The new coronavirus vaccine has already been on the market, but clinical trials have not yet ended

Since different COVID-19 vaccines were launched on the market at the beginning of this year, the debate over the effectiveness and side effects of vaccines has never stopped. Pfizer and other companies have released clinical trial data during the vaccine development process, and some articles interpreting these have appeared on the Internet. So, can you understand these data? How many phases of drug clinical trials are required? What are the differences between each phase? After completing three phases, can the vaccine be launched on the market? ... Today's article will introduce the basic outline of drug clinical trials.

Written by | Alalei (Master of Internal Medicine, Tongji University)

I believe many people have seen the announcement of "recruitment of subjects for drug clinical trials" in hospitals. Some well-known large hospitals in China have also set up "clinical trial centers". Does clinical trial mean letting people be guinea pigs? ——This concept is outdated! However, most people only "understand the meaning of the word" and "know a little bit" about clinical research. What exactly does a clinical trial do? Are clinical trials and clinical trials the same? Can new drugs that pass clinical trials be put on the market? ... Today we will learn about the basic outline of drug clinical trials.

All important large hospitals in the country have clinical trial centers.

The basic process of drug clinical trials

Although different countries or regions have different drug management systems, the process of new drug development is basically the same. Among them, clinical trials are an indispensable and important part of drug development and marketing.

Nonclinical studies/preclinical studies

↓

Discovery of lead compounds

↓

Phase I Clinical Trial

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Phase II Clinical Trial

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Phase III clinical trial

↓

Obtain marketing authorization

↓

Phase IV clinical trials and adverse reaction monitoring

Drug clinical trials refer to systematic studies of drugs conducted on humans (healthy volunteers or patients) to understand the drug's pharmacology, efficacy, adverse reactions, absorption, distribution, metabolism, excretion, etc., so as to determine the effectiveness and safety of the test drug. Drug clinical trials are also a key step before new drugs are put on the market, providing an important basis for drug supervision and management departments to approve new drugs.

As can be seen from the flowchart above, clinical trials are divided into several stages and are carried out step by step. What are the differences between clinical trials in each stage? Below we will introduce them one by one, supplemented by classic case interpretations.

2. The purpose of each phase of clinical trials

Phase I clinical trial: Safety study The main purpose of Phase I clinical trial is to observe the human body's tolerance and pharmacokinetics of new drugs, and provide a basis for formulating dosing regimens (dosage, method of administration). Tolerance studies are to find out the human body's maximum tolerated dose of new drugs and the adverse reactions they produce. Pharmacokinetics is to observe the absorption, distribution, biotransformation, and excretion of new drugs in the human body.

In the Phase I clinical trial stage, healthy volunteers are generally used; for cancer drugs, cancer patients are usually used to participate in the trial. The number of subjects in this stage is usually between 10 and 100.

Tumor immunotherapy is one of the hottest topics in the medical field in recent years, and it is also a therapy that the public has always been concerned about. Pembrolizumab, the "anti-cancer miracle drug" launched in 2018, is a well-known immunotherapy drug. Its road to approval can well reflect the characteristics of "progressing step by step" in clinical trials. Now, Pembrolizumab has been approved for a variety of solid tumors such as lung cancer, melanoma, and esophageal cancer. Its series of clinical trials are named "KEYNOTE", and the numbers behind them represent different clinical trials. Let's take the non-small cell lung cancer (NSCLC) related trials as an example.

Pembrolizumab is on a roll

Product Name: Keruida

Common name: K drug

Pharmaceutical company: Merck

Phase I clinical trial, KEYNOTE-001

The KEYNOTE-001 trial included not only patients with non-small cell lung cancer but also patients with melanoma. It consists of five parts in total. Detailed information can be found in the Clinical Trials Database (ClinicalTrials.gov) [1]. Two parts are excerpted here for illustration.

Part 1: First, based on the results of preclinical trials, multiple trial doses were designed according to pharmacology, and pembrolizumab was given intravenously to the subjects (i.e., patients with melanoma and non-small cell lung cancer).

