Oncology Drug Discovery & Development: Industry-Academic-Regulatory Axis PDF

Oncology Drug Discovery & Development: The Industry- Academic-Regulatory Axis Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School The Drug Approval Process  Drug approval process New drug development in the US is a complex, hig...

Oncology Drug Discovery & Development: The Industry- Academic-Regulatory Axis Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School The Drug Approval Process  Drug approval process New drug development in the US is a complex, highly regulated process that often involves academic institutions, the pharmaceutical industry, and government agencies. Much of the primary and clinical research conducted in the United States is funded by the National Institutes of Health. The Food and Drug Administration (FDA) provides regulatory review and oversight of the drug development process. The Investigational New Drug application (IND) is the primary mechanism that the FDA uses to regulate clinical testing in humans. A New Drug Application summarizing all of the data necessary to perform risk/benefit analysis of the new drug is submitted to the FDA for review and approval once sufficient testing has been completed. A thorough understanding of the regulatory development process and the National Institutes of Health funding process is necessary for any investigator involved in clinical trials.  Regulatory Health Authorities USA: FDA – Food and Drug Administration – Center for Drug Evaluation and Research (CDER) and – Center for Biologics Evaluation and Research (CBER) Europe: EMEA – European Medicines Agency – Committee for Human Medicinal Products (CHMP) Japan: - Ministry of Health, Labor and Welfare (MHLW), - Pharmaceuticals and Medical Devices Agency (PMDA) Canada - Health Canada -Therapeutic Products Directorate ( TPD )  Drug approval process (cont.) If a product has a promising profile, the preclinical development history and a proposed clinical development plan are compiled in an Investigational New Drug application (IND) that is submitted to the FDA for review. An active IND permits clinical testing in humans. INDs are dynamic documents that reside with the sponsor (company or individual) and are updated annually. An IND will include data and information in 3 broad areas: - Animal pharmacology and toxicology testing to determine whether a product is reasonably safe for initial testing in humans - Manufacturing information to ensure that the sponsor can adequately produce and supply consistent batches of the drug - Clinical protocol and investigator information to determine whether the initial trials will expose subjects to unnecessary risks and whether the physician investigators are qualified to fulfill their clinical trial duties.  Drug approval process (cont.) The clinical development process consists of 3 phases of testing and post-marketing follow-up: - Initial phase 1 studies to establish safety and pharmacology - Phase 2 studies to establish proof of concept, efficacy, and various dosing regimens in patients with the disease or condition in question - Phase 3 studies to gather information used to evaluate risk versus benefit that form the basis of the prescribing information (package insert) and must follow strict regulatory and statistical criteria. The information gathered in phases 1 through 3 is compiled in an NDA for review by the FDA. A typical NDA summarizes all of the data on the product: chemistry; manufacturing; preclinical pharmacology/toxicology; human pharmacokinetics; bioavailability and pharmacology; pharmacodynamics and clinical efficacy and safety. A letter code is assigned to each application by the FDA. This indicates the review priority: ‘‘S’’ for standard review of a drug similar to those currently available or ‘‘P’’ for priority review of a drug that may represent a significant advance over existing therapy. A drug may be marketed only after an approval action letter is signed by the appropriate individual within the FDA. Robuck PR; Wurzelmann JI Inflammatory Bowel Diseases. 11 Suppl 1:S13-6, 2005  Drug and biologics approval process OfficeofHealthEconomics  The drug development process Robuck PR; Wurzelmann JI Inflammatory Bowel Diseases. 11 Suppl 1:S13-6, 2005  History of drug development 1938 Food, Drug, and Cosmetic Act: Safety: every new drug brought to market in the US must be approved by the FDA through the New Drug Application (NDA) process. 1962 – Efficacy: congressional Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act required that drugs be shown scientifically to be effective before being marketed and confirmation that the benefits of the drug outweigh its known risks. 1960s–1980s, drug developers, the academic community, and regulators developed and refined ways to design, conduct, and analyze randomized controlled clinical trials that could produce the needed evidence for efficacy. Many important advances in pharmacotherapy (e.g., cardiovascular therapies, psychiatric drugs, anti-infectives, and cancer treatments) were introduced during this era. However, the evidence generated in drug development programs was still somewhat limited: eg. - dose-response information was scanty - few women were studied - few minorities were studied - data on long-term use or chronically administered drugs were lacking - evaluations of subgroups such as patients with renal or hepatic insufficiency were not conducted - data on drug-drug interactions were not available. 