Ethics codes and use of new and innovative drugs

Abstract

Treatment with new and/or innovative drugs with uncertain safety and efficacy profile is associated with substantial ethical concerns. The main objective of this paper is to present guidance on the use of such drugs contained in: (i) major international codes and guidelines pertaining to medical ethics and biomedical research; (ii) national codes of medical ethics and professional conduct of the USA, Canada, Australia, New Zealand, the UK, Ireland, France and Germany. Out of the four international codes and guidelines analysed, only the Declaration of Helsinki addresses the question of the use of unproven drugs. Among national codes, only two (USA and New Zealand) explicitly allow for use of new or innovative drugs. Moreover, treatment with unproven drugs seems to be permissible under the French code, though this is not stated explicitly. The remaining codes do not contain any articles on the use of new and innovative drugs. An update of existing articles, as well as the addition of new guidelines to the codes, should be considered in view of the rapid pace of development and introduction to clinical practice of new drugs. This work is relevant to innovative off‐label applications of approved drugs and expanded access to investigational drugs.

Introduction

In clinical practice, there are certain situations where all drugs approved for use in a given disease have insufficient effectiveness or effective medicines do not exist at all. Situations of this kind often result in a necessity to use innovative therapy that significantly differs from standard medical treatment, has not been validated by reliable research, and is lacking in sufficient evidence to confirm its safety and effectiveness 1. Examples of such therapy include some off‐label applications of drugs, especially those which are novel and lack strong scientific evidence to support a given application 2. Another possibility is the use of investigational drugs. In this case, when investigational drugs are used in patients with serious, including life‐threatening, diseases outside of clinical trials, the treatment is termed expanded access or compassionate use 3. A feature that innovative therapy with approved drugs has in common with expanded access is that they are used not to investigate a drug's safety and efficacy, but rather to obtain therapeutic benefit for the patient. However, the therapeutic use of unproven drugs, as well as drugs whose efficacy and safety have not been proven for a given disease, population of patients, or dosage is also associated with substantial ethical concerns pertaining, among others, to possible harms to patients and informed consent 2, 4, 5, 6. An important problem and at the same time source of controversy is what kind of evidence can be considered sufficient to justify the use of unproven drugs in the treatment of patients.

In general, the primary source of ethical guidance for physicians are different ethics codes and guidelines. In this paper, we perform an analysis of selected codes to determine whether they provide any guidance for doctors who would like to use new and/or innovative drugs whose safety and efficacy have not been proven yet. We address the following questions: first, do these codes permit therapeutic use of such drugs and, if so, on what conditions? Moreover, do they draw the attention of doctors to ethical challenges associated with innovative treatments? A discussion of ethical guidelines regarding the use of new and innovative drugs will be preceded by a brief characterization of expanded access and off‐label use.

The problems discussed in this article are particularly important in view of recent initiatives aiming to promote the development of new and innovative drugs including the Innovative Medicines Initiative in the European Union and the 21st Century Cures Act in the USA 7, 8.

Expanded access and off‐label applications of drugs: general characteristics and legal regulations

Expanded access (also called compassionate use) is the therapeutic use of unauthorized (mostly investigational) drugs outside of clinical trials. Expanded access regulations have been introduced in the USA, the European Union, Canada and Australia. While these regulations differ by country, in principle, expanded access treatment can be performed in patients with serious, including life‐threatening diseases who cannot be treated satisfactorily with authorized drugs. In addition, the use of an investigational drug must be supported by sufficient evidence of its safety and efficacy, and a doctor must obtain informed consent from the patient 9, 10, 11, 12, 13, 14.

In the USA, independently from the existing Food and Drug Administration regulations, most states have recently introduced so called right‐to‐try laws which are meant to facilitate access of terminally ill patients to investigational drugs that have completed Phase I of a clinical trial. In addition, the US Congress has just passed a bill to create a similar national law. These laws have received extensive coverage in both biomedical and lay journals and have resulted in very lively discussions about patients' access to investigational drugs. Notably, they have been heavily criticized by experts for offering false hope to patients without providing any actual improvements in access to investigational drugs 15, 16.

