Presentation on theme: "U.S. Regulation of Drug Development and the Role of The Information Professional Alberto Grignolo, Ph.D. Corporate VP and General Manager PAREXEL Consulting."— Presentation transcript:
U.S. Regulation of Drug Development and the Role of The Information Professional Alberto Grignolo, Ph.D. Corporate VP and General Manager PAREXEL Consulting
- 2 - If you had to sign a letter authorizing the availability of a new medicine to 250 million Americans -- What kind of information (and how much of it) would you want to have about the drug? Think about it...
- 3 - What is Drug Development? Discovery Development Commercial Product Launch Sales IIIIIIIIIbIV Basic Research Pre- Clinical Clinical TestingMarketing INDNDA LabMarket SNDAs
- 4 - The Purpose of Drug Development From Lab to Label: The Outcome of Drug Development is the Negotiated Language of the Prescribing Information P.I.
- 5 - What Disciplines Are Involved in Drug Development? Drug Discovery Scientists Pharmacologists Toxicologists Microbiologists Biopharmaceuticists Chemists (Process, Engineers, Organic, Analytical) Clinicians Biostatisticians Information Professionals Regulatory Affairs Project Management Financial Management Executive Management Regulatory Agencies Volunteers Patients Advocacy Groups Investors The Media
- 6 - Drug Development Begins with the End in Mind: Product Labeling New Drug Labeling Description Indication Precautions Warnings Contraindications Dosage / Administration How Supplied Development Pharmacology Toxicology Pharmacokinetics Drug Metabolism Clinical Efficacy Clinical Safety VISION Lit Searches
- 7 - Role of Regulatory Affairs in the Drug Development Universe FDA Clinical Pharmacology ToxicologyBasic Research Biostatistics Biopharmaceutics Senior Management Project Management Regulatory Affairs Regulatory Affairs is the Companys Ambassador to FDA Info Professionals
- 8 - The Regulation of Drug Development In the United States, the entire process of drug development and commercialization is regulated (except the price of the drug, but... just wait)
- 9 - Functions of Regulation To protect patients from harmful medical products To facilitate the availability of beneficial medical products to patients
The legal framework for drug regulation in the United States LAWS REGULATIONS GUIDELINES CONGRESS FDA INDUSTRY
Definitions Laws: legislation passed by the United States Congress and signed by the President Examples: FDCA (Food Drug and Cosmetic Act, 1938) PDUFA (Prescription Drugs User Fee Act, 1992, 1997, 2002) FDAMA (FDA Modernization Act, 1997)
NDA (NME) Approval Time Has Decreased Since PDUFA 1992 Source: FDA
Definitions Regulations: rules issues by FDA consistently with Laws, published in the Federal Register and contained in Code of Federal Regulations (CFR) Examples INDs: 21 CFR 312 NDAs: 21 CFR 314 IRB and Informed Consent (21 CFR 50 and 56)
Definitions Guidelines: informal documents issued by FDA to clarify requirements; often specific to therapeutic areas or technical disciplines Examples: Guidelines on Drug Stability Testing Guideline on How to Develop Anti- Inflammatory Drugs
REGULATIONS GUIDELINES The Difference (Credit: Steve Wilson, FDA)
Proactive Information Needs New regulations (Federal Register) Proposed, draft and final guidances (Federal Register, Whats New in CDER and CBER) Advisory Committee meeting announcements (Federal Register) Industry news (journals, newspapers) Drug development process research (Tufts CSDD, IoM, etc.)
Fundamental Principle No drug can be marketed in the United States until substantial evidence of its quality, safety and effectiveness has been provided to FDAs satisfaction.
Some Definitions Quality: the characteristics of the drug, including its manufacturing Safety: the relative risk of harm Effectiveness: the benefit provided to the patient Risk/Benefit Ratio: the degree to which risk is acceptable, given the amount of benefit provided to the patient
Substantial Evidence: What Is It ? Quality: tight procedures, reproducibility of manufacturing, specifications, pass FDA inspection Safety: low risk demonstrated in tests on animals and patients Effectiveness: benefit demonstrated in tests in animals and patients
Substantial Evidence: How Do We Get It ? Test the product in animals and patients; see if it works and if it does any harm Use controlled conditions of testing to eliminate the possibility that test results are wrong Apply rigorous scientific, medical and regulatory standards throughout
FDAs Satisfaction: How Do We Know What FDA Wants ? Regulations state what must be done, in general Guidelines provide advice on what is required for specific products Meetings: very specific technical discussions and negotiations on individual products Correspondence: technical negotiations on very fine points
The Role of the IND Doing Clinical Trials in the U.S.
