Patient information and informed consent for device investigations
The patient information and informed consent form for a clinical investigation of a medical device answers to the Declaration of Helsinki, ISO 14155, local regulations and the ethics committee, and takes its content mainly from the study protocol. It carries every element the standard requires, at the depth the study's regulatory status calls for, and its writer also has to settle what an implant changes, what the study may need later, how vulnerable subjects consent, how local versions stay complete, how a long document stays readable, and how the ethics committee's first response is met.
The document and its names
Informed consent is the process by which an individual is provided with information and asked to volunteer to take part in a clinical investigation, and it is documented by a written, signed and dated informed consent form. The document has two parts, the information and the written consent, and consent has to be given before any study-specific action is taken.
In device studies the same document goes by several names, among them patient information, patient informed consent, informed consent form and the abbreviation PIC. All of them mean the information given to the patient before a study and the patient's written consent to take part.
The rules the content answers to
The content is shaped by the Declaration of Helsinki, ISO 14155, local regulations, the ethics committee's requirements, the study protocol and future needs.
The Declaration of Helsinki
The Declaration of Helsinki, the principles for medical research involving human subjects, is the overarching ethical principle of clinical research, and it applies to pharmaceutical studies as well. Its content requirements are the study aims, the study methods, the source of funding, any possible conflict of interest, the institutional affiliation of the researcher, the potential risks or discomforts against the anticipated benefits, any other relevant aspects of the study, and the right to refuse to take part or to withdraw consent at any time without reprisal. The right to refuse or withdraw is stated in a standard phrase that always has to be included. The declaration also makes clear that the physician must fully inform patients which aspects of their care are related to the study. Research using identifiable human material or data has to seek consent for its collection, analysis, storage and reuse.
One experienced writer has never seen a patient informed consent form state the possible conflict of interest of the investigator, the physician who conducts the clinical research at a hospital or practice. That writer has not seen such a statement in an ethics committee's template either, and ISO 14155 does not mention conflict of interest. That writer attributes this to conflict of interest being a vague term. The only good definition of a declaration of interest that writer has found is in Title 21 of the US Code of Federal Regulations, which applies to clinical research but is not fully applicable to a patient informed consent form. The same writer has never added the statement to a form, would feel safe ignoring it, and would ignore no other requirement.
ISO 14155
ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice, is the most important source of the content. It is the device counterpart of ICH GCP for the pharmaceutical industry, and compared side by side the two read as the same. It covers every aspect of the conduct of the clinical research and gives the minimum requirements of a patient informed consent form.
The standard applies in full to a device study for regulatory purposes: a study with an investigational device, a study with a CE-marked, commercially available device used outside its label, or a study with an additional invasive assessment such as an X-ray. A registry uses a CE-marked device within its indication with no additional invasive assessment, and is basically a data collection, comparable to phase 4 in pharmaceuticals. A registry needs to adhere to ISO 14155 only as far as applicable, so a study of a commercially available device, for instance, does not perform device accountability.
A form that adheres strictly to ISO 14155 meets in principle every requirement of the Declaration of Helsinki except the source of funding and the possible conflict of interest.
Local regulations and the ethics committee's template
Local regulations mostly add nothing new, but some countries have different data protection laws, so the local regulations are worth checking. Most ethics committees have a standard patient informed consent template with standardised paragraphs on confidentiality and data protection, and that template should cover the local regulations, so a writer who uses it should be reasonably safe.
An ethics committee's template may not contain every requirement of ISO 14155, and ethics committees are still more familiar with ICH GCP than with ISO 14155. A form the ethics committee has approved does not relieve the writer of responsibility for it, just as a tax adviser preparing a tax return does not relieve the taxpayer.
The required content
In one experienced writer's view, writing a patient informed consent form is easy, since it includes everything ISO 14155 lists and can use the ethics committee's template. The only difficult part is the non-technical language: expressing complicated medical terms in easy-to-understand language is an art of its own.
The study protocol, also called the clinical investigation plan, supplies all or most of the information, such as the aim and purpose of the investigation, the study design, the device information, the assessments and the risk-benefit analysis.
What the study involves
The information part has to include a statement that the clinical investigation involves research, and a description of its purpose, as in this study is intended to assess the safety and efficacy of product XYZ. It gives the anticipated duration and extent of each subject's involvement and responsibility, as in the anticipated duration of the investigation is five years, and you will be asked to return to the hospital for follow-up visits at years one, two, three and five. It describes the investigational device and any comparator, including whether the device is CE marked and so available for commercial use.
It describes all procedures involving the subject and which aspects of the investigation are experimental, as in a statement that a blood draw and an ECG at baseline are routine tests before the procedure, and that an X-ray will be taken in addition. It describes the investigation, including any comparison group and the method of assignment to each group, as in this is a randomised trial comparing device A with device B, and randomisation will be done by an automated computer system in a two-to-one ratio, all of it in lay language. It gives the number of subjects expected to take part, as in at least 100 subjects will be enrolled.
