S6-3 Davis DoH Vatican

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World Medical Association (WMA) Conference on
Declaration of Helsinki 1964-2024
Post-Trial Access and the Declaration of Helsinki (Part B)
Session 6: 11 am to 12.30 pm, 19 January 2024
Aula Vecchia del Sinodo, Vatican City
Prof. Dr. habil. J. Charles Davis
Associate Director, St. John’s Medical College and St. John’s Research Institute, Bangalore
Privatdozent, Albert-Ludwigs University of Freiburg, Germany
Corresponding Member, Pontifical Academy for Life, Vatican City
Humboldt-Alumnus Fellow, Alexander von Humboldt Foundation, Bonn
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Post-Trial Access
Research in Resource-Poor Settings
• Symposium
• at St. Johns National Academy of Health Sciences, Bangalore
• Date: 11th Dec 2023, 14:30 to 16:30.
• Venue: Video Conference Room, St. John’s Research Institute,
Bangalore
• Chair: Rev. Dr. Charles Davis
• Speakers: Dr. Prem Pais, Dr. Cecil Ross, Dr. G D Ravindran, Dr. Suman
Rao, Dr. Hari Menon, Dr. Jayanthi Savio, Dr. Prashanth T
• Moderator: Dr. Tony D S Raj
• Others: Dr. Dhinagaran D, Dr. Abijeet Waghmare, Dr. Ryan Fernandez
acknowledgement
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Content of the Presentation
1. Clinical Trials and Post-Trial Access
2. Post-Trial Access and Bioethical Principles and Ethical Guidelines
3. Review of Post-Trial Access Case Studies and the Patient
Experience
4. Ethical and Pragmatic Frameworks for Assessing the Costs
and Benefits of Scientific Gains in LRSs
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Clinical Trials and Post Trial Access
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Clinical Trials are done to test safety and efficacy of new drugs to help improve public health.
Drug trials have different Phases-I, II, III and IV. Post Trial Access (PTA) generally refers to Phase-
III drug trials.
§ Current Protocol states that at trial completion if trial medication is to be stopped, trial
participants are to be treated as usual at the physician’s discretion.
§ What if the New drug is effective but not available outside of a trial and/ or is very
expensive, and current treatment methods are not satisfactory.
§ Post-Trial Access is necessary –
§ For both Intervention and Control arms
§ For Participants who have shown benefit from treatment
§ If there is a potential negative consequence if treatment is stopped
§ There is a lack of guidance and over-arching frameworks for PTA. While Clinical Trials are
highly regulated, regulations for PTA are unclear.
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• In investigator Initiated Clinical Trials, usually the Drug molecule is already in the market and is being re-
purposed for a new use, it is not very expensive and hence there is no need for PTA.
• In Sponsor-Driven Clinical Trials, Molecule is new, costly and not available in the market for patients, hence
there is a need for PTA.
• Trial Insurance normally stops once the trial is over.
• Investigators must take a stand regarding toxicity/harmfulness.
• In case of hereditary defects or illnesses, trials need to be continued lifelong.
• In India, PTA was added to ICMR 2008 guidelines after people started demanding PTA.
• In PTA, apart from the actual drug, testing facilities and staff training need to be also considered.
• PTA is mandatory till the drug is approved by the Drug Controller/ regulator.
• Investigators need to advocate to make policy changes to fast-track drug/therapy towards the standard of
treatment/care and the addition of drugs to the essential medications list (EML).
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Bioethical Principles and Ethical Guidelines
to Regulate Post-Trial Access in LRSs
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The principle of non-maleficence demands continued access if
withdrawal of an investigational medicine after the end of the trial
would cause harm. Participants with chronic diseases who are
benefiting from the research will be harmed if they are taken off
treatment. This would violate the duty of non-maleficence.
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• Autonomy demands information to trial participants at the start of the trial whether
there will be continued access to an investigational medicine and under what
conditions. PTA should not become inducement to get informed consent.
