تطوير دواء كوڤيد-19

عودة للموسوعة

تطوير دواء كوڤيد-19

تطوير دواء كوڤيد-19 COVID-19 drug development، هي عملية البحث لتطوير preventative vaccine or therapeutic prescription drug that would alleviate the severity of 2019-20 coronavirus disease (COVID-19). Internationally as of March 2020, some 100 drug companies, biotechnology firms, university research groups, and health organizations were involved in stages of vaccine or drug development. The World Health Organization (WHO),European Medicines Agency (EMA), US Food and Drug Administration (FDA), and the Chinese government and drug manufacturers were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and monoclonal antibody therapies.

By March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development, and committed to investments of US$100 million in vaccine development across several countries. In early March, the Canadian government announced نطقب:CAD in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, with plans to establish a "vaccine bank" of new vaccines for implementation if another coronavirus outbreak occurs.

By late March, 536 clinical studies were registered with the World Health Organization International Clinical Trials Registry Platform to develop post-infection therapies for COVID-19 infections, with numerous established antiviral compounds for treating other infections under clinical research to be repurposed. In March, the World Health Organization initiated the "SOLIDARITY Trial" inعشرة countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.

Vaccine and drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. In February 2020, the WHO said it did not expect a vaccine against SARS-CoV-2 – the causative virus for COVID-19 – to become available in less than 18 months, and conservative estimates of time needed to prove a safe, effective vaccine is one year. Several national regulatory agencies, such as EMA and FDA, approved procedures to expedite clinical testing.

By late March 2020, four potential antiviral therapies – favipiravir, remdesivir, lopinavir and hydroxychloroquine (or chloroquine) – were in the final stage of human testing – Phase III-IV clinical trials – and several possible vaccines had entered the first stage of human safety evaluation, Phase I. On 21 March, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia."

عملية التطوير

نطقب:AI4 Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery. It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I-III trials – to approved vaccine or drug typically takes more than a decade.


الهجريبات الكيميائية الجديدة

Development of a COVID-19 vaccine or therapeutic antiviral drug begins with matching a chemical concept to the potential prophylactic mechanism of the future vaccine or antiviral activity in vivo.

خط زمني يوضح مسارات اعتماد ومراحل أبحاث الأدوية المتنوعة

تصميم الدواء والاختبار المعملي

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery to specify a vaccine or antiviral candidate. These have promising activity against a biological target related to COVID-19 disease. At the beginning of vaccine or drug development, little is known about the safety, toxicity, pharmacokinetics, and metabolism of the NCE in humans. It is the function and obligation of drug development to assess all of these parameters prior to human clinical trials to prove safety and efficacy. 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]).

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).

Many aspects of drug development focus on satisfying the regulatory requirements of drug licensing authorities. These generally constitute tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a regulatory 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 vaccine is to be delivered by skin injection). Increasingly, these tests are made using in vitro methods (e.g., with isolated cells), but many tests can only be made by using experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.

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) or Biologics License Application application for a vaccine. If the IND is approved, development moves to the clinical phase, and the progress of performance in humans – if a vaccine under development in the United States – is monitored by the FDA in a "vaccine approval process."


مراحل التجارب السريرية

Clinical trial programs involve three, multiple-year stages toward product approval, and a fourth, post-approval stage for ongoing safety monitoring of the vaccine or drug therapy:

  • Phase I trials, usually in healthy volunteers, determine safety and dosing.
  • Phase II trials are used to establish an initial reading of efficacy and further explore safety in small numbers of people having the disease targeted by the NCE.
  • Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of people with the COVID-19 infection. 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 to begin marketing.
  • Phase IV trials are post-approval trials that may be a condition attached by the FDA, also called post-market surveillance studies. Until a vaccine is provided to the general population, all potential adverse events remain unidentified, requiring that vaccines undergo Phase IV studies with regular reports by the manufacturer to the Vaccine Adverse Event Reporting System (VAERS) to identify problems after use in the population begins.

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). 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.

التصميمات العتمدة لتجارب كوڤيد-19

A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide insight about positive or negative efficacy of the treatment. Adaptive designs within ongoing Phase II-III clinical trials on candidate therapeutics for COVID-19 may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success. The European Discovery Trial of hospitalized people with severe COVID-19 infection is rapidly implementing trial design changes as results from the four experimental therapeutic strategies emerge.

