REGULATORY AND OTHER PITFALLS IN

DRUG DEVELOPMENT

Michael A. Swit, Esq.Vice President, Life Sciences

Pharmaceutical Education Associates

From Pipeline to Product: Navigating the FDA Approval

Process

Alexandria, VANovember 30, 2007

2

Disclaimer

• This outline is intended to support an oral briefing and should not be relied upon solely to support any conclusion of fact or law.

• The views reflected in this presentation are solely those of the presenter and do not necessarily reflect the position of my firm, any of its clients, or any of my friends and colleagues that contributed their thoughts to this presentation.

3

WHERE THE PITFALLS LIE

• Overall Planning• Working With FDA• Clinical Trial Execution• CMC Issues• Safety Issues• Labeling• Ingredients – Active And Inactive• Final Sermons

4

OVERALL PLANNING

• Create A Project Plan With Well-defined Go/No-go Decision Points – – Difficult, But Vital To Know When

To Shift Gears.– Plan With The End In Mind – your

ultimate labeling will drive what you need to do – create a “Product Profile” early and try to stick to it.

5

OVERALL PLANNING …

• Make Sure You Are Ready To Go From “R" to “D" – Internally - people and systems; change in mindset

from research to development.– Formulation Has Been Rigorously Reviewed -- so

as to optimize your chances when going into humans.– Once Clinical Evaluation With A Compound

Begins, Preclinical Efficacy Experiments -- should be limited or undergo rigorous review and oversight.

– Educate Scientists And Researchers – on the realities of the demands of development, especially documentation

• Example -- report writing -- may be a weakness in research, but is important in development.  Start early in the process.

6

OVERALL PLANNING …

• Make Sure Regulatory, Clinical, And Sales & Marketing Are All Talking Early On – – Ensure Indication (Thus, Endpoints) Being

Studied Is One You Want To Sell– Some Consideration

• Study Design –while marketing may want superiority if you go for that sort of study and fail, the FDA won’t let you reanalyze  the study for non-inferiority -- hence failed development program…

• Indication Choice – consider limited initial indication that can be the starting point for subsequent bigger indications

– can be key to optimal product lifecycle management

7

OVERALL PLANNING …

• Beware of "Divergent Evolution" between Product Development and Intellectual Property Efforts!  – How Patents Can Evolve

• Attaining patent protection for a novel chemical entity or formulation is a multiyear process,

• In process, claims often become more limited in number and in scope, due to prior art, Patent Examiner concerns, etc 

– Ensure A Strategic Linkage Between The Product Development And Patenting Efforts -- to best assure:

• Patent(s) granted actually cover critical features of the product being studied in clinicals

• Clinicals actually cover patented/able claims

8

OVERALL PLANNING …

• Understand Approval Is Not Enough, Somebody Has to Pay for It!! - coverage (on formulary) and reimbursement (at a reasonable copay tier). – Some keys:

• Label claims -- Is there anything novel you can say?• Comparative effectiveness:

– future of reimbursement– future for competitive/comparative claims

– clinicals will be needed (FDA/FTC)

9

OVERALL PLANNING …

• Other Key Planning Efforts– Product Name –

• Globalize the product name (be careful with different meanings)

• Seek regulatory agency concurrence early.– Find Collateral Support; e.g., Patient

Groups, Thought Leaders• can help with identifying investigators• can help with patient recruitment

– Identify Enemies -- commercial and otherwise (e.g., special interest groups)

• Anticipate their moves (e.g., Citizen Petitions)– Pediatric Assessments -- -need a plan to

address pediatric usage

10

OVERALL PLANNING …• Management

– Must Understand Process.– Must Support Company's Quality System,

Especially As A Company Matures.– Don’t Let Financial Milestones Drive

Development – recipe for disaster (e.g., Refuse To Files, Clinical Holds).

– Contrast:“What is the minimum we need to do to get

approval?"vs.

"What is necessary for us to provide in order to get a first cycle review approval".

[if your CEO thinks first option is OK, time to update your CV]

11

WORKING WITH FDA

• Early interaction -- essential to understanding your path and what you need in your kitbag– FDA encourages and appreciates (usually)

being consulted early in the development stage -- helps build a relationship with Agency that can pay off during the approval process.

– Take advantage of all Regulatory “value-added” initiatives – e.g., Fast Track, Accelerated Approval, Orphan Drug, SPA (but be careful on this)

12

WORKING WITH FDA …• Ensure You Get Agency Agreement On Exactly

What Is The Indication – will drive related labeling language, especially if related to disease, treatment or metrics– Example: “Chronic sinusitis”

• Not in DSM or accepted text books -- really a term of art among ENTs.

