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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%

7 Billion in 2000 1.7 Johnson & Johnson AstraZeneca Roche Merck Bristol-Myers Squibb Eli Lilly American Home Products Schering-Plough  $4.0 3.2 .5 2.1 1.7 3.Pharmaceutical R&D Spending 1999 Total R&D Spending ($ 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 4.6 2.9 2.1 2.8 1.8 1.8 2.4 2.

1 5.5 billion • $22.Financing R&D Product Sales $B 2000 3.5 billion in prescription drugs .0 1.0 1.4 1.4 2.3 Actual 2000 revenue: $29.3 2.6 1.

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) .

000 molecules screened will make it to the market – Only 30% of all products invented return more than was invested in them • .000 to 1 in 10.15 years from idea to marketed drug versus a 20 year patent life -Estimated cost varies from $300 to $500 million Risks – 1 in 5.Business Commitment • Resources invested – 11 .

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 .

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

malaria drugs .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. Cancer etc Drug resistance of existing medications ex antibiobics. Diabetes.

 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 . HIV malaria..  symptom relief/undesirable side effects  Resistance and tolerance –ineffective against pathogenic invasions (Tuberculosis.Why discover New Medicines.

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 .

000-10.000 potential Candidate substances 2-3 years development 20-30 remaining Substances Clinical Trials Registration.Drug Development Process Research Concept & Preclinical Testing Discover Active Lead Compound 2-20 years research 8. 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 .

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 .An Overview: Drug Development Timeline Research Discovery Phase Candidate Profiling Phase Early Development Pre.

Discovery of Active Lead Compounds • Complicated.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 . time-consuming and costly process – 2-20 years • Hundreds to thousands of chemical – Up to 10.

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 .

if no response from the FDA An IND contains the following sections Table of contents ..Investigator Investigator’s Brochure .Additional information Pharmacology & toxicology 21 .Facilities and IRB General investigational plan .Protocols for each planned study Introduction .Manufacturing and control Previous human experience .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….

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 .

QoL. 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.Clinical Trials .Phases Phase Purpose Safety. ADME. surveillance Hundredsthousands 1-5 yrs 23 . bioactivity. new formulations Several hundred Hundredsthousands 1-2 yrs 2-3 yrs IV New indications. drug-drug interaction Subjects Healthy volunteers or subj.

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. 24 .S. often single center Not always performed in the U.

often the first time drug is used in population for which it is intended Phase IIa – proof of concept. meet with the FDA to pave the way for “pivotal trials” 25 . positive control or placebo. side effects • Efficacy – dose response • Double-blind. feasibility.Phase II • Safety. usually healthy volunteers Phase IIb – well-controlled in target population Following completion of Phase II. pilot. multi-center • • • utilizing a limited number of subjects (100-300).

positive or placebo control. multiple illnesses. etc. concomitant medications.Phase III • 2 or 3 studies are pivotal (critical) studies – To prove safety and efficacy of primary endpoints – Double-blind.47 26 . multicenter – Study population resembles the intended population – Support package labeling – New Drug Application (NDA) • Special population. • IIIb studies – post NDA-submission trial looking at additional indications • Pre-NDA meeting with the FDA near conclusion of Phase III 21 CFR 312.

000 pages or longer • Must provide all relevant data collected during R&D • Consists of: – – – – – – – – Index .New Drug Application (NDA) • The average NDA is 100. 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 .case report tabulations pediatric data .CRF’s safety update .patent information / certification ISES (Integrated Summary of Efficacy and Safety) CER (Clinical Expert Report – summary of drug impact.clinical data non-clinical pharm .statistics PK / Bioavailability .human toxicity .non-clinical pharm .

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  28 .

3 years • Process: – Register Product with Health Authorities (FDA) – Prepare Sales Teams 29 .Registration & Launch • Product Registration and Launch • 2 .

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 .

CMC. 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.Chronology of the Drug Discovery/ Development Process (cont. marketing support .) • NDA Process: 1 . product and packaging.2 yrs – Submit all preclinical and clinical data.comparison with competitors. and new indications/formulations .

Chronology of the Drug Discovery/Development Process • Discovery (idea to CAN): 1 . and toxicology): 1 .3 yrs • IND Submission Process: 0. and Control). CMC (Chemistry.1 .5 yrs • Preclinical Development (pharmacology. Manufacturing.1 yr – Submit all preclinical data. and proposed Phase I studies to FDA . pharmacokinetics.

and Welfare – International Conference on Harmonization (ICH) Guidelines – Policy. Labor. 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 • US Food and Drug Administration (FDA) • European Economic Community – Code of Federal Regulations • Japan Ministry of Health.