Off‐label application of an authorized drug is its use for an indication, dosage, route of administration, or group of patients other than those specified on‐label 17. Certainly, not all off‐label applications of drugs can be considered a kind of innovative treatment. On the contrary, some off‐label uses have become widely accepted clinical practice or even a standard of care 18. However, it is also known that a very large proportion of off‐label applications of drugs – >70% according to some analyses – is not based on strong scientific evidence 19, 20. This is an important problem because off‐label uses lacking strong scientific evidence are associated with a substantially higher rate of adverse drug events compared with on‐label applications 21.

Unlike the use of unauthorized drugs in expanded access/compassionate use programmes, off‐label use as such is generally unregulated in most countries. In principle, in the USA, Canada and Australia, once a drug has been approved by a relevant regulatory agency, the doctor may use it at his/her discretion, not necessarily for the indication, dosage, route of administration, and group of patients listed on‐label 18, 22, 23. Off‐label use of drugs has not been regulated at the level of the EU either 24. However, some European countries have developed national regulations concerning off‐label use 24.

Ethics codes and guidelines and the use of new and innovative drugs

Generally, international codes and guidelines concern medical ethics or biomedical research involving humans. The World Medical Association International Code of Medical Ethics (ICME) is the primary example of the former category, while major codes and guidelines pertaining to biomedical research include the Declaration of Helsinki (DH), the International Ethical Guidelines for Health‐related Research Involving Humans by the Council for International Organizations of Medical Sciences and the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research by the Council of Europe 25, 26, 27, 28.

We also analysed selected national codes of medical ethics and professional conduct from English‐speaking countries including the AMA Code of Medical Ethics by the American Medical Association (AMA^US), the CMA Code of Ethics by the Canadian Medical Association (CMA), the AMA Code of Ethics by the Australian Medical Association (AMA^Aus), the Good Medical Practice: a Code of Conduct for Doctors in Australia by the Medical Board of Australia, the Good Medical Practice by the UK General Medical Council, the Guide to Professional Conduct and Ethics for Registered Medical Practitioners by the Medical Council of Ireland, the Good Medical Practice by the Medical Council of New Zealand, as well as the Code of Ethics for the New Zealand Medical Profession by the New Zealand Medical Association 29, 30, 31, 32, 33, 34, 35, 36. Moreover, we included in our analysis the codes of Germany and France which are available in English (Professional Code for Physicians by the German Medical Association and the French Code of Medical Ethics by the French National Medical Council) 37, 38.

International codes and guidelines

The principal international code that addresses the question of the use of unproven treatments is the DH 26. Relevant guidelines are contained in Paragraph 37, Section: Unproven Interventions in Clinical Practice. According to the DH, the physician has the right to use an unproven intervention in situations when proven treatments do not exist or have been ineffective. Before use of an unproven intervention, the physician should seek expert advice and obtain informed consent from the patient or a legally authorized representative. An unproven intervention may be used when it offers hope of saving the life of the patient, re‐establishing their health, or alleviating suffering. The DH also underscores that an unproven intervention should subsequently be made the object of research to evaluate the efficacy and the safety of the intervention. Moreover, the DH obliges the physician to record all data about the unproven intervention; where applicable, these data should be made publicly available 26.

Unlike the DH, the International Ethical Guidelines for Health‐related Research Involving Humans by the Council for International Organizations of Medical Sciences and the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research by the Council of Europe do not contain any guidelines on therapeutic use of unproven drugs 27, 28.

The principal international code of medical ethics – the ICME – is quite brief (especially when compared with most other codes and guidelines that are analysed in this paper) and lists general duties of physicians 25. According to one of these duties, a physician shall act in the patient's best interest when providing medical care. However, this statement is rather ambiguous in the context of unproven treatments. On the one hand, having no approved treatment options, a physician may try to use an unproven drug as the therapeutic last resort. On the other, when the safety and efficacy of a given drug are uncertain, can we really state that the doctor is acting in the patient's best interest? In some cases. such drugs can even lead to a deterioration in the patient's health 39. Unfortunately, apart from this fairly general article, the ICME does not contain any specific guidelines about the use of new and innovative drugs. However, it does underscore that a physician should use due caution in divulging discoveries or new techniques or treatment through nonprofessional channels (this is listed as one of the Duties of Physicians in General).