معدل الإخفاق

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.

A study covering clinical research in the 1980-90s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–15, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16.2% specifically for vaccines. 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.


التكلفة

One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market as about US$1.8 billion and $870 million, respectively. A median cost estimate of 2015-16 trials for development ofعشرة anti-cancer drugs was $648 million. In 2017, the median cost of a pivotal trial across all clinical indications was $19 million.

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, possibly as high as $345 million. 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. 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 2003-13 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.

Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources.

العلاجات المرشحة

التجارب ثلاثية ورباعية المراحل

Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. For an already-approved drug (such as hydroxychloroquine for malaria), Phase III-IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection.

Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials, such as BDB-1, brilacidin, and APN01, or numerous treatment candidates in Phase I trials, are also excluded. Drug candidates in Phase II trials have a low success rate (under 12%) for eventual approval.

كوڤيد-19: الأدوية المرشحة في التجارب ثلاثية ورباعية المراحل
الدواء المرشح الوصف السقم المعتمد حالياً رعاة التجربة المسقط النتائج المتسقطة الملاحظات،
الهوامش
رمدسيڤير antiviral protease inhibitor against coronaviruses investigational Gilead, WHO, INSERM China, Japan initially; expanded to multiple countries in Europe and N. America in Global Solidarity and Discovery Trials April (Chinese, Japanese trials) to mid-2020 Selectively provided by Gilead for COVID-19 emergency access.
هيدروكسي‌كلوروكين أوكلوروكين (پلاكنل ، أرالـِن) antiviral, generic manufactured by Bayer, Novartis, Mylan, Teva, others malaria, rheumatoid arthritis, lupus (International) CEPI, WHO, INSERM Multiple sites in China; Global Solidarity and Discovery Trials, Europe, international April 2020 (Chinese trials); mid-2020 multiple side effects, some severe; possible adverse prescription drug interactions; trials
فاڤي‌پيراڤير (أڤيگان) antiviral against influenza influenza (China) Fujifilm China April 2020
لوپيناڤير + ريتوناڤير مع أوبدون ربيف antiviral, immune suppression investigational combination; ritonavir-lopinavir approved CEPI, WHO, UK Government, Univ. of Oxford, INSERM Global Solidarity and Discovery Trials, multiple countries mid-2020
Sarilumab (Kevzara) human monoclonal antibody against interleukin-6 receptor rheumatoid arthritis (USA, Europe) Regeneron-Sanofi Multiple countries Spring 2020
ASC-09 + ritonavir (oral tablet) antiviral combination not approved; ritonavir approved for HIV Ascletis Pharma Multiple sites in China Spring 2020
Tocilizumab (atlizumab, Actemra) human monoclonal antibody against interleukin-6 receptor immunosuppression, rheumatoid arthritis (USA, Europe) Genentech-Hoffmann-La Roche Multiple countries mid-2020

الهيدروكسي‌كلوروكين والكلوروكوين

On 28 March 2020, the US FDA enabled use of oral tablets of chloroquine phosphate or hydroxychloroquine sulfate under an emergency use authorization at the discretion of physicians treating people with COVID-19. The FDA official stated "that it is reasonable to believe that the known and potential benefits of chloroquine phosphate and hydroxychloroquine sulfate, when used for the treatment of SARS-CoV-2 and used consistently with the Scope of Authorization of this letter (Section II), outweigh the known and potential risks of these products."

Preliminary results had found that chloroquine may be effective and safe in treating COVID-19 associated pneumonia. The Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health and Health Commission issued a report stating that chloroquine phosphate "improves the success rate of treatment and shortens the length of patient's hospital stay" and recommended it for people diagnosed with mild, moderate and severe cases of novel coronavirus pneumonia.

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19, although these agencies and the US CDC noted contraindications for people with heart disease or diabetes. In February 2020, both drugs were shown to effectively reduce COVID-19 illness, but a further study concluded that hydroxychloroquine was more potent than chloroquine and had a more tolerable safety profile. Preliminary results from a trial indicated that chloroquine is effective and safe in COVID-19 pneumonia, "improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course." Hydroxychloroquine is more commonly available than chloroquine in the United States.

