Alternative Approaches to FDA Approval for Drug and Device Firms
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The document discusses alternative approaches for FDA approval of drugs and medical devices, focusing on frameworks such as 'accelerated approval,' 'fast track,' and 'breakthrough therapies.' It outlines eligibility criteria, regulatory processes, and the importance of post-marketing studies for ensuring safety and effectiveness. Additionally, it highlights specific guidelines and modifications regarding the submission of new drug applications and device modifications.
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Fast Track Drugs
• "Fast Track" -- FDAMA § 112 – created new
Section 506 of the Federal Food, Drug, and
Cosmetic Act (“the Act”) – essentially codifies
Accelerated Approval
• Eligibility
– Treats a "serious or life threatening condition“
“life threatening” – same as under Subpart E – 21 CFR 312.81(a) [see
SLIDE 3]
“serious” –
Life threatening
Associated with a morbidity that has substantial impact on day-to-day
functioning & treats a serious aspect of that disease
» To illustrate -- if drug treats alopecia due to Lupus, the indication is
not serious, even though Lupus is; thus drug is not fast track
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![www.duanemorris.com
HDEs …
• Qualifying under SMDA:
– Device treats or diagnoses a condition < 4,000
– Device would not be available but for an HDE and there is no
available comparable device
– Device will:
not expose patients to an unreasonable or significant risk of
illness or injury, and
Probable benefit to health by using device outweighs risk,
taking into account the probable risks and benefits of currently
available treatments [device or otherwise]
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Alternative Approaches to FDA Approval for Drug and Device Firms
- 1. www.duanemorris.com ©2012 Duane Morris LLP. All Rights Reserv ed. Duane Morris is a registered serv ice mark of Duane Morris LLP. Duane Morris – Firm and Affiliate Offices | New York | London | Singapore | Los Angeles | Chicago | Houston | Hanoi | Philadelphia | San Diego | San Francisco | Baltimore | Boston | Washington, D.C. Las Vegas | Atlanta | Miami | Pittsburgh | Newark | Boca Raton | Wilmington | Cherry Hill | Lake Tahoe | Ho Chi Minh City | Duane Morris LLP – A Delaware limited liability partnership Alternative Approaches to FDA Approval for Drug and Device Firms A Compliance2go Seminar February 21, 2013 Michael A. Swit, Esq.
- 2. www.duanemorris.com Standard Disclaimers • Views expressed here are solely mine and do not reflect those of my firm or any of its clients. • This presentation supports an oral briefing and should not be relied upon solely on its own to support any conclusion of law or fact. • These slides are intended to provide general educational information and are not intended to convey legal advice. 2
- 3. www.duanemorris.com Early Efforts to Speed Drug Approval • “Subpart E” Regulations – 53 Fed. Reg. 41516 (October 21, 1988) -- – IND rules – “Procedures for Drugs Intended to Treat Life – Threatening and Severely Debilitating Illnesses” – codified at 21 CFR 312.80 - 312.88 • Basics – “life threatening” – 21 CFR 312.81(a) likelihood of death is high unless disease course is interrupted; and Diseases with potentially fatal outcomes where the endpoint of clinical trial analysis is survival – “severely debilitating” – diseases that cause major irreversible morbidity – 21 CFR 312.81(b) 3
- 4. www.duanemorris.com Subpart E … • Provisions to Speed Development – Early consultation – 312.82 – “to review and reach agreement” on preclinical and clinical studies Pre-IND meetings End of Phase 1 Meetings -- to try to ensure that Phase 2 studies are sufficient to support approval Meeting Process – per 312.47(b)(1) for EOP2 meetings – Treatment Protocols – 312.83 – FDA can ask for if Phase 2 data appear promising – Risk-Benefit Analysis in Review of Applications – 312.84 – Phase 4 Studies – 312.85 4
- 5. www.duanemorris.com Accelerated Approval • Accelerated Approval – very similar to Fast Track (see late slides), but developed by regulation before FDAMA – 21 CFR 314.500-560 – “Subpart H” – promulgated at 57 Fed. Reg. 58942 (Dec. 11, 1992) • Eligible Drugs -- must: – treat serious or life-threatening illnesses – provide meaningful therapeutic benefit to patients over existing treatments 21 CFR 314.500 • Approval can be based on: – a surrogate endpoint that is “reasonably likely” – based on “epidemiologic, therapeutic, pathophysiologic or other evidence” – to predict clinical benefit; or – on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity 21 CFR 314.510 5