There are three single-dose regimens: 1 mg/kg, 3 mg/kg and 10 mg/kg (Note: This dose is based on animal test data from preclinical studies. There are many factors that affect pharmacokinetics/pharmacodynamics, and optimization and adjustment may be required during the test), and the drug is administered every 2 weeks. The unit mg/kg indicates the dosage per kilogram of body weight, and each subject has a different dosage based on their own body weight.

In addition, a dose titration test was also conducted. Dose titration means starting with a small dose and gradually increasing the dose. There are also three schemes:

0.005mg/kg→0.3mg/kg→2mg/kg

0.02mg/kg→0.3mg/kg→2mg/kg

0.06mg/kg→1.0mg/kg→10mg/kg

And record various conditions of the subjects.

Part 2: Low-dose (2 mg/kg) or high-dose (10 mg/kg) pembrolizumab treatment (once every 2 weeks or every 3 weeks) was given to patients with previously treated or untreated non-small cell lung cancer who were positive for PD-L1 expression. The efficacy and safety of the drug, as well as the relationship between PD-L1 expression level and drug efficacy, were recorded. The KEYNOTE-001 trial laid the foundation for subsequent studies of pembrolizumab.

(Note: PD-L1, or programmed cell death receptor ligand-1, is an important detection indicator for tumor cell tissue. Under normal circumstances, the human body's T cells can recognize and attack tumor cells, but the PD-L1 protein on the surface of tumor cells can bind to PD-1 (programmed cell death receptor-1) on the surface of T cells, thereby avoiding the attack of T cells. Pembrolizumab, a PD-1 inhibitor, can block the binding of the two and restore the attack ability of T cells.)

Phase II clinical trials: efficacy studies In Phase I clinical trials, the therapeutic effects of new drugs cannot usually be confirmed in healthy volunteers. Moreover, the way drugs work in patients is usually different from that in healthy people, especially those that can affect the intestines, stomach, liver, and kidneys. For example, vonoprazan, which is used to treat reflux esophagitis, is a drug that inhibits gastric acid. After taking the drug, the blood drug concentration (the total concentration of the drug in the plasma after absorption) of patients with renal impairment is higher than that of patients with normal renal function. Therefore, Phase II clinical trials will administer the drug to a small number of patient volunteers (generally 100 to 500 cases), re-observe the drug's tolerance and pharmacokinetics, and preliminarily evaluate the drug's therapeutic effects.

Benefit-risk assessment Through the first two phases of clinical trials, drug development units must evaluate the benefit/risk ratio of the test drug to determine whether it is necessary to further study the drug. Generally speaking, the benefits of taking a drug to treat a certain disease should outweigh the risks of using the drug. A drug with an unacceptable benefit/risk ratio will not be approved by the drug regulatory authorities.

In 2013, the European Medicines Agency (EMA) announced that it would suspend the marketing authorization of oral ketoconazole in the EU on the grounds that "the risk of liver damage outweighs the benefits of oral ketoconazole in the treatment of fungal infections". On the one hand, the efficacy data of oral ketoconazole is limited, and there are other alternative drugs. On the other hand, although liver damage is a known side effect of antifungal drugs, the incidence and severity of liver damage with oral ketoconazole are higher than those of other antifungal drugs, and liver damage will occur early in the treatment of recommended doses. There is no measure that can completely reduce the risk of liver damage. Therefore, the marketing authorization of the drug was suspended. [2] (Note: This refers to oral ketoconazole, not ketoconazole topical preparations, such as creams and ointments, because the amount of ketoconazole absorbed by the body from topical preparations is very small.)

Sildenafil's unexpected success

Trade Name: Viagra

Common name: the little blue pill

Pharmaceutical company: Pfizer

We know that in drug clinical trials, it is very important to observe various adverse reactions. However, are adverse reactions necessarily "negative"? - Not really! The "famous" sildenafil, a drug for the treatment of erectile dysfunction (ED), is a model of timely adjusting the adverse reactions found in clinical trials as the main direction and achieving great success.

