## Issues for HUD review

- HUD designation does not mean HDE approval is automatic
- Designation is for a disease or condition; marketing approval is for a device indication
- HUD designation may be broader than the final HDE indication (i.e., HDE indication may be narrower than HUD designation)

- AdvaMed Device Submissions Workshop May 25, 2005

## NOTE:

- Use of HDE device is not necessarily limited to the HDE indication
- Device may have other HDE-approved or PMA-approved indications
- Example: HDE-approved PFO closure device is also PMA-approved for VSDs

- AdvaMed Device Submissions Workshop May 25, 2005

## OOPD and CDRH 

- Communication during HUD  designation review
- Acknowledge that with rare diseases   or conditions, may not be enough patients to generate same amount       of clinical data as for more common conditions

- AdvaMed Device Submissions Workshop May 25, 2005

## OOPD and CDRH 

- Collaborate in HUD/HDE Program Review
- Understand intent of each program
- Understand challenges and concerns
- Educational activities
- Stakeholder outreach:  NIH, CDC, academic researchers, patient organizations, regulated industry

- AdvaMed Device Submissions Workshop May 25, 2005

- Office of Orphan Products Development FDA
**5600 Fishers Lane**
**Rockville, MD 20857**
**301-827-3666; 800-300-7469**
**http://www.fda.gov/orphan**

- AdvaMed Device Submissions Workshop May 25, 2005

- Humanitarian Device Exemption Program  CDRH/FDA
**elisa.harvey@fda.hhs.gov**
**301-594-1190 x 106**
**http://www.fda.gov/cdrh/deviceadvice**

- AdvaMed Device Submissions Workshop May 25, 2005