These items need not follow the standard's sequence. They can stand in a logical, easy-to-read order, provided all the required information is included.
Benefits and risks
The form describes the potential benefits, risks and inconveniences, which usually come from the study protocol.
A registry in which patients are treated according to standard of care, with a commercially available CE-marked device used within its indication and no invasive assessment, usually has no direct patient benefit, because it is basically a data collection. Its form can say so, as in there is no expected benefit for you from taking part in registry X; however, the results will help to get further details on XYZ, which will help future patients. Having no direct benefit for the subject is acceptable, but the potential benefits for others have to be highlighted. A registry's form can also say that the risks are not increased, because the patients are treated according to standard of care.
The risks include those of the additional procedures the protocol requires, so an additional X-ray assessment brings the risk of an X-ray into the risk section. The risk section is usually broken down into the risks related to the device and, where wanted, those related to the procedure and to the additional assessment.
Alternative procedures
The form gives information about alternative procedures.
A drug information sheet usually describes the alternative treatments in a standard text saying what the patient can expect if they choose not to take part. In a device study, especially of an implant, the surgeon decides which device is implanted, for reasons such as size and the complexity of the anatomy, so the alternative treatments can be a difficult passage.
How far the passage goes depends on the study's regulatory status. For a study of a commercially available CE-marked device used within its indication, the alternatives need no great detail, and a sentence such as your doctor will discuss the alternative treatments with you may be enough. For an investigational device that has no CE mark and is not yet approved for commercial use, or for a device tested outside its indication, the alternative procedures have to be explained clearly and comprehensively, with their potential benefits and risks.
The study protocol usually has a section on alternative procedures. Otherwise the writer has to know the alternative procedures and their benefits and risks, or ask people from the company. Nearly all heavily invasive implantation procedures have guidelines, and one experienced writer uses them to find the alternative treatments and to state their benefits and risks quickly.
Confidentiality and publication
The form includes a confidentiality paragraph stating that participation and the records identifying the subject will be kept confidential, and that representatives of the ethics committee, the sponsor and the regulatory bodies have direct access to the subject's medical records. It states that the results will be published.
Compensation and expenses
The form informs the subject about compensation: most importantly how the patient will be reimbursed in case of injury related to the study, which basically means the patient insurance; additional health care for subjects who suffer an adverse event as a result of taking part; and financial compensation for participation, if applicable. In device studies, in one writer's view, financial compensation relates mostly to travel expenses, because unlike pharmaceutical studies they usually do not run in healthy volunteers: most are studies of implants, and implanting something in a healthy volunteer would be unethical.
The form also states the anticipated expenses for the subject, although in one experienced writer's view these rarely arise.
The sponsor's representatives
The role of any sponsor representative in the investigation has to be included, and it is frequently forgotten. The form states, for instance, whether an implant specialist or an engineer will attend the operation or procedure. The point can look benign at first sight, but one experienced writer, facing surgery, would want to know whether others might see them naked or lying on the operating table before they were prepped.
A writer should produce a form they would feel comfortable signing themselves, having thought through everything that could happen.
Contacts, new findings and termination
The contact persons are usually left as a blank line, because they may vary from centre to centre. The form states that new findings that are the reason for an amendment to the protocol affecting the subject's continued participation will be made available to the subject. It states that the subject's personal physician will be informed if the subject approves. Lastly, it informs the patient of the circumstances in which the principal investigator or the sponsor can terminate the subject's participation or the whole investigation.
The consent page
The part of the form the patient signs includes:
- a statement that refusing to take part incurs no penalty for the subject
- the subject's voluntary agreement to take part in the study and to follow the investigator's instructions
- a statement that discontinuing at any time incurs no penalty
- a statement on the possible consequences of withdrawal
- confirmation that all questions have been answered
- a statement confirming that the subject agrees to the use of their relevant personal data
- a statement confirming that the subject agrees that the sponsor's representatives, the regulatory authorities and the ethics committee's representatives will be granted direct access to the subject's medical records
Entries completed by hand
The question whether the personal physician may be informed is best asked as a yes-or-no question rather than as a single tick box. A blank tick box does not show whether the subject disagrees or has forgotten to complete it. In one audited study about 80% of the consent forms did not have that box ticked, and it is doubtful that 80% of the patients were against their personal physician being informed.
Everything that has to be completed by hand is best put on one page, ideally the last. Entries to be completed on pages two, five and seven get forgotten.
Withdrawal from an implant study
A drug information sheet typically tells the subject they can withdraw from the study or stop treatment, but many devices are implants, and a participant in a study of an implantable device can withdraw from the study but not from the device. In one experienced writer's practice no company has stated in the form that the implant stays in the body after withdrawal. That writer thinks companies take it as given that patients understand the device will not be explanted, and that nobody would want an additional surgery. The risk section always carries the risk of explantation.
Provision for future needs
Being mindful of future needs is held to make the difference between a good and an excellent medical writer. One such need arises because a clinical investigation may eventually become a registry, as is frequently done, and a consent form may need to allow for that.
