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FDA Update: FDA’s increasing expectations, Ways to address and capitalize on them, and Alternate FDA Update: FDA’s increasing expectations, Ways to address and capitalize on them, and Alternate ways to survive in the current environment Mike Druckman, Partner, Pharmaceutical and Biotechnology Practice November 11, 2010 Food and Drug Group / Washington, D. C. Office

Overview • FDA’s Increasing Expectations – Comparative Effectiveness Data – Biomarkers, including genomic biomarkers Overview • FDA’s Increasing Expectations – Comparative Effectiveness Data – Biomarkers, including genomic biomarkers • Ways to Address and Capitalize on Them – Anticipate new expectations; avoid surprises; listen carefully; keep updated; build credibility with FDA – Capitalize on opportunities, and consider creative approaches • Alternate Ways to Survive in the Current Environment – Federal grants and cooperative agreements – Partnerships and licensing deals www. hoganlovells. com 2

FDA’s Increasing Expectations: Comparative Effectiveness Data • Comparative effectiveness data are not statutorily required FDA’s Increasing Expectations: Comparative Effectiveness Data • Comparative effectiveness data are not statutorily required for drug approval • C. Estes Kefauver, co-sponsor of the 1962 Drug Amendments, stated: – It was “only intended that the manufacturer satisfy the Food ad Drug Administration that it (a drug) was efficacious for the use intended and claimed by the manufacturer, not [that] it is better than some other drug or poorer than some other drug. ” • The preamble to the prescription drug labeling rule, 44 Fed. Reg. 37446 (June 26, 1979), stated: – “The Commissioner advises that [section] 201. 57(c)(3)(v) does not require that comparative safety or efficacy data be developed for a drug; rather, it requires that comparative statements of safety or effectiveness in prescription drug labeling be supported by substantial evidence or other adequate scientific evidence. ” www. hoganlovells. com 3

FDA’s Increasing Expectations: Comparative Effectiveness Data • But for years, doctors have been calling FDA’s Increasing Expectations: Comparative Effectiveness Data • But for years, doctors have been calling for more comparative data, to help inform their prescribing decisions • FDA desires more comparative effectiveness data developed during drug development, and that expectation has increased over the years www. hoganlovells. com 4

FDA’s Increasing Expectations: Comparative Effectiveness Data • FDA created a requirement for comparative effectiveness FDA’s Increasing Expectations: Comparative Effectiveness Data • FDA created a requirement for comparative effectiveness in drugs intended to treat lifethreatening and contagious diseases, and those with irreversible morbidity (e. g. , heart attack), where approved therapies already exist, on safety grounds • Articulated in 60 Fed. Reg. 29180 (Aug. 1, 1995) – Acknowledged that superiority to placebo is the norm, but: – “In certain circumstances, however, it may be important to consider whether a new product is less effective than available alternative therapies, when less effectiveness could present a danger to the patient or to the public. ” www. hoganlovells. com 5

FDA’s Increasing Expectations: Comparative Effectiveness Data • FDA has been expanding that concept to FDA’s Increasing Expectations: Comparative Effectiveness Data • FDA has been expanding that concept to cover more categories of drugs, particularly late entrants into crowded therapeutic classes – E. g. Fanapt (iloperidone) – atypical antipsychotic for schizophrenia • • • July 25, 2008 Not Approvable Letter: Even though the sponsor showed superiority to placebo, FDA rejected the application based on concerns that iloperidone demonstrated inferior effectiveness compared to active comparators in the same drug class FDA stated that for schizophrenia, inferior efficacy is a safety risk Ultimately, FDA approved the application because the sponsor showed that apparent difference in effectiveness was skewed, that any difference did not equate to safety risks, and that iloperidone has safety advantages over other drugs in its class – Ultimately, complex comparative analysis was required www. hoganlovells. com 6

