Investigational Medical Product Research Articles

A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping

IntroductionAneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research questionThe study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methodsIn this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. ResultsTen patients across four dose groups were treated with NicaPlant® (3–13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusionThe placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies.

Acute myocardial infarction reparation/regeneration strategy using Wharton's jelly multipotent stem cells as an 'unlimited' therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial.

CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day ~5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. In 10 consecutive patients (32-65 years, peak CK-MB 533 ±89 U/l, cMRI-LVEF 40.3 ±2.7%, cMRI-infarct size 20.1 ±2.8%), 30 × 106 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 ±8 vs. 44 ±9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 ±7.6 g to 25.5 ±6.4 g at 1 year and 23.1 ±5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 ±2.6% vs. 51.0 ±3.3%, 36.0 ±3.9% vs. 44.9 ±5.0%, and 38.4 ±2.5% vs. 48.0 ±2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application ~5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.

ES20.02 Charting a New Path: Defining Better Endpoints in Immune Therapy Trials in Lung Cancer

The use of immune checkpoint inhibitor therapy has transformed the face of lung cancer management. Trials of such agents for metastatic and locally advanced disease have used the traditional endpoint of overall survival (OS) by time-to-event analysis. However, obtaining this endpoint in a randomized trial takes some time and other endpoints are being considered, particularly for the radical or operable setting. To consider the most appropriate endpoint to use for immunotherapy, we must consider the aims of our treatment of lung cancer. For radically treatable disease through surgery is the aim always to improve the cure rate, or is another aim such as delaying recurrence (e.g., disease-free survival) just as clinically meaningful, if it doesn’t correlate with OS? We must also consider the magnitude of the effect size we wish to observe, particularly when using a surrogate endpoint of OS. Here, hazard ratios of 0.85 may not be clinically meaningful anymore, and we need to consider if we are prepared to accept uncertainty in effect by using a surrogate (earlier) endpoint for more rapid regulatory approval. If using a surrogate endpoint, will this give enough information to be able to pass HTA reimbursement value thresholds? We have clear guidance from the regulatory agencies on endpoints to be used for clinical trials. EMA give different definitions of endpoints for phase 1 and 2 trials from confirmatory phase 3 trials, giving a different stance for trials of cytotoxics to those non-cytotoxic based1. They recognize that immunomodulatory treatments may work most effectively where tumour bulk is low, and may take time to generate an defect, indeed with effect occurring post progression, and for phase 3 trials, progression-free survival remains acceptable. In the curative setting, EMA is clear that if event-free survival (EFS) is being used then this is justified under certain conditions and they give clear direction on using surrogates for the (neo)adjuvant setting1. The FDA also gives clear guidance on endpoints, with OS as the gold standard, but may allow other endpoints, recognizing that non-small cell lung cancer (NSCLC) is a heterogeneous disease, and the effects of different subsets should be explored2. When immunotherapy is being considered as the investigational medical product, endpoints such as progression-free survival (PFS), objective response rate (ORR) and even OS can have several benefits and risks. Measuring the benefit from immunotherapy can be difficult due to different patterns of benefit, and altered kinetics of benefit from cytotoxic therapy, alongside the heterogenous nature of NSCLC. Several surrogate endpoints e.g., ORR, duration of response, relapse-free survival, major pathological response or complete pathological response can be considered, but each give several benefits, but are prone to biases that need accounting for. The latter pathology-based endpoints have unclear definitions and the IASLC have proposed a structure for their definition3. When considering such surrogate endpoints, we should consider if such surrogates really to result in earlier approval or whether OS-based randomized trials are the main strategy- giving the example of extensive-stage small cell lung cancer4. Finally, if considering disease-free survival (DFS), multiple considerations need to be given. There are multiple emerging endpoints such as minimal residual disease in myeloma and the field of surrogate endpoints continues to evolve5. 1. EMA. Guideline on the clinical evaluation of anticancer medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-evaluation-anticancer-medicinal-products-man-revision-6_en.pdf 2. FDA. Clinical Trial Endpoints for the Approval of Non- Small Cell Lung Cancer Drugs and Biologics. Published 2015. https://www.fda.gov/media/116860/download 3. Travis WD, Dacic S, Wistuba I, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. Journal of Thoracic Oncology. 2020;15(5):709-740. doi:10.1016/j.jtho.2020.01.005 4. Gill J, Cetnar JP, Prasad V. A Timeline of Immune Checkpoint Inhibitor Approvals in Small Cell Lung Cancer. Trends in Cancer. 2020;6(9):736-738. doi:10.1016/j.trecan.2020.05.014 5. EMA. Guideline on the use of minimal residual disease as a clinical endpoint in multiple myeloma studies. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-use-minimal-residual-disease-clinical-endpoint-multiple-myeloma-studies_en.pdf endpoint, Clinical trials, immunotherapy

