Registering with the Care Quality Commission (CQC) is compulsory for all providers of health and social care in England, not just those as part of the NHS, and it is against the law not to do so. The provider can be an individual, a partnership or an organisation and knowing which of these legal entities applies is important. The CQC’s aims are to set standards, ensuring that they are met and, where possible, improved upon. With a growing number of non-health care organisations, these standards exist in order to protect users and improve their experiences of health and social care.

Providers should be prepared to register by understanding what is involved in the application process, what information should be given and how much it costs. Here are a few pointers to give providers an idea of how to get ready for registration.

Getting the right checks
Applying for a CQC-countersigned DBS check is the first absolute must when it comes to preparing. This covers individuals who carry on or manage a care service, all partners, and registered managers. To avoid common mistakes that will hinder registration, visit the CQC website.

Stating the purpose
Providers should be in a position to describe what they do, where they do it and who they do it for so that they can write this in their statement of purpose. This statement also includes some of the details listed below.

Understanding ‘regulated activities’
Organisations need to be aware of the 14 health care services that are regulated by the CQC and then consider which of these ‘regulated activities’ they will continue with.

Having a registered manager
Alongside this, at least one registered manager must be in place to manage the regulated activities. This person must work routinely in the activities and have some legal responsibility in relation to their position. The new registered manager should apply at the same time as the new provider.

Who can be contacted
It is important that the organisation has a nominated individual who can be contacted about the regulated activities and has some supervision responsibilities for these. It is advised that this person is not the registered manager if it can be avoided.

Where the activities take place
A regulated activity might be carried out as one service but at many locations. In this case, the locations must be clearly stated as this is a declaration about compliance with the relevant activity standards at each location.

Supporting the application
Providers need to know how to get hold of policies that can support their application, such as those on Management, Safeguarding and Governance. There will also need to be some evidence of the registered manager’s position.

Providing references
Individual providers need to supply details of employment history and medical fitness, whilst
partnerships need to supply the same information for all partners. However, organisations do not need to supply this information for their nominated individual.

Covering the fees
Applicants need to be aware of the fees involved as this will need to be paid on the same date each year. The fee amount depends on the type of provider and how many people benefit from the service.

Applications for registration are made online via the CQC website, where there are also a number of guidance documents to help with registration.

Registering with the CQC may seem like a lengthy and cumbersome procedure. However, it is worth bearing in mind that they are looking for ‘fitness’ and compliance with the relevant regulations, and if applicants are found to be non-compliant they will have their application refused. There are many conditions that the CQC needs to consider so it is worth taking the time to prepare and get registration right first time.

With the Lundbeck Decision, the European Commission’s (the “Commission” and the “Decision,” respectively) ended its ten-year investigation on reverse payment settlements and found that the Danish pharmaceutical company, Lundbeck, and four generics producers had concluded anticompetitive agreements, in breach of Article 101 of the Treaty on the Functioning of the European Union (the “TFEU”).[2]  According to the Commission, this would have allowed Lundbeck to keep the price of its drug citalopram artificially high.

On 8 September 2016, the EU General Court (the “General Court”) confirmed that certain pharmaceutical “reverse payment settlements” can constitute a breach of the EU antitrust rules (the “Ruling”).[3]  Under the so-called “reverse payment settlement agreements”, an original pharmaceutical manufacturer, or “originator”, settles an IP challenge from a manufacturer of generics by paying the latter to stay out of the market.

II. Background

According to its website, Lundbeck is “ a global pharmaceutical company specializing in psychiatric and neurological disorders”.[4]  These include medicinal products for treating depression .[5]  From the late 1970s, Lundbeck developed and patented an antidepressant medicinal product containing the active ingredient ‘citalopram’.[6]

After its basic patent for the citalopram molecule had expired, Lundbeck only held a number of the so-called “process” patents, which, according to the Commission, provided only “a more limited protection”.[7]  In particular, Lundbeck had filed a salt crystallisation process patent.[8]

According to the Commission, in 2002, Lundbeck concluded six agreements concerning citalopram with four entities active in the production or sale of generic medicinal products, namely Generics (UK), Alpharma, Arrow and Ranbaxy.  Always according to the Commission, in return for the generic undertakings’ commitment not to enter the citalopram market, Lundbeck paid them substantial amounts .[9]  In addition, Lundbeck purchased stocks of generic products for the sole purpose of destroying them, and offered guaranteed profits in a distribution agreement.[10]

In October 2003, the Commission was informed of the existence of the agreements at issue by the Konkurrence- og Forbrugerstyrelsen (the “KFST”, the Danish authority for competition and consumers).[11]  The Commission took over the case and, by decision of 19 June 2013, made the following findings:  (i) Lundbeck and the generic undertakings were at least potential competitors;[12] and (ii) the agreements at issue constituted restrictions of competition by object, in breach of the prohibition of anticompetitive agreements provided for under Article 101 TFEU.[13]  The Commission imposed a total fine of €93.7 million on Lundbeck and € 52.2 million on the generic undertakings.  The Commission took into consideration the length of its investigation (almost ten years) as a mitigating circumstance which led to fine reductions of 10%.[14]  Lundbeck and the generic undertakings brought actions before the General Court, seeking the annulment of the Commission’s decision.  The Court dismissed the actions brought by Lundbeck and the generic undertakings and confirmed the fines imposed on them by the Commission.[15]

