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Abstract

Objectives

To investigate the drugs and indications that have passed through the UK's Early Access to Medicines Scheme (EAMS) to date, the type of evidence the regulator considers when accepting a drug into the EAMS, and potential risks to patients.

Design

Analysis of publicly available data: MHRA Public Assessment Reports; Electronic Medicines Compendium database; interactive Drug Analysis Profiles database; Eudravigilance database.

Setting

United Kingdom.

Participants

The 51 ‘scientific opinions’ available on the MHRA website in June 2024.

Main Outcome Measures

Public Assessment Reports, pharmacovigilance data.

Results

After exclusions, there were 48 EAMS submissions, consisting of 48 indications and 32 drugs. 60% of indications were for cancer. Only 7% of EAMS submissions were based on double-blind, placebo-controlled randomised trials. The average sample size of studies conducted for the EAMS was 654. Most studies used surrogate (76%) and/or survival (57%) outcomes. Only 17% used subjective outcomes. For 17% of the indications, no ongoing studies were being conducted. Animal studies were conducted preclinically for all drugs and 35% also conducted in vitro studies. 47% of the drugs had elevated rates of suspected adverse reaction reports according to pharmacovigilance data.

Conclusions

We recommend that the EAMS drugs with elevated reporting rates are reviewed, that future studies of EAMS drugs use patient-centred outcomes, that preclinical studies make greater use of human biology-based approaches, that post-approval trials are conducted, and that future reviews of the EAMS centre the experience of patients.

Keywords

adverse drug reactions pharmacovigilance accelerated access drug safety cancer

Introduction

In April 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) introduced its Early Access to Medicines Scheme (EAMS). The scheme aims to provide access to medicines that do not yet have a marketing authorisation for UK patients with life-threatening or seriously debilitating conditions if there is a clear unmet medical need. The medicine should be likely to offer a significant advantage over existing approaches and its benefits should outweigh its potential adverse effects.¹ If a drug meets the EAMS criteria,² a ‘positive scientific opinion’ is issued which describes the balance of risks and benefits based on the data available. The MHRA then publishes a Public Assessment Report (PAR) which summarises the clinical evidence, risks, benefits and uncertainties and supplies information about ongoing clinical studies and risk management measures. The EAMS period then starts.

The EAMS was the first UK fast-track scheme to be developed. Others (150-day National Assessment, Rolling Review, Innovative Licensing and Access Pathway, International Recognition Procedure and Project Orbis) emerged in the wake of the UK's departure from the EU and are perhaps intended to signal that the UK remains ‘open for business’. They offer various routes to faster licensing depending on the nature of the application or market readiness of the drug in question. There are no recent figures, but in 2020, the MHRA approved 36% of new drugs through accelerated pathways.³ The US has fast-tracked drugs since 1988, and between 1992 and 2021, the FDA approved 278 drugs under accelerated approval. Initially, most were for infectious diseases but an increasing number of cancer drugs began to be fast-tracked, such that 83% between 2012 and 2021 were for oncology indications.⁴ However, many expedited cancer drugs fail to demonstrate benefit in confirmatory trials^5–7 and while – shockingly – some of these remain on the market,⁷ a substantial number has been withdrawn in the United States of America due to a lack of overall survival benefit.⁸ This clearly demonstrates the importance of confirmatory trials,⁹ especially since pre-approval studies are often exploratory, using non-randomised, uncontrolled designs and surrogate outcomes.⁸ Despite the obvious need for post-approval studies, however, there is little incentive for companies to conduct them; recruitment may be difficult, they risk financial loss if the results are negative, not all regulators require them and those that do fail to impose penalties for missing deadlines. Consequently, some expedited drugs remain on the market for years without good evidence of efficacy.^10–12

Expedited drugs also raise safety concerns. In the United States of America, almost 57% received a black box warning (the FDA's highest safety-related warning)¹³ and compared with regular drugs, they have a 48% higher rate of changes to boxed warnings and contraindications.¹⁴ Drugs in a Canadian fast-track scheme were significantly more likely than those following a standard pathway to receive a serious safety warning and/or be removed from the market.¹⁵ Several fast-tracked drugs have been withdrawn following deaths and severe adverse events^9,13 including rofecoxib which was approved in the United States of America in 1999. In the 5 years until its withdrawal, there were an estimated 88,000–140,000 excess cases of serious coronary artery disease,¹⁶ many of which were fatal.

Clearly then, patients taking expedited drugs face significant risks and uncertain benefits. For pharmaceutical companies, however, the advantages are manifold. Having drugs in fast-track schemes can generate early demand and help companies prepare for the global launch of their product.¹⁷ EAMS drugs are more likely to receive a positive recommendation from the National Institute for Health and Care Excellence (NICE) than those going through standard pathways (58% vs. 43%, respectively).¹⁸ Reviews of the EAMS^19–24 all emphasise the potential gains to industry, including signalling to investors that therapy is on the ‘right track’, early advice and guidance from the regulator, access to patient populations and expert clinicians, early interaction with the NHS and NICE, a controlled environment for delivering treatments, the ability to collect real-world data, and a prioritised NICE appraisal. As for economic benefits, the same reviews note that the EAMS signals that the UK remains the ‘go to location’ for companies to develop and market their innovative therapies. When it comes to advantages for patients, however, most reviews simply assume that early access is beneficial. As of mid-2023, nearly 3000 patients have been treated under the EAMS²⁴ but we have no idea whether the expedited drugs actually helped these patients, or were safe because the reviews did not investigate this.

Ten years have passed since the introduction of EAMS in the UK. We examine how many drugs have passed through the scheme to date and for which indications, consider the quality of data upon which the MHRA based its decisions to expedite the drugs, and investigate their safety.

Methods

We examined all 51 scientific opinions available on the MHRA website as of 11 June 2024. These are ‘expired' opinions, that is, opinions on drugs that have gone through the EAMS and (typically) received market authorisation.²⁵ We extracted data on the drugs, companies and indications. From the PARs, we extracted data on pre-approval studies, including design, sample size and study outcomes, as well as ongoing studies and risk monitoring.