1980s-1990s, as more drug therapies became available, the FDA expanded requirements that such information would be obtained during most drug development programs. Therefore, modern development programs usually are much more extensive and contain many more clinical studies and patient exposures than was usual in 1960–1985. Additional laws pertinent to development of drug therapy 1983 - Orphan Drug Act, which provided incentives for the research, development, and approval of products to treat rare diseases (affecting 200,000 individuals) 1992 - prescription Drug User Fee Act of, which established user fees for applications and expedited the drug approval process within the FDA 1997 - FDA Modernization Act, which further reduced review times and allowed for electronic submissions 2001 - Best Pharmaceuticals for Children Act, which established a specific office within FDA devoted to pediatric therapeutics  The 3 phases of regulatory development: the IND, the NDA, and post-marketing (phase 4) studies IND submissions are evaluated within 30 days. If the IND is not rejected within this time period, the sponsor may begin clinical trials. FDA review of an NDA is considerably longer, 6 months priority and 10 months for standard reviews, with the possibility of extensions. - Possible outcomes of the NDA review process are a) approval, b) approvable (warranting further study), or c) not approved. - From a sponsor’s viewpoint, the key document resulting from the NDA review is the ‘‘package insert,’’ which not only includes a summary of data but also serves as the guide for review of subsequent marketing, advertising, and communication regarding the product. One of the most important functions of the FDA resides in the Office of Drug Safety, which oversees post-marketing safety. – In the United States, post-marketing reporting of adverse events by health care professionals is not mandatory. – Therefore, the FDA relies on voluntary reporting by clinicians with mandatory periodic reporting by manufacturers. – Clinicians may report adverse events through the MedWatch system (http://www.fda.gov/medwatch/). This form may be used to report an adverse event that occurs outside of a clinical trial. – Of note, adverse events occurring within a clinical trial are reported by the sponsor as part of the periodic update to the IND.  Improvements in FDA Regulations FDA Process Eligibility Requirements Effect on Approval Process Fast Track Medical need not addressed by Seek FDA input into (FDAMA 1997) a product or claim before development plan Allows submission of NDA or BLA in sections Allows for study of drugs via surrogate endpoints Priority Review Drugs must “address unmet Reduces the drug review “Subpart E” medical needs” process from ten months to (PDUFA 1992) six months Accelerated For serious or life-threatening Allows for approval based on Approval (1992) illnesses and that provide a surrogate endpoint likely to “Subpart H” - meaningful therapeutic benefit predict clinical benefit or with Drugs to patients over existing restrictions to assure safe treatments use. “Subpart E” - Biologics http://www.aei.org/events/filter.all,eventID.1666/event_detail.asp  Accelerated Approval Accelerated approval (AA) for oncology drugs was established in 1992 by the Food and Drug Administration (FDA) as a means of expeditiously providing new drugs to patients with life-threatening illnesses After AA is granted, sponsors are required to complete larger trials, generally phase III studies, confirming clinical efficacy - termed Subpart H commitments In 2003 and 2005, the Oncologic Drugs Advisory Committee (ODAC) provided guidance to drug sponsors for 13 cancer indications who were behind schedule in completing confirmatory clinical trials Confirmatory clinical trials are difficult to complete for sponsors of AA drugs, particularly those drugs used to treat cancers that affect small numbers of patients http://www.aei.org/events/filter.all,eventID.1666/event_detail.asp  Oncology vs. Others: FDA Process Journal of Clinical Oncology, Vol 25, No 2 (January 10), 2007: pp. 209-216  Challenges to progress in drug development in early 2000s Challenges and uncertainty of drugs coming to market still remain: - Data from long-term use are still usually limited. - Drug development programs cannot detect drug-related adverse outcomes that represent a small increase in frequency of a problem that is already common in the treated population (e.g., ischemic cardiovascular events). - Technologies to predict the occurrence of rare, catastrophic side effects are not available. - Patients enrolled in trials do not reflect the full range of the population or treatment situations that occur in practice. - As a result, new safety issues are often identified only after drugs enter the market. Medical practice has become more complex since the 1962 amendments. - Multiple subgroups and disease stages were defined, and many therapeutic options exist. - Drug development programs are rarely designed to answer the questions posed by evidence-based medicine and by insurers: What therapeutic option has the best outcomes in various patient groups? - What option provides the best value? - Comparative premarket trials usually involve a demonstration of “noninferiority” in comparison with a single control drug.  