Extended follow-up
One question for the writer or the company is whether the follow-up might be extended. A novel device is often tested only for the minimum follow-up duration, because it is not known whether it will gain a CE mark, and a sponsor that may stop enrolment and go to market with an improved device does not want 20 years of follow-up. Alternatively, the company may not yet have the funding for a 20-year follow-up.
Where a study starts with three years of follow-up but could extend to 10 or 20, a short sentence saying that follow-up might be extended can help a later amendment that extends it. The sentence does not remove the need to resubmit, but it can make the resubmission easier.
Further use of the data
Strictly speaking, the patient information applies only to its own study. So when echocardiographic examinations of a novel device are stored at a core laboratory and, six months after the study, a parameter of interest calls for pooling data from studies A, B, C and D, consent for study A alone does not permit the further analysis. A sentence saying that the echocardiographic examinations may also be used for other purposes might help, and so might a sentence where the data are planned for use in FDA submissions.
The ethics committee may push back on such a sentence and not want it included. So a writer should add it only when already experienced in patient informed consent forms, not in a first job at a new company, and with an established reputation in the company, so that a rejection the first time is not held against them.
Vulnerable subjects
Consent in vulnerable subjects is a special form of patient informed consent that rarely occurs. Vulnerable subjects include, for instance, patients with a mental handicap, unconscious patients and minors. In general, research can be conducted in them only if it targets their disease or the data cannot be generated otherwise.
Patients receiving heart-valve therapy, for example, are usually very old, above 60, and some already have some form of dementia. Because heart valves can be studied in patients who can understand the information provided, vulnerable subjects would not be allowed in those studies. A study of a device to treat severe dementia, by contrast, has to involve patients with severe dementia, and the legally authorized representative then signs on the patient's behalf.
The one exception is research that cannot be delayed. A study of a resuscitation device cannot wait until the legally authorized representative arrives, so it can proceed without a signed patient information and informed consent form. That situation has to be described very clearly in the study protocol and approved by an ethics committee, and it needs a very sound risk-benefit analysis. Consent for the subject to remain in the research should then be obtained as soon as possible, from the subject or the legally authorized representative.
The subject's assent should be asked for as far as possible, and dissent should be respected. A 17-year-old, for instance, is not an adult and so counts among minors and vulnerable subjects, but is old enough to articulate dissent, which should then be respected. How far this goes depends on how far the person can understand.
ISO 14155 defines vulnerable subjects, vulnerable populations, subjects needing a legally authorized representative and the legally authorized representative. It also explains how to deal with subjects who are unable to read or write, and with emergency treatment.
The master document and its local versions
The suggested workflow creates a master document that includes all the content requirements of ISO 14155, for which a checklist is recommended. The master document serves as the basis for all local and country versions of the patient information.
Local versions are created for two reasons. One is language: a version is in the country's language in any case, and further languages can be added. Berlin, for example, has a large Turkish population, so a study there that wants to enrol fast and not exclude those people from the research can add a Turkish translation. The other reason is that requirements may differ from country to country, and even within a country, where different ethics committees want different forms.
A checklist is recommended for the local versions too. In one audit the patient information and informed consent form resulted in a major finding because not all requirements of ISO 14155 were met. Several items were missing from the master document, one of them from one country's version and another from the Australian version, and a checklist avoids that.
Back-translation is also recommended, and it facilitates audits.
Length and lay language
A form that implements everything ISO 14155 requires runs to at least ten pages. In some studies the average age is above 80, as in studies of transcatheter heart valves, and it is questionable how far a reader over 80 can understand 10 or 20 pages of information, even in the best language.
One experienced writer adds a one-page summary of the patient information and informed consent form. Not every ethics committee likes this approach, because some are concerned that the physician will then discuss only that one page. That writer's view is that one page clearly understood is better than 20 pages not understood. A writer settled in a company that values them can try it, but a writer new to a company and not yet settled should not experiment.
Pictures help with lay language, because patients usually do not have good anatomical knowledge, and a picture makes the matter much easier to understand and imagine. The internet and PubMed can also help with lay language, provided plagiarism is avoided.
The ethics committee's first response
The patient information form nearly always gets rejected the first time, and the likelihood is very high even for the best form. In one case a confidentiality paragraph copied one-to-one from an ethics committee's template was returned by that committee for changes, and the committee kept to its request when told where the paragraph came from. In the end, the writer has to do what the committee wants.
Because one more round is needed anyway, one experienced writer dares to try experiments with the form.
Model documents
Ideas can be taken from other patient informed consent forms found by searching PubMed or Medline. Some journals, usually the high-ranking ones such as the New England Journal of Medicine, demand that the study protocol be added to the manuscript. A search combining, for instance, transcatheter heart valves with New England Journal of Medicine finds such a study. Its supplementary material holds the study protocol, and the patient information is highly likely an appendix to the protocol.
Such a form gives ideas but should not be copied, because of plagiarism. One, for example, set out its risks in a table, with the risks in the left column and their descriptions in the right.