Regulatory Class - Oct 31

Question 1

Office of Orphan Products Development (OOPD)

Answer 1

Promote development of products that demonstrate promise for diagnosis/treatment of rare diseases and conditions

Serves in an advisory role to FDA review divisions on issues related to orphan products

1/3 of all approvals are now orphan drugs

Question 2

Orphan Drug Designation

Answer 2

Can be a previously unapproved drug or a new orphan indication for an approved indication

Must submit request for designation prior to submitting a marketing application

Must treat a rare disease that affects fewer than 200,000 in the US. Or it can affect more if there is no reasonable expectation that costs of development would be recovered from future sale in the US (NIH has database and papers for disease prevalence)

Manufacturer must notify FDA at least 1 year prior to discontinuing production of the drug (so they could find another manufacturer - market exclusivity would follow the drug)

Question 3

Orphan Drug Financial Incentives

Answer 3

 Exemption from Prescription Drug User Fees
 Tax credit
 Federal grants for clinical testing
 7 years of market exclusivity from date of approval (extended for an additional 6 months for pediatric indications)

Question 4

Orphan Drug Financial Incentives - Tax Credit

Answer 4

50% of the cost of conducting human clinical trials against Federal taxes owed

Only applicable for testing between designation date and marketing approval

Must be a trial performed in the US under an IND, unless there aren’t enough people in the US to do a trial

The earlier the designation, the more money they’ll get with the credit

Question 5

Orphan Drug Financial Incentives - Orphan Drugs Grants Program

Answer 5

 Phase 1 studies eligible for up to $200,000 per year for up to 3 years
 Phase 2 and 3 studies are eligible for up to $400,000 per year for up to 4 years
 Studies must be conducted under IND

Question 6

Orphan Drug Financial Incentives - Market Exclusivity

Answer 6

 7 years of market exclusivity – no approval given to a subsequent sponsor of the same product for the same indication

Different from a patent that covers the active ingredient and all its uses

Can be withdrawn if manufacturer can’t supply sufficient quantities, the manufacturer waives it, or another sponsor demonstrates clinical superiority

Question 7

Criteria for Clinical Superiority

Answer 7

 Greater effectiveness (effect on clinically meaningful endpoint, usually a direct comparative clinical study is necessary)
 Improved safety (eliminate an ingredient that causes adverse events)
 In the absence of greater effectiveness or safety, the new drug makes a major contribution to patient care (ex. going from 4x a day injections to 1x a month)

Question 8

Orphan Drug Regulatory Incentives

Answer 8

Sponsor may request written FDA recommendations for nonclinical and clinical investigations

Must have specific questions for the FDA; can be for any stage of development; must provide sufficient info to assess questions

FDA may request more info and the sponsor has 90 days to respond

Question 9

Orphan Drug Designation Request Contents

Answer 9

 Sponsor, manufacturer and drug information
 Description of rare disease or condition
 Proposed indications
 Reasons why therapy is needed
 Manufacturer info
 Scientific rationale (demonstrate potential for this therapeutic)
 Data from nonclinical and clinical studies; copies of pertinent publications
 Regulatory status and marketing history
 Documentation supporting rare disease or no reasonable expectation of cost recovery

Question 10

Orphan Drug Designation Request - If claiming no reasonable expectation of cost recovery, must submit:

Answer 10

 All costs incurred or expected to be incurred in course of developing the drug for the U.S.
 If developed outside U.S., data and justification regarding costs incurred outside U.S.
 Production and marketing costs up through first 7 years
 Estimate of U.S. sales revenues for first 7 years (when FDA thinks they’ll make the most money)
 Must include CPA report

Question 11

Orphan Drug Designation Request - Designation of orphan subset of common disease

Answer 11

 Must be medically plausible group

 Plausible bases: toxicologic profile, pharmacologic property, mechanism of action, etc.

Question 12

Why FDA would refuse to grant Orphan Drug Designation?