Challenges to progress in drug development in early 2000s (cont.) The pharmaceutical industry was facing a productivity crisis. - Despite rising investment in pharmaceutical R&D, successful development of new drugs was slowing -> 2004 represented a 20- year low in introductions of new chemical entities (NMEs) worldwide and the US - The investment needed per successful NME has risen to an estimated $800 million or more in 2004, now over $2 billion. - This cost is driven by the high rate of clinical failure, estimated at 70%– 90% of candidates. - The rising percentage of late-stage clinical failures, ~ 50% of compounds tested in phase 3 trials, was a concern. The high cost of successful drug development discourages investment in more innovative, risky approaches, as well as treatments for diseases that represent smaller markets. - The need to recoup this investment during the period of market exclusivity, prior to the introduction of generic copies, is an incentive for aggressive marketing techniques. - However, rapid market uptake means that a large number of individuals may have already been exposed by the time a drug problem is discovered after marketing.  Challenges to progress in drug development in early 2000s (cont.) Rising social demands for greater certainty of outcomes of drug therapy coincided with the pharmaceutical industry’s difficulty in sustaining innovation. This coincided with the public demand to therapies for medical conditions that currently have unsatisfactory or no therapeutic options. The FDA is charged with dual roles in protecting and promoting health: - implementing policies that ensure that the benefits of new products will outweigh their risks - promoting innovations that can improve health. These challenges to the “pipeline problem” led to the genesis of the Critical Path Initiative: 2004 - FDA published a White Paper entitled “Innovation or Stagnation: Challenges and Opportunities on the Critical Path to Medical Product Development” - acknowledged that a combination of factors has likely led to the current drug development situation - called attention to an important and generally unrecognized problem: the lagging science of drug development. - identified the “Critical Path” as a process beginning with identification of a drug candidate and culminating in marketing approval – intended to modernize drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. - along path to marketing, a product is subjected to a series of evaluations to predict its safety and effectiveness and to enable its mass production. - use public-private partnerships & consortia to accomplish the research.  Comparison of global pharmaceutical industry R&D investment and global output of new molecular entities. Drug development was incresing and steady from 1994 to 1999 then quickly decreased during 2000 to 2004 Although drug development was decresing, much more money was being invested into R&D. Pharmaceutical spending continued to increase while drug sales remained flat. Targeted therapies started to enter the market, therefore an increase in New Molecular Entities (NME). Mullard A. Nature Reviews. Drug Discovery. 18(2):85-89, 2019  New Molecular Entities Approved by the FDA in 2018 by Disease Classification FDA approved more NMEs for orphan drugs in oncology in 2018 compared to orphan&non-orphan drugs for other diseases. Kinch and Griesenauer. Drug Discovery Today 24:1710 (2019)  Number of new applications by review type Zhou, et al. Journal of the National Cancer Institute. 111(5):449-458, 2019  Number of approved Oncology drug applications by approval type Increase in both standard and priority review of oncology drug applications. Zhou, et al. Journal of the National Cancer Institute. 111(5):449-458, 2019 Phases of R&D The Science  Types of Drug Targets Host or Pathogen TARGET MECHANISM Enzyme Inhibitor – reversible or irreversible Structural Protein Activator Receptor/Ligand Agonist or Antagonist Nucleic Acid Binder, modifier (alkylating agent) or mimic Ion Channel Blockers or Openers Transporter Uptake Inhibitors Drug targets are typically proteins, but could also be nucleic acids Almost any molecular target is amenable to some level of small molecule drug discovery and potential development  Pharmaceutical Development LEAD Compound Desired Activity Crude Compound Known In vitro In vivo Clinical of Known Target Activity Activity Extract Activity Structure Establishment Establishment of Establishment Purification & of molecular target organ or of test in Characterization target cell animals  Drug Development Related Activities IND NDA/BLA Clinical Clinical Clinical Discovery Preclinical