• Company – started clinical trials, – Then, went to FDA – “we’re treating chronic sinusitis!!”

• FDA -- “what’s’ that?” -- leading to a rather lengthy debate about symptomatology of “chronic sinusitis”.

• Result – company had already studied something not entirely covered by the now agreed upon definition of “chronic sinusitis” both as to:

– outcomes– method of measuring

• Consequence – also can end up proving a labeled indication that does not jibe with original marketing projections

13

WORKING WITH FDA …

• Safety is Lynchpin Today – – Focus On Signals/AE’s Early

• Ensure personnel evaluating are qualified

– “REMS” – • “Risk Evaluation and Mitigation Strategies”• Future is now – due to Food & Drug

Administration Amendments Act of 2007 –• You Need to control REMS process; don’t let

FDA– Example: anticipate Phase IV, Post-Approval

Study, but drive its design

14

WORKING WITH FDA …

• Logistics: – Understand IND Regulations – especially on

changes:• Amendments• Annual reports

– Keep Detailed Records Of All Interactions between the sponsor and the regulatory agencies.

– After Submission -- Be Very Diligent with Follow-Up.

• Ensure mandatory review milestones are achieved by the reviewer.

• “Force” dialogue if necessary.

15

WORKING WITH FDA …

• Logistics …• Respond To FDA Deficiency Letters and Other

Comments During Review Promptly, Fully, And Honestly

– Know how the system works - if you don't agree with a reviewer's decision, work up the chain of command

– In responding to a deficiency letter:» Respond to FDA's comment in the first sentence. » Give clear and concise responses -- do not ramble

and do not discuss other topics.– In a interacting with an FDA official, if you do not know

the answer to a query, do not guess.» Refer to a colleague who could provide the response.

or tell reviewer you will get back with correct reply

16

WORKING WITH FDA …• Formal Meetings

– Don’t Guess Who’s Coming to Dinner --• FDA:  learn as much as possible about the regulatory agency

meeting attendees – background (full CVs, hot buttons, past publications)

• Company:  carefully pick who you will be taking to the meetings to represent your company – internal people, consultants

– Rehearse, Rehearse, Rehearse: a well-rehearsed meeting = productive meeting

• Anticipate questions -- have a plan of how and who will respond• Use outsiders to prepare – otherwise, you lose perspective

– Consider technology assistance -- for advisory meetings – Hide your lawyers!!

• unless there is a clear legal issue -- and FDA will bring in theirs– Outside Experts –

• Use judiciously• Ensure qualified – and vette their publications and other

statements

17

WORKING WITH FDA …

• Late in Review Process– a tip:– Prepare For An Advisory Committee

Meeting, Even If One Is Not Likely –• helps to marshall your arguments before

hand should the regulatory agencies signal a need to negotiate.

18

WORKING WITH FDA …

• Listen!!– If You Get Regulatory Agency Advice -- Do It!

(well, almost all the time)• Failure to adhere to any given advice may only

subsequently antagonize the reviewer.• Caveat -- If you don’t want to do it or think it’s wrong,

engage FDA promptly to gain its buy-in to your position

– Don’t just ignore FDA and go down your own path

• Keep your Promises!! – A sure way to lose credibility – fail to deliver

what you promised

19

CLINICAL TRIAL EXECUTION

• Unfortunate, But Often Accurate Generalization -- failure to design and execute study properly too often characterizes clinical studies at both small and even large companies

• Inadequate Toxicology Review Prior to Phase I – use an outside set of eyes if you can

20

CLINICAL TRIALS …

• Poor Design Issues: – Result -- leads to protocol violations,

deviations and half effective amendments. – Consequence of deviations, violations

-- study “mutates” – • progress and treatment of first patient barely

resembles last patient -- study population no longer homogeneous

• Final Mutation -- heterogeneous population defies statistical analysis

21

CLINICAL TRIALS …

• Primary Efficacy Endpoints– Must do adequate Phase 2 studies…dose, dosing

regimens, etc. so that you aren’t second guessing the appropriate dose in Phase 3

– Be Sure Endpoint Is Validated And Acceptable to FDA

• this includes Phase 2b studies

• Involve Statisticians In Clinical Design– Don’t Delay Until Problem Occurs – Can Help Define The Study Design At The

Correct Stage -- speeds clinical development process

22

CLINICAL TRIALS …

• Key Opinion Leaders: – Include KOL’s In Clinical Program– But, don’t let Sales/Marketing drive

this•Stark Act issues – distinguish KOL’s from

big ‘scribers•Financial disclosure challenges – cost of

studies vs. consulting fees

23

CMC ISSUES

• Design Product Physical Characteristics To Be As Robust As Possible– Validate And Qualify – e.g., dosage form,

stability, content uniformity – Keep A Lot History/Change Control System At

The Earliest Stage -- even if very rudimentary form (such as memos to file)– it may be important later to track back to what was done even at early stages

• Ideally just as soon as something in "R" starts to show potential of interest to those in "D"!

