Characteristics of the Interviewees
In total, fourteen interviews with medical specialists were conducted. Interviewees were specialists in oncology (n = 7) with sub-specializations in hematologic, gynaecologic, gastrointestinal, and lung cancers, neurology (n = 3), endocrinology (n = 2), and psychiatry (n = 2). Nine worked in academic hospitals, five worked in rural or teaching hospitals. Six out of fourteen interviewees were female, and the median age was 50.0 years (interquartile range 41.8–55.3). All but one physician were (sometimes) involved in clinical research, participating in multicentre trials conducting observational studies or early-phase clinical trials. The interviewees treated patients for whom curative or satisfactory treatment options were lacking; their patients were either without any standard treatment options altogether or without any standard treatment options that sufficed. Interviewees’ characteristics are reported in Table 2.
Characteristics of the Questionnaire Respondents
The response rate for the questionnaire following our mailing efforts was extremely low: the questionnaire was sent to 5724 physicians and physicians-in-training, and we received sixty-one complete responses after the first round of email and postal mail. After we sent reminders and made the questionnaire publicly accessible, another sixty-eight respondents completed the questionnaire. As the characteristics of the respondents in the first and second round did not differ, the data were grouped and analysed together. In total, 129 respondents completed the questionnaire. Thirty-nine respondents were excluded as they did not work in a hospital (n = 10) or did not lack standard treatment options that could cure their patients or prolong their lives. A total of ninety respondents matched our target population of medical specialists in rural, teaching, or academic hospitals who would be in a position to consider expanded access. Respondents’ characteristics are reported in Table 2.
We identified five themes: limited knowledge of and experience with expanded access, disparate attitudes towards expanded access, reasons for expanded access, reasons against expanded access (including practical hurdles), and views on physicians’ responsibilities regarding expanded access.
Limited Knowledge of and Experience with Expanded Access
Apart from the psychiatrists and the gynaecologist, most interviewees had had some experience with compassionate use. Compassionate use programmes had mostly been run post-trial, to bridge the gap between completion of the clinical trial and market authorization (see Table 1). When interviewees had applied for compassionate use, they had treated a handful of patients, at most. The familiarity with named-patient programmes was much more limited. Some interviewees (n = 3) had never heard of this route to access an investigational drug:
Well, barely. Uhm … I never understand completely, what it is about. (neurologist)
No, I only remember that I had to sign a statement … about the unapproved drug so that the pharmacy could import it. It was very complicated. I had to write down a motivation for why I did that, and that I would accept the responsibility for the administration and the side effects of that drug. I remember that it was one piece of paper … This was fifteen years ago. I have not done it since. (endocrinologist)
Other interviewees did have some experience requesting a drug through named-patient programmes. Their total experience typically consisted of one or a few individual requests. Physicians working in academic hospitals mentioned specific genetic mutations in tumour biology and exclusion from a clinical trial as reasons for having pursued named-patient expanded access for their patients in the past.
According to our interviewees, only a small percentage of patients ask for expanded access. These patients may have heard about investigational treatment options in the news, on the Internet, or from patient advocacy groups. The largest group of patients, however, is worn out by the time they reach the end of a standard treatment trajectory and no longer willing to try. A doctor can usually tell who among his or her patients will continue to look for other options. These are commonly the patients who are proactive and habituated to being in charge:
You know, beforehand you can tell which ones are the fighters, right, the ones who will never stop. You know that, they will go down fighting, you know it. (oncologist)
Experiences with the Named-Patient Programme: Questionnaire Results
In our questionnaire, nineteen respondents (21.1 per cent) reported having had experience with requesting an investigational drug through a named-patient programme. All but one respondent had been able to acquire the drug for their patient, and all but two claimed that patients had benefited in some way (mostly medically) from use of the investigational drug. The costs for the investigational drug were covered by the pharmaceutical company (n = 6), hospital (n = 4), health insurer (n = 7), or by the patient (n = 1). Respondents’ experiences with the application process were variable: seven respondents experienced the process as extensive and cumbersome, but seven other respondents said it was quick and easy. One respondent had varying experiences. In free-text responses, a gastro-intestinal oncologist and an internal oncologist commented, respectively: “[It took] paperwork … But in the end, it did happen,” and “[It was] a lot of administrative hassle, therefore took a long time.” Two respondents from academic hospitals specifically mentioned that they were supported by the hospital pharmacist in applying for the unapproved drug. Their experience of the process was positive. One respondent noted: “Good. The pharmacist at our department arranges these things.”