Answer 12

 Drug is not intended to treat a rare disease or
condition
 Sponsor failed to establish medically plausible basis for expecting drug to be effective
 Drug is the same as an approved orphan drug and sponsor has provided insufficient evidence of possible clinical superiority
 Contains untrue statement of material fact

Question 13

Changing Orphan Drug Designation

Answer 13

Sponsor may amend designation if new info was found and the initial designation was made in good faith, and at the time, prevalence and cost thresholds were met

FDA may revoke designation if request contained untrue statement, omitted material, or doesn’t meet criteria (if drug is approved, it loses exclusivity but not approval)

Question 14

Orphan Drug Progress Reports

Answer 14

Within 14 months after date of designation must submit annual report to OOPD, and every year until submission of marketing approval

Includes:
 Drug development progress
 Review of preclinical and clinical studies
 Coming year’s investigational plan
 Change that may affect product’s orphan drug status

Question 15

Definition of Same Drug

Answer 15

Identical active moiety - the part responsible for the action of the drug

If it’s a large molecule - must have the same principal structural features

The same drug will be considered different if it is clinically superior.

Question 16

Special Protocol Assessment

Answer 16

FDA will review certain protocols to assess whether they are adequate to meet scientific and regulatory requirements
FDA feedback is binding and they respond within 45 days of receipt

FDA will respond only to the specific questions and may request more info; sponsor could request type A meeting after SPA

FDA could setup an Advisory Committee, not open to the public, respond to SPA within 45 days of meeting

Can change agreement if both the FDA and sponsor agree or if the FDA find an essential and substantial scientific issue

Question 17

Special Protocol Assessment: Types of Protocols

Answer 17

 Animal carcinogenicity protocols
 Final product stability protocols
 Phase 3 trial protocols

Phase 3 - FDA to meet with sponsors to reach agreement on design and size of clinical trials intended to form basis of efficacy claim (discuss at end of Phase 2 meeting)

Question 18

Requesting SPAs

Answer 18

 Separate request submitted for each protocol
 Each request is an IND amendment
 Submit to FDA at least 90 days prior to anticipated study start date (cannot submit one after the start date)

Carcinogenicity studies should be discussed at end of phase 2 meetings and a letter of intent should be sent to director 30 days before SPA request

Stability protocols are only reviewed if different from the standard

Question 19

Contents of SPA Requests

Answer 19

Final study protocol
Specific questions regarding the protocol
 Study design, goals, data analysis, etc.
Detailed information regarding:
 Role of the study in overall drug product development
 Design features of the trial – control, duration, assessments
 Proposed labeling

Question 20

Expanded Access

Answer 20

To facilitate the availability of investigational new drugs for:
 Patients with serious diseases or conditions
 No comparable or satisfactory alternative therapy to treat (or diagnoses) the disease or condition

Submission required for each type of expanded access (a new IND or an amendment to an existing IND)

IND effective 30 days after FDA receipt

Question 21

Types of Expanded Access submissions

Answer 21

 Individual Patient IND
 Intermediate-size patient populations
 Treatment IND or treatment protocol

Question 22

Serious disease or condition

Answer 22

 Morbidity that has a substantial impact on day-to-day functioning
 Likelihood that the disease, if left untreated, will progress from less severe condition to more serious condition

Question 23

Immediately life-threatening disease or condition

Answer 23

Stage of disease where there is reasonable likelihood that death will occur within months or premature death is likely without early treatment

Question 24

Criteria for Expanded Access Approval

Answer 24

 Patient has a serious or immediately life-threatening disease or condition and there is no comparable or satisfactory alternative therapy
 Potential benefit justifies the potential risk
(Risks are not unreasonable in context of the disease or condition)
 Providing investigational product will not interfere with a clinical trial or otherwise compromise potential development of the expanded access use

Question 25

Expanded Access Submission Requirements

Answer 25

 FDA Form 1571
 Rationale for intended use and list of available therapies
 Criteria for patient selection or description of individual patient’s disease
 Method of administration of drug, dose, duration of therapy
 Description of facility where drug manufactured
 CMC information, pharmacology and toxicology information
 Clinical procedures, laboratory tests, monitoring necessary to evaluate effects and minimize risks

Question 26

Expanded Access – Individual Patient IND

Answer 26

Compassionate Use
Submission by sponsor or physician must explain that risks from the drug aren’t greater than risks from drugs and that patient couldn’t obtain drug from current IND