After the Lundbeck case, in 2013 and 2014, the Commission imposed fines on companies in two other reverse settlement investigations – one concerning fentanyl, a pain-killer[16], and the other concerning perindopril, a cardiovascular medicine.[17]  The Fentanyl decision was not appealed.  Several appeals against the Servier decision are pending before the General Court.[18]  In 2016 in the Paroxetine Investigation, the UK Competition and Market Authority issued infringement decisions to a number of companies regarding ‘pay-for-delay’ agreements over the supply of an antidepressant.[19]

In addition, since 2009, the Commission has been continuously monitoring patent settlements in order to identify settlements which it regards as “potentially problematic” from an antitrust perspective, namely those that limit generic entry against a value transfer from an originator to a generic company.  The latest report was published in December 2015.[20]

III. The Ruling

First, like the Commission, the Court analysed whether Lundbeck and the generic manufacturers concerned were indeed potential competitors at the time the agreements at issue were concluded.[21]  The General Court made the following findings in this regard:

In order for an agreement to restrict potential competition, it must be established that, had agreement not been concluded, the competitors would have had “real concrete possibilities” of entering that market.[22]  The Court held that the Commission had carried out a careful examination, as regards each of the generic undertakings concerned, of the real concrete possibilities they had of entering the market.  In doing so, the Commission relied on evidence such as the investments already made and the steps taken in order to obtain a marketing authorisation[23]

Moreover, the Court noted that in general the generic undertakings had several real concrete possibilities of entering the market at the time the agreements at issue were concluded.[24]  Those possible routes included, inter alia, launching the generic product with the possibility of having to face infringement proceedings brought by Lundbeck (i.e., the so-called launching ‘at risk’).[25]  More precisely, the General Court was of the view that “the presumption of validity cannot be equated with a presumption of illegality of generic products validly placed on the market which the patent holder deems to be infringing the patent”.[26]  Consequently, the Court, continued, “’at risk’ entry is not unlawful in itself”.[27]

As rightly noted by commentators, these considerations introduce a further layer of complexity in the already intricate relationship between EU Competition law and IP law. In addition, since the right to exclude lies at the core of any IP right, it can be argued that the Commission’s findings infringes Article 345 TFEU, according to which “[t]he Treaties shall not prejudice the rules in the Member States governing the system of property ownership”.  Thus, Ibañez Colomo has noted that “Lundbeck departs from the principle whereby an agreement is not restrictive by object where it remains within the substantive scope of an intellectual property right”.[28]  This principle would derive from the Eraw-Jacquery,[29] Coditel II,[30] BAT v. Commission and Nungesser[31] rulings of the ECJ.  Ibañez Colomo’s point becomes particularly clear at para. 335 of the (Lundbeck) Ruling where the General Court expressly noted that “even if the restrictions set out in the agreements at issue fall within the scope of the Lundbeck patents – that is to say that the agreements prevented only the market entry of generic citalopram deemed to potentially infringe those patents by the parties to the agreements and not that of every type of generic citalopram – they would nonetheless constitute restrictions on competition ‘by object’ since, inter alia, they prevented or rendered pointless any type of challenge to Lundbeck’s patents before the national courts, whereas, according to the Commission, that type of challenge is part of normal competition in relation to patents (recitals 603 to 605, 625, 641 and 674)”.[32]

Second, the Court analysed whether the Commission was entitled to conclude that the agreements at issue constituted a restriction of competition by object, a point to which we will turn next.

IV. Conclusions:  On Reverse Payments as Restrictions of Competition by Object

The Lundbeck ruling brings a number of what Donald Rumsfeld would probably refer to as “known unknowns”, that is things we know we do not know, in relation to reverse payment settlements.[33]  Indeed, the findings of the Lundbeck ruling can be summarised as follows:

1. There are certain patent settlements which are likely to be considered compatible with Article 101 TFEU. This is the case of settlements:

   a. In which, in the words of the General Court, “(i) payment is linked to the strength of the patent, as perceived by each of the parties; (ii) [payment] is necessary in order to find an acceptable and acceptable and legitimate solution in the eyes of two parties and (iii) [payment] is not accompanied by restrictions intended to delay the market entry of generic”.[34]