Disparate Attitudes Towards Expanded Access
Not only was the level of knowledge and experience with expanded access highly variable across interviewees, so too were their views on the desirability of expanded access. They were more willing to consider applying for existing compassionate use programmes run by pharmaceutical companies than to consider requesting expanded access for individual patients on their own initiative. There were interviewees who were categorically opposed to expanded access, citing the principles of evidence-based medicine. When pressed, they explained that they made clinical decisions in accordance with clinical guidelines and would only prescribe drugs that were sufficiently tested, approved for marketing, and suggested in clinical guidelines issued by professional organizations.
Others were sceptical that new drugs would bring substantial benefits to patients:
I have never felt I was held back, I have not at all had the impression that there was a pot of gold at the rainbow’s end, and I couldn’t reach it. Not at all. (oncologist)
On the other hand, four interviewees were adamant proponents of expanded access—under strict conditions—and felt it was part of the core of their care provision for patients. They considered it their task to seek beyond standard treatment options or clinical guidelines when standard options had run out but believed that not all physicians would do the same.
It is doctor-dependent and context-dependent and knowledge-dependent and however much we would want to have it otherwise, it is true that these out-of-standard procedures, well, that [access to these procedures is] not levelled. No, not all, not everyone is equal. Not everyone has equal chances. It is what it is. (oncologist)
Disparate Attitudes Towards Expanded Access: Questionnaire Results
In our questionnaire, fifty-three respondents (58.9 per cent) either agreed or strongly agreed with the statement that physicians should not prescribe investigational drugs outside of clinical trials (Fig. 1).
I believe that physicians should not prescribe investigational drugs outside of clinical trials.
I believe that it is the responsibility of a physician to refer patients without curative or life-prolonging treatment options to (highly) specialized care.
I believe that it is the responsibility of a physician to identify clinical trials in which a patient without curative or life-prolonging treatment options may possibly be enrolled.
I believe that physicians should inform their patients about the options for accessing investigational drugs.
I believe that the decision to use an investigational drug should be made by the patient him- or herself.
I believe that it is the responsibility of a physician to look, at his/her own initiative, for investigational treatments for patients without curative or life-prolonging treatment options.
Reasons for Expanded Access
Interviewees mentioned multiple reasons why they would prescribe investigational drugs. The most important reason was that it might help their patient—for example, by improving their prognosis or quality of life. Interviewees indicated that they would need scientific evidence to determine the balance of potential risks and benefits. Respondents had different standards for what is “enough information”: some required “positive phase 3 trials” (oncologist 1), whereas others would consider an investigational drug based on “a sound biological rationale” (oncologist 2) or “clinical experience after some time without head-to-head trials” (neurologist 1)
[I should be] convinced of the possible utility [of the drug] for this patient. Maybe in the absence of alternatives with a prognosis that does not look very favourable ... Well, in the back-against-the-wall situation, I should be at ease with the little information that I’ve got on the potential side effects. (endocrinologist)
Interviewees often spoke of “being with their backs against the wall” as a reason to consider expanded access: they might pursue it (only) if there were no other options for a patient. Two interviewees, however, mentioned that under very exceptional circumstances, they would prefer to prescribe an investigational drug before standard of care, thereby diverging from one of the classic conditions for expanded access (i.e., that there should be no approved alternatives). If, for instance, standard of care consisted of combination chemotherapy, which would wear down patients and offer a poor prognosis, then it might be better to start with the investigational drug straightaway instead of trying standard of care first. Of course, these interviewees thought it preferable to enrol a patient in a clinical trial, but if trials were non-existent, they would wish to resort to applying for a named-patient programme before trying—ineffective and harmful—standard of care.
In general, physical fitness was an important condition for interviewees: patients would have to be in a relatively good condition to try an investigational drug. At the end of a standard treatment trajectory, patients often have long medical histories behind them and are not physically fit enough to try investigational drugs.
Sometimes you know that you’ve got four lines of treatment, then, then you know, like, well, if I go and try all these lines of treatment first, the patient will become cooked-through like butter. Then he will not be able to try the investigational treatment. So then I [would want to] refer him sooner. (oncologist)
Interviewees needed to feel comfortable when prescribing an investigational drug. For some, this required not only a sufficient level of evidence about the risks and benefits but also the favourable opinion of their peers. Interviewees would prescribe investigational drugs much more readily when the medical profession made positive statements about the drug or when they felt supported by colleagues. It is considered important to discuss expanded access with colleagues from in- or outside the hospital, beforehand. One interviewee reported that after discussing with colleagues,
… now I had the feeling, I had enough external information and I had, well, I had enough safeguards. So I did not have the idea that … I was doing something like that [expanded access] on my own, without anyone looking in. (psychiatrist)
In the process of expanded access, the help of a hospital-based pharmacist was considered very valuable. Some interviewees mentioned that it was the hospital-based pharmacist who had actually brought up the possibility of expanded access and guided them through the application process.