Preclinical studies

Information about preclinical studies is not included in the PAR so we searched for this on the Electronic Medicines Compendium (eMC).²⁶ This database holds up-to-date information about medicines licensed for UK use. Searches were conducted on 29–30 August 2024.

Safety

We searched i. the MHRA's interactive Drug Analysis Profiles (iDAPs) database for serious adverse reactions reported to the Yellow Card scheme and ii. the EMA's Eudravigilance database for reports of suspected adverse reactions, for each EAMS drug. Searches were conducted on 29–30 August 2024. Eudravigilance records suspected adverse reactions to medicines that have been authorised or are being studied in clinical trials in the European Economic Area. Since Brexit, it is no longer standard practice for the UK to submit data to Eudravigilance but we searched this database because many EAMS drug approvals predate Brexit and because it provides additional data about the EAMS drugs. We use the reports to provide an indicator of potential safety concerns about the EAMS drugs, not the specific EAMS indications. To enable comparisons between drugs, we divided the number of Yellow Card and Eudravigilance reports by the number of months since the drug was approved for the EAMS, and by the number of indications (if >1), to give a monthly rate per drug. As no ‘acceptable’ or ‘unacceptable’ rate of suspected adverse reaction reports exists, we made a judgement about which drugs appeared to have elevated reporting rates by reviewing the distribution of reports across all the drugs.

The MHRA lacks a system equivalent to the FDA's ‘boxed warnings’ that highlight potential safety concerns,²⁷ but it does require ‘additional Risk Minimisation Measures’ (aRRMs) for drugs associated with important risks (i.e. extra information for patients and health professionals).^28,29 Another UK risk indicator is the Black Triangle, denoting that a drug's safety is not yet well established and that intensive monitoring is required, usually because the drug is new. Using the eMC, we investigated how many EAMS drugs had aRMMs or Black Triangle status (searches conducted on 22 August 2024).

Data extraction

Initially, the three authors extracted data independently but realised this was unnecessary as no judgements or interpretations were involved (data were simply cut and pasted). Consequently, one person (PP) conducted data extraction.

Results

The 51 scientific opinions relate to 51 different disease indications and 34 individual drugs. All drugs received marketing authorisation for their indications, with the exception of three withdrawn by the manufacturer at the time of analysis (raxone, cenegermin and nivolumab for advanced or recurrent gastric or gastroesophageal junction cancer after two or more systemic therapies). The analysis therefore focuses on 48 EAMS submissions relating to 48 indications and 32 individual drugs (nivolumab was approved for eight other indications).

The majority of indications were cancers (60%, 29), followed by severe atopic dermatitis (4), Pompe Disease (2), transthyretin amyloidosis (2) and 11 other diseases (Crohn's, myasthenia gravis, sickle cell, angioedema, spinal muscular atrophy, hyperoxaluria, Sars Cov-2, familial chylomicronemia, haemophilia A, hepatitis C, heart failure). Some drugs were approved for a number of different indications (nivolumab 8; atezolizumab 5; pembrolizumab 3; dupilumab 3; avelumab 2). In eight cases (seven of which were for cancer) the drug was studied in combination with another drug or drugs. Roche made 10 submissions to the EAMS and Bristol Myers Squibb made 8. The remaining companies made three or fewer submissions each (Table 1).

Table 1.
Drugs submitted to EAMS.

Drug Trade name Indication Company

1 Dostarlimab^a Jemperli Endometrial cancer GlaxoSmithKline

2 Glofitamab Columvi Relapsed or refractory diffuse large B-cell lymphoma Roche

3 Cipaglucosidase alfa^a Pombiliti Late-onset Pompe disease Amicus

4 Risankizumab Skyrizi Crohn's disease AbbVie

5 Lutetium (177Lu) vipivotide tetraxetan Pluvicto Prostate cancer Advanced Accelerator Applications

6 Efgartigimod alfa Vyvgart Myasthenia gravis Argenx BVadd

7 Asciminib Scemblix Philadelphia chromosome-positive chronic myeloid leukaemia Novartis

8 Voxelotor Oxbryta Sickle cell disease Pfizer

9 Abrocitinib Cibinqo Severe atopic dermatitis Pfizer

10 Avalglucosidase alfa Nexviazyme Pompe disease Aventis

11 Berotralstat Orladeyo Hereditary angioedema Biocryst

12 Nivolumab^a Opdivo Advanced/metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma cancer of the stomach or oesophagus Bristol Myers Squibb