   The inclusion of the word “and” is worrying.  The requirements set out in the preceding paragraph should be alternative and not cumulative.  Otherwise for a settlement to be lawful it must not delay entry (which probably is enough, in and of itself, to avoid the antitrust concern, namely, a delayed entry of generics) and it must be necessary (i.e., it probably needs to meet the requirements of an ancillary restraints defence, more on which below) and the payment might be linked to the strength of the patent “as perceived by each of the parties”.  Such an intrinsically subjective requirement appears to the writer as particularly complicated to administrate and at odds with the objective nature of Article 101(1) TFEU.  It would appear that the Court is encouraging conversations such as the following: “let’s settle, but only if we can ensure the settlement reflects (and comes across as reflecting) your and my perception of the strength of the patent (and a number of other cumulative requirements my lawyers and I need to meet), otherwise we might have an antitrust concern”.

   b. Qualifying for an ancillary restraints defence. e., settlements in relation to which the parties to the settlement (for the burden of proof will be on them) can demonstrate they are objectively necessary and proportionate in order to defend their IP rights.[35]

2. There are certain patent settlements which are likely to be considered incompatible with Article 101 TFEU as restrictions of competition by object. The ruling is not particularly clear in this regard.

   a. Aliteral reading of paragraph 334 of Lundbeck could potentially make “problematic” each patent settlement “where they [provide] for the exclusion from the market of one of the parties, which was at the very least a potential competitor of the other party, for a certain period, and where they were accompanied by a transfer of value from the patent holder to the generic undertaking liable to infringe that patent (‘reverse payments’).”

   b. A more holistic reading of Lundbeck would confine the Commission’s finding to the facts of the case. Even though it is difficult to pinpoint what the court considered to be the decisive factors when stating that a reserve settlement constituted a restriction by object, the following factors appear to have been relevant:

   1. The allegedly “disproportionate nature” of such payments “combined with other factors, such as the fact that the amounts of those payments seemed to correspond at least to the profit anticipated by the generic undertaking”.[36] Referring to the US Supreme Court ruling in Actavis,[37] the Court indicated that “the size of a reverse payment may constitute an indicator of the strength or weakness of a patent”.[38]  According to the Commission “the higher the originator undertaking estimates the chance of its patent being found invalid or not infringed, and the higher the damage to the originator undertaking resulting from successful generic entry, the more money it will be willing to pay the generic undertaking to avoid that risk”.[39]
   2. Indeed, the correspondence between the amount of the payment that seemed and the profit anticipated by the generic undertakings if they had entered the market.[40] According to the Commission “the value which Lundbeck transferred, took into consideration the turnover or profit the generic undertaking expected if it had successfully entered the market”. [41]
   3. The absence of provisions allowing the generic undertakings to launch their product on the market upon the expiry of the agreement without having to fear infringement actions brought by Lundbeck.[42]
   4. The presence in those agreements of restrictions going beyond the scope of Lundbeck’ s patents,[43] such as restrictions with regard to citalopram products that could have been produced in a non-infringing manner.[44]
   5. According to the Court, “the agreement at issue transformed the uncertainty in relation to the outcome of such litigation into the certainty that the generics would not enter the market which may also constitute a restriction on competition by object when such limits do not result from an assessment, by the parties of the merits of the exclusive right at issue, but rather from the size of the reverse payment which, in such case, overshadows that assessment and induces the generic undertaking not to pursue its independent efforts to enter the market”.[45] The generics thus no longer had an incentive to continue their independent efforts to enter the market[46].

3. There are certain patent settlements which (presumably) are considered to be incompatible with Article 101 TFEU as restrictions of competition by their effects. Hic sunt dracones.  More precisely, given that none of the pay-for-delay decisions dealt with by the  Commission conducted an effects analysis, we are left without guidance as to how that analysis will be conducted.  Again, a known unknown.  The Commission’s ten-year investigation on reverse payment settlements has not shed light to how to conduct an effects analysis under Article 101(1) TFEU.  We are left, perhaps, with the findings of the US Supreme Court in Actavis, according to which, “the likelihood of a reverse payment bringing about anticompetitive effects depends upon its size, its scale in relation to the payer’s anticipated future litigation costs, its independence from other services for which it might represent payment and the lack of any other convincing justification.  The existence and degree of any anticompetitive consequences may also vary among industries”.[47]

Moreover, to the extent that the case for restrictions of competition by object is administrability, this author cannot but note that the Lundbeck ruling does not constitute a positive evolution.  The General Court noted that “it is established that certain collusive behaviour […] may be considered so likely to have negative effects, in particular on the price, quantity or quality of the goods and services, that it may be considered redundant, for the purposes of applying Article 101 TFEU to prove that they have actual effects on the market”.[48]  However, the Decision has 464 pages.  Given that the Fentanyl and Servier decisions occupy 147 and 813 pages, respectively, in investigations that lasted for almost ten years, 27 months and 5 years (again, respectively), one cannot but wonder whether the Commission’s resources would have been better spent analysing the actual effects of the agreement and not defending a legal category.