Reasons for Expanded Access: Questionnaire Results
Questionnaire respondents were also asked whether and under what conditions they would consider prescribing an investigational drug and what their reasons were for prescribing investigational drugs outside of clinical studies. A slight majority of forty-seven respondents (52.2 per cent) would consider prescribing investigational drugs through compassionate use or named-patient programmes or would support referral to a foreign country (based on question 13 of the questionnaire, see Appendix). Their most important reasons for pursuing expanded access pertained to patients’ health: to improve their health, to prolong their lives, or to improve quality of life (Table 3). Also, confidence in the effectiveness of the investigational drug was an important condition and the fact that a pharmaceutical company would offer a compassionate use programme. None of the respondents would pursue expanded access to provide hope, to protect the physician–patient relationship, or “because the patient will pay for it him- or herself.”
Reasons Against Expanded Access
Interviewees mentioned a wider range of reasons not to prescribe an investigational drug. Lack of scientific evidence was most important in physicians’ decisions against expanded access. Interviewees who were hesitant about expanded access were sceptical about the limited data on effectiveness and safety that is commonly available after phase II clinical trials, commenting that many drugs fail in later stages of drug development. These interviewees required more certainty regarding the drug’s potential benefit before they would consider exposing their patients:
After all, the one receptor is not the other. And the fact that something works in A does not mean that it works in B. And that a phase I study has been conducted somewhere, does not mean anything. At that point you are close to being nowhere. (oncologist)
Moreover, according to interviewees in various medical fields, there are very few (or no) break-through life-saving drugs in the pharmaceutical pipeline. Interviewees believed that most new drugs will not make much of a difference to patients and that the possible medical benefit will likely be marginal. Some interviewees believed that drugs that are exceptionally beneficial and/or life-saving will be evaluated fast-track and will be quickly approved for marketing through conventional channels and made available to patients. Expanded access would thus not be necessary for patients:
The gains of these drugs are of course limited. If they were very spectacular, I would have known about them. That happened once with Herceptin, in breast cancer. This is the only example that I can remember: the gains were so high that everyone thought it was unethical to wait until the authorization process had been completed. But even then, you could question [whether expanded access is appropriate]. (oncologist)
By not prescribing or proposing investigational drugs, interviewees say they are protecting their patients against “false hope.” Every subsequent treatment option brings new hope for a patient. When that hope is based on only limited data, showing limited potential for medical benefit, it is considered false. Additionally, drugs are never without risks. The principle of primum non nocere entails that patients should be protected from such risks. A respiratory physician states that, often, patients think that
… it does not hurt to try. But that is of course not true, that is simply not true … Of course, you derive hope from [investigational drugs]. And as a doctor, too, to be honest, I always hope. (respiratory physician)
Patients may be exposed to false hope, burdens, and possible risks when trying investigational drugs.
Interviewees emphasized that it would be unethical to expose patients to such risks without learning from it. Data collection was considered an important condition for expanded access, also in light of the resources (e.g., physicians’ time and effort, the expense of the compound) dedicated to a single patient. Future patient populations should also benefit from the knowledge that is gathered from individual cases of expanded access:
That I find may be the most important thing: that if we do things outside of clinical trials, that we register accurately what we do, so that we can learn from it. (oncologist)
What kept interviewees from pursuing expanded access for their patients with unmet medical needs were most often reasons but sometimes also practical obstacles. Interviewees mentioned lack of experience, the administrative burden, the time and effort that it takes to request expanded access, problems with funding or reimbursement, and lack of cooperation by other parties, notably pharmaceutical companies or hospital management. An oncologist states: “No, with all of those formal boxes you need to tick and God knows with all the bureaucratic horror. No, there are a lot of bells and whistles attached to it.” A respiratory physician states:
The tempo and the time and energy that you have to put into [expanded access]. That is the biggest problem, right? Because ultimately, you prefer spending most of your time by the patient’s bedside. (respiratory physician)
Funding issues are frequently mentioned as a major obstacle. An interviewee explains:
Then it goes to the departmental budget. And you cannot turn to the health insurer either. You can try, but in our experience, you immediately get: zero. They simply look at: is this an approved drug? If it is not approved, it does not fall in the basic package, we do not need to reimburse it. (endocrinologist)
Reasons Against Expanded Access: Questionnaire Results
All respondents, including respondents who had never considered expanded access, were asked about the most important reasons not to seek expanded access. For questionnaire respondents, the most frequently selected reasons were safety risks, “false hope,” the low chance of effectiveness, the “experimental nature” of the drug, and the fact that there is no systematic data collection (Table 4).