• Distributive justice demands continued access not just to research participants but to
the host population. In life threatening conditions, where the trial drug is proven
effective, it might be inhumane to deprive non-trial patients of the same benefit.
• From the perspective of beneficence, sponsors and researchers have a duty to make
efforts to safeguard the wellbeing of the research participants by maximizing the
possible benefits and minimizing potential harm.
• Above all, the inviolable principle of human dignity, which is inseparable from the
human condition, demands the continued intervention to avoid manipulation of
vulnerable population and prevent harm to poor patients whom trial might have been
the only hope. In other words, the trial participants are not mere means for research.
Humanity precedes science, research and norms.
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Ethical Guidelines:
1. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(ICH): The ICH Good Clinical Practice (GCP) Guidelines do not describe any responsibilities for continuing
treatment after a trial.
2. Declaration of Helsinki: In advance of a clinical trial, sponsors, and governments should make provisions for
PTA for all participants who still need an intervention identified as beneficial in the trial. This must be
disclosed to participants during the informed consent process..
3. CIOMS/WHO: The Council for International Organizations of Medical Sciences (CIOMS), in collaboration with
the World Health Organization (WHO), states in its International Ethical Guidelines for Biomedical Research
Involving Human Subjects that companies should consider whether, when and how products proven by the
research to be safe and effective will be made available to subjects after they have completed their
participation in the research, and whether they will be expected to pay for them.
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4. ICMR guidelines: National Ethical Guidelines for Biomedical and Health Research
Involving Human Participants, 2017
• Where possible, for example, if the drug is found useful and the standard of care is
not available, the Institutional Ethics Committee should ensure post-trial access for
the participants.
• Sponsors and researchers should strive to continue to provide beneficial
interventions, which were part of the research initiative even after the completion
of research and till the local administrative and social support system is restored to
provide regular services.
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The New Drug and Clinical Trials (NDCT) rules 2019
MINISTRY OF HEALTH AND FAMILY WELFARE
(Department of Health and Family Welfare)
Drug Controller General of India (DCGI)
New Clinical Trials rules 2019, Part II Sec 3.1
#27: PTA is s legal requirement.
Where any investigator of a CT of an
investigational new drug (IND) has
recommended PTA after completion of trial
and this is approved by Institutional Ethics
Committee (IEC), PTA shall be provided by
the sponsor trial subject free of cost.
o If a clinical trial is being conducted for a condition for which no alternative therapy is available
o Investigational New Drug is beneficial
o The participant has consented in writing to use post-trial use of the investigational new drug and that the
sponsor shall have no liability for post-trial use.
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Review of Post-Trial Access Case Studies
and the Patient Experience
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Difference between Efficacy and Effectiveness
Clinical Trials like
Randomised Clinical
Trials( RCT)
determine Efficacy
(What can work)
Under
controlled
circumstances
RCTs may not determine
Effectiveness
(What does work)
Effect in the
general
population
CER
determines
Effectiveness
St John’s Take on Clinical Trials
Comparative Effectiveness Research (CER)
Sometimes operation is
successful, but patient may
die…
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In 2009, Institute of
Medicine (IOM) convened a
committee and issued a
report on CER on 30 June
2009
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Definition of CER:
Generation and synthesis of evidence that compares the benefits and harms of alternative methods to
prevent, diagnose, treat and monitor a clinical condition or to improve delivery of care.
CER
“what works best for
which patients under what
circumstances”
Purpose
Inform consumers, clinicians,
purchasers and policy makers
to make informed decisions to
improve health care
Real Life
Patients seek medical attention
for subjective reasons like relief
of pain, Regain of function or
enjoy life.
Doctors use objective and
easily measurable parameters
like BP control, Patency of
coronary, Size of mass….