The Investigational New Drug (IND) Application as the Platform for Drug Development Discovery Development Commercial Product Launch Sales IIIIIIIIIbIV Basic Research Pre- Clinical Clinical TestingMarketing INDNDA LabMarket SNDAs STRATEGY
Information Needs for Regulatory Strategy Identify similar drugs/treatments for specific indications Obtain regulatory approval documents (EPARs, FDA Approval Packages/SBAs) Identify all relevant guidance documents, both regulatory (EMEA, FDA) and medical (ASCO, etc.)
Information Needs for Clinical Development Strategy Define market size for indication, including by class of drugs Incidence & prevalence of indications in various countries to develop strategy for selection of patient groups and trial locations re: proof-of-concept studies Identify competing products in development (pipeline) Literature search to identify pivotal clinical trials re: standard trial protocol examples
Why do we need an IND? IND (Investigational New Drug Application) is an exemption from the law that prohibits interstate shipment of unapproved drugs An IND is required in order to conduct clinical trials in the United States
IND Submitted NDA Submitted Time Synthesis & Purification Formulation Development Short term AnimalLong term Animal Phase 1 Phase 2 Phase 3 Mfg Scaleup Clinical Studies Animal Studies Chem & Mfg PK Studies
Clinical Protocol Subject must not be exposed to unnecessary risks CMC CMC procedures ensure that the drug is adequately reproducible and stable Preclinical/Other Data Adequate evidence that the drug is reasonably safe for administration to humans IND Principal Goals SAFETY
Information Needs for INDs Safety, pharmacokinetics, and toxicity of study drug or drugs similar to study drug in animals and humans – to provide evidence that drug is reasonably safe for administration to humans Safety and efficacy of a class of drugs via a specific administration (IV, oral, etc.) in specific indications to justify a protocol dose selection
The Phases of Clinical Development Phase 1 Phase Subjects Patients or Normal Volunteers Metabolism/Pharmacologic Actions Side Effects with Increasing Dose Early Efficacy Information ADME Several Hundred Subjects Patients with Disease Under Study Well Controlled Studies Efficacy and Safety Phase 3 Phase 4 Hundreds to Thousands of Subjects Patients with Disease Under Study Well Controlled Studies Efficacy and Safety Post-NDA Approval Epidemiology Studies Marketing Studies
The New Drug Application (NDA) The vehicle through which sponsors formally request that the FDA approve a new pharmaceutical for marketing in the US, on the basis of demonstrated quality, safety and efficacy.
The Common Technical Document Format for the NDA CTD Module 1 Regional Administrative Information 1.1 Submission ToC Module 3 Quality ToC Module 4 Nonclinical Study Reports ToC Module 5 Clinical Study Reports ToC Quality Overall Summary 2.3 Nonclinical Overview 2.4 Nonclinical Written and Tabulated Summaries 2.6 Clinical Summary 2.7 Clinical Overview 2.5 Module 2 Not Part of the CTD CTD Table of Contents 2.1 CTD Introduction 2.2
Information Needs for NDA Submission and Beyond Literature search for safety and efficacy in humans of study drug in comparable indications, administrations, or dosages – clinical trials, review articles, case studies, etc. Literature search on all published studies for specific drug and indication for 505(b)(2) submissions (paper NDAs) After NDA approval, the obligation to report drug safety information from patients and/or additional studies grows exponentially and is a significant information management challenge (pharmacovigilance)
Interactions with FDA
Meetings with FDA During Early Drug Development Can Shorten NDA Review and Approval Time Source: DiMasi and Manocchia, DIA Journal 1997 NDA Review Time (mos)
Meeting Regularly with FDA is a Success Factor in Drug Development Maintain ongoing relationship Avoid misunderstandings Communicate new data Highlight and jointly resolve problems before they become too large Anticipate difficulties Monitor changes in FDA attitude or expectations of data Avoid surprising each other Accelerate development process FDA Center for Drugs holds >1000 industry meetings every year