*                                              *                                              *

   [1]   Pablo Figueroa and Suzanne Nusselder are, respectively, a senior associate and a trainee with Gibson, Dunn & Crutcher LLP’s Brussels office.  In addition, Pablo Figueroa is a visiting Lecturer at Queen Mary University (London, United Kingdom), a guest lecturer at Oxford University and a guest lecturer and senior external researcher at Deusto Translaw Research Group.  The author is grateful to Fredrik Löwhagen, from Linklaters, Rais Amils, from Clifford Chance, Paulius Mencas from Valiunas Ellex and Professors Herbert Hovenkamp, Stephen Calkins and Pablo Ibañez, and to Rakhal Zamal, trainee at the Brussels office of Gibson Dunn & Crutcher LLP, for their comments.  Any remaining mistake is of the authors.  The views in this article do not represent those of Gibson, Dunn & Crutcher LLP or its clients.

   [2]   Commission Decision C(2013) 3803 of 19 June 2013 relating to a proceeding under Article 101 [TFEU] and Article 53 of the EEA Agreement, Case AT.39226 — Lundbeck (the “Decision”).

   [3]   See T-472/13 Lundbeck v. Commission [NYR] (the “Ruling”).

   [4]   See, for more detail, http://www.lundbeck.com/global/about-us.

   [5]   See Ruling, at para. 1.

   [6]   See Ruling, at para. 16.

   [7]   See European Commission Press Release IP/13/563, 19 June 2013, available at:  http://europa.eu/rapid/press-release_IP-13-563_en.htm?locale=en.  It should be recalled, in this regard, that, according to Article 27 of the TRIPS (WTO) Agreement, “patents shall be available for any inventions, whether products or processes, in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application“.

   [8]   See Ruling, at para. 20.

   [9]   See Ruling, at paras. 26; 35; 39; 42-43 and 47-48.

  [10]   See Ruling, at para. 26; 35; 39; 42-43; 47-48.

  [11]   See Danish Competition and Consumer Authority Press Release 1120-0289-0039/VIS/SEK, 28 January 2004 , available at: http://www.kfst.dk/Afgoerelsesdatabase/Konkurrenceomraadet/Styrelsesafgoerelser/2004/Undersoegelse-af-Lundbeck?tc=E538038EB1E04A96B9964BE4C0F85F46 (Only available in Danish)

  [12]   See Decision at paras. 610 ff.

  [13]   See Decision at paras. 647 ff.

  [14]   See Decision, at paras. 1306, 1349 and 1380.

  [15]   See Ruling, Operative part.

  [16]   See European Commission Press Release IP/13/1233, 10 December 2013, available at: http://europa.eu/rapid/press-release_IP-13-1233_en.htm.

  [17]   See European Commission Press Release IP/14/799, 9 July 2014, available at: http://europa.eu/rapid/press-release_IP-14-799_en.htm.

  [18]   See OJ L C-462/25, 22.12.2014

  [19]   See Case CE/9531-11 Paroxetine 12 February 2016.  For a comment on the case see Ezrachi, A., EU Competition Law: An Analytical Guide to the Leading Cases, 5^th Edition, Bloomsbury, 2016, 396

  [20]   See, European Commission, “6th Report on the Monitoring of Patent Settlements (period: January-December 2014)”, 2 December 2015, available at:  http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/patent_settlements_report6_en.pdf.

  [21]   See Ruling.  The General Court separately analysed each agreement.  See, inter alia, in relation to Lundbeck and Merck, para. 225; in relation to Lundbeck and Arrow, paras. 266-270, in relation to Lundbeck and Alpharma, para. 290 and, in relation to Lundbeck and Ranbaxy, para. 330.

  [22]   See Ruling, at para. 100.  See further Case T-360/90 E.ON Ruhrgas and E.ON v Commission, at para. 98.

  [23]   See Ruling, at para. 129.

  [24]   See Ruling, at para. 97.  See further Decision, at para. 635.

  [25]   See Ruling, at paras. 121.

  [26]   See Ruling, at paras. 97.

  [27]   See Ruling, at para. 122.

  [28]   See Ibañez Colomo, P., “GC Judgment in Case T-472/13, Lundbeck v Commission: on patents and Schrödinger’s cat”, at Chillin’ Competition, 13 September 2016, available at:  https://chillingcompetition.com/2016/09/13/gc-judgment-in-case-t-47213-lundbeck-v-commission-on-patents-and-schrodingers-cat/.

  [29]   See Case 27/87 SPRL Louis Erauw-Jacquery v La Hesbignonne SC.

  [30]   See Case 262/81 Coditel SA, Compagnie generale pour la diffusion de la television, and others v Cine-Vog Films SA and others.

  [31]   See Case 258/78 Nungesser v Commission.

  [32]   See Ruling, at paragraph. 335.

  [33]   See Rumsfeld, D., Known Unknown:  A Memoir, Sentinel, 2011.

  [34]   See Ruling, at para. 350.

  [35]   See Ruling, at paras. 451 ff, in particular, at paras. 458 and 460.

