Drug Development Process

Estella Tembe-FOKUNANG (PhD)

Types of Pharmaceutical companies

Pharmaceutical Drug Discovery/Development
Pharmaceutical Drug Delivery Biotech-Pharmaceuticals

Major Challenges to Pharmaceutical Companies

Time and money Competition R&D spending Patent life Price controls Government legislation

Regulatory

requirements Managed health care Cost of new enabling technology Management of alliances and biotech venture

PGRD Therapeutic Areas

Tissue Repair 9% Psychotherapeutics 15% Urogenitals 7%

Allergy/Resp. 9% Pain 2% Osteoporosis 6% Anti-Infectious 2% Atherosclerosis 4%

Obesity 7% Cancer 13% Neurodegeneration 7% Inflammation Diabetes 6%Immunology 4% 2%

Cardiovascular 7%

Pharmaceutical R&D Spending

1999 Total R&D Spending ($ Billions)
New Pfizer
Glaxo/SmithKline Aventis Novartis PNU/Monsanto
90 80 70 60 50 40 30 20 10 0 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr East West North

4.0 3.7 3.1 2.9

2.8
2.6 2.5 2.4 2.1 1.8 1.8 1.7

Johnson & Johnson

AstraZeneca Roche Merck Bristol-Myers Squibb Eli Lilly American Home Products Schering-Plough

$4.7 Billion in 2000

1.2

Financing R&D
Product Sales $B 2000
3.4 1.0 1.3 2.6 1.4 2.1

5.0
1.3

Actual 2000 revenue: $29.5 billion $22.5 billion in prescription drugs

Avenues to Increase Likelihood of Success

45000 40000 35000 30000 25000 20000 15000 10000 5000 0

Reduce CAN-to-POC attrition Earlier evidence of efficacy

Cumulated Cost ($'000)

to FIM

to Phase II

to Phase III

to R2D2(1)

Business Commitment
Resources invested
11 - 15 years from idea to marketed drug versus a 20 year patent life -Estimated cost varies from $300 to $500 million Risks 1 in 5,000 to 1 in 10,000 molecules screened will make it to the market Only 30% of all products invented return more than was invested in them

Drug Discovery Process

Receptor ligands (agonist & antagonists) Knowledge developed in
the last 30 years
Protein-Protein interaction inhibitors Many physiological & pathological processes are mediated by proteinprotein interactions

Enzyme inhibitors
Enzymes important in
controlling many physiological and pathological processes peptides degraded by converting enzymes into inactive fragments

Biologically active

What is drug Development?

Clinical development The process of taking a new chemical entity (NCE) through the stages necessary to allow it to be tested in human Clinical trials testing of novel drug candidates

DRUG DISCOVERY- The Big Questions

Is there a medical need? What is prevalence of the disease? What is the market potential? Do we have a biochemical target? Can we synthesise compounds that are

target selective, potent, in vivo, and bioavailable? Are the compounds efficacious in disease models, show dose response, and are not toxic?

Why Discover New Medicines

Increased discovery of large therapeutic

an increased pharmaceutical

compounds from natural products

companies in the last 50 yrs Academic /research institutions on the increase Progress in understanding disease processes Mechanism to control or eliminate diseases accelerated Need to discover treatment for old and evolving diseases has decreased Inadequacies of current medicines for HIV, Diabetes, Cancer etc Drug resistance of existing medications ex antibiobics, malaria drugs

Why discover New Medicines...

symptom relief/undesirable side effects Resistance and tolerance ineffective against
pathogenic invasions (Tuberculosis, HIV malaria. Changing lifestyle/increase in life span Changing social attitudes creates market for lifestyle drugs. Progress in molecular biology (Sequencing of Human genome) OMICs & protein engineering more understanding of precise disease mechanismBiochem pathways & discovery of new targets

Fundamental Clinical Development

Essentials of Clinical Research
Phases of Drug Development Basics of Drug Development Clinical Research Design

