Drug development

Broadly, the process of drug development can be divided into preclinical and clinical work.

File:Drug Evaluation Process.jpg

{{Main|Pre-clinical development}}

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]).{{cn|date=February 2024}}

In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale. They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC).{{cn|date=February 2024}}

Many aspects of drug development focus on satisfying the regulatory requirements for a new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using in vitro methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.{{cite journal|pmid=31621554|pmc=7202182|vauthors=Madorran E, Stožer A, Bevc S, Maver U |title=In vitro toxicity model: Upgrades to bridge the gap between preclinical and clinical research|journal=Bosnian Journal of Basic Medical Sciences|year=2020|volume=20|issue=2|pages=157–68|doi=10.17305/bjbms.2019.4378}}

The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase.

Clinical trials involve four steps:{{cite journal | vauthors = Ciociola AA, Cohen LB, Kulkarni P | title = How drugs are developed and approved by the FDA: current process and future directions | journal = The American Journal of Gastroenterology | volume = 109 | issue = 5 | pages = 620–3 | date = May 2014 | pmid = 24796999 | doi = 10.1038/ajg.2013.407 | s2cid = 205100166 }}

• Phase I trials, usually in healthy volunteers, determine safety and dosing.
• Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.a
• Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage.
• Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.

The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).{{cite book|title=Assay Guidance Manual|vauthors=Strovel J, Sittampalam S, Coussens NP, Hughes M, Inglese J, Kurtz A, Andalibi A, Patton L, Austin C, Baltezor M, Beckloff M|date=July 1, 2016|publisher=Eli Lilly & Company and the National Center for Advancing Translational Sciences|chapter=Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies|pmid=22553881 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK92015/}}{{cite web|date=30 January 2018|title=Vaccine Product Approval Process|url=https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-product-approval-process|archive-url=https://web.archive.org/web/20190506165354/https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-product-approval-process|url-status=dead|archive-date=May 6, 2019|access-date=21 March 2020|publisher=U.S. Food and Drug Administration (FDA)}}

If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it. In the United States, this process is called a "new drug application" or NDA.

Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials. Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.{{cite journal | vauthors = Van Norman GA | title = Phase II Trials in Drug Development and Adaptive Trial Design | journal = JACC. Basic to Translational Science | volume = 4 | issue = 3 | pages = 428–437 | date = June 2019 | pmid = 31312766 | pmc = 6609997 | doi = 10.1016/j.jacbts.2019.02.005 }}{{cite journal | vauthors = Fogel DB | title = Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review | journal = Contemporary Clinical Trials Communications | volume = 11 | pages = 156–164 | date = September 2018 | pmid = 30112460 | pmc = 6092479 | doi = 10.1016/j.conctc.2018.08.001 }}

A study covering clinical research in the 1980–1990s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing.{{cite journal|date=June 1, 2003|title=R&D costs are on the rise|url=http://www.highbeam.com/doc/1G1-102908512.html|url-status=dead|journal=Medical Marketing and Media|volume=38|issue=6|pages=14|archive-url=https://web.archive.org/web/20161018194503/https://www.highbeam.com/doc/1G1-102908512.html|archive-date=October 18, 2016}} During 2006–2015, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines.{{cite web|date=June 2016|title=Clinical development success rates: 2006–2015|url=https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf|publisher=BIO Industry Analysis}} The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures.{{cite journal|vauthors=Wang Y|year=2012|title=Extracting knowledge from failed development programmes|journal=Pharmaceutical Medicine|volume=26|issue=2|pages=91–96|doi=10.1007/BF03256897|s2cid=17171991}}

{{Main|Cost of drug development}}

There are a number of studies that have been conducted to determine research and development costs: notably, recent studies from DiMasi{{cite journal | vauthors = DiMasi JA, Grabowski HG, Hansen RW | title = Innovation in the pharmaceutical industry: New estimates of R&D costs | journal = Journal of Health Economics | volume = 47 | pages = 20–33 | date = May 2016 | pmid = 26928437 | doi = 10.1016/j.jhealeco.2016.01.012 }} and Wouters{{cite journal | vauthors = Wouters OJ, McKee M, Luyten J | title = Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018 | journal = JAMA | volume = 323 | issue = 9 | pages = 844–853 | date = March 2020 | pmid = 32125404 | pmc = 7054832 | doi = 10.1001/jama.2020.1166 }} suggest pre-approval capitalized cost estimates of $2.6 billion and $1.1 billion, respectively. The figures differ significantly based on methodologies, sampling and timeframe examined. Several other studies looking into specific therapeutic areas or disease types suggest as low as $291 million{{cite journal | vauthors = Jayasundara K, Hollis A, Krahn M, Mamdani M, Hoch JS, Grootendorst P | title = Estimating the clinical cost of drug development for orphan versus non-orphan drugs | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | pages = 12 | date = January 2019 | pmid = 30630499 | pmc = 6327525 | doi = 10.1186/s13023-018-0990-4 | doi-access = free }} for orphan drugs, $648 million{{cite journal | vauthors = Prasad V, Mailankody S | title = Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval | journal = JAMA Internal Medicine | volume = 177 | issue = 11 | pages = 1569–1575 | date = November 2017 | pmid = 28892524 | pmc = 5710275 | doi = 10.1001/jamainternmed.2017.3601 }} for cancer drugs or as high as $1.8 billion for cell and gene therapies.{{cite journal | vauthors = Sabatini MT, Chalmers M | title = The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies | journal = Pharmaceutical Medicine | volume = 37 | issue = 5 | pages = 365–375 | date = September 2023 | pmid = 37286928 | doi = 10.1007/s40290-023-00480-0 }}