Ph I Ph II Approval Market Ph III Target ID Proof of Mechanism Phase 0 Microdosing Phase IV Receptor Binding Species Differences Phase 1-III Trials Safety Occupancy PK/PD Safety Efficacy Time on Target ADME Efficacy Diagnosis Drug Targeting Safety Human PK Staging Dose Ranging Dose Selection Treatment Planning & Monitoring Drug Delivery Bioavailability Prognosis Efficacy Post-marketing Surveillance Clinical Validation Competitive Advantage  Biologicals Biological therapies include endogenous compounds that are present in the body as either defense mechanisms or as part of naturally occurring biochemical processes. Protein/Peptide Therapeutics Monoclonal Antibodies Aptamers or antibody derivatives Oligonucleotides (Antisense) RNA (SiRNA, microRNA) Gene Therapy Cell Therapy Immunotherapy The Cost of Drugs Development The Statistics  Disclosure Data on cost of drug development vary based on the source and whether it is based on large pharmaceutical or biotechnology company numbers Probability of success also seems to vary dramatically Directionally, costs of R&D are increasing, number of drugs being approved correlated to spending is decreasing, probability of success is decreasing Newer technologies in genomics, proteomics, are having variable impact on this  Stages of Pharmaceutical R&D Investigational new drug application is submitted after preclinical development and prior to phase 1 clinical trials. New drug application/biologic license application is submitted after phase 3 but before licensure. IND NDA/BLA TIME 3-7 yr 0.5-2 yr 1-2 yr 2-3.5 yr 2.5 -4 yr 1-2 yrs PIPELINE PHASE COST** $100M -130M $60-70M $70M-100M $130M-160M $190M-220M $18M-20M 1-3% 5 - 17% 10 - 25% 18 - 35% 45 – 70% 90% PROBABILITY OF SUCCESS TO LICENSURE PER PROJECT (Industry benchmarks**) * Out of pocket costs from Discovery through Licensure to develop a single successful product (includes attrition) Sources: **Cost, duration and probability of success assumptions for each DiMasi, et al, 2007, PRTM Reports phase do not reflect licensure based on Animal Rule which may add Lehman Bros. & McKinsey 2001 time and expense.  Fig 1. Mean clinical development and regulatory approval times for new oncology and other therapeutic molecular entities approved by the US Food and Drug Administration from 1990 to 2005 DiMasi, J. A. et al. J Clin Oncol; 25:209-216 2007 Copyright © American Society of Clinical Oncology  General Statistics For Oncology New Oncology Drugs Entering Clinical Trials – 1990-1993 - ~150 – 2002-2005 - ~325 FDA Approved New Molecules for Oncology – 1990-1999 - ~38 – 2000-2007 - ~17 Approval Rate ~8% Compared to ~20% for Non-Oncology Drugs Median Clinical Trial Times – Non-Oncology Drugs – 6.3 years – Oncology Drugs – 7.8 years More than $1 Billion Dollars Per New Drug – Many Years to Develop a New Drug Recouping however is highly lucrative: globally, the United States represents the largest market for pharmaceuticals, accounting for 46% of annual sales or approximately $226.7 billion in 2004 for all drugs. Source: 1 Various  Linear increase in approved oncology drugs over the years. Cancer Discovery. 9(11):1477, 2019  Costs Per Phase Of Development Phase 1 is the cheapest phase of drug development. Phase 3 is the most expensive of all phases. Drug Information Journal, Vol. 38, pp. 211–223, 2004  Probability Of Success Preclinical Phase I Phase II Phase III Registration Industry Average1 Overall Success Phase Success rate 60% 54% 29% 75% 100% FDA Approval Rate: 7% 30% of phase 2 drugs are successful enough to move on to phase 3. Source: 1 KMR Group benchmarking, PRTM analysis  The Market Understanding the Customer  Understanding the Customer Begin early Never stop Market research Segmentation Targeting Positioning Know that your product is not for everyone  Profit/Loss (Income) Statement + Revenue - COGS (cost of goods sold) - SG&A (Selling, general and administrative - Marketing and Sale line) - R&D - Interest - Taxes = Net Income  Earnings After Approval Once drug is approved, pharmaceutical companies earn billions for years until their patent expires due to release of generics or biosimilars. Drug Information Journal, Vol. 38, pp. 211–223, 2004  Intellectual Property (IP) Trademark Copyright Trade Secret Patent Patent Term Restoration (Hatch-Waxman Provision) Data Exclusivity (Hatch-Waxman) Orphan Drug Exclusivity Pediatric Exclusivity  Effect of Short Patent Lives on Safety Development of a new chemical entity (NCE) is highly complex and long lived. After intensive basic research, potential drug targets are identified. Large chemical libraries are screened and NCEs synthesized for evaluation of the desired interaction with a putative target. The number of NCEs initially needed to eventually obtain an approved drug is high (on average about 10,000). Development of the NCE into an effective and safe medication is a lengthy process. Following preclinical development (~5 years) and extensive clinical testing (Phase I, II, and III; another ~6 years), regulatory approval for clinical application may be obtained. After a few years of administrative organization and post-approval marketing, the