Right to attempt
Valeria Mishina, "The Attic"
At the end of May, US President Donald Trump signed a document that gave all US citizens the so–called right to try - now terminally ill people can get access to medicines that have not yet passed all stages of clinical trials and have not received approval from the FDA. We are talking about patients who have already exhausted all available treatment options at the moment. "The Attic" figured out what opportunities Russian patients have to access unregistered drugs.
Trump didn't exactly shock the country with his act. In the USA, the days of the "Dallas Buyers Club" have long passed, and the "right to try" in recent years could be used on the territory of 40 states, and 10 more continued to ponder whether to introduce a similar law at home. So the US president, having signed a federal law on May 30, has already consolidated the prevailing approach at the federal level.
What exactly does the appearance of a federal law mean for the states? According to Yuri Rogulev, director of the Franklin Roosevelt Foundation for the Study of the USA at Moscow State University, the laws adopted by the US federal authorities have an advantage over local ones, although they are not canceled: "If there are serious discrepancies, then state laws are brought into line with federal law. If there are no such laws, a federal law begins to take effect." So now the "right to try" has extended, firstly, to those states that did not have time to introduce it on their own.
How it works
Where it is already possible to "try", the procedure looks like this: a patient who has decided to exercise his right asks his doctor to consider options for experimental treatment, and after consultation, the doctor can contact the manufacturer with an appropriate request.
The websites of the Congress and the White House emphasize that the new law opens access "to certain unregistered, experimental medicines" to patients in terminal conditions if they have already exhausted all available treatments in the United States and are unable to participate in clinical trials of medicines. The only condition is that the drug must pass the first phase of clinical trials.
During the first phase, the safety of the drug is checked, this is done on small groups of volunteers – up to 100 people. In the second phase, the effectiveness of the dose is studied, and up to 300 people become participants, and in the third their number is already in the thousands, where the effectiveness of the drug is compared with placebo and standard treatment, as well as side effects are recorded.
Manufacturers will have to notify the FDA of each use of their experimental drugs as part of the Right to Try. The FDA will have to post an annual report on the application of the law on its website. At the same time, the law protects manufacturers and doctors prescribing the drug from liability. If they do not agree with the patient's wish, they can use their "right of refusal", sewn into the new law.
Pros and cons
"Patients who are terminally ill should not travel from country to country in search of the right remedy, I want to give them a chance to get it here at home," the words of the US president are quoted on the White House website.
They contain a reference to an already fairly common practice. Supporters of the Right to Try initiative cite the example of a Texas doctor Ibrahim Delpassend, who since 2015 has helped about 200 patients with the last stages of neuroendocrine cancer (for example, pancreatic cancer) to gain access to a drug that has not been approved in the United States, but has been used in European countries for 15 years. Subsequently, this drug was approved by the FDA, but it took 2.5 years, which the patients of Delpassend might not have.
As supporters of the Right to Try approach also note, only about 3% of patients in the last stages of the disease can participate in clinical trials of new drugs, and for so–called early access (compassionate use) - manufacturers' programs, according to which new experimental drugs are provided for humanitarian reasons to needy patients who cannot participate in clinical trials due to-due to their location, condition or age, only about 1.2 thousand people per year can count. At the same time, according to the same activists, more than a million Americans suffering from terminal diseases die every year.
According to Roman Ivanov, vice president for Research and Development of the biopharmaceutical company BIOCAD, what has now been done in America by adopting the law on the "right to try" has gone even further than the early access system: "Patients can get access to medicines outside the early access program, and at the discretion of the doctor. Whether it's good or bad is another question. In principle, if there is a clear criterion in which cases to consider the situation hopeless, then it is, of course, for the benefit of patients. But there should be clear criteria to exclude cases of abuse, as well as tragic cases associated with the use of an incompletely studied drug."
Opponents of the "right to try" also note that most of the drugs that have passed the 1st phase of clinical trials still do not receive FDA approval as a result. And not because the agency is too bureaucratic or unscrupulous, but simply because a huge proportion of medicines eventually turns out to be ineffective and even harmful. Why give desperate people false hope and let them spend a lot of money to play the lottery?