FDA’s Increasing Expectations: Comparative Effectiveness Data • The American Recovery and Reinvestment Act of FDA’s Increasing Expectations: Comparative Effectiveness Data • The American Recovery and Reinvestment Act of 2009 (the stimulus bill) provided $1. 1 billion for Comparative Effectiveness Research (CER), all of which had to be appropriated by September 2010 • The Patient Protection and Affordable Care Act of 2010 (the Healthcare bill) provides sustained federal funding for CER through 2019 – It also created the Patient-Centered Outcomes Research Institute (PCORI), a non-profit corporation designed to set priorities and help channel CER funding (with sources for at least $650 million through 2019) www. hoganlovells. com 7

FDA’s Increasing Expectations: Comparative Effectiveness Data • Result of federally funded CER will be FDA’s Increasing Expectations: Comparative Effectiveness Data • Result of federally funded CER will be that more comparative effectiveness data on drugs will ultimately be available • Doctors, patients, and the public will come to expect more comparative effectiveness data for all drugs • Companies will face increased pressure to include such information in labeling, and FDA will face increased pressure to require comparative effectiveness information in labeling and for approval www. hoganlovells. com 8

FDA’s Increasing Expectations: Biomarkers • Definition: A characteristic that is objectively measured and evaluated FDA’s Increasing Expectations: Biomarkers • Definition: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pathological responses to a therapeutic intervention • Examples: – – – Cholesterol Blood pressure QT/QTc interval prolongation Titer levels (suggesting protection against infection) Certain DNA sequences (that cause disease or indicate susceptibility to disease) www. hoganlovells. com 9

FDA’s Increasing Expectations: Biomarkers • FDA has initiated many efforts to develop and validate FDA’s Increasing Expectations: Biomarkers • FDA has initiated many efforts to develop and validate biomarkers to improve drug safety and efficacy – The Biomarker Consortium, a public-private research partnership launched by FDA, the Foundation of the National Institutes of Health (FNIH), and Ph. RMA, has funded multiple biomarker projects – The Critical Path Institute (C-Path), an independent nonprofit institute, created in 2005 by FDA and the University of Arizona, has helped develop drug-induced organ toxicity biomarkers – Oct. 2010,FDA issued a draft Guidance: Qualification Process for Drug Development Tools, to encourage industry to qualify drug development tools like biomarkers www. hoganlovells. com 10

FDA’s Increasing Expectations: Biomarkers • 7 biomarkers that signal kidney injury were accepted by FDA’s Increasing Expectations: Biomarkers • 7 biomarkers that signal kidney injury were accepted by FDA in May 2008 (and by EMA) for use in preclinical tests – Qualified based on a data package developed by the Predictive Safety Testing Consortium • www. hoganlovells. com a group of 16 companies formed by C-Path to allow firms to pool the resources to develop biomarkers for preclinical safety testing 11

FDA’s Increasing Expectations: Biomarkers • Biomarkers for drug-drug interactions based on effect on transporter FDA’s Increasing Expectations: Biomarkers • Biomarkers for drug-drug interactions based on effect on transporter proteins – Drugs are actively transported into and out of cells by a variety of transporter proteins – Certain drugs are substrates of those transporter proteins • • • interfere with transporter proteins’ activity affect the body’s ability to metabolize them cause drug-drug interactions – This past March (2010), FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology voted that all new molecular entities should be routinely evaluated during drug development for whether they are substrates of five critical transporter proteins • Pre-clinical expectations are constantly evolving www. hoganlovells. com 12

FDA’s Increasing Expectations: Genomic Biomarkers • One class of biomarker of particular interest to FDA’s Increasing Expectations: Genomic Biomarkers • One class of biomarker of particular interest to FDA is the genomic biomarker – Defined as: “A measurable DNA and/or RNA characteristic that is an indicator of normal biological processes, pathogenic processes, and/or response to therapeutic or other interventions. ” – Pharmacogenomics (PGx): “The study of variations of DNA and RNA characteristics as related to drug response. ” • Explores ways to predict whether a patient will have a good or bad response to a drug, or no response at all • PGx is a category of personalized medicine - the concept that people’s differences in genetic makeup, environment, and lifestyle are critical factors in the diseases to which they are susceptible and therapies to which they will respond www. hoganlovells. com 13