medication may start to be widely used in clinical practice. At this time, patients can start to benefit from the vast effort by numerous scientists and the expenditure of enormous sums of money. Estimates for these development costs range from just over US $800 million to US $2 billion. By the time of approval, patent lives of usually 20 years are largely eroded. The result is that only a short period of 4 to 8 years under patent protection may be left during clinical use During this short period of useful patent life, the safety of the NCE in general clinical use has to be monitored continuously and communicated appropriately to health care providers and patients, while the large development costs plus any recovery on investment must be generated. Despite phase I–III testing, large scale human exposure to a NCE still results in unexpected adverse drug reactions (ADRs) and are only discovered years after regulatory approval and general clinical use.  Unexpected Adverse Drug Reactions (ADRs) often are discovered only years after regulatory approval and general clinical use 1. Some human ADRs may not occur in test animals 2. Rare events cannot be detected reliably in clinical trials on carefully selected patients as their incidence is inherently too small 3. Clinical trials may be too short in duration to detect ADRs that occur only after chronic exposure 4. Some ADRs occur only in certain genetically susceptible individuals 5. Some ADRs occur only in the presence of other drugs6. Some ADRs occur only with special diets 7. Some ADRs occur only in patients suffering from other diseases 8. The current FDA system of spontaneous ADR reports from different sources, without an active drug surveillance system, is not sufficiently accurate 9. Only 10% ADRs in wide clinical use are reported to regulators in the current practice of “spontaneous reporting” There are calls for increasing the patent period to extend past a mandatory phase IV testing to permit recouping of investment and supervise safety. This however would extend the time to marketing, delay entry of good drugs into practice and also increase the expense to the public.  Generics Generic industry has been aggressive in getting low-cost options available as soon as exclusivity expires Generic industry has also become more aggressive in challenging existing patents (Paragraph IV challenges) Biogeneric legislation is highly anticipated in the US – Already available in the EU and other parts of the world  Change in the Average Relative Price of a Drug as the Number of Generic Versions Increases Increased number of generic manufacturers leads to a decrease in generic drug pricing. Frank RG. New England Journal of Medicine. 357(20):1993-6, 2007 Generic and orphan drug sales have increased over the past 10 years. Important Considerations for the Pharmaceutical Industry  Industry- Academia-Government Axis Industry-Sponsored Trials Cancer Cooperative Groups – NCI-funded and/or funded by other sources (Foundations, Companies, etc.) – Conduct major trials some in Ph II and Ph III as well as several post-marketing trials (Ph IV) – More than 1700 Institutions participate in the system Investigator-Initiated Studies  Level Of Evidence: Types Of Studies When there is evidence to treat patients for oncology there are multiple levels of evidence Meta analysis: Most patients fall on this level. This is when somebody has collected all of the data from clinical trials for a specific disease or specific drug. Randomized: level 1 evidence. Randomized placebo controlled double blinded multicenter phase 3 trials. Holy grail of clinical Trials. Controlled cohort studies and Uncontrolled cohort studies: level 2 evidence. Retrospective anecdotal: level Meta Analysis 3 evidence. Randomized Controlled Cohort Uncontrolled Cohort Retrospective Anecdotal  Improvements To Pharmaceutical R&D IND NDA/BLA PHASES Preclinical Production Discovery Development Phase I Phase II Phase III Licensure & Delivery IND Exploratory Developing Preclinical Early Phase Screen Leads Evaluation Clinical Trials Development NDA/BLA Specialized Phase I Ext Adaptive Cooperative NDA/BLA Accelerated Stability Priority New Formats  Utilizing Emerging Technology Genomics Proteomics Metabolomics Imaging Technologies Targeted therapy Immune checkpoint inhibitors “Designer Drugs” and cell therapy Personalized Medicine  External Innovation Licensing Deals – e.g. BMS – ImClone Mergers – e.g. sanofi-aventis Acquisitions – Eli Lily – ImClone Scientific Collaborations – Shared IP rights  Medical Device and Interventional Approaches Non-pharmacologic therapies are also important in the treatment of cancer Radiotherapy is an area of continue exploration and growth especially in combination with newer pharmacologic agents – e.g. Head & Neck Cancer- RT + cetuximab Interventional approaches such as surgical tools are also a key area of growth in the treatment of cancer  Perspectives Scientific breakthroughs have resulted in life-saving drugs – e.g. imatinib, trastuzumab The key is cooperation between the industry-academia-government axis Need for scientists, clinicians and healthcare workers is great!