- 6. www.duanemorris.com Accelerated Approval • Surrogate Marker – a laboratory measurement, sign or symptom, that if changed by a therapy, would not, in and of itself, be clinically significant enough as a basis to evaluate therapeutic success • Surrogate Endpoint – is a pre-defined change in a surrogate marker that is a primary or secondary outcome of a treatment trial 6
- 7. www.duanemorris.com Accelerated Drug/Biologic Approval … • Evidence to support that a drug has the effect required (see prior slide) – may come from: – epidemiological, pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or other scientific methods or tools.” §506(c)(1)(B) • Still have to do post-approval studies – – but, those studies no longer have to validate a surrogate endpoint or confirm effect on the clinical endpoint – rather, “verify and describe the predicted effect on the irreversible morbidity or mortality or other clinical benefit” 7
- 8. www.duanemorris.com Accelerated Approval • To assure safety, FDA can restrict distribution or impose other post-marketing restrictions, such as: – Distribution limited to certain facilities or types of physicians – Contingent on certain testing 21 CFR 314.520 • Promotional materials – subject to prior review, both before and after approval 21 CFR 314.550 • Phase 4 Studies – commonly required to verify and describe the drug’s clinical benefit • Still exists after FDAMA, but Fast Track may have more flexibility as to eligibility – – e.g., -- even if a drug is approved under Accelerated Approval for a condition, another drug to address that is possible under Fast Track 8
- 9. www.duanemorris.com Accelerated – FDASIA Changes • “Serious or life-threatening disease or condition” • Fast track = accelerated situation with an unmet need • Based on: – determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.” § 506(c)(1)(A) 9
- 10. www.duanemorris.com Accelerated -- FDASIA Changes … • Evidence to support that a drug has the effect required (see prior slide) – may come from: – epidemiological, pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or other scientific methods or tools.” §506(c)(1)(B) • Still have to do post-approval studies – – but, those studies no longer have to validate a surrogate endpoint or confirm effect on the clinical endpoint – rather, “verify and describe the predicted effect on the irreversible morbidity or mortality or other clinical benefit” 10
- 11. www.duanemorris.com Fast Track Drugs • "Fast Track" -- FDAMA § 112 – created new Section 506 of the Federal Food, Drug, and Cosmetic Act (“the Act”) – essentially codifies Accelerated Approval • Eligibility – Treats a "serious or life threatening condition“ “life threatening” – same as under Subpart E – 21 CFR 312.81(a) [see SLIDE 3] “serious” – Life threatening Associated with a morbidity that has substantial impact on day-to-day functioning & treats a serious aspect of that disease » To illustrate -- if drug treats alopecia due to Lupus, the indication is not serious, even though Lupus is; thus drug is not fast track 11
- 12. www.duanemorris.com Fast Track … • Eligibility … – Shows "potential to address unmet medical needs for such condition“ Condition not addressed adequately by an existing therapy Can be non-drug therapy Unmet medical need not limited to efficacy, can also be an improvement in safety or side effects Note – if only other approval is under Accelerated Approval rules, then it is still unmet due to potential Phase 4 Studies of previously-approved drug will undermine the approval of that drug • Have to request designation as Fast Track in writing – at time of filing IND or after (but before NDA/BLA approval) • If eligible, FDA must "facilitate the development and expedite and review" of the drug – using mechanisms similar to with AA – – Pre-IND, EOP1, EOP2, and pre-NDA/BLA meetings 12
- 13. www.duanemorris.com Fast Track … • Approval – as with Accelerated -- can be made on the basis of clinical or surrogate endpoints or under normal approval standards (thus avoiding Phase 4 studies, commonly) • “Rolling NDA/BLA” -- may be eligible to submit – At FDA’s discretion Clinicals must be near completion or done FDA agrees drug continues to meet eligibility criteria FDA agrees preliminary evaluation of data supports a determination that the drug may be effective 13