FDA’s Increasing Expectations: Genomic Biomarkers • Pharmacogenomic information is contained in about 10% of FDA’s Increasing Expectations: Genomic Biomarkers • Pharmacogenomic information is contained in about 10% of approved drug labels – List of validated genomic biomarkers in drug labeling: http: //www. fda. gov/Drugs/Science. Research/Research. Are as/Pharmacogenetics/ucm 083378. htm – Can play an important role in: • • • www. hoganlovells. com Identifying responders and non-responders Avoiding toxicity Adjusting drug dosages to optimize their safety and efficacy 14

FDA’s Increasing Expectations: Genomic Biomarkers • Most labels, to date, do not provide an FDA’s Increasing Expectations: Genomic Biomarkers • Most labels, to date, do not provide an immediate recommendation for a specific action (like genetic testing) • Some labels recommend or require genetic testing to be used for reaching a therapeutic decision, e. g. , – Erbitux (cetuximab): indicated for patients with Epidermal Growth Factor Receptor (EGFR)-expressing metastatic colorectal cancer – Herceptin (trastuzumab) is indicated for patients whose tumors have been evaluated with an assay validated to predict overexpression of the protein known as human epidermal growth factor receptor 2 (HER 2) www. hoganlovells. com 15

FDA’s Increasing Expectations: Genomic Biomarkers • FDA encourages all sponsors conducting pharmacogenomic tests to FDA’s Increasing Expectations: Genomic Biomarkers • FDA encourages all sponsors conducting pharmacogenomic tests to submit the results to FDA, but only require the submission in certain circumstances: – For INDs: • • • Where the test results relate to a valid biomarker Where the results are used to inform clinical trial decisionmaking Where the results are used to inform drug use decisions (like dose selection and schedule) – For NDAs / BLAs: • • Where the test results relate to a valid or probable valid biomarker When the results will be included in the drug’s labeling or will be submitted to support approval • All other exploratory or observational PGx data may be submitted to FDA on a voluntary basis, as a Voluntary Exploratory Data Submission (VXDS) www. hoganlovells. com 16

FDA’s Increasing Expectations: Genomic Biomarkers • A VXDS will not be used for regulatory FDA’s Increasing Expectations: Genomic Biomarkers • A VXDS will not be used for regulatory decision making and will not impact FDA’s review • FDA encourages VXDS because it can benefit both the industry and FDA in a general way by providing a means for sponsors to ensure that regulatory scientists are familiar with and prepared to appropriately evaluate future genomic submissions. • FDA issued the October 2010 draft guidance on the qualification process for drug development tools in part to encourage sponsors to collaborate in qualifying genomic biomarkers www. hoganlovells. com 17

FDA’s Increasing Expectations: Genomic Biomarkers • Required pharmacogenomic data will be evaluated by FDA FDA’s Increasing Expectations: Genomic Biomarkers • Required pharmacogenomic data will be evaluated by FDA as part of the standard review process • Based on its assessment, FDA may include pharmacogenomic data in the drug label, either in an informational manner (that can be considered by the physician) or to identify appropriate dosages or patients www. hoganlovells. com 18

FDA’s Increasing Expectations: Genomic Biomarkers • FDA has issued significant other guidance on genomic FDA’s Increasing Expectations: Genomic Biomarkers • FDA has issued significant other guidance on genomic data, e. g. : – Guidance for Industry: Pharmacogenomic Data Submissions (March 2005), http: //www. fda. gov/downloads/Regulatory. Information/Guidances/UCM 126957. pdf – Attachment to Guidance on Pharmacogenomic Data Submissions: Examples of Voluntary Submissions or Submissions Required Under 21 CFR 312, 314, or 601 (March 2005), http: //www. fda. gov/OHRMS/DOCKETS/98 fr/2003 d-0497 -gdl 000201. pdf – E 15 Definitions for Genomic Biomarkers, Pharmacogenomics, Genomic Data and Sample Coding Categories (April 2008)(ICH), http: //www. fda. gov/downloads/Drugs/Guidance. Compliance. Regulatory Information/Guidances/ucm 073162. pdf – Genomics: Frequently Asked Questions, http: //www. fda. gov/Drugs/Science. Research/Research. Areas/Pharmac ogenetics/ucm 083893. htm www. hoganlovells. com 19