National codes of medical ethics and professional conduct

Out of the 10 national codes of medical ethics and professional conduct that we analysed, only two (the AMA^US and the NZMA) contain articles that explicitly allow for therapeutic use of new or innovative drugs. In the former guidelines on use of such drugs are contained in Chapter 1: Opinions on Patient–Physician Relationship, Section 1.2.11 Ethically Sound Innovation in Medical Practice [in this code there is also a chapter entitled Opinions on Research & Innovation (Chapter 7) but it concerns clinical research only] 29. The opinions from Chapter 1 refer to a broad category of innovation that may include improving an existing intervention, introducing an innovation to clinical practice for the first time, using an existing intervention in a novel way or translating knowledge from one clinical context to another. The AMA^US code stresses that innovation is neither research nor patient care, although it has some features in common with both.

An important point raised by the AMA^US code is that developing and disseminating innovative practices is in accordance with key responsibilities of the physician's profession including advancing medical knowledge, improving quality of care and promoting the well‐being not only of individual patients, but also the community.

The AMA^US code lists several requirements that should be met by physicians who wish to employ innovative modalities. Firstly, any innovation should be based on sound scientific evidence (although the code does not specify what kind of evidence can be considered sufficient in this regard). Secondly, innovations should be designed to minimize risks to individual patients and maximize the probability of benefit for populations of patients. A recommendation to use an innovative treatment should be based on the patient's medical needs only, but physicians should be aware of other factors that can influence the development of innovative practices. An innovative treatment that is of no benefit to the patient should be discontinued. However, not only positive, but also negative findings from the use of an innovative treatment should be disseminated. In addition, the physician should consider the cost implications of innovation.

The AMA^US code also specifies what information is essential for informed decision making by the patient. This includes differences between the innovative treatment and the standard one, the reasons for which the physician is recommending an innovative treatment, the known and anticipated risks, benefits and burdens of the innovative therapy and of its alternatives, previous experiences with the innovative treatment as well as the physician's potential conflicts of interests.

The physician should not only possess appropriate knowledge and skills to use an innovative treatment, but also seek input from other physicians and medical professionals as early as possible. An important question is professional oversight of innovative practices that should include ensuring that the physician possesses the proper qualifications and encouraging them to collect and share information with peers about the resources necessary for the intervention 29.

According to the NZMA code, doctors have the right to recommend, and patients have the right to receive, a new drug or treatment that, in the doctor's considered judgement offers hope of saving life, re‐establishing health or alleviating suffering (Article 50) 36. Before offering the drug to the patient, the physician should consult a suitably qualified colleague. The NZMA code requires that the physician fully inform the patient about the drug including that the treatment is new or unorthodox. Because there is no strict boundary between innovative treatment and clinical research, the physician should always consider whether therapeutic use of a new drug should be subject to formal research protocols (Articles 50 and 51). The NZMA code also requires that all innovative approaches to medical practice should undergo review and promulgation through professional channels including ethics committees as well as medical scientific literature (Article 44). Importantly, contributing responsibly to innovation is listed in the NZMA code as one of the basic Principles of Ethical Behaviour of doctors (Principle 7) 36.

Articles 44, 50 and 51 of the NZMA code are complemented by guidelines regarding informed consent for innovative treatments from the Good Medical Practice by the New Zealand Medical Council; these are contained in the section Supplementary guidance – Informed consent in specific situations 35. According to these guidelines, a doctor should obtain written informed consent for any procedure that is experimental or carries a significant risk of adverse effects. If a patient has to choose between evidence‐based therapy and innovative treatment lacking scientific evidence, the doctor should present to the patient a clear and well‐balanced summary of the scientific information available. If the treatment is risky or controversial, and the doctor is unsure whether the patient is competent to make a certain decision, the doctor should seek advice of a senior colleague or obtain legal advice. Other than the guidelines about informed consent, the Good Medical Practice by the New Zealand Medical Council does not contain any further articles devoted to innovative treatments 35.