• Do even if project is still under "Research" control -- don't wait for a refined QA system to be implemented or for the researchers to be trained in drug development concepts. 

24

CMC ISSUES …

• Plan For Commercial Scale Production Early – – pre-NDA meeting is no time to learn that you

need additional stability or a bioequivalence study to qualify your commercial product (e.g., larger scale, imprinting/debossing etc.) against the one studied in development.

• Track And Validate Changes In Processing And Formulations – ensure studied process/formulation will support commercial process/formulation

25

SAFETY

• Detect As Early As Possible– Use Newer In Vitro Approaches to predict

at potential safety problems (if possible)– Cardiovascular Signals – Key Driver (e.g.,

HERG)

• Dose-Response Data --– Seek Early On In Animal Studies (if

possible) – Vital To Ensure Proper Dose for Phase II

26

LABELING

• FDA Concurrence On Main Indication -- NOT Enough -- Must Get Sign-off on Other Key Label Claims – – Example -- secondary endpoints

• TIP -- Prepare optimal labeling and at least three defensible fall-back positions for each key statement.

27

OUTSIDE VENDORS

• Audit Aggressively– Types: CROs, clinical investigators,

contract manufacturers, API makers, nonclinical testing facilities

– Don’t Miss Any• Joint venture partners - e.g., Cialis® - Lilly

manufacturing plant problems - delayed about one year

• MDS problems – analytical testing – delayed approvals

• IRBs - have been shut down in past

28

OUTSIDE VENDORS …

• How To Handle:– Audit SOPs, Training, Documentation &

Follow-Up – keys to auditing• If don’t have internal expertise, hire qualified

consultants (of course, you have to qualify them)

– Insist Contractors Include Sponsor On Document Reviews, such as

• Clinical Protocols• Manufacturing-related [master and production batch

records, analytical data, stability protocols/data, deviations, etc.]

• Nonclinical [draft protocols and reports] documents. 

29

OUTSIDE VENDORS …

• How To Handle:– Keep Control -- do not let a contractor

direct your project– Avoid “CRO Creep” – use stringent

and explicit contract language– Liability - even when you outsource,

you are ultimately liable for what happens -- you still need to have systems and people in place to ensure your vendors are working correctly

30

INGREDIENTS – ACTIVE AND INACTIVE

• Assure Adequate Supplies -- of all components of the product, packaging, etc.

• Naturally-Derived Products– Supply Chain And Cost-of-goods – key

issues down the road as well as with potential investors –

– Investigate Alternative (e.g., synthetic) Sources•Challenge or Opportunity? –

– synthetic source may require new clinicals– may delay or bar generic competition

31

FINAL SERMONS

• Don't Bury Your Head To Problems -- investigate and disclose promptly

• Don't Fall Madly In Love With Your Technology – – You Have To Prove Safety And

Effectiveness – – "I just know it works" -- not the standard

in the Federal Food, Drug, and Cosmetic Act – … your baby may have some warts

32

Call, e-mail, fax or write:

Michael A. Swit, Esq.Vice President, Life SciencesTHE WEINBERG GROUP INC.

336 North Coast Hwy. 101Suite C

Encinitas, CA 92024Phone 760.633.3343

Fax 760.633.3501Cell 760.815.4762

D.C. Office 202.730.4123michael.swit@weinberggroup.com

www.weinberggroup.com

Questions?

33

About your speaker…Michael A. Swit, Esq., is Vice President, Life Sciences at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to clients, both directly and through outside counsel. His expertise includes FDA and CMS development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the food and dietary supplement industries.

Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius.

Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA.

34

For more than twenty years, leading companies have depended on THE WEINBERG GROUP

when their products are at risk. Our technical, scientific and regulatory experts deliver the

crucial results that get products to market and keep them there.

Washington, D.C. ♦ San Francisco ♦ Brussels ♦ Edinburgh