In the 1980s, Pfizer conducted clinical trials on sildenafil for the treatment of angina pectoris. Although sildenafil performed well in laboratory and animal experiments, it did not show the expected efficacy in clinical trials. The research and development plan was terminated and the company had to recall the trial drugs. Surprisingly, many subjects refused to hand in the trial drugs. Researchers found that sildenafil could cause adverse reactions such as penile congestion in subjects, so they suggested that Pfizer adjust its research and development direction and develop sildenafil for the treatment of ED. It was eventually confirmed that sildenafil was effective for ED. In 1998, sildenafil was approved for marketing by the US FDA and became a legendary story in the industry. [3]

Phase III clinical trials are based on Phase I and Phase II clinical studies. The trial drugs are used on a larger range of patient volunteers (usually hundreds to thousands of people) to conduct expanded clinical trials to further evaluate the therapeutic effect and safety of the drugs on patients with target indications and to evaluate the benefit/risk ratio.

Phase III clinical trials are the stage for confirming the therapeutic effect and are also the key stage for providing the basis for approval of drug registration applications.

Optimization of clinical trial design: Phase II/III clinical trials Traditionally, Phase II clinical trials should be conducted first, followed by Phase III clinical trials. However, each phase takes time, and waiting for the previous phase of the trial to be completed before conducting the next phase of the trial will result in a longer total trial time. This is one of the reasons why it used to take several years to develop a new drug.

As theoretical methods continue to mature, simulation computing capabilities continue to improve, and practical experience continues to accumulate, clinical trial design is also constantly improving. Phase II/III clinical trial design is to "seamlessly connect" Phase II and Phase III clinical trials, aiming to shorten the time interval between Phase II and Phase III clinical trials, reduce the total sample size of the trial, improve research efficiency, and gradually increase clinical applications. This trial design has advantages in accelerating drug development, especially in anti-tumor drugs. However, before applying this trial design, it is necessary to comprehensively evaluate issues such as design methods, operations, and statistical analysis, and communicate with regulatory authorities. [4]

Similarly, this "seamless connection" can also be applied to other phases, such as Phase I/II clinical trials. During the COVID-19 pandemic, the clinical trials of Pfizer/BioNTech, Clover Biopharmaceuticals/Dynavax, and Inovio's COVID-19 vaccines all used Phase II/III clinical trial designs.

Phase II/III clinical trial number of pembrolizumab: KEYNOTE-010
Following the Phase I clinical trial of pembrolizumab above, let us continue to look at its Phase II/III clinical trials.

In the KEYNOTE-010 trial, a total of 202 medical centers from 24 countries participated, and a total of 1,034 patients with advanced non-small cell lung cancer who had previously received other treatments and had positive PD-L1 expression (≥1%) were included. These patients were randomly divided into two groups, receiving chemotherapy or pembrolizumab (2 mg/kg or 10 mg/kg, once every 3 weeks). The results showed that compared with chemotherapy, the use of pembrolizumab can significantly prolong the patient's survival and has milder adverse reactions. In addition, the survival time of patients receiving 2 mg/kg and 10 mg/kg doses was similar in the two groups. [5]

Undoubtedly, this is an encouraging result. We can interpret the results of the KEYNOTE-010 trial from the following aspects (especially the third point):
First, the efficacy of pembrolizumab is better than that of traditional chemotherapy, and its adverse reactions are also milder. This shows that the drug meets the requirements of benefit-risk assessment;
Second, monotherapy was used in the trial, and there was no disadvantage of the lower dose compared with 2 mg/kg and 10 mg/kg;
Third, it should be noted that the results of this trial cannot be extrapolated to all lung cancer patients. The patients included in the trial are restricted: "previously received other treatments", "positive PD-L1 expression", "advanced stage", "non-small cell lung cancer". In fact, the patient inclusion and exclusion criteria of the trial are very detailed and include many indicators, which are not listed specifically here. There are many types of histopathology and molecular pathology results of lung cancer. In other words, if the lung cancer is "PD-L1 expression negative" or "pathological results are not non-small cell lung cancer", then the KEYNOTE-010 study alone cannot prove that pembrolizumab is effective.