13 Tepotinib Tepmetko Advanced non-small cell lung cancer Merck Serono

14 Nivolumab^a Opdivo Mesothelioma Bristol Myers Squibb

15 Risdiplam Evrysdi Type 1 and type 2 spinal muscular atrophy Roche

16 Pemigatinib Pemazyre Locally advanced or metastatic cholangiocarcinoma Incyte Biosciences

17 Lumasiran Oxlumo Primary hyperoxaluria type 1 Alnylam

18 Avelumab Bavencio Bladder cancer Merck Serono

19 Dupilumab Dupixent Children aged 6–11 with severe atopic dermatitis Sanofi

20 Nivolumab Opdivo Unresectable advanced, recurrent or metastatic oesophageal cancer Bristol Myers Squibb

21 Atezolizumab^a Tecentriq Unresectable hepatocellular carcinoma Roche

22 Remdesivir Veklury Suspected or laboratory-confirmed SARS-CoV-2 Gilead

23 Isatuximab^a Sarclisa Adult patients with relapsed and refractory multiple myeloma Aventis

24 Tafamidis Vyndaqel Transthyretin amyloidosis Pfizer

25 Polatuzumab vedotin Polivy Relapsed/refractory diffuse large B-cell lymphoma Roche

26 Avelumab Bavencio Advanced renal cell carcinoma Merck Serono

27 Atezolizumab^a Tecentriq Extensive-stage small cell lung cancer Roche

28 Atezolizumab Tecentriq Triple-negative breast cancer Roche

29 Dupilumab Dupixent Patients aged 12–18 with severe atopic dermatitis Sanofi

30 Volanesorsen Waylivra Familial chylomicronaemia syndrome Akcea Therapeutics

31 Atezolizumab^a Tecentriq Metastatic non-squamous non-small cell lung cancer Roche

32 Patisiran LNP Onpattro Hereditary transthyretin-mediated amyloidosis Alnylam

33 Emicizumab Hemlibra Haemophilia A Roche

34 Alectinib Alecensa Anaplastic lymphoma kinase-positive advanced non-small cell lung cancer Roche

35 Dupilumab Dupixent Adult patients with severe atopic dermatitis Sanofi

36 Glecaprevir/pibrentasvir Mavyret and Maviret Chronic hepatitis C (HCV) infection in adults AbbVie

37 Atezolizumab Tecentriq Locally advanced or metastatic urothelial carcinoma Roche

38 Pembrolizumab Keytruda Metastatic non-small cell lung cancer whose tumours express PD-L1 and who have not received prior systemic therapy and are negative for EGFR sensitising mutation and ALK translocation Merck Sharp & Dohme

39 Venetoclax Venclexta Chronic lymphocytic leukaemia AbbVie

40 Nivolumab Opdivo Hodgkin lymphoma Bristol Myers Squibb

41 Pembrolizumab Keytruda Metastatic non-small cell lung cancer whose tumours express PD-L1 and whose disease has progressed on or after platinum-containing chemotherapy Merck Sharp & Dohme

42 Nivolumab Opdivo Renal cell carcinoma Bristol Myers Squibb

43 Nivolumab Opdivo Non-squamous non-small cell lung cancer Bristol Myers Squibb

44 Osimertinib Tagrisso Locally advanced or metastatic epidermal growth factor receptor (EGFR) T790 M mutation-positive non-small-cell lung cancer AstraZeneca

45 Sacubitril/valsartan Entresto Symptomatic heart failure and reduced ejection fraction Novartis

46 Nivolumab Opdivo Advanced lung cancer (characterised by squamous non-small cells) Bristol Myers Squibb

47 Pembrolizumab Keytruda Advanced melanoma Merck Sharp & Dohme

48 Nivolumab Opdivo Advanced melanoma Bristol Myers Squibb

32 individual drugs 48 indications (of which 29 cancer)

a
Studied in combination with another drug or drugs.

Information recorded in the PAR

At the time of the searches, PARs were missing for two indications (dupilumab for children aged 6–11 with atopic dermatitis; cipaglucosidase alpha for late-onset Pompe disease), leaving 46 PARs relating to 46 indications.

Study design

The design of the clinical studies conducted for the EAMS was not always clearly described in the PARs and the clinical data presented by companies varied in form and quantity, suggesting the MHRA does not demand this information in a consistent format. According to the PARs, only 3 (7%) of the 46 submissions were based on double-blind, placebo-controlled randomised trials. Eighteen PARs (39%) reported studies comparing the experimental drug with usual or another treatment (4 of which mentioned randomisation); 10 (22%) reported studies comparing the experimental drug with placebo; 8 (17%) reported studies in which no comparison was made; 5 (11%) reported ‘open label’ trials; 1 reported a study comparing different doses of the experimental drug and 1 reported a study comparing the experimental drug with no treatment. The average sample size was 654 (OSF File 1 https://osf.io/3wvb2?view_only=8aa44000a7414c999df977344f23ac35).

Study outcomes

Thirty-five studies (76%) used surrogate outcomes such as improvements in various scores, reductions in illness episodes, or changes in tumour growth, the latter being most common (n = 15). Twenty-six (57%) of the 46 studies used survival outcomes, most of which (n = 21) measured both overall survival and progression-free survival. Eight studies (17%) used self-reported outcomes, that is, quality of life (n = 8), sleep quality (n = 3) and symptom improvement (n = 6). Ten studies (22%) used survival outcomes only and 13 (28%) used surrogate outcomes only (Figure 1; OSF File 2 https://osf.io/kxsvr?view_only=8aa44000a7414c999df977344f23ac35).

Figure 1.
Studies using survival, surrogate, and patient-reported outcomes for 46 indications (missing data, n = 2).

Ongoing studies and monitoring

Eight (17%) of the PARs clearly stated that there were no ongoing studies for the specific EAMS indication. For the remaining 38 (83%), companies stated that some kind of study or studies were ongoing, but it was not always clear whether these related to the specific EAMS indication (OSF File 3 https://osf.io/5ukj2?view_only=8aa44000a7414c999df977344f23ac35). All PARs included a risk management plan stating that healthcare professionals and patients would be given information about the medicine, that healthcare professionals would receive specific training and be asked to report adverse effects, and that patients would receive a card summarising important risks. The amount of detail provided by companies varied.

Preclinical studies

Animal studies were conducted for 31 drugs (preclinical data were missing from the eMC for isatuximab) and in vitro studies were also conducted for 11 (35%), mainly to test for genotoxicity (OSF File 4 https://osf.io/k7fuj?view_only=8aa44000a7414c999df977344f23ac35).

Safety

The drugs with the most Eudravigilance suspected adverse reaction reports were voxelotor (192 reports per month), sacubitril/valsartan (183), pembrolizumab (136), dupilumab (115), risankizumab (94), osimertinib (86), remdesivir (48), nivolumab (39) and alectinib (33). The remaining drugs had reports of 30 per month or less (Table 2, Figure 2). The drugs with the most Yellow Card reports for serious adverse drug reactions were sacubitril/valsartan (8 reports per month), venetoclax (5), rizankizumab (3.5), pembrolizumab (3), dupilumab (3), patisiran-NLP (3), remdesivir (2), avelumab (1.6), dostarlimab (1.5), polatuzamab vedotin (1.4) and emicizumab (1.4). Yellow Card reports were missing for voxelotor. The remaining drugs had reports of 1 per month or less (Table 2, Figure 3). In terms of fatalities reported to the Yellow Card system, venetoclax had the highest rate at 1.4 per month. Reports of fatalities for the remaining drugs were less than 1, although alectinib stands out at 0.9 per month (Table 2, Figure 3). Twenty (62%) of the drugs had Black Triangle Status and 15 (47%) had aRMMs in place. Taking into account both the Eudravigilance and Yellow Card schemes, 15 (47%) of the drugs raise safety concerns (Table 2, bold text) of which 6 (sacubitril/valsartan, pembrolizumab, dupilumab, risankizumab, remdesivir, alectinib) had elevated reporting rates under both schemes.