Planning and Initiating a Clinical Trial

Company Sponsored

Investigator Selection Initiating a Clinical Trial

Conducting a Clinical Trial

Company Sponsored

GCP Informed Consents Case Report Forms and Source Documents Safety Reporting Study Close-out
14

The Drug Discovery and Development Process

Registration Full Development

Exploratory Development

Discovery

Essentials of Clinical Research

Phases of Clinical Research Basics of Clinical Research Clinical Study Design

16

Drug Development Process

Research Concept & Preclinical Testing Discover Active Lead Compound
2-20 years research 8,000-10,000 potential Candidate substances 2-3 years development 20-30 remaining Substances

Clinical Trials

Registration, Launch and Sales

2-3 years development 1 remaining substance

3-5 years development

5-10 remaining 4-5 2-3 substances Remaining substances 1 remaining

Research Target Discovery of lead compound Selection of product candidate

Biological Tests Regulatory clearance Pharmacy/ Chemical Development

Clinical Trial Phase 1 Phase 2 Phase 3

Registration Launch with and Health Sales Authorities

Biological Tests

Preparation for Launch

Pharmacy/Chemical Development

17

An Overview: Drug Development Timeline

Research
Discovery Phase Candidate Profiling Phase

Early Development
Pre- Clinical Trials clinical Phase 1 Phase

Full Development
Phase IIa Phase IIb

Life Cycle Management

Phase III Phase IV

CSP
Candidate Selection Point

sPoC
Selected for Proof of Concept

DDP
Development Decision Point

FDP
Full Development Point

3CP

SDP
Submission Decision Point

IND Investigational New Drug

NDA New Drug Application

Phase III Checkpoint

Discovery of Active Lead Compounds

Complicated, time-consuming and costly process
2-20 years

Hundreds to thousands of chemical

Up to 10,000 screened

compounds/biologics/botanicals must be screened

No standard route through which drugs are developed

Some major sources of new drugs:

Synthetic compounds Discovery of a new use for an old-drug Natural chemical

Process:

Research Target Discovery of Lead Compound Candidate Selection

19

Pre-Clinical Research
Animal pharmacology/toxicology testing Is it
safe to proceed to human trials? (The Nuremberg Code)
20-30 substances

Approximately 2-3 yrs development

Minimum FDA requirements:

pharmacological profile Determine acute toxicity in at least 2 species of animals Conduct short-term toxicity studies (2 wks 3 mos)
20

Investigational New Drug Application

(IND)

Documentation that allows investigational clinical testing of a new medicine Must be filed with FDA before drug administered to humans Studies may begin within 30 days of application..if no response from the FDA An IND contains the following sections
Table of contents - Protocols for each planned study Introduction - Investigator Investigators Brochure - Facilities and IRB General investigational plan - Manufacturing and control Previous human experience - Additional information Pharmacology & toxicology

21

Clinical Trials
IND filed first 3-5 years Process:
Clinical Trials - Phase I Phase III On-going Biological tests (safety) On-going formulation work

22

Clinical Trials - Phases

Phase Purpose
Safety, ADME, bioactivity, drug-drug interaction

Subjects
Healthy volunteers or subj. w/ indications Subjects with indications Subjects with indications Subjects with indications

Scope

Length
(per phase)

I II III

20-80

6-12 mos

Short-term side effects & efficacy

Safety & efficacy Basis for labeling, new formulations

Several hundred Hundredsthousands

1-2 yrs

2-3 yrs

IV

New indications, QoL, surveillance

Hundredsthousands

1-5 yrs
23

Phase I
First time in human subjects Small number of healthy volunteers or

severely ill patients Safety profile and dosage range Single and multi-dose studies Pharmacokinetics / pharmacodynamics Open label, often single center Not always performed in the U.S.