Treatment is limited to one course and afterwards physician must write summary with AEs

Question 27

Expanded Access – Individual Patient IND: Emergency use

Answer 27

Make request by phone, fax, or email; FDA can authorize use over the phone

Must justify the emergency use

Sponsor or physician agrees to provide IND submission/amendment within 15 working days

Question 28

Expanded Access – Intermediate Populations

Answer 28

Investigational drug for a patient population smaller than in a typical treatment IND or treatment protocol:
 Drug is not being developed
(Disease or condition is so rare that sponsor is unable to recruit)
patients for a clinical trial
 Drug is being developed but patients requesting expanded access are unable to participate
(Different disease or stage of disease than IND study or clinical trial site not geographically accessible)
 Approved drug is no longer marketed for safety reasons or unavailable due to failure to meet conditions of approval

Sponsor will monitor treatment

Question 29

Expanded Access – Intermediate Populations Submissions

Answer 29

 Explanation whether or not drug is being developed
 Description of patient population to be treated
 If drug is not being developed, explain why it cannot be developed for the expanded access use
 If drug is used in a clinical trial, explain why the patients to be treated cannot be enrolled in the clinical trial

FDA will approve if there is enough evidence that drug is safe at the proposed use and some clinical evidence that provides effectiveness

Question 30

Expanded Access – Treatment IND (Protocol)

Answer 30

Permits widespread use of an investigational drug under the following conditions:
 Drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use
 All clinical trials have been completed
 Sponsor is actively pursuing marketing approval with due diligence

Must be a serious or immediately life threatening disease with sufficient clinical data to show safety and effectiveness.

Question 31

Fast Track Designation

Answer 31

 Facilitate development and expedite review
 For drugs intended to treat serious or life threatening conditions
 That demonstrate the potential to address unmet medical needs

For drugs that treat serious conditions, have superior effectiveness, or reduce significant toxicity; designation for drug and indication, not drug alone

Designation is done during drug developments: from original IND until marketing submission. Designation is submitted as a IND amendment

FDA will respond within 60 calendar days of receipt.

Designation can be withdrawn if it is not an effective drug or if it does’t meet the unmet need (or another drug has met that need)

Question 32

Fast Track Designation Program

Answer 32

More frequent FDA meetings: Pre-IND consultation; End of Phase 1 meeting; End of Phase 2 meeting; pre-NDA meeting; Labeling meeting

*some companies try to make Phase 2 effective to skip a Phase 3

Question 33

Fast Track Designation – Rolling Review

Answer 33

Submission of portions of NDA - can start answering FDAs concerns for the earlier portions submitted
 Request this review in information package for pre-NDA meeting

Question 34

Fast Track Designation – Accelerated Approval

Answer 34

 Available for drug products: Intended to treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments
 Approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit
 Post-approval studies are required to verify and describe the clinical benefit (FDA can terminate if they prove the drug is safe and verifies the clinical benefit)
 FDA may require postmarketing restrictions to ensure safe use of the drug product: restricted distribution

FDA may withdraw approval if clinical benefit can’t be verified; postmarketing studies aren’t performed; drug is not safe

Approval is based on safety not effectiveness (only potential); requires REMS

Question 35

Fast Track Designation – Priority Review

Answer 35

Reduced time for FDA review of NDA/BLA to 6 months (rather than standard 10 months)

Applies to drugs that offer major advance in treatment (improved safety, effectiveness, or compliance) or where no adequate treatment is available

Requested by sponsor prior to submission of NDA and the FDA will respond within 45 days of request; this will not alter requirements of safety and effectiveness for approval

Question 36

Humanitarian Use Devices (HUD)

Answer 36

Intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect fewer than 4,000 people in the U.S. annually; these devices rarely make money

Request designation from OOPD

Marketing approval submitted as HDE; doesn’t contain the usual effectiveness data