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St. John’s National Academy of Health Sciences
St. John’s Medical College
St. John’s Medical College Hospital
St. John’s Research Institute, Bangalore, INDIA
Statistics of Clinical Trials
from 2001 – 2023
Year No of Clinical
trials received
No of clinical Trials
completed / closed
Ongoing
Clincial Trials
2001-2023 1069 1045 23
CTRI: Clinical Trials Registry of India: 61,541 Trials in 2023
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Post Trial
Access
Cost Issues
Post Trial Access
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Clinical Trials In
Hematology
Clinical Trials in Clinical Hematological Dept 2004-
2023
Hematological Oncology and BMT,
St John’s Medical College Hospital Bangalore
Dr Cecil Ross
Professor and Head Clinical Hematology
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Clinical Trials in Clinical Hematological Dept 2004-
2023
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Pt PR 52 year old male Severe Hemophilia FIX
Recurrent
Joint Bleeds
since
childhood
• Bleeding
Gums
• Rx ->Blood Tx
• Diagnosed at
age 10
Severe
Hemophilia F IX
• Multiple Tx with
Fresh Frozen
Plasma
• Target Joints Rt
Knee
• Left Elbow
Disability
• Bleeds twice a
month
• Advised
Prophylaxis F IX
Cost is Rs
20,000/bleed
• Hence on
Episodic Rx
Affordability
Clinical Trial Long
Acting F IX 2004
Excellent QOL.
1-2 Bleeds/ year on
Prophylaxis till 2008.
Extension Study-
2008-2012 ( Post Trial
Access)
Co Brought over
by Sanofi
Evolution of Patient with Bleeding Disorder
An Open-Label, Multicenter
Evaluation of the Long-Term Safety
and Efficacy of Recombinant Human
Coagulation Factor IX Fusion Protein
(rFIXFc) in the Prevention and
Treatment of Bleeding Episodes in
Previously Treated Subjects With
Hemophilia B.
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Value of single bleed
Value of a single bleed =
Loss of Life Expectancy × 365 ×N/12
N × Median age of Hemophilia A Patient
23×365
12×45 ×12/12
=15.54 days/bleed
A single bleed = Reduces life expectancy by 15.54 days
Cost of Rx of one Joint bleed is ~ Rs. 20,000. Cost of Brain Bleed is Rs 10 Lakhs
• = 68 years
Median life expectancy in Gen
Population
• = 45 years
Expected median life
expectancy Hemophilia
• = 23 years
No. of years of loss of life
expectancy
• = N= 12
Average number of
bleeds/patient/year
• = 12×45 =
540
Total expected bleed in a life
span
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Pt PR 52 year old male Severe Hemophilia.
Factor IX
Pt got enrolled in
a new study
(company: Nord-
Disc) – Explorer
Had hepatitis
C virus (HCV)
related chronic
liver disease
(CLD)
Covid Issues
PSE- Needed
Liver Tx
Randomized to
SOC Rx
• Pt was admitted
and supportive
care given
AHF from
Pharmacy Free
• Shifted to another hospital for Liver Tx
• ANTI-HEMOPHILIA (AHF) FACTOR 9
Alprolix provided by the
previous PTA Rx
• Cured of Hemophilia
Now well
Evolution of Patient with Post Access Care
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Trials in Mother and Child
• Pregnancy is transient, PTA – application
to next pregnancy?
• Does PTA apply to siblings / next baby?
• How long to provide PTA?
• Changing physiology, monitoring?
• Role of clinicians?
Pregnancy is transient.
Is PTA – application to next
pregnancy?
Does PTA apply to siblings /
next baby?
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• The above study identified that most researchers were not aware of the concept of PTA.
• No impact on maternal vaccine trials.
• 0/7 and 0/17 discussed in protocol
• Half of researchers had no knowledge on PTA
• Even with the revised Declaration of Helsinki in 2013 and the CIOMS guidelines, there was no increase
in provisions for maternal vaccine trials.
• Inclusion of PTA provisions in trial protocols and publications on trials in mother-child care is essential
to increase transparency on the form and content of these provisions.
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Post Trial Access in Oncology:
• Oncology trials do not start without a PTA clause in the Clinical Trial Agreement
• For Oncology Clinical Trials in India, large number of participants are easily available. It costs less to
conduct trials in India.
