Compassionate Drug Use Research Articles

Critical role of ethics in clinical management and public health response to the West Africa Ebola epidemic.

The devastation caused by the Ebola virus disease (EVD) outbreak in West Africa has brought to the fore a number of important ethical debates about how best to respond to a health crisis. These debates include issues related to prevention and containment, management of the health care workforce, clinical care, and research design, all of which are situated within the overarching moral problem of severe transnational disadvantage, which has very real and specific impacts upon the ability of citizens of EVD-affected countries to respond to a disease outbreak. Ethical issues related to prevention and containment include the appropriateness and scope of quarantine and isolation within and outside affected countries. The possibility of infection in health care workers impelled consideration of whether there is an obligation to provide health services where personal protection equipment is inadequate, alongside the issue of whether the health care workforce should have special access to experimental treatment and care interventions under development. In clinical care, ethical issues include the standards of care owed to people who comply with quarantine and isolation restrictions. Ethical issues in research include appropriate study design related to experimental vaccines and treatment interventions, and the sharing of data and biospecimens between research groups. The compassionate use of experimental drugs intersects both with research ethics and clinical care. The role of developed countries also came under scrutiny, and we concluded that developed countries have an obligation to contribute to the containment of EVD infection by contributing to the strengthening of local health care systems and infrastructure in an effort to provide fair benefits to communities engaged in research, ensuring that affected countries have ready and affordable access to any therapeutic or preventative interventions developed, and supporting affected countries on their way to recovery from the impact of EVD on their social and economic lives.

Compassionate use of drugs and medical devices in the United States, the European Union and Japan.

Compassionate use, also called expanded access, provides an important pathway for patients with life-threatening conditions to gain access to unapproved investigational drugs, biologics and medical devices. Although the United States (US) and the countries of the Europe Union (EU) have mechanisms that are associated with the use of unapproved products, as of May 2015 there was no such mechanism in Japan. Instead, unapproved products are used under a physician's discretion in conjunction with the Japan Medical Practitioners' Act or Advanced Medical Care B. However, there are some issues and questions to consider under the current circumstances in Japan as follows: (A) it is difficult for the local regulator to monitor the use of unapproved products; (B) there is no information collected on the safety of these products to protect patients; (C) it is difficult to assure the quality of the products; (D) it is difficult for patients to obtain detailed information about unapproved products and their availability; and (E) it is not clear who should cover the cost of the unapproved products.In this paper, we assess the current compassionate use, or expanded access-related mechanisms, of the US, the EU and Japan in regard to drugs, medical devices and biologics, including human cells and tissue products, and discuss the benefits and issues of these mechanisms. The purpose of these mechanisms is principally to save patients with life-threatening condition. However, the information obtained after the compassionate use is potentially useful to facilitate marketing authorization. In fact, the data from compassionate use cases are employed in some approval review reports to indicate the product safety.

Compassionate use of orphan drugs.

BackgroundEU regulation 726/2004 authorises manufacturers to provide drugs to patients on a temporary basis when marketing authorisation sought centrally for the entire EU is still pending. Individual Member States retain the right to approve and implement such ‘compassionate use’ programmes which companies will usually provide for free. Nevertheless some companies have opted not to partake in such programmes, in effect restricting access to drugs for patients in need. Here we survey the state of compassionate use programmes in the EU with particular reference to the rare disease field, and provide legal and ethical arguments to encourage their increased compassionate use in the EU and beyond. We contend that if enacted, these recommendations will be mutually beneficial to companies as well as patients.MethodsRequests for information from the European Medicines Agency were made under the UK Freedom of Information Act 2000. Legal, ethical and economic/pragmatic analysis identified means by which provision of therapy in compassionate use programmes might be increased.ResultsMore than 50 notifications of compassionate use programmes have been submitted to the EMA by Member States since 2006. About 40 % relate to orphan drugs. As there is a compulsory register of programmes but not of outcomes, their success is difficult to evaluate but, for example, the French programme expedited treatment for more than 20,000 (orphan and non-orphan) patients over a period of three years.ConclusionCompelling self-interested, legal and ethical arguments can be mounted to encourage manufacturers to offer therapies on a compassionate use basis and these are often equally applicable to provision on a humanitarian aid basis. The EU’s compassionate use programmes are instrumental in ensuring continuity of access to drugs until approval and reimbursement decisions are finalised. We propose the creation of a registry of drugs offered on a compassionate use basis; further transparency would allow such programmes to be evaluated and direct patients to sources of treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0306-x) contains supplementary material, which is available to authorized users.

"Right-to-Try" Legislation: Progress or Peril?