  [36]   See Ruling, at paras. 354; 355.

  [37]   See Federal Trade Commission v. Actavis, 570 US (2013).

  [38]   See Ruling, at paragraph 353.

  [39]   See Decision, at para. 640.

  [40]   See Ruling, at paras. 354; 383; 414.

  [41]   See Decision, at paras. 6; 788; 824; 874; 962; 1013; 1087.

  [42]   See Ruling, at paras. 354; 383; 410.

  [43]   See Ruling, at paras. 354; 383.

  [44]   See Decision para. 693.

  [45]   See Ruling, at para. 336.

  [46]   See Ruling, at paras. 355; 360.

  [47]   See Federal Trade Commission v Actavis 570 US 2013.

  [48]   See Ruing, at para. 341.

Back in the early part of 2016 I looked at how changes to the costs rules since April 2013 had benefitted Defendants at the expense of Claimants. I pointed out that many had commented that successive governments had been increasingly pro-Defendant in their reforms.

The announcement earlier in 2016 by the then Health Minister, Ben Gummer, seemed to be consistent with that view insofar as Mr Gummer had announced that the government intended to bring in fixed costs for all litigation cases worth £250,000 or less, including clinical negligence, and these reforms were to be introduced in October 2016.

Well, the long awaited consultation on fixed costs initially set for the end of 2015, then put back to early 2016, is still nowhere to be seen!

However, recent news reports seem to suggest that the government has reviewed the idea of fixed costs for clinical negligence cases and now intends to set the level for inclusion in the fixed costs regime for clinical negligence cases of £25,000 or less (not £250,000).

What will actually happen?

The consultation paper is still awaited and the government will need to review the outcome of the consultation before proceeding to introduce their reforms.

The national Law Society has welcomed news of some reversal of thinking by the government, but the Law Society has highlighted the difficulties in imposing fixed costs in clinical negligence cases where complex medical issues are involved. Such a regime should only apply to modest value claims of £25,000 or less where liability has been admitted.

Equality before the law is a fundamental principle behind our justice system. Fixed costs will save Defendants money at the expense of Claimants. In cases against the NHS, the State is ultimately responsible for paying successful Claimants and for paying for the defence in claims against NHS Trusts.

The State has deep pockets. Hence, the playing field is not equal now and creating further costs obstacles for Claimants will make the current lack of equality even worse.

Let us not forget that legal aid for clinical negligence cases was removed in April 2013, save for a small minority of cases. No legal aid and the introduction of fixed costs – do you now wonder why I title this commentary, “Stacking the Deck – Again!”

 

New GMC Guidelines

As of June 2016, new guidance from the GMC regarding doctors carrying out cosmetic procedures will come into force. The new guidelines will highlight the need for accountability from the doctors involved in the treatment, and consideration of patient safety at all times. Various cosmetic procedures have come under fire in the last few years, with the 2010 PiP implant scandal one of the industry’s better documented failings. Despite the bad press, the cosmetic sector is a rapidly emerging market which is now widely available, and prospective patients are faced with more options than ever before.

In the wake of recent problems, Professor Sir Bruce Keogh, National Medical Director of NHS England, has led an independent review of the cosmetic industry. This review was tasked with identifying the current risks associated with cosmetic interventions and how best to protect the public in this area. As a result of the review, the GMC’s new guidance for doctors carrying out cosmetic procedures will come into force in the summer. The guidelines apply to all cosmetic procedures, including both surgical and non-surgical treatments, with the aim of improving standards and making the ethical responsibilities of the industry clear to all doctors who work within it.

Thankfully, the majority of doctors in this field already practise ethically and to a high standard. However, the cosmetics sector is not without examples of unsafe practices, poor follow-up care and inappropriate marketing campaigns. The new guidelines are in place to protect patients from these more unsavoury elements, and to hold any unethical practitioners fully responsible for their actions. I will now take a look at some key areas in the new guidelines, and what they mean for practitioners.

Responsible Advertising and Marketing

One of the major changes coming in the summer will be the tighter regulation of advertisements. Though cosmetic surgery adverts will not be banned, as some campaigners have called for, they will have to obey certain rules. The adverts are no longer allowed to entice potential customers with cut-price deals, and marketing campaigns can no longer offer cosmetic surgery as a prize in a competition. These outlawed practices are designed to encourage people to make quick decisions without considering all of the implications – something that the new guidelines want to put an end to in the interest of patient safety. In addition, adverts are not allowed to make any unjustifiable claims. Patients must be presented with accurate information, and able to make their decision in their own time without feeling under any pressure to respond to outside influences.

Time for Reflection

Linked to the implications of the advertising guidelines is the rule that patients must be able to make fully informed decisions about prospective cosmetic procedures, and able to change their mind at any point. This means that patients cannot be rushed into their treatment; they must be able to reflect on their choice given all of the available information, including any associated risks. Under no circumstances should practitioners encourage patients to undergo these procedures lightly or without serious consideration.