Thus, only three out of 10 analysed codes explicitly refer to the use of new or innovative treatments. However, there is also an article in the French Code of Medical Ethics according to which, within the limits laid down by law and based on scientific evidence, the doctor can use the treatment that they consider to be the most appropriate (Article 8) 38. This article seems to indirectly allow for use of new or innovative drugs if the treatment is based on solid scientific rationale.

Most of the remaining codes express only very general requirements any therapy should meet. For instance, according to the Irish code, any treatment should be safe, evidence‐based and in the patient's best interests (Article 42.5) 34. The Good Medical Practice by the Medical Board of Australia states that physicians should consider the balance of benefit and harm in all clinical‐management decisions (Article 2.2.4) and provide treatment options based on the best available information (Article 2.2.6) 32. The CMA Code of Ethics requires that physicians take all reasonable steps to prevent harm to patients (Article 14) 30. According to the Good Medical Practice by the UK General Medical Council a physician must provide effective treatments based on the best available evidence (Article 16 b) 33.

Remarkably, the Code of Ethics by the AMA^Aus and the Professional Code for Physicians by the German Medical Association do not contain any guidance regarding therapy 31, 37.

Codes of ethics and biomedical research and the use of unproven drugs: critical discussion

In our view, each code should contain some guidance on the most important issues concerning use of new and/or innovative drugs. This results from the fact that over the last decade or so the importance and prevalence of experimental treatments in different medical specialties has substantially grown 40. Growing interest in novel therapies results from a variety of reasons including the existence of serious unmet medical needs, high activity of patient advocacy groups and the availability of data about emerging treatments in the Internet 41. Moreover, therapeutic use of unproven treatments is associated with a number of tough ethical dilemmas 4, 5, 6; therefore, relevant guidance contained in ethics codes would be very helpful for doctors of various specialties.

Two of the analysed international codes and guidelines – the International Ethical Guidelines for Health‐related Research Involving Humans and the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research – do not contain any articles on the use of unproven treatments 27, 28. This results from the fact that both documents generally pertain to biomedical research rather than clinical practice. The principal international code that refers to unproven treatments is the DH 26. The presence in the DH of Article 37 may be criticized because the DH is also a code of biomedical research and Article 37 clearly concerns clinical practice. However, according to guidance contained in this article, an unproven intervention should be made an object of research; this indicates an important relation between unproven treatments and biomedical research. While guidelines contained in Article 37 of the DH are certainly not flawless, in our view, four specific problems arise that should be addressed to provide doctors with at least basic guidance regarding unproven treatments. These are: (i) the nature of innovative treatment (in particular that it constitutes clinical practice rather than research, but in addition should be incorporated into a formal research protocol); (ii) situations in which unproven treatments can be used (serious condition of the patient along with a lack of proven treatments); (iii) safeguards that should be employed (expert advice and informed consent); and (iv) additional duties of doctors (especially collection and publication of data about the safety and efficacy of a given treatment).

The question of the nature of innovative treatment, especially whether it should be considered clinical practice or a kind of biomedical research is very important because research, unlike clinical practice, is associated with a duty to meet several formal requirements including obtaining approval of an institutional review board 42. Thus, a doctor who wants to perform innovative treatment may have justified concerns over whether they should have to meet these requirements. Furthermore, the traditionally sharp distinction between practice and research has been increasingly blurred 42. Therefore, a decision whether a given innovative treatment can be considered clinical practice or should be performed within a formal research protocol is sometimes not easy. For instance, it was reported that, in some cases, treatments originally proposed by doctors as innovative off‐label applications of drugs were eventually designated as clinical research 43. This problem has been recognized in medical ethics for a long time. We share the view expressed by the authors of the landmark Belmont Report, who noted that significant departure from standard or accepted practice does not make an innovative treatment research. However, according to this report, radically new interventions should be made the object of formal research at an early stage 44. In this regard, according to the AMA^US code, innovative treatment is neither research nor patient care, although it has some features in common with both (this issue is, however, not elaborated further in this code) 29.

A similar view on the nature of innovative treatments is contained in the NZMA code, which underscores that there is no strict boundary between such treatment and clinical research 36. Consequently, the physician should decide in each case whether a new drug should be used within a formal research protocol typical of clinical research.

