Overview%20of%20Drug%20Development:%20From%20Lab%20to%20Market%20to%20Generic

1
Overview of Drug Development From Lab to Market
to Generic

• Presented by Scott Gottlieb, M.D.
• American Enterprise Institute for Public Policy
  Research

2
Session Objectives

• In this session, we will
• Discuss the usual process a product undergoes
  from development through to launch
• Laboratory Research
• Pre-clinical Testing
• Investigational New Drug Approval
• Clinical Trials
• New Drug Application Approval
• Post-Marketing Commitments

3
The Path from Test Tube to Patient
The intersection of business strategy and public
policy
4
The Typical Path Requires Several Testing Stages,
FDA Approvals, and Commercialization
10 to phase 1
Pre-clinical Testing
Phase 1 Trials
IND
250 to pre-clinical testing
3 to phase 2
Research
Phase 2 Trials
Phase 4 Studies
Millions of compounds
2 to phase 3
FDA Approval
Phase 3 Trials
NDA/ BLA
Product Launch
Pharma Activity
1 approved
5
The Process Starts with Laboratory Research

• Understand normal and abnormal body functions
• Understand mechanism underlying disease with
  unmet need
• Develop concept for a potential drug

Basic (Bench) Research

• Identify mechanism associated with disease
  (target)

Target Identification

• Assess target association with disease
• Assess target ability to regulate compounds in
  the body
• Confirm that interactions are associated with
  desired change in diseased cell behavior and have
  potential for intervention with a drug
• Identify compounds that effect target

Target Validation
Specific to drugs biologics undergo a similar
process
6
The Process Starts with Laboratory Research
(continued)

• Discover or invent compound that alters the
  target
• Compare to known substances to estimate
  likelihood of success
• Develop potential leads as collections, or
  libraries, of molecules and test each to confirm
  effect on the drug target

Compound Selection

• Compare various compound properties to assist in
  selection
• Alter compounds to increase potential efficacy
  and minimize potential side effects, adjust PK/PD
  parameters

Compound Optimization
Specific to drugs biologics undergo a similar
process Pre-clinical studies often occur
concurrent with compound optimization
7
Potential Drugs Undergo Pre-clinical Testing

• Pre-clinical testing assesses how much compound
  is absorbed, how the body breaks it down, and how
  it reacts to, or excretes, break-down products,
  how it hits its intended target
• Uses two or more species of living animals
  because the potential compound may affect species
  differently
• Determines the potential drugs safety at
  different doses
• Identifies any toxic side effects, latent
  toxicities (carcinogenicity)
• Assesses on target effects, off target effects
• Provides information for the design of proposed
  human studies

Specific to drugs biologics undergo a similar
process
8
The FDA Must Approve Progression to Clinical
Testing
Investigational new drug (IND) application process

• The FDA reviews
• Pre-clinical test results
• Manufacturing information
• Human test plans

Local institutional review boards (IRBs)
concurrently review the clinical trial protocols
30 days for review
Chart is from http//www.fda.gov/cder/handbook/ind
.htm
9
Clinical Trials Establish Safety and Efficacy in
Humans
Phase One Phase Two Phase Three
Assess Safety (and sometimes efficacy) Assess Efficacy Further Assess Safety and Efficacy
20-80 healthy volunteers 6-12 months 50-300 subjects 12-24 months 100s-1000s of subjects 18-24 months
Most frequent side effects How the drug is broken down excreted Sometimes done in patients with condition being studied (cancer) In people with the disease or condition compared to those receiving a placebo Short-term side effects Basis for discussion with FDA on how to conduct Phase 3 Different populations Different dosages Combinations with other drugs
Specific to drugs biologics undergo a similar
process
10
The FDA Must Approve the Drug Before Launch
New drug application (NDA) process

• 10 month review
• Approved Can be marketed in the US
• Approvable Not officially approved can probably
  be approved after resolving specific issues
• Not Approvable Deficiencies that make it unclear
  that it can be approved in the future

60 days to decide if file is ready for review

• Assess
• Safety efficacy
• Appropriate drug labeling
• Adequate manufacturing methods

Consider reviewer assessments
Chart is from http//www.fda.gov/cder/handbook/nda
.htm Some biologic products must submit a
biologic license application (BLA) instead
11
The Company Prepares for Product Launch During
FDA Review and Approval

• Define the current market and target customers
• Set prices, have some advance discussions with
  payers where permissible
• Determine distribution strategy, REMS, post
  market safety management
• Determine strategies to address reimbursement
  hurdles
• Define label strategy (life-cycle planning,
  follow-on studies and indications)
• Execute launch plan

Company launches drug at a time they determine
appropriate, not necessarily immediately after
FDA approval
12
Post Launch Consists of Life-Cycle Management

