Monday, February 5, 2018

What went wrong? A Doctor's confession on Dengvaxia controversy


In yet another controversy that rooted from the previous administration, medical experts share their much needed opinion in the wake of Dengvaxia fiasco.
Photo from Dr. Francisco P. Tranquilino

One of them is the Special Assistant to the Dean and College Secretary at the University of the Philippines College of Medicine (UPCM), Dr. Francisco P. Tranquilino.

In a Facebook post, Dr. Tranquilino shared his thoughts about the issue surrounding the dengue vaccine.

The UP Doctor however clarified at the start of his post that his statement does not have anything to do with his political views. Thus, such post was solely intended for his opinion as an expert in his field concerning the said vaccine.

'Ito ay walang kinalaman sa aking pampulitikang pananaw. Ito ay aking pahayag batay sa aking kakayahan bilang isang manggagamot at mananaliksik. Ito ay isang obhektibo at hindi madamdaming pagsusuri ng mga impormasyon sa isyung ito.', Tranquilino wrote.

Entitled 'DENGVAXIA: What went wrong?', check out his full post below:

Kasama si Dr. Esperanza I Cabral sa Kapihan sa Manila Hotel ngayong umaga.
Photo from Dr. Francisco P. Tranquilino

Ito ay walang kinalaman sa aking pampulitikang pananaw. Ito ay aking pahayag batay sa aking kakayahan bilang isang manggagamot at mananaliksik. Ito ay isang obhektibo at hindi madamdaming pagsusuri ng mga impormasyon sa isyung ito.

DENGVAXIA: What went wrong?
Francisco P. Tranquilino, M.D., FPCP

An international consensus exists that clinical development of dengue vaccines should not be forestalled by certain hypothetical safety concerns. (1) And a dengue vaccine should have a substantial public health impact in the Asia-Pacific region which hosts more than 75% of the 2.5 billion people at risk of dengue worldwide constituting a so called “silent disaster.” (2)

Vaccine hesitancy has been a constant threat to immunization programs. The foundation of vaccination acceptance is public trust, trust in vaccines and vaccine producers, in the healthcare profession and the government.(3) All these aspects were crashed by the Dengvaxia fiasco. What went wrong?
Photo from Google

Is it Efficacy Issue?

Efficacy based on 2 large Phase 3 clinical trials (Capeding Lancet 2014 and Villar NEJM 2015) showed a 65.6% overall pooled vaccine efficacy among 9 year olds and above and for less than 9 years old, 44%. (4,5) WHO deemed this acceptable. In fact, in Europe, even lower rates may be accepted, and effectiveness will just be determined post-registration.

European regulatory framework allows the benefit/risk assessment of vaccines to rely on post-approval evidence of population benefit in lieu of pre-approval individual efficacy.

Several vaccines have already been approved in Europe even in the absence of vaccine efficacy data, relying either on non-inferiority to licensed vaccines (PCV 10, PCV 13, conjugate serogroup C meningococcal vaccine) or on surrogate markers of protection (influenza or HPV).

Or Safety Concerns?

WHO did not even recommend testing individuals for antibody before inoculation.
Photo from Google

The SAGE noted “DUE TO LIMITATIONS OF AVAILABLE TESTS AND LOGISTICAL CHALLENGES IN IMPLEMENTING A SCREENING TEST PRIOR TO VACCINATION AS WELL AS LACK OF DEMONSTRATED HARM IN THE OLDER AGE GROUP, THIS WAS NOT AN ADVISABLE APPROACH.”

Based on considerations of superior efficacy and possibly safety and duration of protection in seropositives, the 50-90% seroprevalence range in the clinical trial countries and forecasts from mathematical modelling, SAGE recommended seroprevalence thresholds as the best population level strategy but not to be given when seroprevalence is below 50%.

WHO further concluded that consideration of introduction must take into account local priorities, national and sub-national dengue epidemiology, predicted impact and cost-effectiveness with country-specific hospitalization rates and costs, affordability and budget impact. Further, it must be considered only in geographical settings with high endemicity, indicated by seroprevalence of approx. 70%
Dr. Francisco P. Tranquilino | Photo from Facebook

FROM A PUBLIC HEALTH PERSPECTIVE, THEREFORE, DENGUE VACCINE, EVEN WITH ONLY PARTIAL EFFICACY SHOULD BE CONSIDERED TO HELP CONTROL THE EVER-GROWING PROBLEM OF DENGUE IN AFFECTED COUNTRIES.” (6)

Or maybe the railroading of regulatory proceses?

FDA did not simply approve without enough safety data. The experts reviewed pooled data from the 2 Phase 3 trials and noted vaccine efficacy of 65.6% (95%CI 60.7-69.9) over 25 months from the first vaccine dose among 9-16 year olds.

Regulatory agencies evaluate the potential benefits of an effective vaccine against potential risk of adverse effects following immunization. Although RCTs are still the gold standard, other considerations may be looked at in the registration process. RCTs require rigorous control for biases and rely on laboratory-confirmed clinical outcomes, but expensive and require large sample size. Despite this, 2 large scale Phase 3 Trials as cited above were still made available to the FDA for review.
Dr. Francisco P. Tranquilino | Photo from Google

In Europe, regulatory framework allows the benefit/risk assessment of vaccines to rely on post-approval evidence of population benefit in lieu of pre-approval individual efficacy.

