Shock news: Tolvaptan initial rejection by NICE

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5 June 2015

UPDATE, 26 June 2015...Today was the deadline for responding to the NICE Committee. THANK YOU everyone for your support. We will update you after the next Committee meeting on 7 July.

The Polycystic Kidney Disease (PKD) Charity is saddened and deeply disappointed that the National Institute for Health and Care Excellence (NICE) has not recommended tolvaptan within its European marketing authorisation for treating autosomal dominant polycystic kidney disease (ADPKD)[i].

The NICE Appraisal Committee (which met on 1st April) concluded that the relative benefit of tolvaptan compared with placebo (as reported in the TEMPO 3:4 trial) is associated with some uncertainty, and also that tolvaptan is not a cost-effective use of NHS resources.

The NICE Appraisal Committee did conclude that tolvaptan is an innovative treatment and the first shown to specifically impact on ADPKD progression. The Committee further noted that the availability of Tolvaptan gives hope for people with ADPKD, their children and families.

The PKD Charity recognises that the Appraisal Consultation Document or ACD (issued May 2015) is not the final guidance on Tolvaptan. The Charity is preparing a comprehensive response for submission to NICE by 26 June 2015 to be considered by the Committee at the second Appraisal Committee meeting on 7 July 2015.

Below, however, are our initial reactions.

We do not feel that the NICE Committee has taken all relevant evidence into account. In particular, we do not feel that the Committee has understood the full impact – the medical, psychosocial, emotional and cost burden – of living with APDKD.

The current situation for someone with ADPKD

  • ADPKD is a chronic, progressive, systemic condition and the most commonly inherited kidney disease. First reported in the 16th century, ADPKD is incurable, with those affected enduring a relentless progression towards end-stage renal disease (ESRD), accompanied by a plethora of renal and extra-renal complications.
  • Global prevalence rates range from 1 in 500 to 1 in 4000[ii], with a large number of individuals being undiagnosed during life. ADPKD can, however, be diagnosed at any time, in adulthood or in children (sometimes in utero). Being dominantly inherited, the risk of passing on ADPKD to children is 1 in 2. Many patients with ADPKD will know similarly affected family members; many will have lost loved ones from ADPKD. 
  • ADPKD is characterised by the formation, growth and multiplication of fluid-filled cysts in the kidney and other organs. The bulging cysts profoundly enlarge the kidneys replacing healthy tissue. A normal kidney weighs approximately 150g; in one extreme case, two ADPKD kidneys together weighed 22kg or approximately one fifth of the patient’s body weight. Individual cysts themselves can expand to 9 or 10cm – which is the size of an average, normal human kidney.
  • Symptoms such as burst kidney cysts, bleeding, infections, plus chronic and acute pain are common. The PKD Charity recently conducted a survey of UK Patients’ and Carers’ Experiences of ADPKD[iii] in which nearly half of all patients reported suffering acute severe pain at least once a month, 1 in 10 on a daily basis. Most said that pain interfered with normal daily life ‘extremely’ and that pain relief was inadequate.
    “I don’t think my drugs deal adequately with the type of pain that I have… the pain that interferes with my sleep.”
    “Had to wait a long time to get treatment for pain. Ended up in casualty for pain relief.”
  • Kidney failure occurs in most ADPKD patients, on average before the age of 60 years[iv]. Not all patients will reach ESRD but if that occurs, dialysis and/or transplantation are the only life-saving treatments. In the UK, approximately 1 in 10 persons under 65 on dialysis has ADPKD; whilst 1 in 8 of all kidney transplants are due to ADPKD. Some people may also require removal of their native kidneys (by surgical nephrectomy) to enable transplant to go ahead or deal with complications such as pain and infections from massive cystic kidneys.
  • Additional complications include lifelong hypertension, increased risk of sudden fatal rupture from brain aneurysms and debilitating polycystic liver disease (which sometimes necessitates liver transplantation). Nearly 8 out of 10 patients in the PKD Charity survey were taking prescription medicines as a result of their ADPKD.
  • Aside from the clinical manifestations, people with ADPKD are frequently profoundly affected by the psychological, emotional and social side-effects of this inherited, long-term condition. The PKD Charity survey found that over 9 in 10 people admitted to feelings of anxiety, sadness, guilt, loss of self-confidence and hopelessness. Over two-thirds reported impact on overall family life, nearly half reported impact on their sex life and 1 in 3 had made career sacrifices due to pain and general debility.
    “Failure of marriage, lack of earning potential and constant guilt for being a burden when unwell and passing it to children.”
  • The economic cost burden of ADPKD to the NHS varies according to kidney function stage and extent of complications. Pain relief, antibiotics, anti-hypertensive drugs, plus costs of dialysis and/or transplantation are significant direct healthcare costs. In addition – not considered by the NICE Committee – are the costs of welfare benefits and related social care associated with long-term, debilitating conditions.
  • In the PKD Charity survey, people reported loss of personal and family earnings of between £10,000 and £100,000. Costs fall on carers as well as patients: 1 in 5 carers in the PKD survey said they had left their employment to take care of affected family members (spouses and children). Most people diagnosed with ADPKD will also experience increased travel insurance premiums and the majority will be denied life insurance.
  • In severe cases of ADPKD, people can reach kidney failure at the peak of their earning potential and in the prime of their personal and family lives – resulting in sometimes cataclysmic loss of jobs and future earnings/pensions/tax contributions, combined with devastating consequences on parenthood decisions.
  • Moreover, where many family members are affected or may have died prematurely - whether parents, siblings or children – “ADPKD can feel like a death sentence”.
    “On the balance of probability you face death in your later 50s early 60s if there is no intervention. My family who had it all had aneurysms and I'm very aware of the dangers these pose to my health. So I fear for my future and the fact that I could die prematurely and as a single parent not be there for my children.”