Figure 2.
Monthly Eudravigilance suspected adverse reaction reports since EAMS commencement.

Figure 3.
Monthly Yellow Card reports for serious adverse drug reactions and facilities since EAMS commencement.

Table 2.
Eudravigilance and yellow card reports.

Drug No. of indications Months since earliest EAMS SO granted, up to/including August 2024 Eudravigilance suspected adverse reaction reports Eudravigilance suspected adverse reaction reports per month (per no. indications) Yellow Card serious adverse drug reaction reports Yellow Card serious adverse drug reaction reports per month (per no. indications) Yellow Card fatalities Yellow Card fatalities per month (per no. indications) Black Triangle status additional Risk Minimisation Measures (aRMMs)

Pembrolizumab 3 114 46,488 408 (136) 913 8 (3) 151 1 (0.4) No Yes

Nivolumab 9 111 38,970 351 (39) 1003 9 (1) 132 1 (0.1) No Yes

Sacubitril/valsartan 1 108 19,724 183 897 8 69 0.6 No No

Osimertinib 1 105 8997 86 133 1 21 0.2 No No

Venetoclax 1 96 2610 27 464 5 134 1.4 No Yes

Atezolizumab 5 91 9595 105 (21) 209 2 (0.4) 34 0.4 (0.07) No Yes

Dupilumab 3 88 30,413 346 (115) 702 8 (3) 21 0.2 (0.08) No No

Glecaprevir/pibrentasivir 1 88 2182 25 40 0.4 4 0.04 No No

Alectinib 1 84 2793 33 56 0.6 8 0.9 No No

Emicizumab 1 80 1932 24 116 1.4 3 0.04 No Yes

Volanesorsen 1 75 167 2 5 0.06 0 0 Yes Yes

Patisiran-LNP 1 73 688 9 195 3 10 0.14 No Yes

Tafamidis 1 63 1868 30 12 0.2 5 0.08 Yes Yes

Avelumab 2 62 1044 17 (8) 203 3 (1.6) 34 0.5 (0.02) Yes Yes

Polatuzumab vedotin 1 62 1736 28 86 1.4 14 0.2 Yes No

Isatuximab 1 57 429 7 28 0.5 16 0.3 Yes Yes

Remdesivir 1 51 2451 48 106 2 18 0.3 Yes No

Lumasiran 1 50 113 2 Missing Missing Missing Missing Yes No

Risdiplam 1 47 726 15 50 1 8 0.2 Yes No

Berotralstat 1 46 100 2 15 0.3 1 0.02 Yes No

Pemigatinib 1 44 227 5 21 0.5 2 0.05 Yes No

Abrocitinib 1 43 669 15 41 1 1 0.02 Yes Yes

Avalglucosidase alfa 1 42 46 1 Missing Missing Missing Missing Yes Yes

Cipaglucosidease alfa 1 39 15 0.38 2 0.05 0 0 Yes Yes

Tepotinib 1 38 118 3 16 0.4 2 0.05 Yes No

Asciminib 1 32 267 8 Missing Missing Missing Missing Yes No

Voxelotor 1 31 5967 192 Missing Missing Missing Missing Yes No

Risankizumab 1 29 2732 94 103 3.5 5 0.17 No No

Lutetium 177Lu 1 29 612 21 8 0.3 2 0.07 Yes No

Efgartigimod alfa 1 27 305 11 5 0.7 0 0 Yes No

Glofitamab 1 14 34 2 15 1 2 0.14 Yes Yes

Dostarlimab 1 14 119 8 21 1.5 1 0.07 Yes Yes

Total 32 drugs 20 Black Triangle 15 aRMMs

Bold text indicates the drugs with elevated report rates.

Discussion

The pre-approval evidence upon which the MHRA based its decisions was limited; samples were generally small and most studies were non-randomised, unblinded comparisons. Most (76%) used surrogate outcomes. Eudravigilance and/or Yellow Card reports were elevated for almost half the drugs submitted to the EAMS. Most of the drugs had Black Triangle status and almost half had aRMMs. In vitro studies were conducted alongside in vivo preclinical studies for around a third of the drugs.

To our knowledge, this is the first review of the EAMS to examine outcomes rather than process and to investigate the risks for patients rather than the benefits for industry. Nevertheless, limitations include the lack of a definitive ranking of risk and the lack of comparison with non-EAMS drugs. Another limitation is our use of spontaneous reporting systems as indicators of risk. Not only do these systems suffer from underreporting,^30,31 they cannot establish a causal link between the drug and the reports. Nevertheless, the reports can signal real safety concerns: a month after our analysis, which found that voxelotor had the highest monthly rate of Eudravigilance reports, Pfizer withdrew voxelotor due to ‘an unfavourable imbalance in the number of vaso-occlusive crises and fatal events’.³²

Most of the EAMS submissions were for cancer, as has been found elsewhere,⁴ and as with other fast-track schemes,³³ the majority of studies conducted for EAMS submissions used surrogate outcomes. While these shorten trial duration, enabling rapid approval, they correlate poorly with overall survival and lack relevance to patients who are more concerned with safety, survival and quality of life.^{6,9,11,13,34–38} Our finding that most of the studies conducted for the EAMS were not robustly designed has been found in the context of expedited schemes elsewhere^8,33 as has the lack of consistency with which companies supplied methodological information and important details of study design.³³ The MHRA and other regulators do not appear to insist upon a specific format for supplying these data, although this would encourage companies to think more carefully about study design.

