Doubtless,
regardless of their location, badly run clinical trials are anathema,
delaying development of much-needed treatments and cures, shaking public
confidence in biomedical research, and eroding public trust in the
biopharmaceutical enterprise.
Who's accountable for clinical trial mishaps in India?
Let's
not forget that a clinical trial in India typically has multiple
partners, only one or few of whom may be a foreign entity funding the
trial, be it a pharma company or a non-profit. When a clinical trial
goes wrong, who's responsible? Only the foreign entity? If someone
answers yes, they also have to explain why, something impossible to do.
OTOH, vilifying only the foreign partner(s), one of the many entities
involved in a clinical trial, certainly makes for some easy poutrage.
For example, in the case in question, the Phase V HPV (Human Papilloma
Virus) vaccine trials consisted not of dangerous drugs, as the question
sensationally asserts, but rather of two HPV vaccines, Gardasil and Cervarix,
approved for use in many countries years ago, with the former approved
in 121 countries as of 2011 (1). As well, it wasn't sponsored by a
western drug company but by PATH (global health organization), a non-profit that over the years has become the largest beneficiary of public health funding from the Bill & Melinda Gates Foundation.
So with the predictable misinformation out of the way, let's examine
global clinical trial responsibility through this trial's lens.
Typically,
foreign drug companies can't conduct clinical trials directly. They
need local partners, for legal, logistical, operational and cultural
reasons, partners such as ICMR (Indian Council of Medical Research), DCGI (Drug Controller General of India),
state and central governments, different ministries, public health
departments, etc., who know the local laws, rules, regulations and
language, and most importantly know and/or oversee the local
infrastructure. Thus emerges a daisy chain of partners with different
expertise and priorities. Issue is whether each of these partners is
equally well-versed in conducting clinical trials.
With decades of experience under its belt, the foreign pharma or non-profit entity knows or should
know how to conduct clinical trials. OTOH, the local partners may
typically not be as well-versed, especially in crucial details such as
importance of informed consent, and need for careful monitoring and
reporting of adverse events. These weren't learned by clinical trial
professionals in one smooth, fell swoop either. Countries well-versed in
conducting clinical trials today went through their share of the
learning curve, unfortunately often at the expense of hapless trial
participants. *, **, ***, ****.
What about the
responsibilities of the local partners? Each trial partner has a stake
in ensuring that clinical trials uphold the highest standards of ethics
and medical care, all of which which begs the question why they would be
or ever become badly run in the first place. As clinical trials
increasingly globalize, hiccups are inevitable because the core issue is
culture clash. From all accounts, this was the situation with
this Indian clinical trial. How well trial partners communicate across
their daisy chain, particularly in plugging crucial knowledge gaps with
respect to risks and risk assessments, is key. Not sufficient to explain
what to do when and how but also why. If
the local partner on the ground pays lip service to informed consent or
adverse outcome monitoring, it's not just a question of who's
responsible but also why it turned out that way. This is where cultural
differences weigh in. Maybe the foreign trial partner explained what adequately but not why. So, who's responsible? Everyone involved, not just the foreign entity. Investigations revealed the trial in question had a two-fold problem (2, 3).
1. Informed consent,
a cornerstone of clinical trials. Medicine already walks a tightrope
between patient autonomy and welfare. Life itself doesn't come with a
risk-free guarantee so it's unrealistic to expect medicine, let alone
experimental medicine, to do so. This is only accentuated in a clinical
trial, where the risks of a possible drug/intervention remain largely
unknown. After all, one of the purposes of clinical trials is to reveal
such risks. Clinical trial participants need to understand these risks
as fully as they can, understand that their participation comes with
inherent risks. Sometimes those risks may be minor such as local,
temporary injection site reactions yet they range all the way to
life-threatening. Comprehensively explaining these risks is the purpose
of informed consent. Since this trial involved minors, parents/guardians
were required to give informed consent. Instead in thousands of cases,
teachers and school principals were found to have signed them, even when
the children concerned had parents/guardians.
2. Adverse effect,
another cornerstone of clinical trials. One of the purposes of clinical
trials is to carefully monitor and assess harmful effects of any
drugs/interventions. Perhaps nowhere else is the phrase, 'safety in numbers'
more appropriate than in medicine. More people assessed for a
drug/vaccine's safety during its journey to approval through the
clinical trial process, more robust the data that underpin its safety
profile. Investigations revealed this particular trial had paid
lip-service to monitoring and recording adverse events.