According to the US CDC, either chloroquine or hydroxychloroquine is recommended for treatment of hospitalized people infected by COVID-19 in several countries, although there is no such evidence from clinical trials in the United States, as of March 2020. Preliminary clinical trials to evaluate the safety and efficacy of hydroxychloroquine for treating COVID-19 infection are planned in the United States, but the CDC stated that "the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection" were not yet established.

Hydroxychloroquine and chloroquine have numerous, potentially serious, side effects, such as retinopathy, hypoglycemia, or life-threatening cardiomyopathy. Both drugs have extensive interactions with prescription drugs, affecting the therapeutic dose and disease mitigation. Some people have allergic reactions to these drugs.

الأبحاث ما قبل السريرية للعلاجات المحتملة لكوڤيد-19

The term "preclinical research" is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a vaccine, antiviral or monoclonal antibody therapy, such as experiments to determine effective doses and toxicity, before a candidate compound is advanced for safety and efficacy evaluation in humans. To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 vaccines and therapies, according to several reports in early 2020. Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the drug development process for treating infectious diseases is 19%, and, for vaccine candidates specifically, only 11.5%.

On 2 April 2020, researchers at the University of British Columbia reported the discovery of a trial drug that can substantially block early stages of the COVID-19 disease in engineered human tissues.

المثبطات

Genetic map of the Lily-Mottle virus: the wedges show where the protease breaks up the polyprotein. The principle may apply to the SARS-CoV-2 virus main protease

In March 2020, the main protease of the SARS-CoV-2 virus was identified as a target for post-infection drugs. This enzyme is essential to the host cell to reproduce the ribonucleic acid of the virus. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease. Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS. As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID-19. A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID-19.

مضادات الڤيروسات، الأدوية المناعية والأجسام المضادة

One report indicated that 29 advanced clinical trials of post-infection drug candidates at hospitals in China would be reported in April. As of March 2020, IFN-alpha and umifenovir were being developed in early-stage research as post-infection antiviral agents. Numerous other candidates, including immune therapy and antibody compounds, were in development.

الدراسات الميدانية الفاشلة

In adults with severe COVID-19 hospitalized in Wuhan, China, treatment using a combination of antiviral HIV drugs – lopinavir–ritonavir (HIV/AIDS therapies) – provided no significant benefit (when trialed on its own).

الاستراتيجيات

إعادة استخدام الأدوية المعتمدة

During the COVID-19 outbreak, drug repurposing (or "repositioning") is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. In the usual drug development process, confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19.

Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution. In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II-III trials on four promising treatment options – the SOLIDARITY trial – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020.

الوقاية بعد التعرض

Based on experience with antimicrobials, pre-exposure prophylaxis and postexposure prophylaxis (PEP) with antiviral drugs may be effective procedures to minimize infection by COVID-19. PEP using the antibiotic, rifampicin, is recommended by WHO for people at high risk of infection before or after exposure to pandemic influenza. Antiviral drugs administered shortly after onset of COVID-19 infection symptoms may reduce illness and lower the risk of infecting other people by reducing viral shedding in respiratory secretions.

مبادرات من أجل التجارب السريرية

انظر أيضاً

  • تكلفة تطوير الأدوية
  • كوڤيد-19

المصادر

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قراءات إضافية

  • McCreary, Erin K; Pogue, Jason M (23 March 2020). "COVID-19 Treatment: A Review of Early and Emerging Options". Open Forum Infectious Diseases. doi:10.1093/ofid/ofaa105. ISSN 2328-8957.

وصلات خارجية

  • COVID-19 (Questions & Answers) by the World Health Organization
  • COVID-19 (Q&A) by the US Centers for Disease Control and Prevention (CDC)
  • Coronaviruses by US National Institute for Allergy and Infectious Diseases
  • COVID-19 (Q&A) by the European Centre for Disease Prevention and Control
  • COVID-19 by the China National Health Commission
تاريخ النشر: 2020-06-09 07:57:29
التصنيفات: CS1 errors: PMC, CS1 errors: PMID, CS1 الصينية-language sources (zh), Pages with DOIs inactive as of 2020, صفحات بالمعرفة فيها قوالب حماية خاطئة, صفحات شبه محمية للأبد في المعرفة, Articles with short description, Anti-influenza agents, Clinical research, COVID-19, Drug discovery, Drugs, National agencies for drug regulation, Pharmaceutical industry, Regulators of biotechnology products, Vaccines

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