• Monitor product performance, e.g. revenue and
  market share
• Tackle barriers to adoption, compliance
• Address market or competitive changes
• Incorporate new clinical findings, expanded
  indications, new formulations

13
Some Drugs Take a Different Path

• New drugs may undergo an expedited review
  process
• Drugs classified as a real advance over available
  treatments undergo a 6 month priority review
  instead of the 10 month standard review
• Drugs that treat a range of serious diseases and
  fill an unmet need may request and receive a
  fast track designation at any point during drug
  development
• Fast track drugs are eligible for accelerated
  approval or rolling review
• Accelerated approval uses findings that are
  likely to predict clinical benefit rather than
  direct measurements results
• Rolling review allows companies to submit
  completed NDA sections individually rather than
  the entire application all at once, allowing
  earlier resolution to potential problems

Accelerates review but does not guarantee
approval
14
Phase 4 Studies Monitor and Gather Additional
Data

• Post-marketing commitments can occur when
• FDA requests phase 4 studies, often before
  approval, and sponsor agrees (most phase 4
  studies, authority to require studies under
  FDAAA)
• Approved drug that underwent accelerated approval
• Approved drug not adequately labeled for children
  or with incomplete pediatric testing
• Approved drug with only animal data or that could
  not ethically be tested in humans
• Phase 4 studies provide more information, e.g.
  about risks, benefits, efficacy, new indications,
  and optimal use

15
FDA Has Regulatory Authority to Approve Innovator
and Generic Small Molecule Drugs Through the FDCA
Innovator Small Molecule Drug
Generic Small Molecule Drug
Abbreviated New Drug Application (ANDA) 505
(j)(1) pathway
New Drug Application (NDA) 505 (b)(1) pathway
New Drug Application (NDA) 505 (b)(2) pathway
Applicants rely on data from bioequivalent drugs approved by an NDA for expedited approval Typically, existing drugs used to gain approval for new therapeutic indications or new dosage forms, or for use in combination with another drug
Approval via the 505 (b)(1) pathway requires submission of significant clinical trial data, in three phases, proving drug safety and effectiveness drug chemistry information labeling description of manufacturing

• Requires proof of bioequivalence to demonstrate
  that the proposed product is identical to a
  previously approved product based on safety and
  efficacy

FDCA Federal Food, Drug, and Cosmetic Act NOTE
Further detail on strategies for bringing
biosimilars to market are included in Task D
Evaluation of Alternative Strategies for Bringing
Biosimilars to Market
16
Policy and Marketplace Challenges Facing Drug
Developers

• Rising cost of development, and a frontloading of
  clinical development process
• Increasing data demands post market
• Slowing sales ramps, tougher launches
• Declining venture investments, shrinking RD
  budgets as drug margins come down, and
  consolidation of facilities, manufacturing

17
Drug Shortages No Single Cause, or a Single
Solution

• Market for parenteral generics has been squeezed
  by declining profits, margins
• At the same time manufacturing requirements have
  been tightened following safety issues
• End result about 30 of U.S. manufacturing
  capacity is now offline with no clear resolution

18
Prior to the ACA, FDA Approval Pathway Existed
Only for Innovator Biologics

• BLA was created under the US Public Health
  Service Act (PHSA)

• Trials, in three phases, proving safety, purity,
  and potency product information labeling
  manufacturing/ packaging
• Particular emphasis on manufacturing process and
  licensing of facilities

• FDA states that no regulatory authority exists to
  approve generics under PHSA

Note Some older types of biologics are approved
under FDCA pathways, primarily insulin and human
growth hormone.
19
Several Uncertainties Remain for Biosimilars
FDA failed to release guidelines by end of 2011
FDA draft guidance regulations released
Final FDA regulation will likely follow a 60-day
comment period
ACA passes creating the pathway for biosimilars
1Q10 2Q10 3Q10-3Q11 4Q11 1Q12
Vehicle FDA released draft guidance regulations to govern the biosimilar pathway CMS may release guidance on how the agency will treat biosimilars for HCPCS coding assignments linked to payment rates CMS also could release a NCD on biosimilars even in the absence of a biosimilar coming to market and/or in the absence of external requests for a NCD In the absence of a NCD, local contractors could enact LCDs once a biosimilar enters the market Private payers and Medicaid programs likely will evaluate each biosimilar on a case-by-case basis
Drivers Affecting Implementation Companies legally challenging biosimilars or the legislation could slow the release of final regulation Looming questions remain on interchangeability standards despite the release of draft guidance
Opportunity to Influence Interested parties will be able to comment on the draft FDA regulation FDA held a public meeting in December 2010 to hear from interested stakeholders and may hold other meetings in the future Stakeholders can also work directly with individual private payers and Medicaid programs
HCPCSHealth Care Common Procedure Coding System
NCDNational Coverage Determination LCDsLocal
Coverage Decisions