The high proportion of EAMS drugs with elevated pharmacovigilance reports, the ongoing Black Triangle status of most of the drugs and the high proportion with aRMMs all indicate a substantial risk to participating patients. The MHRA usually reviews Black Triangle status 2 years after marketing, so the fact that some EAMS drugs approved more than 2 years ago retain Black Triangle status indicates that their safety is not yet well established. Furthermore, the proportion of EAMS drugs with aRMMs (47%) is higher than for drugs in standard approval pathways (27%²⁹). Many EAMS drugs then, do not have an established safety profile, and several appear to have significant risks. Again, this is not uncommon for expedited drugs, as we noted in the introduction.^13–15

The safety of expedited drugs might be improved with greater preclinical use of human biology-based technologies, the value of which is increasingly evident.^39–43 The use of advanced in vitro technologies such as organoids and organ chips, or of in silico modelling and virtual clinical trials, makes particular sense in this context where time is of the essence and recruiting patients into clinical studies can be challenging.

While the MHRA appears to rely on pharmacovigilance to monitor safety, it is less clear how it determines whether the EAMS drugs are effective, or more effective than existing treatments, since it does not demand post-approval trials. In response to our query about this, the regulator stated: ‘There is no requirement that EAMS products perform clinical trials at any part of their lifecycle,’ noting that companies perform Phase IV clinical trials at their discretion. However, it stated that if EAMS drugs receive a conditional marketing authorisation, conditions and expectations are stipulated on approval and the ongoing ability to market the product is subject to the provision of clinical or real-world data.⁴⁴

The FDA, however, not only requires post-approval trials to be conducted on expedited drugs to confirm or disprove earlier studies but also monitors whether these trials are conducted.⁴⁵ The UK regulator's approach appears lackadaisical by comparison, particularly since post-approval trials often fail to confirm benefit.^6,7 Even prior to the introduction of the EAMS, a House of Commons Health Committee report highlighted the MHRA's focus on bringing drugs to market fast, without adequate consideration of whether patients would benefit sufficiently. The report accused the regulator of a lax approach to its public health responsibilities and of failing to ensure that the pharmaceutical industry works in the public interest.⁴⁶ It also raised concerns about the UK government's excessive focus on ensuring the competitiveness of the pharmaceutical industry, to the detriment of the NHS and patients. The current government appears keen to work with big pharma, promising to reduce red tape that ‘hampers the swift approval and implementation of new treatments’.⁴⁷ But as Huseyin Naci writes, ‘The idea that any new clinical trial is good, any new product is good and that the numbers of new drugs coming on to the market is the only metric of success, need to be questioned. What we should really be looking at is the number of new products that are coming on the market that are adding new benefits to patients.’⁵ Naci's team recently found that, at the population level, new drugs displace more health than they generate, creating a financial burden for health systems and opportunity costs for patients.⁴⁸

The approval rate for new drugs from Phase 1 is below 8%.⁴⁹ To expose the most vulnerable patients to expedited drugs that seem even less likely to be successful (given the lack of requirement for robust evidence) is far from compassionate. Cancer is the most common indication for accelerated approvals in the UK, yet cancer patients are a particularly vulnerable population, with evidence indicating that many feel pressured to take part in clinical trials (up to half of those in cancer drug trials appear to believe that participation is their only option).³⁵ Many cancer patients also seem unaware that for most, treatment prolongs life by around only 3 months.^50,51 Would they take the drugs if truly aware of this, or of the potential severity of side effects, or the fact that they are more likely to die in hospital compared with patients who receive supportive care?³⁵ Pembrolizumab, an expedited immunotherapeutic for cancer, is the highest-grossing drug globally, with sales of $25 billion in 2023.⁵² It is also one of the EAMS drugs with potential safety concerns according to our analysis. Are desperate patients, likely unaware of the uncertainty surrounding the risk-benefit profile of EAMs drugs, simply a money-making machine for pharmaceutical companies?

Conclusion

There needs to be honest communication with patients about the risks of participating in expedited drug trials. Fast-track schemes offer benefits to industry but the safety and well-being of patients cannot be assured while regulatory bodies fail to insist on robust evidence and when trial outcomes fail to reflect patients’ concerns. Given that one of the 15 drugs we highlighted as having potential safety concerns was recently withdrawn, it would seem prudent for the safety of the others to be reviewed as soon as possible, particularly since another, remdesivir for the treatment of COVID-19, continues to be administered to substantial numbers globally. We recommend that preclinical studies make greater use of human-relevant approaches, that clinical studies use patient-centred outcomes and are more robustly designed, and that the MHRA requires companies to provide consistent data in their submissions and demands post-approval trials. Future reviews of the EAMS need to centre patients’ concerns. The adoption of such measures will benefit us all since fast-tracked drugs show every sign of becoming the norm.