The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug,{{cite journal | vauthors = DiMasi JA, Grabowski HG, Hansen RW | title = Innovation in the pharmaceutical industry: New estimates of R&D costs | journal = Journal of Health Economics | volume = 47 | pages = 20–33 | date = May 2016 | pmid = 26928437 | doi = 10.1016/j.jhealeco.2016.01.012 | url = https://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/12742/DiMasi-Grabowski-Hansen-RnD-JHE-2016.pdf;sequence=1 | hdl-access = free | hdl = 10161/12742 }} possibly as high as $345 million.{{cite journal |vauthors=Moore TJ, Zhang H, Anderson G, Alexander GC |date=November 2018 |title=Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016 |journal=JAMA Internal Medicine |volume=178 |issue=11 |pages=1451–1457 |doi=10.1001/jamainternmed.2018.3931 |pmc=6248200 |pmid=30264133}} The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million.

The full cost of bringing a new drug (i.e., new chemical entity) to market—from discovery through clinical trials to approval—is complex and controversial.{{cite journal|vauthors=Taylor D|date=2015|title=The Pharmaceutical Industry and the Future of Drug Development|journal=Issues in Environmental Science and Technology|publisher=Royal Society of Chemistry|pages=1–33|doi=10.1039/9781782622345-00001|isbn=978-1-78262-189-8}}{{cite journal | vauthors = Sertkaya A, Wong HH, Jessup A, Beleche T | title = Key cost drivers of pharmaceutical clinical trials in the United States | journal = Clinical Trials | volume = 13 | issue = 2 | pages = 117–26 | date = April 2016 | pmid = 26908540 | doi = 10.1177/1740774515625964 | s2cid = 24308679 | doi-access = free }} In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%. Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance.{{cite web|date=11 August 2013|title=The cost of creating a new drug now $5 billion, pushing Big Pharma to change|url=https://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/|access-date=17 July 2016|work=Forbes|vauthors=Herper M}}

Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources.{{cite journal | vauthors = Maxmen A | title = Busting the billion-dollar myth: how to slash the cost of drug development | journal = Nature | volume = 536 | issue = 7617 | pages = 388–90 | date = August 2016 | pmid = 27558048 | doi = 10.1038/536388a | bibcode = 2016Natur.536..388M | doi-access = free }} An example of a collaborative drug development initiative is COVID Moonshot, an international open-science project started in March 2020 with the goal of developing an un-patented oral antiviral drug to treat SARS-CoV-2.{{cite news | vauthors = Whipple T |title=Moonshot is the spanner in the Covid-19 works the country needs |url=https://www.thetimes.com/uk/healthcare/article/moonshot-is-the-spanner-in-the-covid-19-works-the-country-needs-bnf0z5t7t |access-date=5 November 2021 |work=The Times |date=October 23, 2021}}{{cite journal | vauthors = Lee A, Chodera J, von Delft F |title=Why we are developing a patent-free Covid antiviral therapy |journal=Knowable Magazine |date=27 September 2021 |doi=10.1146/knowable-092721-1|s2cid=244170138 |url=https://knowablemag.org/article/health-disease/2021/why-we-are-developing-patentfree-covid-antiviral-therapy |access-date=1 November 2021|doi-access=free }}

The nature of a drug development project is characterised by high attrition rates, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are risk-adjusted net present value (rNPV), decision trees, real options, or comparables.{{cn|date=February 2024}}

The most important value drivers are the cost of capital or discount rate that is used, phase attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the cash flows estimation.Boris Bogdan and Ralph Villiger, "Valuation in Life Sciences. A Practical Guide", 2008, 2nd edition, Springer Verlag.{{cite web | vauthors = Nielsen NH | title = Financial valuation methods for biotechnology | date = 2010 | url = http://biostrat.dk/financial-valuation-methods-for-biotechnology.pdf |access-date=2014-11-25 |url-status=dead |archive-url=https://web.archive.org/web/20120305213601/http://biostrat.dk/financial-valuation-methods-for-biotechnology.pdf |archive-date=2012-03-05 }}

Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical compounds. On average about 250 of these show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on humans.{{Cite journal | vauthors = Stratmann HG |date=September 2010 |title=Bad Medicine: When Medical Research Goes Wrong |journal=Analog Science Fiction and Fact|volume=CXXX |issue=9 |pages=20}} A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing.{{cite journal |title=R&D costs are on the rise|journal=Medical Marketing and Media |date=June 1, 2003 |url=http://www.highbeam.com/doc/1G1-102908512.html |archive-url=https://web.archive.org/web/20161018194503/https://www.highbeam.com/doc/1G1-102908512.html |url-status=dead |archive-date=October 18, 2016 |volume=38 |issue=6 |page=14}} In the time period of 2006 to 2015, the success rate was 9.6%.{{cite web | url = https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf | title = Clinical Development Success Rates 2006-2015 | date = June 2016| work = BIO Industry Analysis}} The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures.{{cite journal | vauthors = Wang Y |title= Extracting Knowledge from Failed Development Programmes |url=http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26020/Extracting_Knowledge_from_Failed_Development.3.aspx |journal=Pharm Med |volume=26 |issue=2 |pages=91–96 |year=2012 |doi=10.1007/BF03256897|s2cid= 17171991 |url-access=subscription }} In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data.{{cite journal | vauthors = Herschel M |title=Portfolio Decisions in Early Development: Don't Throw Out the Baby with the Bathwater |url=http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26020/Portfolio_Decisions_in_Early_Development__Don_t.1.aspx |journal=Pharm Med |volume=26 |issue=2 |pages=77–84 |year=2012 |doi=10.1007/BF03256895 |s2cid=15782597 |access-date=2012-06-12 |archive-url=https://web.archive.org/web/20120616075614/http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26020/Portfolio_Decisions_in_Early_Development__Don_t.1.aspx |archive-date=2012-06-16 |url-status=dead|url-access=subscription }}

Novel initiatives include partnering between governmental organizations and industry, such as the European Innovative Medicines Initiative.{{cite web |title=About the Innovative Medicines Initiative |url=https://www.imi.europa.eu/about-imi |publisher=European Innovative Medicines Initiative |access-date=24 January 2020 |date=2020}} The US Food and Drug Administration created the "Critical Path Initiative" to enhance innovation of drug development,{{cite web | url=https://www.fda.gov/science-research/science-and-research-special-topics/critical-path-initiative | archive-url=https://web.archive.org/web/20190717205405/https://www.fda.gov/science-research/science-and-research-special-topics/critical-path-initiative | url-status=dead | archive-date=July 17, 2019 | title=Critical Path Initiative | publisher=US Food and Drug Administration | date=23 April 2018 | access-date=24 January 2020}} and the Breakthrough Therapy designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder.{{cite web | url=https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy | archive-url=https://web.archive.org/web/20190504035941/https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy | url-status=dead | archive-date=May 4, 2019 | title=Breakthrough Therapy | publisher=US Food and Drug Administration | date=4 January 2018 | access-date=24 January 2020}}

In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery.{{cite news | vauthors = Shankland S |title=Sixteen supercomputers tackle coronavirus cures in the US |url=https://www.cnet.com/news/sixteen-supercomputers-tackle-coronavirus-cures-in-us/|date=2020-03-23 |access-date=27 April 2020 |work=CNET |publisher=ViacomCBS}}{{cite web |url=https://covid19-hpc-consortium.org/|title=The COVID-19 High Performance Computing Consortium |publisher=The COVID-19 High Performance Computing Consortium|date=2020|access-date=2020-04-27}} The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy.{{cite journal | vauthors = Marshall S, Madabushi R, Manolis E, Krudys K, Staab A, Dykstra K, Visser SA | title = Model-Informed Drug Discovery and Development: Current Industry Good Practice and Regulatory Expectations and Future Perspectives | journal = CPT: Pharmacometrics & Systems Pharmacology | volume = 8 | issue = 2 | pages = 87–96 | date = February 2019 | pmid = 30411538 | pmc = 6389350 | doi = 10.1002/psp4.12372 | doi-access = free }} In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19".{{cite web| title=OpenPandemics – COVID-19| url=https://www.worldcommunitygrid.org/research/opn1/overview.do| publisher=IBM| date=2020| access-date=18 May 2020}}

• Drug design
• Drug repositioning
• Pharmaceutical engineering
• Pharmaceutical manufacturing
• Generic drug
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, a consensus between the U.S. Food and Drug Administration (FDA), EU, and Japan.
• List of pharmaceutical companies

{{reflist|30em}}

• [http://www.iuphar.org International Union of Basic and Clinical Pharmacology]

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Category:Drug discovery

Category:Life sciences industry