24

Phase II
Safety, side effects Efficacy dose response Double-blind, positive control or placebo, multi-center

utilizing a limited number of subjects (100-300); often the first time drug is used in population for which it is intended Phase IIa proof of concept, pilot, feasibility, usually healthy volunteers Phase IIb well-controlled in target population Following completion of Phase II, meet with the FDA to pave the way for pivotal trials

25

Phase III
2 or 3 studies are pivotal (critical) studies
To prove safety and efficacy of primary endpoints Double-blind, positive or placebo control, multicenter Study population resembles the intended population Support package labeling New Drug Application (NDA) Special population, concomitant medications, multiple illnesses, etc. IIIb studies post NDA-submission trial looking at additional indications Pre-NDA meeting with the FDA near conclusion of Phase III 21 CFR 312.47

26

New Drug Application (NDA)

The average NDA is 100,000 pages or longer Must provide all relevant data collected during R&D Consists of:
Index - non-clinical pharm - clinical data non-clinical pharm - human toxicity - CRFs safety update - case report tabulations pediatric data - statistics PK / Bioavailability - patent information / certification ISES (Integrated Summary of Efficacy and Safety) CER (Clinical Expert Report summary of drug impact, how data supports) CSR (Clinical Study Reports)

Can now be filed electronically

(a CTD = Commercial Technical Document) Review process: Target 10 months (but often longer)
27

NDA Review Process

Review Process standard expedited (in the case of life threatening diseases for which the only medications available are of little or limited effectiveness). Results of Review Approvable Approved Denied Negotiation of the labeling process
www.fda.gov
28

Registration & Launch

Product Registration and Launch 2 - 3 years Process:
Register Product with Health Authorities (FDA) Prepare Sales Teams

29

Phase IV
Post-licensure studies to confirm the safety in large
population (after NDA is filed) Phase IV commitments Possible types of studies Compared versus competition Post-marketing surveillance Pharmacovigilance (ADR) Special population Rare event incidences Additional long-term usage safety data Pharmacoecomonic and Quality of Life (QoL)

30

Supplemental New Drug Application

sNDA
Label Changes New Dose New Strength New Manufacturing Process

31

Chronology of the Drug Discovery/ Development Process (cont.)

NDA Process: 1 - 2 yrs
Submit all preclinical and clinical data, CMC, product and packaging, and proposed labeling to FDA FDA review and approval process consists of: Advisory Committee meeting Response to queries Periodic safety updates Label negotiations Product launch Phase IV: Post-marketing safety surveillance, marketing support - comparison with competitors, and new indications/formulations

Chronology of the Drug Discovery/Development Process

Discovery (idea to CAN): 1 - 5 yrs
Preclinical Development (pharmacology,
pharmacokinetics, and toxicology): 1 - 3 yrs

IND Submission Process: 0.1 - 1 yr

Submit all preclinical data, CMC (Chemistry, Manufacturing, and Control), and proposed Phase I studies to FDA

Regulatory Agencies and Regulations/Guidelines

US Food and Drug Administration (FDA)
European Economic Community
Code of Federal Regulations

Japan Ministry of Health, Labor, and Welfare

International Conference on Harmonization (ICH) Guidelines

Policy, guidelines (including ICH), and final approval of JNDA Pharmaceutical and Medical Devices Evaluation Center (PMDEC) performs JNDA review, GCP inspections (outside Japan) Organization for Pharmaceutical Safety and Research (KIKO) reviews/approves clinical trials

Regulatory Agencies and Regulations/Guidelines (Cont.)

Good Laboratory Practice Regulations Good Clinical Practice Regulations Good Manufacturing Practice Regulations Declaration of Helsinki

DRUG PATENT
A drug submitted for authorization to be put in

the market for sale has a patent life span During this period only the company has the sole monopoly of the market to sale the drug under the trade name approved by a regulatory authority. This monopoly ranges between 10-15 years of marketing after which the company losses its patent.
36

PATENT of a drug
If a company wants to continue its patency it must submit a supplemented new drug application document to the regulatory authority to show Label Changes New Dose New Strength New Manufacturing Process

37

GENERIC DRUGS
A copy of a drug produced after the patent life

of a parent drug has expired. It is done after bioequivalent studies have been done to show the same active compound, same bioavailability of the drug or 20% variation. The difference with the parent compound could be formulation of dose.