Another important issue that should be addressed by codes of medical ethics and professional conduct is in which situations it is ethical to use an unproven drug. In particular: can such drugs be employed only when no approved treatment options exist or have been ineffective, as required by the DH? Unfortunately, neither the AMA^US or the NZMA codes address this issue.

Use of unproven treatments is usually associated with a significant risk of harm to patients and therefore every effort should be made to employ proper safeguards. However, the only safeguards listed in the DH – expert advice and informed consent – do not seem to provide sufficient protection for patients who are to be treated with unproven drugs 45. According to these authors, Paragraph 37 of the DH, especially when read without consideration of other paragraphs, may have promoted some cases of misconduct associated with use of experimental treatments and it should therefore be revised 45. Like the DH, the AMA^US code requires informed consent and input from other healthcare professionals as basic safeguards for innovative treatments, but in addition it underscores a need for professional oversight of doctors who wish to employ such treatments. The only code that requires an ethics committee approval for innovative treatment is the NZMA code. In this context, it should be noted that especially in the case of expanded access, some countries have specific regulatory requirements. For instance, even though it is not a kind of biomedical research, in the USA and Italy, expanded access treatment does require institutional review board approval 46. Such requirements, which may differ by country, must always be met before initiating treatment with unauthorized drugs.

According to the DH, all data about use of an unproven intervention must be recorded and, when applicable, be made publicly available 26. A necessity to disseminate these data is also underscored by both the AMA^US and the NZMA codes 29, 36; the former is more specific in this regard by obliging the doctors to promulgate not only positive, but also negative findings. It is noteworthy here that observational studies have been increasingly considered an important source of reliable data about the safety and efficacy of drugs especially in real‐world settings 47, 48. Growing importance of real‐world data in medicine is also indicated by the 21^st Century Cures Act 49.

Both the AMA^US and the NZMA codes highlight the importance of innovation in medicine 29, 36. However, the guidelines on innovative treatments in the AMA^US code are much more complex compared with the NZMA code. For example, while both codes underscore a necessity to inform the patient fully about new or innovative treatments, only the AMA^US code specifies the range of information that should be conveyed. Furthermore, only the AMA^US stresses the potential social importance of innovative treatments indicating that these can be beneficial not only to the treated individuals, but also to populations of patients and communities. An important difference between these codes is the evidence to support innovative treatment. While the AMA^US code indicates scientific evidence as a basis for innovative therapy, the NZMA code only refers to the considered judgement of the doctor which is very vague to say the least.

While none of the codes analysed in this work explicitly forbid doctors from using unproven drugs, some of them might be interpreted as quite restrictive in this regard. For example, treatment with such drugs certainly cannot be considered safe, as required by the Irish code 34. Likewise, there is no guarantee that an innovative treatment will be effective, as required by the Good Medical Practice by the General Medical Council 33. When a doctor uses an investigational drug that has merely completed Phase I/II clinical trials, can one confidently state that he took all reasonable steps to prevent harm to patients, as required by the Canadian code 30? In our view, these fairly general statements should be complemented with articles specifically devoted to unproven drugs.

We also believe that a need for guidance about use of new and/or innovative treatments may increase as a result of the development of Learning Healthcare Systems, which promote a better integration of patient care with biomedical research to ensure innovation, quality, safety and value in healthcare 50.

Concluding remarks

Overall, the medical professional codes address the problem of new and innovative drugs either in an insufficient way or not at all. In our opinion, the general requirements of these codes should be complemented with articles specifically devoted to such drugs. Each code of medical ethics and professional conduct should address the question of therapeutic use of these drugs in view of the prevalence of off‐label applications of drugs (including those without strong scientific evidence for efficacy and safety) and a growing number of therapeutic applications of investigational drugs used in expanded access programmes in a variety of medical specialties 21, 40.

This work focused on codes of national scope from English‐speaking countries and some codes from other countries available in English. In future, similar studies should be performed to analyse guidelines on the use of new or innovative drugs contained in the medical ethics codes of other countries.

Competing Interests

There are no competing interests to declare.

Borysowski, J. , Ehni, H.‐J. , and Górski, A. (2019) Ethics codes and use of new and innovative drugs. Br J Clin Pharmacol, 85: 501–507. 10.1111/bcp.13833.