• Population-based intervention (Screening through a self-breast exam) reduced mortality for Cervical
Cancer (by 35%) and breast cancer (by 15%). In such cases, intervention needs to be
implemented for the entire population. PTA can be a challenge.
• Novartis ran an ambitious Patient Access project for LMICs
o 65 thousand enrolled globally and 14 thousand patients benefited in India. It was not scalable
or sustainable.
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• Negative results due to deprivation of PTA
(cf. Usharani P, Naqvi SM. Post-trial access. Perspectives in Clinical Research;
Harmanjit Singh et.al. Posttrial Access to Medical Interventions, 9:1 (2019) 5)
• A placebo-controlled trial in HIV patients evaluating the role of zidovudine in maternal–infant transmission showed
70% risk reduction. It was found later that trial patients in the US had access to zidovudine, while those from
developing countries were not provided access.
• Tenofovir/emtricitabine was licensed in 2012 by the FDA for HIV preexposure prophylaxis due to high efficacy in
reducing infection risk; however, the drug authority of South Africa did not license it, depriving the trial participants
of the benefits.
• Imatinib was approved by FDA in March 2003, although the drug was safe and highly efficacious in the trial
patients, its post-trial access was denied to 3,600 patients who died waiting for the wonder drug to cure them.
• Lapatinib also describes the similar story, where 28,000 women who were positive for the marker against which
the drug works when other drugs fail, died waiting for the drug.
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• Anticancer drug oxaliplatin (used for treatment of colorectal cancer)
was rejected by the FDA despite approval in other countries. In
January 2002, the FDA was requested for PTA to this drug, but
approval was delayed until August 2002.
• Cetuximab, used to treat colorectal and head-and-neck cancers, was
denied approval by the February 2004. Many patients were deprived
of access to this drug and subsequently died.
• Similarly, FDA approval of pemetrexed for lung cancer treatment was
held until February 2004. During this period, several lung cancer
patients died. PTA to this drug could have extended their lifespan.
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Ethical and Pragmatic Frameworks for
Assessing the Costs and Benefits of Scientific
Gains in LRSs
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From the perspective of conducting trials:
Pharmaceutical companies and sponsors prefer to have clinical trials in low resource
settings due to low budgets and easy availability of large number of research
participants.
From the perspective of scientific gains in low resource settings:
The primary goal of conducting clinical research in low resource settings should be to
address the health needs of the host population.
Conducting clinical trials in good for low resource settings, and low-middle-income
countries should encourage clinical trials to primarily to benefit their local population.
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Who will pay for access?
• Usually, the sponsor will pay for PTA.
• If the cost is on patients and families, it will be a burden, but compliance would be great.
• If PTA is given free, compliance would be poor. However, researchers would be able to do
more research.
• If PTA is fully sponsored, it raises costs and depending on financial returns research may not
be encouraged.
• If the drug is not yet approved, PTA can be given after the trial is over by:
• Regulatory approval for open-label trial extension studies, safety studies, or Extended Access
Program (EAP)
• Including a priori in protocols / separate protocols / protocol amendments.
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How long will you give the drug?
There is no clear answer on how long it can be provided. (e.g., cancer is in remission, but relapses if treatment is
stopped)
• Not feasible to provide PTA for an unlimited period.
• ICMR guidelines state that PTA should be given ‘where possible’.
• PTA to be given till the local administrative and social support system provides regular services.
However, in LMICs, where basic services are a question, this could be Infinity.
• If PTA is provided to a baby with a rare disorder, it may be also required for the other siblings who might be at
similar risk.
Lifelong drugs (heart disease, cancer, or drug for controlling cholesterol):
1) The industry has to determine if it can provide the drug for a specific period.
2) The industry will provide the drug until it is approved and locally available in the market.
3) The industry, before initiating the trial, should communicate through Informed Consent on how they are
going to handle access
4) To avoid liability during PTA, the industry may need the participant/guardian to sign a waiver in case of
any adverse event.