38

Essential Drugs
Essential drug is a model list of approved drugs by the regulatory
authorities called essential medicines created by the World Health Organization. This list is subject to modification on a regular basis Essential drugs are published and are the only drugs approved by the WHO to be sold in the market for consumption The list was first published in 1977. The 16th edition for adults and the second edition for children were released in March 2009. The list of essential drugs can be obtained at the WHO website, regulatory authorities FDA sites and the Ministry of Public Health

39

Facts.
Over 700,000 physicians in the US, only 4% of them have participated in clinical trials since 1988.1

1: www. Quintiles.com/investigative services

40

Reasons physicians participate in clinical research

Assist in collection of scientific information

Address questions of local importance

Raise scholarly standards

Build reputation among peers and community

Encourage creativity and independent thinking Provide novel therapies for their patients Provide source of revenue
41

Whos Who in Clinical Research

FDA Sponsor (e.g. Pharma, NIH, WHO, etc.)

Contract/Clinical Research Organization (CRO)

Medical Director

Project Manager

Clinical Research Associate (CRA)

Regulatory Personnel

Investigator Sub-Investigator Clinical Research Coordinator Study Subjects (patients)

IRB / IEC

42

Clinical Research Associate (CRA)

Also known as a monitor Assures study is conducted and
documented properly according to requirements (ICH GCP5.18.4)

Operates under FDA regulations and principles of GCP

(Good Clinical Practice)

May be employees of sponsor or CRO, or independent

43

Investigative Sites
Clinical research occurs in a variety
of settings Private practice Private practice with a separate research facility Clinical research facility Academic or hospital research facility Government (e.g., NIH)

ICH GCP 1.59

44

Investigator
Person responsible for the
conduct of the clinical trial at a trial site

Sub -investigator
Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial related procedures and/or to make important trial-related decisions (ICH GCP 1.56)

If conducted by a team,
the investigator is the responsible leader of the team and may be called the principal investigator (PI)
(ICH GCP 1.34)

45

Clinical Research Coordinator (CRC)

May also be called a Clinical Trial Coordinator Often a nurse at the site Functions as extension of investigators Has personal contact with the human subjects Involved in operational duties recruiting scheduling completing CRFs administering tests

Not specifically mentioned in the FDA regulations Rarely may be listed under FDA 1572 as a sub-investigator

46

Institutional Review Board (IRB)

Required for each research institution (minimum 5 members) Must review protocol for:

merit and ethics consent process / documents Types Local found at almost all university/academic centers meets weekly to monthly Central used by clinical research facilities which are without academic affiliation. quicker response 47

IRB
The investigator must furnish the IRB with the following documents for review and approval:

Trial Protocol Written Informed Consent Forms Written Information for Subjects (Advertisements) Information about compensation to patients Investigator Brochure Available (or additional) Safety Information Investigators CV All amendments to study protocol
48

IRB
The IRBs possible responses: approval or favorable opinion modifications required for approval disapproval or negative opinion withdrawal or suspension of an earlier approval

No subjects should be enrolled until the IRB has issued an approval (21 CFR 56.109)

49

Planning and Initiating a Clinical Trial

Investigator selection Initiating a Clinical Trial

Study Documents IRB/IEC Contract/Budget Investigators Meeting Document Filing & Tracking

50

Investigator Selection
FDA mandates that a sponsor shall select only
Are qualified by training and experience as appropriate experts to investigate the drug Provide evidence of such qualifications

investigators (21 CFR 312.53, ICH GCP 4) that:

51

Investigator Selection
Investigator Characteristics Personnel
CRC : trained, certified, full-time? Work schedules Space Equipment

Facility IRB

Patients
52

Investigator Selection
Investigators Characteristics (general) Prior clinical research experience Experience conducting similar research trials Research interests Experience with new and marketed drugs Publications from previous research Current competing trials