Ways to Address and Capitalize on FDA’s Increasing Expectations • Anticipate new expectations – Ways to Address and Capitalize on FDA’s Increasing Expectations • Anticipate new expectations – Where at all unclear, ask explicitly whether comparative effectiveness data and biomarker data (including genomic biomarker data) will be required – Ask on the record in a setting where FDA must produce official minutes, such as during a formal pre-IND meeting – Ask details about the nature and extent of the data, and about the requirements for designing the trial and qualifying the biomarkers – Having FDA responses in writing helps avoid miscommunications, and forces FDA personnel to focus as a group on the key issues – Although FDA can change its mind based on developments in science or on new facts, sometimes having a strong record can provide a basis for changing FDA’s view (e. g. , iloperidone example), for obtaining concessions from FDA, or for a formal appeal if necessary www. hoganlovells. com 20

Ways to Address and Capitalize on FDA’s Increasing Expectations • Avoid surprises to the Ways to Address and Capitalize on FDA’s Increasing Expectations • Avoid surprises to the extent possible – Seek bad news early, in full detail • Although FDA will occasionally issue a complete response based on something totally new and not previously discussed, often they involve issues FDA or the sponsor raised, which the sponsor incorrectly believed were resolved – Keep in mind that FDA personnel do not know your product or your submission as well as you do • • • www. hoganlovells. com They sometimes base their advice, at least in part, on what you tell them during meetings – be transparent and direct; do not assume they have read everything (example of separate BLA issue) Particularly during early development, they do not have time to review everything in your IND files in depth Although FDA personnel have a lot of experience, they are not clairvoyant and cannot predict everything that might go wrong with your drug development program or whether a certain trial design will be optimal 21

Ways to Address and Capitalize on FDA’s Increasing Expectations • On the other hand, Ways to Address and Capitalize on FDA’s Increasing Expectations • On the other hand, FDA personnel are privy to nonpublic information about drug development programs that failed • If they ask for particular tests or data that appear out of the blue, it often is because they have seen a problem with a related investigational drug that they need to rule out – listen carefully – read between the lines for clues www. hoganlovells. com 22

Ways to Address and Capitalize on FDA’s Increasing Expectations • Keep updated – Science Ways to Address and Capitalize on FDA’s Increasing Expectations • Keep updated – Science and regulatory expectations are evolving quickly – FDA will expect you to incorporate regulatory changes (e. g. , the requirement imposed this past March that all new molecular entities be tested for whether they are substrates of 5 specific transporter proteins that influence drug metabolism) into your development program, even if the change occurred after your pre-IND meeting • Think proactively – Design trials strategically • www. hoganlovells. com E. g. , consider implications of active controls (like iloperidone) 23

Ways to Address and Capitalize on FDA’s Increasing Expectations • Build credibility with FDA Ways to Address and Capitalize on FDA’s Increasing Expectations • Build credibility with FDA – Demonstrate your familiarity with evolving science and regulatory requirements by asking about whether they apply, citing specific guidance documents – To the extent a new guidance or regulatory expectation applies, acknowledge it and demonstrate your understanding and plan to comply (unless you have a basis to object or seek an exception, in which case do so directly) – The relationship you establish early on with FDA is critical • www. hoganlovells. com Don’t be the company that FDA brands as the one that “just does not get it” 24

Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Opportunities for earlier and more frequent conversations with FDA • E. g. , to discuss qualification of biomarkers and design of comparative effectiveness trials – Use or build on already-qualified biomarkers • • www. hoganlovells. com Under the Drug Development Tool (DDT) Qualification guidance, “Once a DDT is qualified for a specific context of use, industry can use the DDT for the qualified purpose during drug development, and CDER reviewers can be confident in applying the DDT for the qualified use without the need to reconfirm the DDT’s utility. ” CDER intends to make DDTs available to the public, such as by issuing new qualification determinations as draft guidance appendices to the DDT Qualification guidance 25

Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Join or partner with consortia or other organizations to defray costs of developing biomarkers – Qualifying a biomarker or implementing a clinical trial arm with an active comparator may give FDA more assurance in the drug’s safety and efficacy • Ultimately may speed the review process and eliminate multiple review cycles – Possibly qualify for accelerated approval (21 CFR Part 314 Subpart H) – On the other hand, early detection of a safety signal might help a sponsor cut its losses early, or alternatively, to come up with an alternate strategy, like focused warnings or a REMS, early in the development process, making it easier to implement www. hoganlovells. com 26

Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on Opportunities – Narrow indicated population to those for whom drug will be effective with a favorable safety profile • • Increase chances of approval Increase likelihood of showing equal or superior efficacy compared to an existing therapy (synergy between biomarkers and comparative effectiveness) – With a favorable head-to-head trial, obtain data to use in comparative advertising and promotion • www. hoganlovells. com But: proceed cautiously – under 21 CFR 201. 6, a false or misleading representation in the labeling of one drug with respect to a second drug or device renders the first drug misbranded 27

Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on benefits – Ways to Address and Capitalize on FDA’s Increasing Expectations • Capitalize on benefits – Use creative strategies to capitalize on benefits – E. g. , if using PGx testing narrows the indicated population to satisfy the criteria for an Orphan Drug (under 200, 000 patients in the U. S. ), seek Orphan Drug Designation and obtain the benefits of an Orphan Drug Approval, including: • • • www. hoganlovells. com 7 years of exclusivity for that use Annual grant funding to defray the cost of clinical testing Tax credits for the cost of clinical research Assistance with clinical research designs Waiver of PDUFA filing fees 28

Alternate ways to survive in the current environment • Government Grants and Cooperative Agreements Alternate ways to survive in the current environment • Government Grants and Cooperative Agreements – As discussed above, comparative effectiveness research will be funded through 2019 – Although most CER grants issued so far went to Universities, non-profit organizations, and some private consulting companies, for-profit companies, including pharmaceutical, biotech, and medical device companies, are eligible if their proposals meet the criteria • At least one CER grant was issued to a biotech company – Was a continuation of a prior Small Business Innovative Research (SBIR) grant – To develop an angiotensin peptide for treating chronic diabetic ulcers – In collaboration with scientists at the USC KECK School of Medicine www. hoganlovells. com 29

Alternate ways to survive in the current environment • Government Grants and Cooperative Agreements Alternate ways to survive in the current environment • Government Grants and Cooperative Agreements – Possible strategy: partner with academic researchers or non-profits on a CER grant – Another possible strategy: if your product has any biodefense or medical countermeasure use, seek a government grant or cooperative agreement, through the Department of Health and Human Service’s Biomedical Advanced Research and Development Authority (BARDA) • • www. hoganlovells. com HHS announced a new initiative in August to improve the nation’s medical countermeasure enterprise BARDA issues RFPs in this area, including one in August seeking the development of animal models for testing medical countermeasures 30

Alternate ways to survive in the current environment • Partnership strategies – Common for Alternate ways to survive in the current environment • Partnership strategies – Common for companies to license out their inventions to marketing partners – Also common to use CROs and CMOs to reduce costs – Medical device companies with novel delivery systems, like autoinjectors and patches, can partner with drug/biotech companies to produce combination products • FDA has indicated that standards for generics to obtain approval will be fairly strict – See FDA Response to Citizen Petition by King Pharmaceuticals on ANDAs referencing products with autoinjector delivery systems, July 29, 2009, Docket Nos. FDA-2007 -P-0128 and FDA-2009 -P-0040. – See also FDA draft guidance, Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products (April 2009) www. hoganlovells. com 31

Alternate ways to survive in the current environment • In due diligence, potential partners Alternate ways to survive in the current environment • In due diligence, potential partners and buyers usually assess potential generic competition – Thus, having a lifecycle management plan is critical • Medical device companies with genomic biomarkers or expertise may be able to partner with drug and biotech companies to pursue a personalized medicine labeling strategy that lengthens the drug’s lifecycle www. hoganlovells. com 32

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