Recommendations from national regulatory agencies for ongoing cancer trials during the COVID-19 pandemic

Recommendations from national regulatory agencies for ongoing cancer trials during the COVID-19 pandemic

Positron emission tomography to image cerebral neuroinflammation in ischaemic stroke: a pilot study

Background Activated microglia play a complex role in neuroinflammation associated with acute ischaemic stroke. As a potential target for anti-inflammatory therapy, it is crucial to understand the association between intensity, extent and the clinical outcome of a stroke. The 18-kDa translocator protein is a marker of cerebral microglial activation and of macrophage infiltration after damage to the brain. It can be imaged by positron emission tomography. Therefore, the recently developed radiopharmaceutical [18F]-GE180 was used in patients after a mild to moderate stroke and compared with [11C]-(R)-PK11195, which has already been established in research but cannot be used in routine clinical settings because of its very short half-life. Objectives Objectives for phase 1 were to evaluate the tolerability of positron emission tomography scanning, to assess the technical feasibility of imaging the 18-kDa translocator protein using [18F]-GE180 as radiopharmaceutical, to compare [18F]-GE180 with [11C]-(R)-PK11195 as reference. Objectives for phase 2 were examining the relation of positron emission tomography imaging with clinical outcome, magnetic resonance imaging and systemic inflammation. However, the study was ended after phase 1 because of the results obtained in that phase and did not enter phase 2. Methods Ten participants (aged 24–89 years, median 68 years) (eight male and two female) with a history of recent ischaemic stroke of mild to moderate severity (modified Rankin scale score of 2–3) in the middle cerebral artery territory were scanned 18 to 63 days (median 34.5 days) after the stroke by magnetic resonance imaging (Philips 1.5 T; Philips, Amsterdam, the Netherlands), [18F]-GE180 (200 MBq, 30-minute dynamic scan) and [11C]-(R)-PK11195 (740 MBq, 60-minute dynamic scan) positron emission tomography (Siemens HRRT; Siemens, Munich, Germany). The two positron emission tomography scans were performed on 2 separate days (mean 3.4 days apart). Five patients were randomised to receive the [18F]-GE180 scan at the first session and five patients were randomised to receive it at the second session. Participants were genotyped for the rs6971 18-kDa translocator protein polymorphism, which is known to affect binding of [18F]-GE180 but not of [11C]-(R)-PK11195. All positron emission tomography and magnetic resonance data sets were co-registered with T1-weighted magnetic resonance image scans. Binding of [18F]-GE180 was compared with [11C]-(R)-PK11195 for the infarct and contralateral reference regions. Spearman’s rank-order correlation was used to compare tracers, t-tests to compare patient subgroups. Results Tolerability of scans was rated as 4.36 (range 4–5) out of a maximum of 5 by participants, and there were no serious adverse events. There was a close correlation between [18F]-GE180 and [11C]-(R)-PK11195 (r = 0.79 to 0.84). The 18-kDa translocator protein polymorphism had a significant impact on the uptake of [18F]-GE180, which was very low in normal cortex. Ischaemic lesions with contrast enhancement on magnetic resonance as an indicator of blood–brain barrier damage showed a significantly higher uptake of [18F]-GE180 than the lesions without enhancement, even in low-affinity binders. Conclusions [18F]-GE180 was safe and well tolerated. However, strong dependency of uptake on blood–brain barrier damage and a genetic 18-kDa translocator protein polymorphism, as well as a high contribution of vascular signal to the uptake and evidence of non-specific binding in ischaemic lesions with blood–brain barrier damage, limits the clinical applicability of [18F]-GE180 as a diagnostic marker of neuroinflammation. Limitations As the study was ended after phase 1, this was only a small pilot trial. Further studies are warranted to fully understand the influence of blood–brain barrier damage on positron emission tomography microglia imaging. Trial registration Registered as a clinical trial with EudraCT 2014-000591-26. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 1. See the NIHR Journals Library website for further information. It was also supported by GE Healthcare (Chicago, IL, USA) by free production and delivery of [18F]-GE180 and by supply of regulatory documents (Investigational Medical Product Dossier, Investigator’s Brochure). There was partial support by the European Commission (INMiND, grant #278850) and the NIHR Sheffield Biomedical Research Centre.