David Gorsky, a physician and managing editor of the Science-Based Medicine portal, warns that at least 85% of the medicines now available to patients according to the "right to try" will not only be useless, but also harmful, and in addition, will cost the patient a lot of money
"In fact, in the Right to Try law, responsibility for the patient is shifted to the shoulders of a doctor or a pharmaceutical manufacturer: the patient is provided with a drug that is produced only for clinical trials, has not passed the necessary regulatory approval, and treatment is not compensated by insurance companies," said a member of the board of the Russian Society of Clinical Oncology (RUSSCO), head of the oncology department Antitumor therapy of the Federal State Budgetary Institution of the Central Committee of the Administration of the President of the Russian Federation Dmitry Nosov. – As a doctor, I believe that this approach should be controlled and limited to the scope of clinical research, a systematic analysis of the safety of the drug and its effectiveness should continue. And here neither the patient nor the doctors have complete information about the drug – it is still poorly studied."
How do early access programs work and are there any in Russia
Abroad, early access programs work in the USA, Canada, Great Britain, Belgium, Germany, France, Italy, Spain, Portugal, Australia and Japan. The mechanism of such programs, as a rule, is as follows: after the completion of the second phase of clinical trials, the manufacturer begins the final, third, study. At the same time, companies begin to prepare an application for registration and, if approved, must provide a large batch of the drug by the start of sales. As a result, a "window" is formed when the drug is already available, its effectiveness and safety have been confirmed, but there is no registration yet. This is where "early access" (aka "advanced", "temporary", "individual") begins to work.
The medicine after certain procedures (the decision of the medical commission, registration in the program, preparation of a dossier on patients, and so on) is transferred to the patient who has given informed consent to the use of an unregistered drug. At the same time, the manufacturer cannot subsequently use data on the effectiveness and safety of the drug, based on its use by patients under the early access program.
Russians also have the opportunity to get access to unregistered medicines, although it cannot be called a direct analogue of early access, much less a "right to try." "This is either in clinical trials, or there is an order allowed for severe patients for vital indications (Federal Law 61 "On the circulation of Medicines"), according to which, for example, many charitable foundations work. They bring drugs that are not registered in Russia from abroad for their wards," says the executive director of the Association of Clinical Research Organizations (AOKI) Svetlana Zavidova. – After a consultation of doctors and with the consent of the patient, foundations or other representatives of the patient receive permission from the Ministry of Health of the Russian Federation to import drugs available in other countries."
In addition, as Roman Ivanov says, according to Federal Law 61, it is impossible to get access to Russian-made experimental medicines. "Unfortunately, the wording of the 61st law is such that this permission applies only to foreign medicines,– explains Ivanov. "The law was written when, in principle, we did not have domestic innovative drugs, and no one thought about the possibility that there would be Russian drugs that patients would need for humanitarian reasons."
According to him, pharmaceutical companies have been sending proposals to the Ministry of Health and other executive authorities for three years, as well as to the State Duma on amendments to the 61st law, so that at least the procedure for the use of unregistered drugs in Russia can be applied to domestic innovative drugs, and as a maximum - there was a process of reviewing and approving applications for the controlled use of unregistered drugs. "Now it is not regulated in any way: the Ministry of Health issues a permit, but then, what is the result of using an unregistered drug for a patient, no one knows and is not responsible," says Ivanov.
Pharmaceutical manufacturers have been trying to influence this situation for some time: it is beneficial for them to reduce the time between the start of drug development and its sale. Thus, according to the proposals of Biocada sent to the Ministry of Health, it is possible either to introduce a mechanism for providing unregistered medicines of Russian and foreign production to patients for free, or to reproduce early access programs in Russia, which is a more difficult task, since it will require serious changes in legislation.