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


• 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.


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


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

1: www. services


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 .

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 . WHO.g. NIH.Who’s Who in Clinical Research FDA Sponsor (e. Pharma.

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 .

NIH) ICH GCP 1.59 44 .g.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..

34) 45 . the investigator is the responsible leader of the team and may be called the principal investigator (PI) (ICH GCP 1.56) • If conducted by a team.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.

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 Investigator’s CV All amendments to study protocol 48 .

IRB The IRB’s 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 .

53. ICH GCP 4) that: 51 .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.

certified.Investigator Selection • Investigator Characteristics • Personnel – CRC : trained. full-time? – Work schedules – Space – Equipment • Facility • IRB • Patients 52 .

Investigator Selection Investigator’s 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 .

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

access to copier. CRFs. phone. source docs. 55 • Place for CRA to monitor • Sample of source documents . and other study supplies • Special Equipment – ECG.Investigator Selection Sponsor’s Tour of Facility / Site visit • Drug Storage • On-site Laboratory • Exam Rooms and Storage area – CRFs. lab kits. lab equipment. etc. defibrillator and rescue meds – Desk. Freezer.

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 drug’s – Pharmacology.53 60 . – Toxicology – Adverse experience profile • Updated each year – Or sooner if needed. due to amendments 21 CFR 312.

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 Source Documents • First place where information is recorded.

Study Documents Case Report Forms (CRFs) • Used to record data on all subjects • Monitored to verify that trial records and data are valid. and up to date • Provide data for analysis and reporting after the trial is completed • Often electronic (eCRF’s) 62 . accurate. complete.

Study Documents • Clinic charts. 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 . doctors’ notes. nursing notes.

Investigator’s 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 .

CRAs.Investigator’s Meeting • Study Coordinators and sub-investigators should also attend the meeting or hold a separate discussion of their own biostatistician. 65 . and CRO personnel • Sponsor participants include the medical expert.

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 .

protocol.14 68 . 21 CFR 312. CV’s.57 – in a secured cabinet – preferably in a secured room/area – per investigator’s brochure. 21 CFR 312.14. ICH 5. or package insert A current log must be maintained. IRB approval.61. Must be verified upon receipt Must be stored ICH 5. Verified by CRA during visits.g.Drug Accountability Study Medication • Cannot be shipped until the sponsor obtains all required • • • documentation (e.18. etc).

Subject Recruitment • Investigator’s 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). • Should be written at the 7th grade reading level • Must explain medical terms • Should be provided in patient’s native language • Should not make it appear that rights have been waived by the participant or liability released by the investigator. and must be dated. sponsor or institution • Consent is a process 70 .

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 .25) (21 CFR § – Trial involves research.Informed Consent • Eight basic elements of informed consent 50.

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 .

visit.11) • Generally organized by subject. optical. or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject.Case Report Form & Source Document Definition: Case Report Form (CRF) • “A printed.” (ICH GCP1. and sequential/chronological order 73 .

. hospital records. pharmacy dispensing records. at the laboratories. and records kept at the pharmacy.g.” (ICH GCP 1. subjects’ diaries or evaluation checklists. microfilm or magnetic media. copies or transcriptions certified after verification as being accurate and complete. memoranda. and at medicotechnical departments involved in the clinical trial).52) 74 . recorded data from automated instruments. photographic negatives. microfiches. data. and records (e. subject files. x-rays.Case Report Form & Source Document Definition: Source Documents (SD) • “Original documents. clinical and office charts laboratory notes .

Sponsor Monitoring Types of Monitoring visits • Pre-study or evaluation (“screening visit”) • Initiation • Interim-monitoring • Audit • Close-out 75 .

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

or probably caused by. the investigator shall report the adverse effect immediately. the drug. • If the adverse effect is alarming.Safety Reporting A Federal regulation: • “an investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by.” (21 CFR § 312.64) 77 .

” which describes intensity • Follow up required with subject.1 78 .11. sponsor and IRB ICH GCP 4.Safety Reporting • Investigator should report SAEs to sponsor and to IRB within 24 hours • “Serious” does not mean “severe.

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 .

destroyed or placed in compassionate use 81 .Objectives of the Close-Out Visit • Verify that the investigator’s 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.

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 .

ICH GCP 4. CFR 312.9.5 • If an investigator leaves an institution. he/she must transfer responsibilities for record retention to another physician and notify the sponsor in writing.Record Retention • Essential documents should be retained until at least 2 years. 83 .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.

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 .

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