After completing Phase I to III clinical trials, the data collected from a large number of patients or healthy volunteers must be analyzed and processed. The researchers and/or the sponsor (pharmaceutical company or development institute) will then write a summary report and submit the report and relevant data, together with preclinical animal experiments and laboratory data, to the drug regulatory department to apply for a new drug marketing license or production approval, which will then be reviewed and evaluated by the drug regulatory department. The drug regulatory department is the Food and Drug Administration (FDA) in the United States and the National Medical Products Administration (NMPA) in my country. It usually takes months or even years to approve a new drug. If the review results are satisfactory, a license will be issued and the drug can be legally produced and sold.

Approval of pembrolizumab in NSCLC

Based on the results of a phase II/III clinical trial (KEYNOTE-010), the U.S. FDA officially approved pembrolizumab for the treatment of lung cancer in October 2015. The indication is: single-agent treatment of patients with advanced non-small cell lung cancer who have positive PD-L1 expression and have disease progression after previous chemotherapy (second-line treatment). The approved dose at the time was 2 mg/kg based on body weight. [6]
Afterwards, the researchers re-analyzed the trial data including KEYNOTE-001 and found that weight-based dosing and fixed-dose dosing had similar pharmacokinetic characteristics. For patients with low body weight, fixed doses are more advantageous and convenient to use. Finally, a fixed dose of 200 mg was determined as the standard dose. Subsequent clinical trials also adopted a fixed standard dose of 200 mg, and the product instructions were also revised.

Since then, clinical trials of pembrolizumab have continued to expand its indications. In October 2016, the FDA approved its monotherapy as a first-line treatment for patients with advanced non-small cell lung cancer whose PD-L1 expression is ≥50% based on the results of the KEYNOTE-024 trial (Phase III). In April 2019, the FDA further expanded the drug's indications based on the results of the KEYNOTE-042 trial (Phase III). Even for patients with advanced non-small cell lung cancer whose PD-L1 expression is relatively low (≥1%), pembrolizumab is a reasonable choice for first-line treatment. [6]

Phase IV clinical trial: Monitors the first three phases of clinical trials before a drug is launched. It is an evaluation of a smaller, specific group of patients, and the test patients are strictly selected. After the drug is launched, many different types of patients will receive new drug treatment. Therefore, it is necessary to evaluate the effectiveness and safety of new drugs in the "general population" under conditions of widespread use.

Different countries have different definitions of Phase IV clinical trials. In my country, not all new drugs need to complete Phase IV clinical trials. Appendix 2 of my country's "Regulations on Drug Registration Management" (Decree No. 28) states that chemical drugs belonging to registration categories 1 and 2 (chemical drug registration is divided into 5 categories) are required to undergo Phase IV clinical trials, and the minimum number of cases (test group) is required to be 2,000.

Adverse reaction monitoring

The approval of a new drug for marketing does not mean the end of its safety evaluation. The clinical trials conducted before a drug is marketed are limited after all. After a drug is marketed, adverse events related to the drug found during clinical use must be reported to the drug regulatory authorities in a timely manner. If it is ultimately determined that the adverse event is indeed caused by the drug, the drug regulatory authorities may require the pharmaceutical company to modify the instructions, add warnings or restrict the scope of use of the drug, and in serious cases even revoke its marketing authorization.

Rosiglitazone has gone through hardships

Trade Name: Avandia

Pharmaceutical company: GlaxoSmithKline

After a new drug is launched, the evaluation of its effectiveness and safety will not stop. In the field of diabetes, the famous "rosiglitazone incident" is a typical example.