It is often thought that a significant proportion of patients seeking cosmetic procedures may be appropriately regarded as vulnerable; from June, doctors will be required to consider the psychological needs of their patients, including whether the patient would benefit from a referral to another professional colleague. This is particularly important when it comes to the treatment of young people; their mental health in relation to the procedures will need to be fully evaluated, and sufficient time needs to be given to them to ensure that their treatment is right.

Practically, the amount of time given to a patient for their decision will depend on their specific circumstances. These include the invasiveness of the surgery, as well as its complexity, permanence, and risks. Above all, the patient needs to know that they can change their mind at any point; they should not feel pressured by advertising or by medical professionals themselves.

Fully Informed Consent

An integral part of the new guidelines is the requirement for the patient’s fully informed consent. It will be the responsibility of the doctor carrying out the cosmetic procedure to personally discuss the procedure with the patient and obtain their consent. This cannot, under any circumstances, be delegated to someone else. These is no longer any place for prescribing injectable cosmetic medicines over the telephone, via video link, online or at the request of others; the doctor may only prescribe treatment in person, and must carry out a physical examination of the patient first. In addition, the doctor must be satisfied that the patient’s request for cosmetic intervention is entirely voluntary, and not the result of any sort of external pressure.

Continuity of Care

As already mentioned, doctors must ensure that patients are fully informed as to the process and risks of the procedure, but the patient must be given information to help them beyond the treatment itself. This information includes contact details for the right person to get in touch with in the unfortunate scenario that something goes wrong with their procedure, to ensure that they are fully supported for as long as they need to be.

Patient Safety

A couple of final points of note are that doctors will be required to make full and accurate records of  all consultations with their patients, and that doctors must identify and immediately act on any patient safety concerns, including fully contributing to programmes designed to monitor quality and outcomes of the treatment. All of this is to make sure that there is never any lack of information regarding the procedure, meaning that any issues or complications can be acted upon quickly and correctly.

Final Thoughts

As I have said, many doctors already practising cosmetic procedures do so with good ethical standards and care for their patients, but there are also some who do not have the same considerations. These guidelines look to be a step forward for the industry, making it very difficult for those doctors who may have acted inappropriately in the past to continue to do so. The emphasis on patient care is important, and if the professionals working in the industry ensure that everything they do is with their patients’ interests at heart, then these guidelines will have gone a long way towards making cosmetic procedures safer for all involved.

A clinical trial on healthy volunteers sponsored by Portuguese pharmaceutical company Bial came to an abrupt halt in early January 2016, when one of the trial participants was declared brain dead and five others were hospitalised soon after with organ failure and suspected brain damage. The trial drug, BIA–102474–101, was intended to target a range of diseases including pain relief. It was being tested in humans for the first time. French contract research organisation BioTrial (“CRO”) had been engaged by Bial (the “Sponsor”) to manage and host the trial at its Rennes trial centre, in France. The tragic outcome raises questions for organisations involved in sponsoring or conducting clinical trials, and is likely to lead to further reform of the clinical trials regulatory regime across the EU.

The legal framework for clinical trials in the EU

Clinical trials involving medicinal products for human use are governed in the EU by Directive 2001/20/EC (the “Clinical Trials Directive”). This framework legislation provides for additional implementing directives and guidelines. It also provides that an application for a Clinical Trials Authorisation (“CTA”) must be made to the national Competent Authority of any member state in which a trial site will be located. In the absence of any objection from the national Competent Authority within 60 days, the CTA will be deemed to have been given. Additionally, approval for the trial protocol must be sought from a Research Ethics Committee before enrolment of any trial subjects can begin. Inevitably, there are variations in the way in which the Clinical Trials Directive has been implemented into national law, leading to a lack of complete harmonisation across the EU. In order to improve the degree of harmonisation and reduce the administrative burden involved in organising cross-border trials in the EU, Regulation (EU) 536/2014 was adopted on 27 May 2014, repealing the Clinical Trials Directive (the “Clinical Trials Regulation”). It entered into force on 16 June 2014, but will take effect no earlier than 28 May 2016. So these upcoming changes did not apply at the time of the Bial trial, which took place under the regime of the Clinical Trials Directive.

Phase 1 clinical trials: “first in man”

Phase I trials, also known as “first in man trials”, are the first stage of testing in human subjects. Normally, a small group of 20–100 healthy volunteers will be recruited. This phase is designed to assess the safety, toxicity, pharmacokinetics[1] and pharmacodynamics[2] of a drug. These clinical trial clinics are often run by contract research organisations (“CROs”) who conduct these studies on behalf of pharmaceutical companies at a dedicated site where participants can be observed by full-time staff and receive 24-hour medical attention and oversight. Phase I trials also normally include dose-ranging studies, also called dose escalation studies to discover the dose at which a compound becomes too toxic to administer. The tested range of doses will usually be a fraction of the dose that caused harm in pre-clinical animal testing. Volunteers are typically paid an inconvenience fee for their time spent in the clinical trials clinic.