Regulatory Approval is Earned Gradually, Not in aFinal and Glorious Battle with FDA Planning for the Target Labeling early in development Thorough development vision and plans Ongoing communication with FDA: Build Trust Data-driven development plan revisions Strong project management on both sides Learn from mistakes and take timely corrective actions in agreement with FDA
Good Mtg Science/ Medicine Regulatory Knowledge Meeting Process Management Key Ingredients of Successful Meetings Information Professionals
Success Factor No. 1: Science and Medicine FDA decision-making is driven by data FDA relies on internal reviewers and external experts to review data and make decisions FDA decisions can change based on changes in science, medical knowledge and medical practice If no data, then no positive FDA decision Good science, good medicine and good study designs are keys to success
Success Factor No. 2: Regulatory Knowledge Company representatives must know the rules (regulations, guidelines) Regulatory precedents (previous FDA decisions on similar issues) are important It is sometimes possible to push the FDA into a dialogue (e.g. post-approval commitments; generic biologics) Being well-prepared is key
Success Factor No. 3: Meeting Process Management FDA meetings must be planned and managed in a very specific way There is a defined process for FDA meetings Preparation and documentation are essential Rehearsals are important for the theater … and they are important for FDA meetings too !
FDA Meetings During Drug Development Discovery Development Commercial Product Launch Sales IIIIIIIIIbIV Basic Research Pre- Clinical Clinical TestingMarketing INDNDA LabMarket SNDAs Pre-INDEOPIIPre-NDAAdComm Label
Types of FDA Meetings TYPE PURPOSE Pre-IND Verify acceptability End of Phase I (rare) Confirm early safety End of Phase II Confirm early efficacy; agree Phase III Pre-NDA Outline NDA approach Ad-hoc Technical Meetings CMC, Tox, Clinical issues Advisory Committee Meetings Address medical establishment Teleconferences Ad hoc Labeling Meeting Negotiate final labeling
FDA Has Provided Guidance for Industry Meetings Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products Type A Meeting: immediately necessary for an otherwise stalled drug development program to proceed (i.e., a critical path meeting). Type A meetings generally will be reserved for dispute resolution meetings, meetings to discuss clinical holds, and special protocol assessment meetings that are requested by sponsors after FDA's evaluation of protocols in assessment letters. Scheduled within 30 days of sponsors request. Type B Meeting: (1) pre-IND meetings (21 CFR ), (2) certain end of Phase 1meetings (21 CFR ), (3) end of Phase 2/pre-Phase 3 meetings (21 CFR ), and (4) pre-NDA/BLA meetings (21 CFR ). Scheduled within 60 days of sponsors request. Type C Meeting: any meeting other than a Type A or Type B meeting. Scheduled within 75 days of sponsors request.
Five Key Success Factors FACTORDRIVERS OF SUCCESS 1. Request Letter Clarity about the purpose of the meeting Clarity about the sponsors position and questions Sufficient detail to justify the meeting 2. Information Package Concise, informative, logical Reader-friendly, well-organized Necessary and sufficient background information 3. Preparation Thorough knowledge of the data Anticipation of objections Reasoned alternatives 4. Meeting Management Sponsor Team Leader The right experts in attendance Listen, clarify, respond / propose 5. Negotiation Skills Professionalism Know when to push back, when to concede Time out: stop, reflect, return another day
Examples of Information Needs re: Meetings with FDA (pre- and post-submission) Background on FDA Reviewers Literature search on specific drug combinations, incidence of adverse events, etc. re: safety concerns Literature search on drug metabolism and toxicity to respond to concerns over dosing studies
Industry View of FDA (Dr. Elengold, CBER)
(Dr. Elengold, CBER) FDA View of Pharmaceutical Company
Conclusions The FDAs regulation of drug development is structured, logical, science-based, data-driven and workable In practice, every drug is developed to the beat of its own drum, with a skillful mix of science, information and diplomatic art Information Professionals play a key role in the drug development process and post-approval pharmacovigilance obligations by providing access to background, data, precedents and adverse event tracking to help meet todays regulatory and patient care challenges