	Drug	Trade name	Indication	Company
1	Dostarlimab^a	Jemperli	Endometrial cancer	GlaxoSmithKline
2	Glofitamab	Columvi	Relapsed or refractory diffuse large B-cell lymphoma	Roche
3	Cipaglucosidase alfa^a	Pombiliti	Late-onset Pompe disease	Amicus
4	Risankizumab	Skyrizi	Crohn's disease	AbbVie
5	Lutetium (177Lu) vipivotide tetraxetan	Pluvicto	Prostate cancer	Advanced Accelerator Applications
6	Efgartigimod alfa	Vyvgart	Myasthenia gravis	Argenx BVadd
7	Asciminib	Scemblix	Philadelphia chromosome-positive chronic myeloid leukaemia	Novartis
8	Voxelotor	Oxbryta	Sickle cell disease	Pfizer
9	Abrocitinib	Cibinqo	Severe atopic dermatitis	Pfizer
10	Avalglucosidase alfa	Nexviazyme	Pompe disease	Aventis
11	Berotralstat	Orladeyo	Hereditary angioedema	Biocryst
12	Nivolumab^a	Opdivo	Advanced/metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma cancer of the stomach or oesophagus	Bristol Myers Squibb
13	Tepotinib	Tepmetko	Advanced non-small cell lung cancer	Merck Serono
14	Nivolumab^a	Opdivo	Mesothelioma	Bristol Myers Squibb
15	Risdiplam	Evrysdi	Type 1 and type 2 spinal muscular atrophy	Roche
16	Pemigatinib	Pemazyre	Locally advanced or metastatic cholangiocarcinoma	Incyte Biosciences
17	Lumasiran	Oxlumo	Primary hyperoxaluria type 1	Alnylam
18	Avelumab	Bavencio	Bladder cancer	Merck Serono
19	Dupilumab	Dupixent	Children aged 6–11 with severe atopic dermatitis	Sanofi
20	Nivolumab	Opdivo	Unresectable advanced, recurrent or metastatic oesophageal cancer	Bristol Myers Squibb
21	Atezolizumab^a	Tecentriq	Unresectable hepatocellular carcinoma	Roche
22	Remdesivir	Veklury	Suspected or laboratory-confirmed SARS-CoV-2	Gilead
23	Isatuximab^a	Sarclisa	Adult patients with relapsed and refractory multiple myeloma	Aventis
24	Tafamidis	Vyndaqel	Transthyretin amyloidosis	Pfizer
25	Polatuzumab vedotin	Polivy	Relapsed/refractory diffuse large B-cell lymphoma	Roche
26	Avelumab	Bavencio	Advanced renal cell carcinoma	Merck Serono
27	Atezolizumab^a	Tecentriq	Extensive-stage small cell lung cancer	Roche
28	Atezolizumab	Tecentriq	Triple-negative breast cancer	Roche
29	Dupilumab	Dupixent	Patients aged 12–18 with severe atopic dermatitis	Sanofi
30	Volanesorsen	Waylivra	Familial chylomicronaemia syndrome	Akcea Therapeutics
31	Atezolizumab^a	Tecentriq	Metastatic non-squamous non-small cell lung cancer	Roche
32	Patisiran LNP	Onpattro	Hereditary transthyretin-mediated amyloidosis	Alnylam
33	Emicizumab	Hemlibra	Haemophilia A	Roche
34	Alectinib	Alecensa	Anaplastic lymphoma kinase-positive advanced non-small cell lung cancer	Roche
35	Dupilumab	Dupixent	Adult patients with severe atopic dermatitis	Sanofi
36	Glecaprevir/pibrentasvir	Mavyret and Maviret	Chronic hepatitis C (HCV) infection in adults	AbbVie
37	Atezolizumab	Tecentriq	Locally advanced or metastatic urothelial carcinoma	Roche
38	Pembrolizumab	Keytruda	Metastatic non-small cell lung cancer whose tumours express PD-L1 and who have not received prior systemic therapy and are negative for EGFR sensitising mutation and ALK translocation	Merck Sharp & Dohme
39	Venetoclax	Venclexta	Chronic lymphocytic leukaemia	AbbVie
40	Nivolumab	Opdivo	Hodgkin lymphoma	Bristol Myers Squibb
41	Pembrolizumab	Keytruda	Metastatic non-small cell lung cancer whose tumours express PD-L1 and whose disease has progressed on or after platinum-containing chemotherapy	Merck Sharp & Dohme
42	Nivolumab	Opdivo	Renal cell carcinoma	Bristol Myers Squibb
43	Nivolumab	Opdivo	Non-squamous non-small cell lung cancer	Bristol Myers Squibb
44	Osimertinib	Tagrisso	Locally advanced or metastatic epidermal growth factor receptor (EGFR) T790 M mutation-positive non-small-cell lung cancer	AstraZeneca
45	Sacubitril/valsartan	Entresto	Symptomatic heart failure and reduced ejection fraction	Novartis
46	Nivolumab	Opdivo	Advanced lung cancer (characterised by squamous non-small cells)	Bristol Myers Squibb
47	Pembrolizumab	Keytruda	Advanced melanoma	Merck Sharp & Dohme
48	Nivolumab	Opdivo	Advanced melanoma	Bristol Myers Squibb
	32 individual drugs		48 indications (of which 29 cancer)

Drug	No. of indications	Months since earliest EAMS SO granted, up to/including August 2024	Eudravigilance suspected adverse reaction reports	Eudravigilance suspected adverse reaction reports per month (per no. indications)	Yellow Card serious adverse drug reaction reports	Yellow Card serious adverse drug reaction reports per month (per no. indications)	Yellow Card fatalities	Yellow Card fatalities per month (per no. indications)	Black Triangle status	additional Risk Minimisation Measures (aRMMs)
Pembrolizumab	3	114	46,488	408 (136)	913	8 (3)	151	1 (0.4)	No	Yes
Nivolumab	9	111	38,970	351 (39)	1003	9 (1)	132	1 (0.1)	No	Yes
Sacubitril/valsartan	1	108	19,724	183	897	8	69	0.6	No	No
Osimertinib	1	105	8997	86	133	1	21	0.2	No	No
Venetoclax	1	96	2610	27	464	5	134	1.4	No	Yes
Atezolizumab	5	91	9595	105 (21)	209	2 (0.4)	34	0.4 (0.07)	No	Yes
Dupilumab	3	88	30,413	346 (115)	702	8 (3)	21	0.2 (0.08)	No	No
Glecaprevir/pibrentasivir	1	88	2182	25	40	0.4	4	0.04	No	No
Alectinib	1	84	2793	33	56	0.6	8	0.9	No	No
Emicizumab	1	80	1932	24	116	1.4	3	0.04	No	Yes
Volanesorsen	1	75	167	2	5	0.06	0	0	Yes	Yes
Patisiran-LNP	1	73	688	9	195	3	10	0.14	No	Yes
Tafamidis	1	63	1868	30	12	0.2	5	0.08	Yes	Yes
Avelumab	2	62	1044	17 (8)	203	3 (1.6)	34	0.5 (0.02)	Yes	Yes
Polatuzumab vedotin	1	62	1736	28	86	1.4	14	0.2	Yes	No
Isatuximab	1	57	429	7	28	0.5	16	0.3	Yes	Yes
Remdesivir	1	51	2451	48	106	2	18	0.3	Yes	No
Lumasiran	1	50	113	2	Missing	Missing	Missing	Missing	Yes	No
Risdiplam	1	47	726	15	50	1	8	0.2	Yes	No
Berotralstat	1	46	100	2	15	0.3	1	0.02	Yes	No
Pemigatinib	1	44	227	5	21	0.5	2	0.05	Yes	No
Abrocitinib	1	43	669	15	41	1	1	0.02	Yes	Yes
Avalglucosidase alfa	1	42	46	1	Missing	Missing	Missing	Missing	Yes	Yes
Cipaglucosidease alfa	1	39	15	0.38	2	0.05	0	0	Yes	Yes
Tepotinib	1	38	118	3	16	0.4	2	0.05	Yes	No
Asciminib	1	32	267	8	Missing	Missing	Missing	Missing	Yes	No
Voxelotor	1	31	5967	192	Missing	Missing	Missing	Missing	Yes	No
Risankizumab	1	29	2732	94	103	3.5	5	0.17	No	No
Lutetium 177Lu	1	29	612	21	8	0.3	2	0.07	Yes	No
Efgartigimod alfa	1	27	305	11	5	0.7	0	0	Yes	No
Glofitamab	1	14	34	2	15	1	2	0.14	Yes	Yes
Dostarlimab	1	14	119	8	21	1.5	1	0.07	Yes	Yes
Total 32 drugs									20 Black Triangle	15 aRMMs