Oversight of Right-to-Try and Expanded Access Requests for Off-Trial Access to Investigational Drugs.

For decades, the U.S. Food and Drug Administration (FDA) has provided an "expanded access" pathway that allows patients who meet qualifying conditions to gain access outside a clinical trial to an investigational medical product being tested to see if it is safe and effective for a specific use. The Right to Try (RTT) Act, enacted in 2018, created a second mechanism for off-trial, or non-trial, access to investigational drugs. In contrast to the expanded access pathway, the federal RTT pathway does not require the involvement of the FDA or an institutional review board (IRB). Given that physicians, drug manufacturers, and medical institutions now have a choice whether to assist individual patients through the expanded access or the federal RTT pathway, we review the differences between these options and discuss the benefits and burdens of IRB involvement in requests to access interventions through the pathways. We also suggest ways in which IRB oversight may be further improved.

P774Transcoronary transfer of Wharton's jelly mesenchymal pluripotent stem cells in patients with chronic ischaemic heart failure shows safety and unprecedented high-grade myocardial uptake

Abstract Background Chronic ischaemic heart failure (CIHF) remains an important health problem on the patient/family- and society level. In animal models, Wharton's jelly (umbilical cord matrix) multipotent stem cells (WJMSCs) effectively promote angiogenesis, can differentiate to cardiomyocytes, and drive functional myocardial regeneration. Effective uptake of regenerative cells in ischaemic-impaired tissue is fundamental for any therapeutic effect. Purpose To evaluate safety and myocardial uptake of WJMSCs transcoronary transfer in CIHF applied as a novel myocardial regeneration strategy employing allogenic yet hypo-immunogenic, off-the-shelf “unlimited” source of therapeutic cells (NCT03418233 pilot cohort). Material and methods In ten consecutive patients (age 62.6±2.5), with stable CIHF and no current need for revascularization (LVEF 29.3±3% by echo and 26.3±6% by SPECT; NT-proBNP 1746±329pg/mL; myocardial scar tissue 39.9±3.9% by SPECT) and patency of at least two major native coronary arteries or by-pass graft(s), the CardioCell Investigational Medical Product, based on 30x106 WJMSCs, was administered to viable yet hypokinetic segments using a novel algorithm including a dedicated catheter for transcoronary delivery of cellular therapies. The cells were labeled with 99mTc-extametazime to routinely evaluate their myocardial uptake magnitude. Results No symptoms or signs of novel myocardial ischaemia occurred with cell delivery and no patient showed any adverse periprocedural events. One hour after administration, myocardial WJMSCs uptake (SPECT) was 40.3±6%; see Fig for a typical raw data image. By 6 months there were no adverse events in the study cohort. Figure 1 Conclusions This work indicates safety and unprecedented high-grade myocardial uptake of WJMSCs in CIHF patients. Together with animal data, this provides basis for continued assessment of this strategy in an endpoint-powered randomized controlled clinical trial employing CardioCell as an “unlimited” off-the-shelf cellular therapy strategy. Acknowledgement/Funding K/ZDS/005644 and 265761 (National Centre for Research and Development STRATEGMED)