Since 2014, state legislators have increased their efforts to find a way for terminally ill patients to gain legal access to experimental drugs not yet approvedbytheU.S.FoodandDrugAdministration(FDA).AsofJune1, 2015,40statesandtheDistrictofColumbiahadexaminedorwillexamine this burgeoning issue with bills that have already been filed and 18 signed so-called “Right-to-Try” laws (Table 1). Patients who are terminally ill and who are facing less than 1 year of life expectancy are willing to take greater risks and endure a higher danger of potential adverse effects than other patients, including taking experimental drugs with unknown risk-benefit ratios. For patients who have exhausted existing pharmacotherapy options, there are two conventional ways to access potentially life-prolonging investigational drugs: join a clinical trial if they are well enough to meet rigorous entry criteria or apply for FDA’s “compassionate use” exception. Although the FDA accepted 5,816 of the 5,849 expanded access applications it received in the last 4 years, some argue that the FDA approval process for allowing expanded access to experimental drugs has been slow and cumbersome. Besides, many of the delays in the process occur before submission to FDA when the drug sponsor is deciding whether or not to provide the drug in question. Although the compassionate use of investigational drugs has been a contentious issue, public debate has centered on whether the gain in providing the terminally ill with a slim chance at prolonging life is worth endangering a process designed to ensure the public health and the development of safe, effective medicines.

Post-trial access to treatment for patients participating in clinical trials.

Clinical trials are the mainstay for bringing out newer and better drugs to serve the mankind. By virtue of participating in a clinical trial, a patient receives access to the newer drugs/therapies, but nothing is generally being offered to them once their participation in the study comes to an end. Though the issue of post-trial access to treatment by patients participating in a clinical trial is debatable, there is no compelling justification either for or against it. We examined a case study in order to evaluate the applicability of post-trial access to treatment for patients participating in clinical trials. The provision of post-trial access to treatment should also keep into consideration the compassionate use of drugs on humanitarian grounds, especially in cases of trial drugs that have offered significant benefit to the trial patients and whose termination would lead to deterioration in patient's overall condition. In the present era of personalized medicine, the incorporation of genetic testing into clinical practice further authenticates the rationale of compassionate use of drugs and post-trial access to treatment.

Neurological and cytological response as potential early predictors of time-to-progression and overall survival in patients with leptomeningeal carcinomatosis treated with intrathecal liposomal cytarabine: a retrospective cohort study

Interesting neurological and cytological response rates after intrathecal (i.t) liposomal cytarabine have been observed in patients with leptomeningeal carcinomatosis (LMC) from solid tumors. However, the potential use of those responses as early predictors of time-to-progression (TTP) and overall survival (OS) is unexplored. 27 consecutive patients with LMC treated with 50 mg i.t liposomal cytarabine under compassionate drug use were retrospectively studied. All patients received i.t treatment every 2 weeks during induction and every 4 weeks during maintenance periods. Neurological and cytological responses were assessed before every liposomal cytarabine cycle. Most of the patients were female (17/27) diagnosed with breast cancer (15/27). A complete neurological response was seen among 11 % of the patients; partial response in 22 % of the patients; stable disease in 30 % of the patients and progressive disease in 37 % of them. Cytological assessment was available in 11/27 patients showing a 26 % complete response rate. The median time to neurological and cytological response was 15 days and 14 days, respectively. Patients showing a combined neurological and cytological response showed a significantly longer median TTP (122 vs. 3 days; p = 0.001) and OS (141 vs. 3 days; p = 0.002) compared to those showing both neurological and cytological progression. No grade 4 toxicities were recorded. According to these preliminary results, early neurological and cytological responses may be further studied as early predictors of TTP and OS in patients receiving i.t liposomal cytarabine for LMC.

DGI-050 Off-Label Uses of Mycophenolate Mofetil

BackgroundThe implementing Law 1015/2009 normalises the compassionate use of investigational drugs, access to off-label and unauthorised drugs in Spain.Mycophenolate mofetil/Mycophenolic Acid (MM/MA) have been used in off-label conditions to treat...

訂正：日本版コンパッショネート使用制度の創設をめざして／序文

訂正：日本版コンパッショネート使用制度の創設をめざして／序文

Compassionate drug use: the experience of the Lecce-Asl ethics committee

BackgroundCompassionate drug use allows treatment with investigational drugs when there are no therapeutic alternatives. In Italy this is regulated by Ministerial Decree 08/5/2003. The reason for, and conditions of, use...

