Regulatory Class - Oct 31 Flashcards
Office of Orphan Products Development (OOPD)
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
Orphan Drug Designation
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)
Orphan Drug Financial Incentives
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)
Orphan Drug Financial Incentives - Tax Credit
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
Orphan Drug Financial Incentives - Orphan Drugs Grants Program
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
Orphan Drug Financial Incentives - Market Exclusivity
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Can be withdrawn if manufacturer can’t supply sufficient quantities, the manufacturer waives it, or another sponsor demonstrates clinical superiority
Criteria for Clinical Superiority
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)
Orphan Drug Regulatory Incentives
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
Orphan Drug Designation Request Contents
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
Orphan Drug Designation Request - If claiming no reasonable expectation of cost recovery, must submit:
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
Orphan Drug Designation Request - Designation of orphan subset of common disease
Must be medically plausible group
Plausible bases: toxicologic profile, pharmacologic property, mechanism of action, etc.
Why FDA would refuse to grant Orphan Drug Designation?
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
Changing Orphan Drug Designation
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)
Orphan Drug Progress Reports
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
Definition of Same Drug
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.
Special Protocol Assessment
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
Special Protocol Assessment: Types of Protocols
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)
Requesting SPAs
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
Contents of SPA Requests
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
Expanded Access
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
Types of Expanded Access submissions
Individual Patient IND
Intermediate-size patient populations
Treatment IND or treatment protocol
Serious disease or condition
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
Immediately life-threatening disease or condition
Stage of disease where there is reasonable likelihood that death will occur within months or premature death is likely without early treatment
Criteria for Expanded Access Approval
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
Expanded Access Submission Requirements
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
Expanded Access – Individual Patient IND
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
Expanded Access – Individual Patient IND: Emergency use
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
Expanded Access – Intermediate Populations
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
Expanded Access – Intermediate Populations Submissions
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
Expanded Access – Treatment IND (Protocol)
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.
Fast Track Designation
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)
Fast Track Designation Program
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
Fast Track Designation – Rolling Review
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
Fast Track Designation – Accelerated Approval
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
Fast Track Designation – Priority Review
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
Humanitarian Use Devices (HUD)
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
HUD Designation Request
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)
FDA Response to HUD Designation Request
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
Humanitarian Device Exemption (HDE) Submission Requirements
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
Humanitarian Device Exemption
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
Humanitarian Device Exemption Reporting
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
IDE Expanded Access - Emergency/Compassionate Use
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
IDE Expanded Access - Emergency/Compassionate Use Submission
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
IDE Expanded Access - Treatment Use
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
IDE Expanded Access - Treatment Use Submission
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
IDE Expanded Access - Continued Access
[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
IDE Expanded Access - Continued Access Submission
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