PNS81 STATUS OF EXPANDED ACCESS PROGRAM (EAP) REGISTRATION INTO CLINICALTRIALS.GOV FOLLOWING 21ST CENTURY CURES ACT

Expanded access is the use of an investigational medical product outside of a clinical trial when no comparable or satisfactory alternative therapies are available for the treatment of a serious disease or condition. Types of EAP are (1) individual patients (including emergency use), (2) intermediate-size patient population (more than one patient), and (3) treatment Investigational New Drug (IND)/protocol (widespread population). Under the Cures Act, and specifically 42 CFR Part 11, US pharmaceutical companies have to post information on expanded access on ClinicalTrials.gov. We aim to review the status of EAP registration into ClinicalTrials.gov over time. We searched ClinicalTrials.gov on 11-Jan-19 using following search terms: Expanded Access Studies, United States, Treatment IND/Protocol, Individual Patients and Intermediate-size Population. 58 studies were identified (49 funded by industry, 8 by academia, 1 by NIH). 16 studies were registered during the period 2005-2016, 15 in 2017, and 26 in 2018. Most studies focus on neoplasms (40%), followed by metabolic disorders (23%), and hematologic disorders (12%). 76% involved a drug, 17% a biological, and the remainder a device or any combination of drug/biological/procedure/device. 38% were individual patients EAPs, 28% treatment IND/protocol EAPs and 16% included intermediate-size populations (the remainder a mix). 72% of studies were conducted in the US only and 16% were multicounty (no information available for the remainder). The distribution of single center vs. multi-center was approximately 50/50. As expected, we observe a sharp increase in registrations following the Cures Act and most EAPs are for drugs treating neoplasms. However, 42 studies since 2017 across a limited number of pharmaceutical sponsors suggests that many EAPs are not (yet) registered, despite this now being mandatory.

Safety & Efficacy of Human Plasma Derived Plasminogen Ophthalmic Drops for Treatment of Ligneous Conjunctivitis: Report of Phase 2/3 Clinical Trial

INTRODUCTIONPlasminogen deficiency is a rare autosomal recessive disorder with variable penetrance with multisystem manifestations that may result in significant morbidity. Most commonly, type-1 (quantitative defect) is associated with characteristic fibrin rich pseudomembranes in mucosal surfaces, the most common site being the eye, called Ligneous Conjunctivitis (LC). Two-thirds of patients have bilateral eye lesions and 1/3 have corneal involvement. Initially, patients present with non-specific conjunctivitis with epiphora, followed by white-red woody lesions replacing normal membranes and resulting in visual impairment/loss. LC may be triggered/exacerbated by infection, inflammation, or trauma. Although some non-specific modalities have been reported to result in lesion improvement/resolution, only FFP and topical/systemic plasminogen are consistently effective. Surgical intervention without effective replacement therapy results in lesion regrowth. Currently, local or systemic plasminogen replacement therapy is unavailable. Therefore, development of locally administered plasminogen concentrate represents an important advance in therapeutic options for LC.OBJECTIVESA phase 2/3 study is being conducted to evaluate the safety and efficacy of Kedrion plasma derived (pd) plasminogen ophthalmologic drops for treatment of LC associated with type I plasminogen deficiency.METHODSAn ongoing open-label, multicenter, historically-controlled trial divided into 3 segments began on 5/22/2012. Three sites (1 US, 2 Italy) enrolled subjects. Segment 1 is 4 week treatment to evaluate clinical safety/efficacy followed by surgical excision of residual pseudomembranous, if required; segment 2 includes 8 weeks post-operative treatment/monitoring; segment 3 is a continuation phase with long-term safety monitoring until product licensure. Treatment regimens range from 2 drops/eye 4-12 times daily based on symptoms, study group and segment. The investigational medical product is a sterile human pd plasminogen, solvent/detergent treatment, nanofiltrated virally inactivated. During processing, the plasma pool is supplemented with bovine aprotinin to prevent plasminogen conversion to plasmin.RESULTSSegments 1 and 2 are complete; segment 3 is ongoing. The interim analysis is according to study protocol. Eleven subjects were enrolled (plasminogen activity range 5.1-34.26%; median 17.08%); age ranged between 1-44 yrs (median 4 yrs) including 4 males and 7 females; 7 had unilateral and 4 had bilateral lesions at enrolment. Three subjects did not require surgical intervention, and 8 required one excision of residual lesions after 4 weeks of therapy. In all compliant subjects, full regression and/or absence of recurrence post-excision were reported. One adult male subject, with bilateral involvement and severe visual impairment, was withdrawn due to noncompliance in study segment 2 after excision with subsequent lesion recurrence. Two subjects (1 during segment 1-2 and 1 during segment 3) developed plasma anti-plasminogen antibodies which are being further characterized as to specificity; these two subjects continue to respond to local therapy and remain symptom-free (Table 1). No viral seroconversion was detected.CONCLUSIONLC in type 1 plasminogen deficiency can result in significant morbidity without an available effective local therapy. Kedrion human pd plasminogen ophthalmologic drops were found to be effective and well tolerated and represent an important advance in the treatment of this unusual manifestation of a rare disease, plasminogen deficiency.Table 1Study Data SummarySubject #Age (Yrs)SexEye LesionsSurgery RequiredTherapeutic ResponsePlasminogen AbWithdrawal (Reason)LeftRight12MXNoFNegativeNo244FXYesPNegativeNo332MXXYesRNegativeYes (poor compliance)41FXNoFNegativeNo54MXXYesPPositiveNo61FXNoFNegativeNo71FXYesPNegativeNo83MXXYesPNegativeNo94FXYesPNegativeNo108FXXYesPPositiveNo117FXYesPNegativeNoTotal968 procedures2115 symptomatic FFull regression of lesions by end segment 1; no surgery required, no recurrence in segment 3 PPartial regression by the end of segment 1 with surgery required for residual lesion(s). No recurrence post-operatively or in segment 3. RRecurrence DisclosuresNakar:Kedrion: Research Funding. Caputo:Kedrion: Research Funding. Price:Kedrion: Research Funding; Alphaeon, Calhoun Vision Inc., Interactive Medical Publishing, Inc., ReVital Vision, TearLab,Valeant Pharmaceuticals/Bausch and Lomb: Equity Ownership; Cornea Research Foundation of America: Membership on an entity's Board of Directors or advisory committees; STAAR Surgical: Consultancy. Sartori:Kedrion: Research Funding. Suffredini:Kedrion SpA: Employment. Thukral:Kedrion: Research Funding. Secci:Kedrion: Research Funding. Jeng:Kedrion: Consultancy. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding.