Footnotes

Declarations

Competing interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no external financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable: this study does not involve human or animal participants. It is an analysis of publicly available data.

Guarantor

Pandora Pound is the guarantor for this paper. She accepted full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish.

Contributorship

Kathy Archibald conceived the idea for the paper. Pandora Pound conducted the analyses and drafted the paper and revisions. Rebecca Ram and Kathy Archibald critically reviewed the paper for intellectual content and accuracy. All three authors approve the final version and agree to be accountable for all aspects of the work and to resolve any issues related to its accuracy or integrity.

Provenance

Not commissioned; peer-reviewed by Joel Lexchin.

Consent to participate

Not applicable: this study does not involve human participants.

Consent for publication

Not applicable.

Data availability

The data and materials necessary to reproduce the findings reported in this manuscript are available at .

ORCID iDs

Pandora Pound

Rebecca Ram

Kathy Archibald

References

MHRA. Guidance for Applicants for the Early Access to Medicines Scheme (EAMS) - Step II. Published 2014. Accessed June 30, 2024. https://assets.publishing.service.gov.uk/media/5a7da50ded915d2acb6ed481/guidance_on_applying_for_a_scientific_opinion__including_the_pre-submission_meeting.pdf.

MHRA. Early Access to Medicines Scheme - Information for Applicants. MHRA website. 2024. Accessed November 11, 2024. https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eams#post-marketing-authorisation-eams-period-and-winding-down-period.

Demasi

. From FDA to MHRA: are drug regulators for hire? Br Med J 2022;377:1–4.

Beakes-Read

Neisser

Frey

, et al. Analysis of FDA’s accelerated approval program performance December 1992–December 2021. Ther Innov Regul Sci 2022;56(5):698–703.

Fleming

. Critics wary over plans to fast-track UK drug-approval model. Nat Index 2023. doi: https://doi.org/10.1038/d41586-023-02426-7.

Liu

ITT

Kesselheim

Cliff

ERS

. Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. JAMA 2024;331(17):1471.

Gyawali

Rome

Kesselheim

. Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study. Br Med J 2021;374:1–8.

Koole

Huisman

Timmers

, et al. Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications. Lancet Oncol 2024;25(3):e126–e135.

Scavone

Di Mauro

Mascolo

, et al. The new paradigms in clinical research: from early access programs to the novel therapeutic approaches for unmet medical needs. Front Pharmacol 2019;10(February):1–8.

10.

Chen

. FDA increasingly approves drugs without conclusive proof they work. PBS news website. 2018. Accessed August 12, 2024. https://www.pbs.org/newshour/amp/health/fda-increasingly-approves-drugs-without-conclusive-proof-they-work.

11.

Banzi

Gerardi

Bertele'

, et al. Approvals of drugs with uncertain benefit-risk profiles in Europe. Eur J Intern Med 2015;26(8):572–584.

12.

Lupkin

. Drugmakers are slow to prove medicines that got a fast track to market really work. NPR Radio website. July 2, 2022. https://www.npr.org/sections/health-shots/2022/07/22/1110830985/drugmakers-are-slow-to-prove-medicines-that-got-a-fast-track-to-market-really-wo.

13.

Chary

. Expedited drug review process: fast, but flawed. J Pharmacol Pharmacother 2016;7(2):57–61.

14.

Mostaghim

Gagne

Kesselheim

. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. Br Med J 2017;358:1–6.

15.

Lexchin

. Post-market safety warnings for drugs approved in Canada under the notice of compliance with conditions policy. Br J Clin Pharmacol 2015;79(5):847–859.

16.

Graham

Campen

Hui

, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365(9458):475–481.

17.

Patil

. Early access programs: benefits, challenges, and key considerations for successful implementation. Perspect Clin Res 2016;7(1):4.

18.

Ringger

Wissinger

. EAMS evidence: a key player in drug value proposition and NICE approval? AmerisourceBergen. May 8, 2024. Accessed July 18, 2024. https://www.amerisourcebergen.com/insights/manufacturers/htaq-summer-2024-eams-evidence.

19.

Chanda

. What have we learned from the UK EAMS process? Remap. 26 January, 2023. https://remapconsulting.com/early-access/what-have-we-learned-from-the-uk-eams-process/.

20.

BioIndustry Association, Association of the British Pharmaceutical Industry. The Early Access to Medicines Scheme. 2014. https://www.abpi.org.uk/media/dfikg1ka/early_access_to_medicines_scheme.pdf . 2014.

21.

Strategy&. The Early Access to Medicines Scheme (EAMS) - An Independent Review. 2015. https://assets.publishing.service.gov.uk/media/5a80a6c9ed915d74e33fba3d/eams-review.pdf.

22.

O’Connor

McDonald

Lam

. Earlier patient access – the UK early access to medicines scheme (EAMS). J Med Access 2017;1(1):maapoc.0000009.

23.

Brazil

. Just out of reach: why the UK must rethink its barriers to novel medicines. Pharm J. 17 November, 2020. https://pharmaceutical-journal.com/article/feature/just-out-of-reach-why-the-uk-must-rethink-its-barriers-to-novel-medicines.

24.