- 14. www.duanemorris.com Fast Track … • “Rolling NDA/BLA” … – Must provide FDA with a schedule for submitting all sections and FDA must agree to the schedule – done at pre- NDA/BLA meeting – Usually, must be complete sections – Must pay user fees at time of first submission, but review clock does not start until full NDA/BLA submitted – Guidances issued for Pilot programs on rolling submissions – provide additional insight on FDA’s rolling review process Reviewable Units – 10/03 – Scientific Feedback – 10/03 -- 14
- 15. www.duanemorris.com Fast Track … • Can lose status along way – Clinical study data fail to establish benefit – New approvals of other products change the unmet need situation • Promotional Materials – also subject to prior review • Section 113 of FDAMA – requires you to submit information on FT and AA effectiveness clinical studies to www.clinicaltrials.gov • For more info, see 2006 Guidance on Fast Track 15
- 16. www.duanemorris.com Breakthrough Therapies • FDA may accelerate approvals -- § 506(a)(1) • Defined as a drug intended to treat, alone or in combination: – a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstratesubstantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development • Designation – any time at or after submitting IND – FDA – 60 days to decide if a breakthrough therapy – If designated, FDA must act to “expedite development and review of the application” via such measures as meetings and development advice – Guidance – no later than January 2014 16
- 17. www.duanemorris.com Breakthrough Therapies … • Early indications – agency might allow some breakthrough therapies to get to market on the basis of a single study – Janet Woodcock – Bloomberg interview • Vertex – already has two “breakthrough” designations – for two CF drugs 17
- 18. www.duanemorris.com FDA Review Priority System • General NDA classification system – 1 -- New molecular entity – 2 -- New Salt of Previously Approved Drug (not a new molecular entity) – 3 -- New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) – 4 -- New Combination of Two or More Drugs – 5 -- Already Marketed Drug Product - Duplication (i.e., new manufacturer) 18
- 19. www.duanemorris.com FDA Review Priority System • General NDA classification system … – 6 -- New Indication (claim) for Already Marketed Drug (includes switch in marketing status from prescription to OTC) – 7 -- Already Marketed Drug Product - No Previously Approved NDA (e.g., Unithroid) • NDA Review Priority: – S - Standard -- drugs similar to currently available drugs -- 10 month PDUFA clock – P - Priority – “significant” advances over existing treatments (including non-drug) – 6 month PDUFA clock 19
- 20. www.duanemorris.com Review Priority • Can lose Priority status if circumstances change, but not during first review cycle (per CDER) – Key reason -- available therapies change so as to undermine prior conclusion that your drug creates a significant improvement -- see FDA Guidance on “Available Therapy” • Accelerated Approval drugs do not necessarily get Priority Review – contrast “meaningful” (AA) vs. “significant” improvements (PR) 20
- 21. www.duanemorris.com CDER vs. CBER on Priority Eligibility CDER • Significant improvement compared to marketed products (including non- drugs) in the treatment, diagnosis, or prevention of a disease • Does not have to be life threatening see CDER MaPP 6020.3 @ http://www.fda.gov/downloads/AboutFDA /CentersOffices/OfficeofMedicalProd uctsandTobacco/CDER/ManualofPol iciesProcedures/ucm082000.pdf CBER Significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a … Serious or life threatening disease see: CBER SOPP 8405 @ http://www.fda.gov/BiologicsBloodVa ccines/GuidanceComplianceRegu latoryInformation/ProceduresSOP Ps/ucm073481.htm
- 22. www.duanemorris.com Antibiotics – G.A.I.N. • Generating Antibiotic Incentives Now (G.A.I.N.) – new § 505E of the Act – “Qualified Infectious Disease Product” (QIDP) – adds five years to existing Waxman-Hatch exclusivity (including extending, for NCE, period during which ANDA can’t be filed, from 4 to 9 years) – QIDP – “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by …” an antibacterial or antifungal resistant pathogen; or certain “qualifying pathogens” 22