Effectiveness and vaccine impact data for these vaccines have been post-approval commitments and have been included in label updates. (4) They have regulatory pathways that allow earlier access to medicines or vaccines through early dialogue with stakeholders, conditional marketing authorization and real-world data following approval to supplement the clinic trials.

Even the US FDA has not defined a specific threshold for vaccine efficacy or a particular endpoint. (6) There is regulatory acceptance of vaccines with moderate efficacy only.

Expedited pathways for accelerated licensure are not uncommon. In the US FDA, this included: fast-track programs (e.g. pneumococcal vaccines, HPV vaccine), breakthrough therapy (e.g. meningitis B vaccine), priority review, accelerated approval (e.g. influenza vaccine) and emergency use authorization.

In effect, there was nothing irregular in the Philippine FDA’s approval process.

In addition, there are also “rolling registrations” whereby all available data are being evaluated by the FDA ahead of whatever other requirements need to be satisfied or completed, so that once the latter becomes available, approval can be given immediately.

And for those who until now insist that railroading occured because a PMS was not conducted, this is not true.

A more rigid, internationally accepted practice of PSUR (periodic safety update reports), PASS (post authorization safety studies), PAES (post authorization efficacy study) and RMP (risk management plans) are actually in place at the FDA.

In fact, sometime in 2011-2013, I was requested to look into the adverse events reporting system of FDA and evaluate their PMS requirement which in most cases is being used only as marketing tools for new product seeding. I submitted a proposal which I believe led to the subsequent adoption of the PSUR system which actually strengthens the pharmacovigilance system implementation in the country. Thus, the PSUR was not developed to facilitate early approval of Dengvaxia.

Meanwhile, burden reduction has also been recommended as a consideration in evaluating vaccines with moderate efficacy or effectiveness, and may be used to support product registrations.

Also, the Formulary Executive Committee do not approve vaccines, they give recommendations and FDA renders final decision/approval.

Similarly, WHO SAGE is merely recommendatory. WHO do not approve licenses for vaccines, it only provides guidance to member States. Said function belongs to the national regulatory agncies (e.g. FDA). (7)

So, if we have the efficacy and safety data and regulatory processes seemed to have been followed, why then do we have all these problems now?

La réunion à Paris - Il n'y a pas de repas gratuit. (The meeting in Paris - there is no such thing as a free lunch)

This meeting in Paris between PNoy and Sanofi SHOULD NOT HAVE HAPPENED. This singular, seemingly innocent dinner in the lovely city of lights, may once again prove that “there is no such thing as a free lunch (or dinner).” This is outright inappropriate & unethical.

As can be derived from The Mexico City Principles Section 13 (Public Sector Relationships and Procurement), decision-making process by Companies and Governments during and including the government procurement process, through bidding or any other procedure of government procurement must be professional and ethical. (11) There should be no attempt to exert inappropriate influence.

That fateful meeting between PNoy and Sanofi is now besmirched with charges of bribery and corruption.

So today, a promising new vaccine instead created havoc, causing anxiety, fear and anger among the populace especially among parents of the almost 850,000 children who received the vaccine.

But why are we all in disagreement on this issue? What should have been a simple label change for a pharmaceutical company suddenly turned into a national nightmare. And why do I find myself debating with colleagues about a possible straightforward public health impact life cycle of a vaccine?

I can think of several reasons, the political divide perhaps? Some personalities involved may have their own personal agenda? Or some are simply grandstanding? But still most of us just analyze things differently and we may agree to disagree. But for the sake of public welfare and the common good, let us attempt to assess the issue more objectively, guided only by our “strong sense of duty and commitment to protect and promote the health and welfare of our countrymen. Let us put public welfare above all else.” (10)

FPT
02/05/18

References:

1. Guidelines for the clinical evaluation of dengue vaccines in endemic areas. World Health Organization. Immunizations, Vaccines and Biologicals. IVB. 08.12.

2. Pang T, Goh Tam Thiam D, Tantawichien T, Ismail Z and Yoksan S. Dengue vaccine – time to act now. Correspondence, Lancet 2015; 385: 1725-1726.

3. Thomson, A and Watson, M. Vaccine Hesitancy; A vade mecum. Vaccine 2016; 34:1989-1992.

4. Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3 randomized, observer-masked, placebo-controlled trial. Lancet Oct. 11, 2014; 394 (9951): 1358-1365.

5. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. Jan. 8, 2015; 372 (2): 113-123.

6. WHO Strategic Advisory Group of Experts (SAGE) on Immunization Summary of Meeting, April 12-14, 2016, Geneva.

7. Conference Report. Beyond Efficacy: The full public health impact of vaccines. Vaccine 2016; 34: 1139-1147

8. Wilder-Smith A, Vannice KS, Hombach J, Farrar J, Nolan T. Population Perspectives and WHO Recommendations for CYD-TDV Dengue Vaccine. Journal of Infectious Diseases 2016.

9. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med Jul 27, 2015.

10. Doctor for the Truth. Statement on the Dengvaxia Controversy. February 2, 2018.

11. The Mexico City Principles 2011

Source: Francisco Pascual Tranquilino

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