Kiani

Metcalf

Morris

, et al. 10 Years of EAMS. Reflections on a decade of securing early access to innovative medicines for rare disease patients. Natl Heal Exec Mag. 2024 (July/August). https://mag.nationalhealthexecutive.com/?m=62920&i=826014&p=18&ver=html5.

25.

MHRA. Early access to medicines scheme: expired scientific opinions. Gov.uk website. 2024. Accessed August 21, 2024. https://www.gov.uk/government/publications/early-access-to-medicines-scheme-expired-scientific-opinions.

26.

Electronic Medicines Compendium. About eMC. Electronic Medicines Compendium website. 2024. Accessed August 23, 2024. https://www.medicines.org.uk/emc/about-the-emc.

27.

Alshammari

Devadasu

Rathnam

. Comparison of the safety information on drug labels in three developed countries: the USA, UK and Canada. Saudi Pharm J 2017;25(8):1103–1107.

28.

Specialist Pharmacy Services. Risk Minimisation Measures. Specialist Pharmacy Services website. 2024. Accessed August 23, 2024. https://www.sps.nhs.uk/articles/including-medicines-with-risk-minimisation-measures-rmm-in-pgds/.

29.

Francisca

RDC

Baba

Hoeve

, et al. Introduction or discontinuation of additional risk minimisation measures during the life cycle of medicines in Europe. Drug Saf 2021;44(1):63–72.

30.

Palleria

Leporini

Chimirri

, et al. Limitations and obstacles of the spontaneous adverse drugs reactions reporting: two “challenging” case reports. J Pharmacol Pharmacother 2013;4(1_suppl):S66–S72.

31.

MHRA. Yellow Card: please help to reverse the decline in reporting of suspected adverse drug reactions. MHRA website. 2019. Accessed November 19, 2024. https://www.gov.uk/drug-safety-update/yellow-card-please-help-to-reverse-the-decline-in-reporting-of-suspected-adverse-drug-reactions.

32.

MHRA. Class 2 Medicines Recall: Pfizer Limited, Oxbryta 500 mg Tablets (voxelotor), EL(24)A/44. MHRA website. 2024. Accessed October 28, 2024. https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-pfizer-limited-oxbryta-500mg-tablets-voxelotor-el-24-a-slash-44#brief-description-of-the-problem.

33.

Lexchin

. Information about confirmatory studies required for new drugs conditionally approved by Health Canada: a cross-sectional study. PLoS One 2022;17(10 October):1–9.

34.

Prasad

Kim

Burotto

, et al.. The strength of association between surrogate end points and survival in oncology. JAMA Intern Med 2015;175(8):1389.

35.

Wise

. Cancer drugs, survival, and ethics. Br Med J 2016;355(Nov 9):1–4.

36.

Sandman

Liliemark

. From evidence-based to hope-based medicine? Ethical aspects on conditional market authorization of and early access to new cancer drugs. Semin Cancer Biol 2017;45:58–63.

37.

Booth

Eisenhauer

Gyawali

, et al. Progression-free survival should not be used as a primary end point for registration of anticancer drugs. J Clin Oncol 2024;41(32):4968–4972.

38.

Mertz

Benjamin

Girvalaki

, et al. Progression-free survival and quality of life in metastatic breast cancer: the patient perspective. The Breast 2022;65:84–90.

39.

Ewart

Apostolou

Briggs

, et al. Performance assessment and economic analysis of a human liver-chip for predictive toxicology. Commun Med 2022;2(154):1–16.

40.

Watkins

. DILIsym: quantitative systems toxicology impacting drug development. Curr Opin Toxicol 2020;23-24:67–73.

41.

Smith

Rowe

Watkins

, et al. Mechanistic investigations support liver safety of ubrogepant. Toxicol Sci 2020;177(1):84–93.

42.

Passini

Britton

, et al. Human in silico drug trials demonstrate higher accuracy than animal models in predicting clinical pro-arrhythmic cardiotoxicity. Front Physiol 2017;8(SEP):1–15.

43.

Mirams

Yoshinaga

, et al. General principles for the validation of proarrhythmia risk prediction models: an extension of the CiPA in silico strategy. Clin Pharmacol Ther 2020;107(1):102–111.

44.

Stephen Maddocks (MHRA). Personal communication, 11th September 2024.

45.

Kim

Prasad

. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival. JAMA Intern Med 2015;175(12):1992.

46.

House of Commons Health Committee. The Influence of the Pharmaceutical Industry. 2005. https://publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf .

47.

nufuture. How the Labour Government Could Impact the UK Life Sciences Industry. nufuture website. 2024. Accessed October 28, 2024. https://www.nufuture.co.uk/blog/view/209/how-the-labour-government-could-impact-the-uk-life-sciences-industry.

48.

Naci

Murphy

Woods

, et al. Population-health impact of new drugs recommended by the National Institute for Health and Care Excellence in England during 2000–20: a retrospective analysis. Lancet 2024;405(10472):50–60.

49.

Thomas

Chancellor

Micklus

, et al. Clinical Development Success Rates and Contributing Factors 2011–2020. https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf?_ga=2.13995511.1342578936.1631707466-2128155138.1631707466 . 2021.

50.

Morgan

Ward

Barton

. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol 2004;16(8):549–560.

51.

Weeks

Catalano

Cronin

, et al. Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012;367(17):1616–1625.

52.

Philippidis

. Top 10 best selling drugs. Genet Eng Biotechnol News. June 2024. https://www.genengnews.com/topics/drug-discovery/top-10-best-selling-drugs/.

The UK's Early Access to Medicines Scheme 10 years on: an evaluation using publicly available data

Abstract

Objectives

Design

Setting

Participants

Main Outcome Measures

Results

Conclusions

Keywords

Introduction

Methods

Preclinical studies

Safety

Data extraction

Results

Information recorded in the PAR

Study design

Study outcomes

Ongoing studies and monitoring

Preclinical studies

Safety

Discussion

Conclusion

Footnotes

Competing interests

Funding

Ethical approval

Guarantor

Contributorship

Provenance

Consent to participate

Consent for publication

Data availability

ORCID iDs

References