- 23. www.duanemorris.com Antibiotics – G.A.I.N. … • “Qualifying Pathogens” – to be included in a list to be maintained by FDA – includes those pathogens that: – have potential to pose a serious risk to public health (e.g., resistant gram positive; multi-drug resistant gram negative bacteria; multi-drug resistant TB; and Clostridium difficile) – list to be made not later than July 9, 2014 • QIDP Designation – may be requested any time before submitting an NDA – FDA must decide within 60 days • Implementing regulations – due by July 9, 2014 • Priority Review – post-FDASIA QIDP NDAs – get 23
- 24. www.duanemorris.com FDA Flexibility on Data Requirements • FDAMA § 115(a) -- data from one adequate and well- controlled study and confirmatory evidence can be used to show substantial evidence of effectiveness • "Pure" proof of clinical effectiveness may not be needed -- e.g., under “Fast Track,” may be able to use: – Surrogate endpoints – Clinical endpoints – Phase IV study will be needed usually 24
- 25. www.duanemorris.com How to Nail Down What FDA Wants • FDAMA § 119(a) -- – FDA must meet with you on design of studies; and – Any agreement on study design must be written and can't be changed later w/o your consent unless a new safety or effectiveness issue arises later – “Special Protocol Assessments” (SPA) – FDA process for implementing 25
- 26. www.duanemorris.com Is an SPA Always the Answer? • Advantages – Binding on FDA (unless subsequent safety or effectiveness issue arises) – Increases predictability Investment community likes – Must be in writing – 45 Days for FDA to address – can be faster to get to a meeting than some other types of agency meetings • Disadvantages – Process can be iterative – too long going to & fro to get final agreement – Binding on you as well – what happens if you find out something that would make you want to change the trial design? – Less flexibility later on if need to “massage” the data a little
- 27. www.duanemorris.com Phase 4 Studies … • Duties while studies ongoing – Post-Marketing Commitments (“PMC”) – file periodic reports – see 21 CFR 314.81 (for drugs) or 21 CFR 601.70 (for biologics) • Post-FDAAA – now can be required as part of a REMS program 27
- 28. www.duanemorris.com The 505(b)(2) NDA • An application where the applicant does not have a right of reference to data being relied upon – erroneously referred to by some as a “Paper NDA” • Examples of such data: – FDA prior conclusions in an NDA – Published literature • Almost a full NDA – Requires a patent certification – Can get Exclusivity under Waxman-Hatch • Handle like a full NDA – pre-IND to IND to NDA 28
- 29. www.duanemorris.com The ANDA Suitability Petition • Creates an exception to the general rule under Waxman-Hatch that you need a “reference listed drug” to support an ANDA – Examples Dosage form -- tablet to capsule change Strength – usually lower or intermediate if consistent with labeled dosing regimen; higher – rare Route of administration – possible, but rarer PPA Patch -- denied Ingredient – only a single ingredient in a combination drug Different salts – not allowed – Advantage – product line extension – Disadvantage – no exclusivity; anyone else can do same thing; timing is important 29
- 30. www.duanemorris.com Alternative Approaches for Devices
- 31. www.duanemorris.com The Not-so “New 510k Paradigm” • Part of CDRH Reengineering in mid-90’s • Sources: – Guidance – March 1998 – – FAQ – October 1998 31
- 32. www.duanemorris.com The “Special 510k” • Modification to already-cleared device – If change could significantly impact safety or effectiveness, needs a new 510k see also “Deciding When to Submit a 510(k) for a Change to an Existing Device” – 1997 (not the Dec. 2011 guidance,which was revoked by FDASIA) – Subject to design controls as of 1997 • If new 510k needed for a change and the modification does NOT affect – the intended use of the device, or – alter its fundamental scientific technology • Can use summary info generated under design controls to support the 510k 32
- 33. www.duanemorris.com Special 510k … • Must do verification and validation to determine that design outputs meet design inputs • Filing contains a “Declaration of Conformity” with design controls for the change • Processed within 30 days of receipt by CDRH • Ineligible changes – Changes to indications of use – Changes to labeling that impact intended use 33