The TGN1412 trial

The oversight and monitoring of Phase 1 clinical trials was strengthened in 2007 following a previous tragedy in the UK. Healthy volunteer research subjects suffered multiple organ failure during a first-in-man phase 1 clinical trial at the private clinical trial research centre at Northwick Park Hospital in in 2006. The trial drug, code-named TGN1412, was being developed for the treatment of rheumatoid arthritis, leukaemia and multiple sclerosis. It was administered by injection over a period of minutes, rather than as an infusion over several hours. Following the very serious adverse reactions, the UK Secretary of State for Health convened an Expert Scientific Group under the chairmanship of Professor Gordon W. Duff to investigate and report back with recommendations. The final report of the Expert Scientific group in December 2006 influenced the provision of guidance in July 2007 by the Committee for Medicinal Products for Human Use (“CHMP”) of the European Medicines Agency on first-in-human clinical trials (the “EMA Guidance”).

The Bial Trial

The trial began on 9 July 2015. A CTA application had been filed with the French Competent Authority, the French National Agency for Medicines and Health Products Safety (“ANSM”), and had received deemed approval. Ethics Committee (“EC”) approval for the trial protocol has also been obtained. The protocol provided for a dose-ranging study in 128 healthy volunteers aged 18—55 years, who were each to be paid €1900. After some single ascending dose studies, four cohorts of volunteers were allocated to multiple ascending dose studies (at 2.5mg, 5mg, 10mg and 20mg).  These passed by uneventfully, with no serious adverse events (“SAE”) being reported to the French authorities. A fifth cohort (made up of eight volunteers) was allocated to receive the highest dose (50mg), administered once daily.

On day 5 of dosing this fifth cohort, serious complications began to develop. Within a week, volunteer 2508 (subsequently named as Mr. Guillaume Molinet) tragically died and five other volunteers from the fifth cohort had been left with suspected brain injuries. The only volunteers in the fifth cohort to escape unscathed were the two control subjects who had been administered a placebo. Various French authorities launched formal investigations which are currently underway, including the General Inspectorate of Social Affairs (“IGAS”),  the ANSM and the Ministry of Justice. The final reports are not yet available. However, interim reports have been released, which have identified procedural and clinical issues and which shed light on regulatory changes which are likely to follow in France and  across the EU.

Key findings – procedural issues

• Delayed trial suspension

Mr Molinet had reported a headache within an hour of being dosed at 8am on day 5 of the study (10 January), and developed significantly slurred speech and double vision by that afternoon. The CRO’s doctor examined him at 3pm, but only prescribed a paracetamol. It was not until the CRO’s staff were challenged by other volunteers concerned by the continuing deterioration in his condition, that he was referred to the local hospital at 8.30pm, where he was admitted as an inpatient. Notwithstanding this SAE, the CRO proceeded to administer another dose of the trial drug to the remaining volunteers at 8am on day 6, without first checking with the hospital on the status of Mr Molinet. Curiously, although the CRO maintains that Mr Molinet had been hospitalised “at the first sign of light symptoms” and that the feedback received from the hospital the previous night had been “re-assuring”, in complete contrast, the letter from the CRO’s onsite doctor referring Mr Molinet to the local hospital describes more serious neurological symptoms (double vision, slurred speech, migraines) that had worsened through that day. The French authorities have criticised the decision not to suspend the trial immediately upon hospitalisation of a previously healthy volunteer with neurological symptoms, after ingesting a high dose of a previously untested drug that was known according to the protocol to interact with the central nervous system.

• Failure to provide appropriate medical care

The second volunteer of the fifth cohort started to complain of similar symptoms on the afternoon of day 6. By this time, Mr Molinet had suffered a stroke and lapsed into a coma. Nevertheless, the second volunteer was also only given a paracetamol by the CRO’s doctor. On the morning of day 7, Mr Molinet tragically was declared brain dead and the second volunteer awoke with black eyelids. Nevertheless, the second volunteer was only offered another paracetamol and an ice pack by the CRO’s doctor. It was only on day 8,  when the second volunteer collapsed from dizziness, that he was finally hospitalised. The principles of Good Clinical Practice require the Sponsor and CRO to ensure that all volunteers who had taken the drug received appropriate medical attention and follow-up to ensure their safety. The French authorities are concerned that this did not happen, perhaps due to a systemic reluctance on the part of the CRO or Sponsor to acknowledge an emerging pattern.