Moreover, some of the reasons selected were actually practical obstacles. Respondents were unfamiliar with the procedure (17.8 per cent), did not know it was possible (8.9 per cent), indicated that it was a lot of work (10.0 per cent) and that they did not have enough time to initiate an application process (7.8 per cent) (Table 4).
The subgroup of respondents who would consider or had first-hand experience with prescribing or referring for an investigational drug indicated that they would expect or had experienced obstacles mostly related to reimbursement. Almost half of the respondents (46.5 per cent) indicated that the health insurance agency would not reimburse the drug, while a quarter indicated that the hospital would not (Table 5). Another major hurdle for respondents was the time it takes to apply for expanded access: 39.5 per cent of respondents indicated that the application takes too much time. Other obstacles included policies at the hospital that discouraged doctors from using unapproved drugs, refusals by pharmaceutical companies, and lack of familiarity with the regulation (Table 5).
Views on Physicians’ Responsibilities Regarding Expanded Access
When confronted with the question: “What do you do when standard treatment options have been exhausted? What do you tell your patient?” interviewees often considered their moral responsibilities. Interviewees in rural hospitals felt that when they run out of standard treatment options, they must refer patients to experts in academic hospitals. Some academic doctors were concerned that this does not always happen and that consequently not all patients in the Netherlands are receiving the best available care. In academic hospitals, it was felt, physicians should look for promising new treatment options, preferably for randomized controlled clinical trials within the country. Being informed about investigational treatment options was considered part of the job of an academic medical specialist.
Also, interviewees stressed that (non-standard) treatment decisions are made together with the patient and cited the ideal of shared decision-making. About half of the interviewees felt that when the end of a standard treatment trajectory comes into view, they must inform patients about all available non-standard options, including investigational drugs. During an interview, one physician explained:
From the very beginning here [in the academic hospital], fifteen years ago, we have been in dialogue with patients, and we have said: “We’ve got something [non-standard] for you, you don’t have to take part, what do you think? What do you think of the risks and benefits?” That is … I find it disconcerting that there is this hype currently going on about this [ideal of shared decision-making]. For to me it is self-evident that this is the way you do things. (neurologist)
According to others, it is up to the physician to decide whether or not expanded access is worth pursuing. Interviewees highlighted that although patients can always refuse a treatment (e.g., chemotherapy) and have the right to a second opinion, they cannot claim access to an investigational drug:
They cannot demand access to an investigational treatment. They have no right to say: you must give me that treatment. That is not how it works. (oncologist)
Interviewees felt that physicians should not transfer the responsibility for clinical decision-making to the patient and they should determine themselves whether or not to inform the patient about remaining options. For example, when the patient might already be too ill or when the physician fears that the unapproved drug cannot be obtained (e.g., because of funding issues), they will not tell the patient about the option. These physicians underlined that they sought to provide only “realistic options” to their patients:
So I find it problematic to say: “I am going to try to get this drug for you.” I would only start to say this if I had the idea that I would succeed in getting the drug. (endocrinologist)
Interviewees said that instead of offering investigational treatments, they considered it their responsibility to discuss the nearing end of life with patients and to help patients to come to terms with the prospect of dying. At the end of life, it was felt, patients had better accept that their lives were going to end, spend time with loved ones, and say goodbye properly. Grasping at straws is not a good way to die.
Views on Physicians’ Responsibilities Regarding Expanded Access: Questionnaire Results
Questionnaire respondents were asked to indicate the extent to which they agreed or disagreed with six statements about physicians’ responsibilities regarding expanded access (Fig. 1). Sixty-five questionnaire respondents (61.1 per cent) agreed or strongly agreed with the statement that physicians have a responsibility to refer patients who lack satisfactory standard treatment options to more specialized care (Fig. 1). The majority (78.9 per cent) also agreed or strongly agreed that it is the responsibility of physicians to identify clinical trials in which patients who lack curative or life-prolonging treatment options may possibly be enrolled (Fig. 1).
In our questionnaire, 50 per cent of respondents either agreed or strongly agreed with the statement that physicians should inform their patients about existing options to use investigational drugs (fig. 1). The majority (53.3 per cent) of respondents either agreed or strongly agreed that the decision to use an investigational drug should be made by the patient him- or herself (fig. 1). While 20 per cent of respondents felt that it is the responsibility of treating physicians to look for investigational treatment options on their own initiative, 47.8 per cent of respondents did not (Fig. 1). Finally, only 23.3 per cent disagreed with the statement that physicians should not prescribe investigational drugs outside of clinical trials (Fig. 1).