As
an entity well-versed in clinical trials, PATH, the foreign non-profit
that conducted this trial had no excuse whatsoever for the lapses in
informed consent and adverse effect monitoring. What about the local
partners though, ICMR, DCGI, the state governments of Gujarat and Andhra
Pradesh where these trials were held, the schools the girl participants
were recruited from? After all, as we proceed lower down the daisy
chain, don't we also come closer to increasing personal responsibility
for the welfare of minors? Thus, in this case, ICMR and DCGI also bear
responsibility at the national level while the local governments, and
local departments of education, public health and child health bear
responsibility at the local level. Public scrutiny of clinical trial mishaps is a public good only when it's accurate and impartial.
Other open questions which remain unanswered:
- Did PATH adequately train and monitor the ground staff, especially on the issues of informed consent and adverse event monitoring?
- Did ICMR and DCGI monitor and ensure that PATH adequately trained the ground staff?
- Who monitored the ground staff during the course of the trial? Was it PATH, ICMR, DCGI, local public health department? Was the monitoring responsibility clearly delineated and did it have checks and balances?
- What kind of recording and monitoring systems were in place to ensure participant safety?
More
entities involved, more difficult to identify and assign blame. Be it
an individual or group, taking responsibility when things go wrong is
often akin to the proverbial flying pig. Yet mishaps like this trial
offer an opportunity to examine and improve the global clinical trial
blueprint, especially the weak links in the chain the open questions
reveal. Finally, when it comes to accountability, it's not just a
question of who but also how. With respect to how, monetary fines
could be imposed on the foreign entity. What about the local partners?
Reprimand or fire local and/or senior officials? Obviously, when it
comes to global clinical trials, more productive to develop processes
for accountability ahead of time, not impose them ad-hoc in a haphazard and reactionary manner. In particular, potential legal redressals need to be developed proactively.
Potential benefits of clinical trials to countries like India
Self-righteous
indignation can easily create a fog that obscures sound thinking.
Clinical trials are hugely expensive. A more pragmatic approach shows
that basing them in countries like India could be a common good from
multiple standpoints,
1. Drug companies save
costs substantially. Less it costs to bring a drug to market, lower the
drug company needs to price it to recuperate R&D costs. In other
words, drug companies lose the fig leaf of high R&D costs in pricing
new drugs outrageously.
2. Historically, drugs approved post-WW II were largely tested on white men.
That's hardly representative of the global human population. By basing
clinical trials in countries like India, the diversity of population
tested increases, theoretically improving drug efficacy and safety
profile data.
3. Conducting clinical trials in countries like India can be an opportunity for meaningful technology transfer.
As life expectancy increases globally, healthcare consumes increasing
proportions of countries' wealth and infrastructure. Need for more novel
drugs and therapies is becoming more, not less, inevitable. In turn,
conducting more clinical trials to develop them becomes more, not less,
inevitable. Makes it all the more worthwhile for a country like India to
thoroughly learn how to conduct them properly, rigorously and
ethically.
4. Conducting clinical trials is
and should be considered an opportunity for a country to use as leverage
to bargain to gain better access and price to drugs and therapies, both
old and novel, for its population.
Bibliography
1. Haupt, Richard M., and Heather L. Sings. "The efficacy and safety of
the quadrivalent human papillomavirus 6/11/16/18 vaccine Gardasil."
Journal of Adolescent Health 49.5 (2011): 467-475.
2. Final Report of the Committee appointed by the Govt. of India, (vide
notification No. V.25011/160/2010 - HR dated 15th April, 2010,) to
enquire into“Alleged irregularities in the conduct of studies using
Human Papilloma Virus (HPV) vaccine” by PATH in India, Feb 15, 2011. http://icmr.nic.in/final/
3. PARLIAMENT OF INDIA RAJYASABHA DEPARTMENT-RELATED PARLIAMENTARY
STANDING COMMITTEE SEVENTY-SECOND REPORT On ALLEGED IRREGULARITIES IN
THE CONDUCT OF STUDIES USING HUMAN PAPILLOMA VIRUS (HPV) VACCINE BY PATH
IN INDIA (DEPARTMENT OF HEALTH RESEARCH, MINISTRY OF HEALTH AND FAMILY
WELFARE) (Presented to the Rajya Sabha on 30th August, 2013) (Laid on
the Table of Lok Sabha on 30th August, 2013). http://www.preventdisease
https://www.quora.com/Do-western-drug-companies-test-more-dangerous-drugs-on-the-poor-in-India-and-should-they-be-held-accountable/answer/Tirumalai-Kamala
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