In September 2017, the research company MAR CONSULT conducted a survey among 350 doctors from 48 regions of the Russian Federation about their attitude to the use of unregistered medicines in Russia. Only 1/5 of the surveyed doctors have experience in using early access programs in clinical practice. At the same time, the majority of respondents (87%) have a positive attitude to the possibility of using innovative drugs that are not registered in Russia.
As for the even more radical "right to try," according to Larisa Popovich, director of the HSE Institute of Health Economics, such a law is unlikely to be adopted in Russia, although "it may change the way things are viewed." "Now modeling is actively beginning to develop, replacing clinical trials, plus now all approaches and the whole philosophy of clinical trials are actively changing in the world," the expert says. "For example, companies unite and use the same patients, testing different drugs that affect different target elements of the body." Larisa Popovich also noted that "very good results of modeling the reaction of protein structures to certain chemical elements have already been obtained in Russia": "I think this will significantly accelerate the search for promising molecules, but I don't think that patients will begin to receive access after the first stage of testing, this is too drastic."
In response to the request of the "Attic" to the Ministry of Health about whether approaches to access to medicines for Russian patients are being discussed in the department, the Ministry of Health replied that "currently, together with the expert community, the issue of introducing similar norms in Russian legislation is being worked out," but did not specify whether access similar to the adopted one is meant now in the USA or we are talking about proposals for the introduction of early access programs.
Clinical trials: how to find them for doctors and patients
In Russia, clinical trials of medicines must be approved by the Ministry of Health, as well as ethical committees under the Ministry and the medical organization where the research will take place. "This is also carried out in accordance with Federal Law 61 and with the standards of the so–called good clinical practice GCP (international standard of ethical standards and quality of scientific research, describing the rules for the development, conduct, documentation and reporting)," says Roman Ivanov. He also notes that "Russian approaches to conducting clinical trials are harmonized with approaches that are used in Europe and the USA."
"It is very difficult for a drug developer to recruit participants for international research," says Dmitry Nosov. – He needs a large cohort of patients, a population with the same diagnosis, the same molecular disorder. Now the criteria for selecting patients are becoming more complicated, as drugs are being developed that affect, for example, only a certain molecular disorder, and it occurs, say, only in 3% of all cancer patients in the world. To understand whether the drug is effective, it is necessary to recruit a large number of patients, and this can only be done within the framework of a cooperative study involving many countries and institutions." According to Nosov, about a hundred international clinical trials of oncological drugs are currently being conducted in Russia.
Svetlana Zavidova admits that in Russia patients may have problems finding information about clinical trials: "It is not easy to find the necessary information from the outside, it is quite specific. There is, for example, a register of permitted studies, it is maintained by the Ministry of Health. If we are talking about international studies, we recommend that the patient find a detailed description in one of the international registries, the most detailed is conducted in the USA."
To help patients, there is a special subsection on the AOKI website "How to find a clinical trial", which contains information about the registry of the Ministry of Health, and links lead to the website of the International Registry of Clinical Trials of the US National Institutes of Health. "If it seems to you that you have found a suitable clinical trial, the next step is to check whether it is in Russia," AOKI suggests. – To do this, try to find this study in the registry of the Ministry of Health of Russia."
"Given that clinical trials are much less common in our country than in the USA, our patients, of course, unfortunately, have limited access to them," Svetlana Zavidova notes. – And often we lose the chance to participate in international studies because of our licensing system. For example, you need to recruit 1.5 thousand patients, no matter from which country. And if in other countries patients have already been recruited for the study, and we have just received permission, then the train has left."
Dmitry Nosov also recalls that the Russian Society of Clinical Oncology, together with the Clinical Research Agency, has launched a service designed for doctors and patients to search for clinical trials. "This is an online service, a navigator for referring patients to clinical trials, launched just two weeks ago. The main user of this service will be a practicing oncologist, but it is primarily created for patients. With its help, it is planned to expand patients' access to innovative antitumor drugs, which are being studied as part of clinical studies conducted in leading oncological institutions in the territory of the Russian Federation."
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