The oral hypoglycemic drug rosiglitazone was approved by the FDA in May 1999, and was launched in Europe in 2000 and in China in the same year. Due to its unique mechanism of action and ideal efficacy, it quickly became a "hot seller". In 2007, a meta-analysis published in the New England Journal of Medicine showed that rosiglitazone may increase the incidence of myocardial infarction and the mortality rate of related diseases, which put rosiglitazone at the forefront of public opinion. [7]

Although this analysis has been questioned statistically, the FDA still imposed sales restrictions on rosiglitazone in 2010, and the European Medicines Agency (EMEA) withdrew rosiglitazone from the European market based on the same data. However, the controversy surrounding the safety of rosiglitazone has not stopped.

In 2001, shortly after rosiglitazone was launched globally, a clinical study to evaluate the cardiovascular safety and glucose-lowering efficacy of rosiglitazone (RECORD) was initiated. A total of 4,447 patients with type 2 diabetes were included and followed up for 5.5 years.

In 2009, the results of the RECORD study showed that compared with the control group, the risk of cardiovascular hospitalization, cardiovascular death, all-cause death, and stroke in the rosiglitazone-treated group was not significantly increased. However, the incidence of congestive heart failure in the rosiglitazone-treated group was higher than that in the control group. [8]

In 2010, the US FDA asked GlaxoSmithKline to commission a third party to review the results of the RECORD study. The Duke University Clinical Research Institute (DCRI) was responsible for this task, and its complete analysis results were published in the American Heart Journal in August 2013. The results of the review were similar to the clinical trial results published in 2009. [9]

In 2013, the FDA organized experts to vote again on the RECORD study results. The results were: 13 votes to relax the restrictions on the use of rosiglitazone; 7 votes to completely lift the restrictions on rosiglitazone; 5 votes to maintain the status quo; 1 vote to withdraw rosiglitazone from the market. In November of the same year, the FDA revoked the sales restrictions on rosiglitazone in 2010, but required pharmaceutical companies to revise the product instructions in response to the heart failure problems found in clinical studies.

3. Clinical trial information needs to be transparent

In the information society, not only medical workers, but also many patients, their families, and people interested in the pharmaceutical industry will search for various information related to drugs. So, can all the information on drug clinical trials be found online? As of January 2009, there are 17 first-level clinical research registries recognized by the World Health Organization (WHO) around the world. The public can search for relevant information on the platforms of these registries.

There is a drug clinical trial registration and information disclosure platform in China (www.chinadrugtrials.org.cn) and the Chinese Clinical Trial Register. Globally, the most commonly used is the clinical trial database (ClinicalTrials.gov) maintained by the National Library of Medicine of the National Institutes of Health (NIH) of the United States.

www.chinadrugtrials.org.cn

As early as 2007, the U.S. Food and Drug Administration Amendments (FDAAA) clearly stipulated that clinical trials conducted in the United States must be registered on ClinicalTrials.gov and that summary information on trial results must be submitted after the trial is completed. However, the enforcement of this law is not ideal. In 2016, the U.S. Department of Health and Human Services (HHS) issued the final rule for clinical trials registration and results information submission, which stipulates that, in general, clinical trial results information should be submitted no later than one year after the completion of the clinical trial. [10]

In 2017, WHO and 15 research organizations published a joint statement on clinical trial transparency in the British Medical Journal (BMJ), requiring that all clinical trial result summaries must be made public on the WHO's clinical trial registration platform11 (Note: this refers to the result summary, not the original clinical research data). [11]

However, in January 2020, The Lancet published a study that investigated clinical trials registered on ClinicalTrials.gov from March 2018 to September 2019 and found that a total of 4,209 clinical trials were required to submit results reports, but only 40.9% (1,722) were submitted within 1 year, and only 63.8% (2,686) ultimately submitted results (regardless of when they were submitted). The average time from completion of a clinical trial to submission of results was 424 days, 59 days later than the one year stipulated in relevant regulations. [12]

So what is the situation in China?