Therapeutic hope of first-ever therapy

  • Until recently, there were no licensed therapies available to slow progression of ADPKD. However, following a successful global clinical trial by Otsuka Pharmaceuticals (TEMPO 3:4[v]), the first-ever drug JINARC® was approved in Europe on 28 May 2015.
  • The active ingredient, tolvaptan, was shown to affect the rate of kidney cyst growth and modify progression. JINARC® has been licensed in Japan and Canada, and represents a significant step forward for thousands of people with ADPKD, their families and carers, and future generations.
  • There was a hope among the many thousands of people with ADPKD that tolvaptan could give a “better quality of life”. From the PKD Charity survey:
    “I hope Tolvaptan to be successful so that my son will never reach end stage renal failure. I hope for him to live his life to the full without ADPKD impacting his life as much as it has mine and my sister.”
  • Whilst not all respondents in the survey were certain about tolvaptan, most welcomed a drug that could potentially delay dialysis and transplantation.

The future without tolvaptan

  • The PKD survey asked patients how they rated current healthcare approaches and one in 2 thought them fair, poor or very poor in managing their ADPKD.
  • Without a licensed therapy, standard healthcare based on symptom management is the only option, up to ESRD. Alas, at present, ‘standard’ care can vary considerably as there are no agreed best practice guidelines for ADPKD patient care. Some patients still report that their doctors have "little understanding of what it’s like to live with ADPKD" and have an attitude of "sit back and wait for inevitable kidney failure".
  • Regrettably, the NICE Committee commented that ‘aggressive blood pressure management and increased fluid intake may have an impact on decline’. There is no evidence to support these statements. Whilst patients with other forms of chronic kidney disease (CKD) such as diabetes have benefited from approaches to slow the decline of kidney function, these have not worked in ADPKD[vi].
  • In conclusion, the PKD Charity reiterates its deep disappointment that people living with this incurable, inherited, life-threatening and debilitating kidney disease may be denied access to a licensed therapy which has the potential to improve the quality of their lives, and the lives of their family members and future generations.

Next steps

  • The PKD Charity will work on a formal response to NICE for submission by 26 June 2015.
  • We urge all patients and carers to respond also, in person, by 26 June.
  • First, visit the NICE website and download the Appraisal Consultation Document (ACD) published on 5 June 2015, plus the Committee Papers.
  • You will have to register with NICE to submit your comments, but this is straightforward.
  • Contact Tess Harris for further information and assistance This email address is being protected from spambots. You need JavaScript enabled to view it.

[i] NICE Appraisal Consultation Document or ACD (issued 5 June 2015)

[ii] Ong et al. Lancet 2015; 385: 1993-2002

[iii] During November and December 2014, the PKD Charity ran a specially-designed survey amongst UK adults with ADPKD, plus their relatives and carers, on the impact of the condition on overall health, wellbeing and quality of life. A total of 651 individuals responded, of whom 513 were ADPKD patients, and 138 relatives/carers.

[iv] Shaw C, et al. Nephrol Dial Transplant 2014;29:1910–8

[v] Torres VE, Harris PC et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. The New England Journal of Medicine. 2012;367 (25): 2407-2418

[vi] Spithoven EM, et al. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney Int 2014; 86:1244–52