Question 37

HUD Designation Request

Answer 37

 Statement that request is for a rare disease or condition or a medically plausible subset
 Sponsor information
 Description of rare disease or condition, proposed indication for use and reasons why therapy is needed
 Description of the device and scientific rationale for use of the device for the rare disease or condition
 Documentation demonstrating device is designed to treat or diagnose a disease or condition that affects fewer than 4,000 people in the U.S. annually (extremely rare)

Question 38

FDA Response to HUD Designation Request

Answer 38

FDA responds within 45 days of receipt
 May request additional information - review period is
extended up to 45 days
FDA may disapprove request if:
 Insufficient evidence to support estimate that disease or condition affects fewer than 4,000 people
 Patient population is not a medically plausible subset
FDA may revoke HUD designation if:
 Request contained an untrue statement of material fact or omitted material information
 Device is not eligible for the HUD designation

Question 39

Humanitarian Device Exemption (HDE) Submission Requirements

Answer 39

 HUD designation
 Explanation why device would not be available unless HDE granted
 Statement that no comparable device is available
 Discussion of the risks and benefits of currently available devices or alternative treatments in the U.S.
 Explanation why probable benefit outweighs risks
 Amount to be charged for device – not exceeding costs of research, development, fabrication, and distribution

Similar to an IDE, even though it’s a marketing application; these are usually PMA devices; no user fee is required

Question 40

Humanitarian Device Exemption

Answer 40

Labeling requires statement that it is a Humanitarian device.

FDA may file within 30 days of receipt (unless it’s incomplete or doesn’t meet HUD designation anymore)

FDA completes review in 75 days of receipt

Device can only be administered with facilities that have IRB approval

FDA can withdraw approval if approval conditions aren’t met; device is ineffective; device isn’t safe, etc

Question 41

Humanitarian Device Exemption Reporting

Answer 41

Sponsor required to submit post-approval reports in accordance with the approval order, including:
 Update of information required in the HUD designation request and the HDE submission
 Number of devices shipped or sold since initial marketing approval
 Clinical experience with the device since initial approval
 Summary of changes to the device

Sponsor must maintain records regarding where HUD shipped and correspondence with IRB

Question 42

IDE Expanded Access - Emergency/Compassionate Use

Answer 42

Allows access for patients who do not meet the requirements for inclusion in a clinical trial
Patients with a serious disease or condition and no alternative device or treatment

Typically for individual patients but may be approved for a small group; FDA approval is required

Question 43

IDE Expanded Access - Emergency/Compassionate Use Submission

Answer 43

Submit IDE supplement requesting protocol deviation
 Description of condition and circumstances necessitating treatment
 Why alternative therapies are unsatisfactory and probable risk is no greater than risk from disease
 Identify any deviations from approved protocol that may be needed in order to treat the patient
 Patient protection measures that will be followed

Must submit a follow-up report to the FDA, including any AEs

Question 44

IDE Expanded Access - Treatment Use

Answer 44

Allows access to investigational device for patients with an immediately life-threatening or serious disease with no comparable or satisfactory alternative treatment available
 Device must be part of a controlled clinical trial for the same use under an approved IDE
 Sponsor must be pursing marketing approval with due diligence

 For serious disease – available at the conclusion of all clinical trials
 For an immediately life-threatening disease – available prior to completion of all clinical trials

Question 45

IDE Expanded Access - Treatment Use Submission

Answer 45

Sponsor submits treatment IDE application
 May begin 30 days after FDA receives the treatment IDE submission

Sponsor must submit progress reports on semi-annual basis to all reviewing IRBs and FDA
 Contents same as IDE progress report

Question 46

IDE Expanded Access - Continued Access

Answer 46

[also called extended investigation]
Allows access to an investigational device while marketing application is being prepared/reviewed
 Following completion of the clinical trial

There must be a public health need or there is preliminary evidence that the device will be effective and there are no significant safety concerns

Question 47

IDE Expanded Access - Continued Access Submission

Answer 47

Requires submission of an IDE supplement to FDA
 Justification of extension
 Summary of preliminary safety and effectiveness data
 Discussion of risks
 Proposed rate of continued enrollment (Number of sites and subjects)
 Clinical protocol – if different from controlled clinical study protocol (Including proposed objectives)
 Discussion of sponsor’s progress in obtaining marketing approval/clearance