CPC-076 Internal Audit on the Labelling of Investigational Medicinal Products

BackgroundThe purpose of labelling is to protect persons who take part to biomedical research. It must enable the product and study to be identified and the drugs to be used...

Positron emission tomography radiopharmaceutical studies in humans

All clinical trials are covered by a series of regulations that seek to protect the rights, safety and welfare of participating patients. The regulations covering PET studies are especially complex to interpret because of the specialized nature of the language of the regulations and of PET studies themselves. It is often unclear whether the application demands that the radiotracer used be treated as an investigational medical product. This paper is intended to act as a general guide for UK researchers planning to perform PET research in humans by clarifying key aspects of the regulations that may affect the study and/or the radiopharmaceutical manufacturing process, providing links to useful information sources, introducing the concept of a UK Medicines and Healthcare products Regulatory Agency (MHRA) PET expert panel and outlining the value of sharing investigational medical product dossiers.

Exploratory Clinical Trials: Implementation Modes & Guidelines, Scope and Regulatory Framework

The working group focused on defining exploratory trials on medicinal products and developing recommendations for their implementation in France (notably concerning non-clinical requirements, the pharmaceutical quality of the investigational medical product and the conditions under which this type of clinical trial may be performed).To this end, the working group took account of existing guidelines (notably those in the USA and Belgium) and a draft revision of the ICH M3 guideline.Exploratory trials are clinical trials performed early in Phase I, prior to dose escalation and safety and tolerability trials. These trials are de facto first-in-man studies but lack a therapeutic or diagnostic goal and do not seek to establish the maximum tolerated dose (MTD). The objective is to answer precise questions which condition the continuation or suspension of the drug’s development program. Exploratory trials include a small number of patients or healthy subjects and expose them (over a short period of time) to a low dose of an investigational medicinal product.The draft revision of M3 describes five approaches (two involving microdoses and three with pharmacological doses).The group’s main recommendations can be summarized as follows:−An exploratory trial may be performed when it is (i) justified, (ii) useful for product development and (iii) consistent with prerequisites.−The pharmaceutical dossier should take account of the low quantity of product available, the short period of product administration and the low doses used. Good Manufacturing Practices can be adapted accordingly.−The non-clinical dossier should also be adapted to suit the development phase and particular features of product use. In this respect, the group has commented on the recommendations in the draft revision of M3.−The protocol must be designed to provide answers to a set of specific, pertinent questions concerning this administration phase – particularly on choice of the initial dose, the size of the dose escalation and the rules for subject withdrawal and trial suspension.−In general, so-called “vulnerable” populations should not be involved in this type of trial, apart from duly justified exceptions.−The group considered that approaches 3 to 5 should only apply to a medicinal product intended for treatment of a severe or rare disease or a condition with significant unmet medical needs.−Pre-filing at the Afssaps (the French Agency for Healthcare Product Safety) is recommended, notably for approaches using pharmacological doses.

Methods in clinical pharmacology - a tale of two worlds

Methods in clinical pharmacology - a tale of two worlds