53

Investigator Selection
Investigators Characteristics (protocol-specific) Is investigator interested in the study? Does the site have the necessary patient population? (e.g. minority %, drug-nave, etc) If special procedures are necessary, does this site have the capability to do this? Central vs. local IRB. What is the timetable for this study?
54

Investigator Selection
Sponsors Tour of Facility / Site visit Drug Storage On-site Laboratory Exam Rooms and Storage area
CRFs, lab kits, and other study supplies

Special Equipment

ECG, Freezer, lab equipment, defibrillator and rescue meds Desk, phone, access to copier, CRFs, source docs, etc.
55

Place for CRA to monitor

Sample of source documents

Planning and Initiating a Clinical Trial

Investigator selection Initiating a Clinical Trial

Study Documents IRB/IEC Contract/Budget Investigators Meeting Document Filing & Tracking

56

Study Documents

Protocol and Signed Protocol Signature Page Approved Informed Consent Signed Form FDA 1572 Investigator Brochure Case Report Form (CRF) Clinical Trial Agreements and Budget IRB Approvals and membership roster Curriculum Vitae of Investigator(s) and Copy of Medical License Lab Normal Ranges and Certifications Financial Disclosure Forms
57

Study Documents
Informed Consent Form Informed consent is a process

A joint effort by the sponsor and the investigator

Must be approved by the IRB and the sponsor,
and accepted by the investigator

58

Study Documents
Form FDA 1572 The regulatory document which, when signed by the investigator, commits him/her to follow the regulatory requirements under penalty of law.

59

Study Documents
Investigator Brochure (IB)

Provides Information on the drugs

Pharmacology, Toxicology Adverse experience profile

Updated each year

Or sooner if needed, due to amendments

21 CFR 312.53
60

Study Documents
Source Documents

First place where information is recorded, either on

paper or computer

All entries must be signed and dated Include any deviations from the study protocol or
procedures

Record of explanations for unexpected occurrences

61

Study Documents
Case Report Forms (CRFs)

Used to record data on all subjects

Monitored to verify that trial records and data are valid,

accurate, complete, and up to date

Provide data for analysis and reporting after the trial is

completed

Often electronic (eCRFs)

62

Study Documents
Clinic charts, doctors notes, nursing notes, pharmacy
notes, original laboratory results, and patient diaries for each study subject must be available for review by the sponsor and the FDA

Records of all study events and patient visits need to be

maintained

All source documents must be available during routine

monitoring visits

63

Investigators Meeting
Review protocol and procedures Get better acquainted with the sponsor and other
investigators

Answer outstanding questions

Generate enthusiasm for the trial
and for recruitment

Identify potential problems May serve as the initiation visit

64

Investigators Meeting
Study Coordinators and sub-investigators should
also attend the meeting or hold a separate discussion of their own biostatistician, CRAs, and CRO personnel

Sponsor participants include the medical expert,

65

Conducting a Clinical Trial I

Good Clinical Practice Drug Accountability Subject Recruitment Informed Consent Protocol Adherence Case Report Form & Source Document Sponsor Monitoring Safety Reporting

66

GOOD CLINICAL PRACTICE (GCP) BASIC TENETS

Study is well-designed and follows scientific principles IRB approval is required to insure rights and safety of
subjects

Informed consent freely given Sponsor/institution monitors study for GCP compliance Investigator accountable for all drugs/devices

Records must be kept properly

Data must be complete and accurate Quality assurance plans must be in place
67

Drug Accountability
Study Medication

Cannot be shipped until the sponsor obtains all required

documentation (e.g. IRB approval, CVs, etc). Must be verified upon receipt Must be stored ICH 5.14, 21 CFR 312.61, 21 CFR 312.57 in a secured cabinet preferably in a secured room/area per investigators brochure, protocol, or package insert A current log must be maintained. Verified by CRA during visits. ICH 5.18.14
68

Subject Recruitment
Investigators patient population

Referrals from other physicians and clinics

Direct advertisement, which must be approved by
the IRB

69

Informed Consent
Must be obtained before subjects participate in any clinical trial
procedure (21 CFR 50), and must be dated.