my country's clinical trial disclosure system started late. With China's joining the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 2017, the National Medical Products Administration (NMPA) has gradually begun to formulate relevant regulations. In July 2020, my country promulgated the "Regulations on the Registration and Information Disclosure of Drug Clinical Trials (Trial)", and Article 15 of Chapter 2 states: "After the completion of the clinical trial, the applicant shall register the clinical trial results information on the registration platform within twelve months of the completion date of the clinical trial"; Article 18 of Chapter 3 states: "The drug clinical trial information registered by the applicant shall be disclosed if it is reviewed and meets the requirements of the drug clinical trial license information and filling guidelines. The main information disclosed includes basic information of the trial drug, applicant information, basic information of the clinical trial plan, principal investigator information, information of each participating institution, ethics committee information, trial status information, etc., except for information and attachments that are only used for supervision and management and are not disclosed."

In February 2020, the Chinese Journal of Medical Research Management published an article in which researchers manually searched Chinese clinical trials registered on ClinicalTrials.gov before July 24, 2009; and used computers to search the China National Knowledge Infrastructure, Wanfang Database, VIP Database, PubMed, and EMbase databases to investigate the publication of Chinese clinical trial results. The article ultimately included 654 Chinese clinical studies, of which only 3.8% (25 items) published their results on ClinicalTrials.gov, and 11.3% (74 items) of the clinical studies had published literature (valid literature) on the results of the clinical studies. The time interval from the completion of the clinical study to the publication of the results was mainly concentrated in 3 years. [13]

In fact, the disclosure of clinical trial results is also an ethical responsibility of clinical trials to the subjects. The 2013 version of the Declaration of Helsinki clearly lists the provisions for the registration, publication and release of clinical research results. With the introduction of regulations and statements on the disclosure of clinical trial results by the FDA, the European Medicines Agency (EMA), the International Committee of Medical Journal Editors (ICMJE), the WHO, etc., the disclosure of clinical trial results will eventually become a trend.

Academician Sang Guowei, a famous clinical pharmacologist in my country, pointed out in the preface to the Practical Guide to Clinical Trials of Drugs and Good Clinical Practice (GCP) (2nd Edition):

"It should be remembered that any clinical trial involving human subjects may have its risks. Therefore, two essential and important aspects must be paid attention to in drug clinical trials: first, protecting the safety and rights of human subjects; second, ensuring the scientificity, accuracy and reliability of the trial data and results."

With the further improvement of the clinical trial system, we believe that the standardization of clinical trials will continue to improve, the level of transparency will continue to increase, and the value of clinical trials will be more fully reflected.

References

[1] https://clinicaltrials.gov/ct2/show/NCT01295827?term=KEYNOTE-001&draw=2&rank=1

[2] https://www.ema.europa.eu/en/medicines/human/referrals/ketoconazole-containing-medicines

[3] https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020895

[4] http://www.cde.org.cn/news.do?method=largeInfo&id=768744135afea3cc

[5] Roy S Herbst, Paul Baas, Dong-Wan Kim, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet. 2016; 387(10027): 1540-1550.

[6] https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process

[7] Nissen SE, Wolski K. Effect of msiglitgzone on the risk of myocardial infarction and death from cardiovascular causes． N Engl J Med. 2007; 356: 2457-2471．

[8] Home PD, Pocock SJ, Beck-Nielsen, et a1. Rosiglitazone evaluated for cardiovascular in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-1abel trial． Lancet. 2009;373:2125．

[9] Mahaffey KW, Hafley G, Dickerson S, et a1. Results of a reevaluation of cardiovascular outcomes in the RECORD trial． Am Heart J. 2013; 166: 240-249．

[10] https://www.federalregister.gov/documents/2016/09/21/2016-22129/clinical-trials-registration-and-results-information-submission

[11] GOLDACRE B． The WHO joint statement from funders on trials Transparency． BMJ. 2017; 357: j2816．

[12] Nicholas J DeVito, Seb Bacon, Ben Goldacre. Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study. Lancet. 2020; 395(10221): 361-369.

[13] Dong Min, Li Manrui, Xu Yang, et al. Registration and publication of clinical studies in China: a re-survey after 8 years. Chinese Journal of Medical Research Management. 2020. 33(1): 70-74.