- 34. www.duanemorris.com Special 510k … • Ineligible changes … – Changes to fundamentalscientific technology Operating principles Mechanism of action e.g., automation of a manual device – Changes in materials In an implant or device that contacts the body or fluids where the material has not been so used before • Examples of eligible changes – Energy type, environmental specs, performancespecs, ergonomics of patient-user interface, dimensionalspecs, software or firmware, packaging or expiration dating, sterilization • General Rule – if need clinical studies, unlikely to get Special 510k 34
- 35. www.duanemorris.com The “Abbreviated” 510k • May be used if any of the following cover the device: – FDA guidance document – Special Controls per Section 513(a)(1)(B) of the Act – An FDA-recognized consensus standard • For an FDA guidance or special controls, submit a summary report saying how you met the guidance or controls during device development and testing • For consensus standards, do same (as in previous bullet), but also include a declaration of conformity to the standard 35
- 36. www.duanemorris.com Reclassification • Traditional Reclassification Petition – Section 513(e) – Slower – 180 days as with any other Citizen Petition • de Novo 510k – for “new” technology – Section 513(f)(2) of Act – result of FDAMA – Old Fiction – have to submit the 510k and then get it denied as NSE; then request reclassification – eliminated by FDASIA – Must give grounds for down classification – In reclassification request, you can recommend the new class and any applicable controls – Faster – FDA has 60 days – Guidance – October 2011 – very detailed and demanding 36
- 37. www.duanemorris.com Humanitarian Device Exemptions (HDE) • Created in 1990 by Safe Medical Devices Act (SMDA) • Humanitarian Use Device (HUD) – per 21 CFR 814.3(n) – device “intended to benefit patients in the treatment of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year” • HDE – a PMA seeking a humanitarian device exemption from the effectiveness requirements of sections 514 and 515 of the Act per Section 520(m)(2) of the Act 37
- 38. www.duanemorris.com HDEs … • Qualifying under SMDA: – Device treats or diagnoses a condition < 4,000 – Device would not be available but for an HDE and there is no available comparable device – Device will: not expose patients to an unreasonable or significant risk of illness or injury, and Probable benefit to health by using device outweighs risk, taking into account the probable risks and benefits of currently available treatments [device or otherwise] 38
- 39. www.duanemorris.com HDEs … • FDA’s Office of Orphan Products must designate the device as a HUD before submitting the HDE to CDRH – per 21 CFR 814.102 • FDA has 75 days to approve the request • Charging: – Originally -- device firm can not charge more than R&D, fabrication and distribution costs – FDASIA change -- Humanitarian Device Exemption (HDE) – now can make a limited profit. Previously, only pediatric devices qualified -- §520(m)(6)(A) 39
- 40. www.duanemorris.com Questions? • Call, e-mail or fax: Michael A. Swit, Esq. Special Counsel, FDA Law Practice Duane Morris LLP San Diego, California direct: 619-744-2215 fax: 619-923-6248 maswit@duanemorris.com • Follow me on: – LinkedIn: http://www.linkedin.com/in/michaelswit – Twitter: https://twitter.com/FDACounsel 40
- 41. www.duanemorris.com About Your Speaker Michael A. Swit, Esq., is a Special Counsel in the San Diego office of the international law firm, Duane Morris, LLP, where he focuses his practice on solving FDA legal challenges faced by highly-regulated pharmaceutical and medical device companies. Before joining Duane Morris in March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes product development, compliance and enforcement, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics and therapeutic biotech products. Mr. Swit has been addressing vital FDA legal and regulatory issues since 1984, both in private practice with McKenna & Cuneo and Heller Ehrman, and as vice president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty drug firm. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of regulatory newsletters and other specialty information products for FDA-regulated firms. He has taught and written on many topics relating to FDA regulation and associated commercial activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at Emory University. 41