The controversy of CCSVI and iron in multiple sclerosis

<h3>Background</h3> The implementing Law 1015/2009 normalises the compassionate use of investigational drugs, access to off-label and unauthorised drugs in Spain. Rituximab is an anti-CD20 monoclonal antibody widely used in off-label conditions to treat autoimmune diseases.^1,2,3,4 <h3>Purpose</h3> The creation of an Autoimmune Diseases Unit (ADU) in our hospital caused an increase in the use of rituximab in off-label conditions. This study aims to identify rituximab off-label use and to describe the dosage prescribed in each indication. <h3>Material and methods</h3> Observational, retrospective study (June 2009 to March 2017). Patients who received off-label rituximab (at least one dose) prescribed by the ADU were included. Collected data, obtained from Farmatools^® software and medical records, were: sex, age, rituximab off-label indication, dosage, number of cycles received. <h3>Results</h3> Forty-four patients (55±15 years’ old, 31/44 females) received off-label rituximab. Off-label indications identified (all of them of autoimmune aetiology) were: systemic lupus erythematosus (16/44), vasculitis (13/44), inflammatory myopathy (6/44), scleroderma (4/44), mixed cryoglobulinemia (3/44), others (2/44). The rituximab prescribed regimen was a cycle consisting of four doses of 375 mg/m² administered weekly, which is the dosage aprobed for the treatment of lymphoma. 23/44 patients received a single cycle of treatment with rituximab, 11/44 received two cycles, 2/44 received three cycles and 2/44 more than four cycles, which is partially consistent with the literature previously published^1,2,3,4 (most patients received one cycle). 6/44 patients did nott start rituximab treatment. <h3>Conclusion</h3> Systemic lupus erythematosus and vasculitis were the most frequently rituximab off-label prescribed indications and 375 mg/m² weekly for 4 weeks was the prescribed dosage. These results agree with the data published in the literature.^1,2,3,4 Considering the variety of off-label indications for which rituximab is prescribed in the ADU, it would be useful to develop protocols for the use of rituximab in these situations. <h3>References and/or Acknowledgements</h3> 1. Murray E, Perry M. Off-label use of rituximab in systemic lupus erythematosus: a systematic review. <i>Clin Reumathol</i>2010;29(7):707–716. 2. Hiemstra T, Jayne D. Newer therapies for vasculitis. Best Pract Res Clin Rheumatol2009;23(3):379–389. 3. Daoussis D, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology2010;49:271–280. 4. Saunders P, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated intersticial luna disease (RECITAL): Study protocol for a randomised controlled trial. Trials2017;18(1):27. No conflict of interest

Documento de consenso de la Sociedad Española de Infectología Pediátrica sobre la tuberculosis resistente a fármacos

Drug resistant tuberculosis (TB-R), and in particular, multidrug resistant tuberculosis (MDR-TB) is a global public health problem, as well as a problem in our country. Cases of TB-R and MDR-TB have increased mainly in HIV, immigrant and socially disadvantaged populations, but a notable increase in the general population has also been observed. This aspect reinforces the need for a systematic study of sensitivity of all the isolates in a reference laboratory to optimally guide the treatment. Children are especially vulnerable to this severe disease due to the limited knowledge of second line anti-tuberculous drugs, in terms of their pharmacokinetic data, optimal doses, or their long term toxicity, all this eventually resulting in the compassionate use of drugs. Another aspect which further complicates the management of R-TB in children is the limited yield of cultures, which frequently leads to clinician designing drug combinations according to the sensitivity of the initial strain. The epidemiological pattern in our country has currently changed. There is a reported increase in isoniazid-resistant strains; therefore, a four drugs regime is mandatory for the initial period in children, until reliable sensitivity results are available. Treatment should be directly observed or at least supervised by paediatricians. The management of latent infections or exposure to a resistant TB case also requires an accurate, strict and prolonged supervision by expert paediatricians. Authorities and health care professionals who deal with TB should be prepared to face this new phenomenon with appropriate measures. The knowledge of second line drugs for children, as well as mechanisms to ensure the therapeutic adherence and long term control of disease, are essential.

Octreotide: A Long-Acting Somatostatin Analog

One of the exciting recent developments in endocrinology research has been the introduction of the somatostatin analog, octreotide into clinical practice. Octreotide provides a new therapeutic tool for diseases in which somatostatin or somatostatin-like products are secreted abnormally. Unfortunately, early experience was obtained largely with uncontrolled, compassionate drug use. When clinical information regarding octreotide is critically reviewed, evaluation is hampered by the lack of long-term studies with adequate numbers of patients and controls. Nevertheless, the information available does indicate that octreotide is promising in the acute treatment of some of the manifestations of the carcinoid syndrome, including carcinoid crisis. Similarly, octreotide ameliorates symptoms of other gut neuroendocrine tumors, particularly vasoactive intestinal peptide (VIP)-secreting tumors. Octreotide also has potential in the management of growth-hormone-secreting tumors. Long-term treatment with octreotide for these diseases requires more information regarding alterations in disease progression and development of adverse effects including variable effects on blood sugar regulation and steatorrhoea. Octreotide also has been used in nonmalignant gastrointestinal disorders, but larger studies are necessary before recommendations regarding these applications can be made. The cost of octreotide, as may be expected, is high but is justified for patients with the specific indications outlined in this review. These indications may change as understanding of the drug increases. Octreotide offers promise, particularly as acute treatment for the troublesome symptoms of several neuroendocrine disorders.(ABSTRACT TRUNCATED AT 250 WORDS)