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In Oncological Trials How long: When to stop PTA in Clinical Trials with anti-cancer medication.
o Till improvement/ Till patient is in remission
o Some Cancer patients may have 5/10-year survival rates, hence sustaining PTA is a challenge.
o In LMICs, even when generic medicines are available in the market, patients may not be able to afford
them.
• As newer/ better drugs become the Standard of Treatment, adapting patients to the next drug
therapy/trial would help sustain PTA
• Keeping in mind the patient’s well-being, one might have to balance and decide based on the benefits Vs
risk of toxicity
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Long Term Support:
• Targeted therapies using Newer drugs for patients have improved their Median
survivable duration.
• There is PTA in targeted therapies if the patient is progressing and deriving
benefits from treatment.
• NGOs need to nudge the government to support the treatment of certain
conditions.
• Research findings on PTA and care practices must be made public via publications.
• IEC Performa should request for details of PTA and management of patients at the
end of Trial.
• Need to bring in Social teaching on the distributed care system. Distributive justice
should be advocated.
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In the context of potential revision to the declaration of Helsinki in relation to
research in resource-poor settings:
• PTA shouldn’t be only for participants in the trial. It should be available for all
those who need that drug, beyond the trial, through dissemination and scale-up.
• Post Trial Access could include ‘Post Trial access to education’ or ‘Post Trial
access to care’ as well.
• When sponsors restrict PTA to study participants, advocacy must be done for
benefits of the larger population
• The participant informed consent should disclose information regarding PTA at
the start of the trials.
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• PTA must be for both arms: ‘intervention’ and ‘control’.
• Monitoring is needed for new drugs against side effects
• If PTA is beneficial, it should be provided for everyone and not just those enrolled as Participants
• Need to disseminate information and scale up, reduce cost, and incorporate it into the ‘Standard of
Care’.
• To reduce the disparity between prosperous and poor nations, treatment proved to be beneficial
should be made available at affordable costs or free of cost without inducing the vulnerable
population to clinical trials.
• Post-trial responsibilities should not be restricted to drugs alone but include equipment, diagnostics,
and care practices.
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• We also need to consider ‘Specific Post-Trial access to care’.
• Researchers must stay connected with their patients to help them out when necessary.
• In studies done in low resource settings, the community needs to be made aware of Clinical Trial results.
• The community must have access post-trial benefits.
• Provisions for post trail access to non-drug trials must also be addressed.
• If the trial is found to be beneficial, the government must make efforts to implement it in a larger
population and launch it as a National policy.
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• Upfront disclosure should be made to IRBs about PTA (some form of time-limited).
• Post-trial access is not valid when the investigational treatment does not provide benefit over standard
treatment.
• The cost of ensuring post-trial access need to be considered before embarking on projects, other potential
research activities should not suffer at the cost of providing PTA.
• The promise of PTA should not interfere with the autonomy of participants in trials.
• Post-trial access should not hinder researchers and sponsors to conduct research in communities demanding
it.
• Special aids may be provided by governments and funding agencies to provide PTA in developing and resource
poor settings.
• Special research grants may be awarded to sponsors and investigators who have invented new
drugs/interventions that were subjected to PTA to balance scientific research and patient care.
• Conferences/workshops on PTA for different stakeholders must be organized.
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Generics
in India
India is known as
the “Pharmacy of
the Developing
world”
Gleevec, which is used to treat chronic myeloid leukemia and other cancers, costs about $2600
(Rs140 000; £1710; €2000) a month. The generic equivalent is currently available in India for just $175.
‘The Supreme Court decision will save a lot of lives in the coming decades.’ —Leena Menghaney, Doctors
Without Borders
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Generics
Generics
in India
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Sponsors, investigators, communities, Institutional Review Boards and
the governments – all concerned parties involved – must accept PTA as
a joint responsibility and decide on its provision before the trial beings.
Post-Trial Access is an ethical imperative, particularly, in low resource
settings.
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Thank you for your attention!
If we keep the
patient at the
center, we will
be doing the
right thing.
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