Should be written at the 7th grade reading level Must explain medical terms Should be provided in patients native language Should not make it appear that rights have been waived by the
participant or liability released by the investigator, sponsor or institution

Consent is a process
70

Informed Consent
Eight basic elements of informed consent
50.25) (21 CFR
Trial involves research, purpose of the research A description of any reasonably foreseeable risks or discomforts A description of any benefits to the subject which may reasonable be expected from the research A disclosure of appropriate alternative procedures or treatment that may be available to the subject A statement describing the extent to which confidentiality of records identifying the subject will be maintained An explanation as to whether any compensation and whether any medical treatments are available if injury occurs An explanation of whom to contact for answers to questions about the research and research subjects rights A statement that participation is voluntary
71

Protocol Adherence
Research studies must be

conducted as detailed in the study protocol conveyed to the PI in writing; the PI must sign and return signature page to sponsor requires IRB approval

Amendments to the protocol are

Amendment or any change

72

Case Report Form & Source Document

Definition: Case Report Form (CRF)

A printed, optical, or electronic document designed to

record all of the protocol-required information to be reported to the sponsor on each trial subject. (ICH GCP1.11)

Generally organized by subject, visit, and

sequential/chronological order

73

Case Report Form & Source Document

Definition: Source Documents (SD) Original documents, data, and records (e.g., hospital records, clinical and office charts laboratory notes , memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medicotechnical departments involved in the clinical trial).
(ICH GCP 1.52)

74

Sponsor Monitoring
Types of Monitoring visits

Pre-study or evaluation (screening visit)

Initiation
Interim-monitoring

Audit
Close-out
75

Sponsor Monitoring
Purpose To verify
protection of rights and well-being of subjects reported trial data is accurate, complete, and verifiable trial is in compliance with: Protocol and amendments Regulatory requirements Enrollment Drug supply
ICH GCP 5.18.1
76

Safety Reporting
A Federal regulation:

an investigator shall promptly report to the

sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately. (21 CFR 312.64)

77

Safety Reporting
Investigator should report SAEs to sponsor and to IRB

within 24 hours

Serious does not mean severe, which describes intensity Follow up required with subject, sponsor and IRB
ICH GCP 4.11.1 78

Closing Out a Clinical Trial

Close-out Visit Drug Accountability Record Retention

79

Close-Out Visit

A study close-out visit is required

at study completion decision to terminate the study short of completion Drop-out of a site

80

Objectives of the Close-Out Visit

Verify that the investigators study files are
complete

Ensure that regulatory requirements for retention

of records are understood

Review final reporting requirements with the

investigator

Ensure all data is complete Ensure that all supplies are

returned, destroyed or placed in compassionate use
81

Drug Accountability

A final reconciliation of all

study drug

Drug dispensing logs will be

verified against a physical inventory

All drug on-site at the close-out

visit will either be disposed of at the visit or shipped back to the sponsor
82

Record Retention
Essential documents should be retained
until at least 2 years.
CFR 312.62
(Novartis requires 15 years)

It is the responsibility of the sponsor to

inform the investigator/institution as to when these documents no longer need to be retained.
ICH GCP 4.9.5

If an investigator leaves an institution,

he/she must transfer responsibilities for record retention to another physician and notify the sponsor in writing.
83

How to Get Involved in Company Sponsored Research

Company Planned
Work with PI to gain experience Get to know Clinical Research Associate or Regional Scientific Director/Medical Liaison

Investigator Initiated Research

Each company has different process Work with Regional Scientific Director/Medical Liaison

84

Bibliography

Leeson PD & Springthorpe B. 2007 Terstappen et al., 2007 Van der Greef J & McBurney RN 2005 Gabrielson J & Weiner D. 2000. Hsieh S. 1995