• Delay in reporting serious adverse event

The hospitalisation of Mr. Molinet occurred on day 6 of the trial, and clearly amounted to a serious adverse events as defined in the Clinical Trials Directive. Due to safety implications, strict reporting obligations require sponsors to be informed by CROs/principal investigators of serious adverse events within 24 hours (paragraph 29, Commission Communication 2001/C 172/01) (the so-called “CT-3” Communication). Hence, CROs tend to have robust measures in place that are triggered as soon as an SAE occurs. This is evidenced by the fact that within hours of the first volunteer slipping into a coma on day 6, Bial and the CRO had agreed to halt the trial. However, the sponsor also has an obligation to notify the national Competent Authority of any suspected, unexpected, serious adverse reaction (“SUSAR”). Where the SUSAR is fatal or life-threating, this must be reported “as soon as possible” and in any event within 7 days after the sponsor is made aware of the case. (paragraph 94, CT-3). Bial eventually notified the ANSM on day 9, four days after the hospitalisation of Mr Molinet. The French authorities are concerned that this did not comply with the obligation to notify “as soon as possible”, even though it was within the seven day longstop. They categorised the delay as a “major failure in the CRO’s crisis management”.

• Failure to obtain informed consent

The Bial informed consent form (“ICF”) presented to every volunteer for signature promised: “You will be informed about any new significant information that could affect your willingness to continue the trial“. The remaining volunteers in cohort 5 were not formally informed of Mr Molinet’s hospitalisation when it happened on day 5, so were never given the opportunity to review their continued participation in the study before the next does of the trial drug was administered at 8am on day 6. While the CRO/Bial were in compliance with EU regulations, they appear to have chosen to ignore the standard set by their own ICF when deciding not to inform the rest of the group regarding the hospitalisation of a participant, before administering them with additional doses. This raises serious ethical concerns.

Key findings – clinical issues

The French authorities have also made various preliminary criticisms about clinical issues, including:

• the volunteer screening (exclusion) criteria did not include a neuro-psychological assessment, even though the trial drug targeted the central nervous system;
• the Sponsor’s pre-clinical animal test data appears to have been insufficient to justify progression to a first-in-man study;
• the dose escalation from 20 mg for the fourth cohort to 50 mg for the fifth cohort was “too sudden”. It is unclear whether the Sponsor presented sufficient pharmacokinetic data to justify this; and
• the choice of 50 mg as the highest does in the dose ranging study was heavily criticised, which was up to 20 to 80 times higher than that needed for the therapeutic mechanism sought to be achieved.

It is unclear why these points were not picked up by either the ANSM or the Research Ethics committee when evaluating the Sponsor’s CTA application. No doubt the full reports of the French Authorities, when they become available, will consider this further.

It is interesting to note that the recommendation in the EMA Guidance as well as similar 2006 recommendations of the French Medicines Agency (AFSSaPS) for allowing sufficient time gaps between dosing of healthy volunteers does not seem to have been followed. Dosing was planned to take place with just 10 minutes between subjects dosed on the same day. Bial has been criticised by French Authorities  as well as in an editorial of the British Journal of Clinical Pharmacology[3] for not planning sufficient time gaps between dosing of patients.

Regulatory response

The ANSM has already ordered that certain precautionary measure should apply from 31 March 2016 to all trials which it has authorised, including:

• Trial suspension and fresh authorisations. Upon the occurrence of new facts/developments in trials involving healthy volunteers, the trial must be suspended immediately and fresh approvals from authorities must be obtained before resuming the trial.
• Immediate reporting. The timeline for expedited reporting by a sponsor of a SUSAR is shortened from “as soon as possible” to “immediately” reporting obligation to authorities (with the longstop of 7 days unchanged)
• Additional global reporting requirement. Any SUSAR occurring in any other trial anywhere in the world on a related compound, including those conducted by an affiliate company of the sponsor, must be reported by the sponsor immediately to ANSM
• Fresh informed consent: upon the occurrence of new facts/developments in trials involving healthy volunteers, written informed consent must be obtained afresh from every participant before administering further doses to them.
  

OUTCOMES

• While the trial was conducted in compliance with the letter of the law, it is clear that serious gaps are emerging from both a procedural and clinical viewpoint that require an urgent review of the clinical trials regime under both the Clinical Trials Directive and the Clinical Trials Regulation. Changes to French law and guidance have already been announced, and any sponsors or CROs conducting trials at sites in France will need to implement these changes immediately. Moreover, the EMA has indicated that the findings of the French Authorities could trigger such a revision to EU-wide guidance from the EMA on first-in-man trials. Revisions to the EMA guidance are likely to have global ramifications, as most jurisdictions seek to harmonise trial standards under the influence of the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (“ICH”). If the ANSM measures are indicative of this potential EU wide reform, changes can be expected in the areas of robustness of pharmacokinetic data, safety measures, screening criteria, reporting and participant consent for phase 1 trials in particular, but possibly for all trials as well.

[1] Pharmacokinetics is the branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolised and eliminated by the body (sometimes also described as what the body does to the drug).

[2] Pharmacodynamics is the branch of pharmacology that studies the effect and mode(s) of action of the drug upon the body.

[3] Br J Clin Pharmacol (2016) 81 582—586.