ROPES & GRAY LLP

Clinical Trials Developments in 2013 Data Sharing and Compensation for Clinical Trial Injuries in India

Mark Barnes Ropes & Gray LLP Multi-Regional Clinical Trials Center at Harvard University

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Agenda

• Clinical Trials Data Sharing – Industry Initiatives – European Medicines Agency (EMA) draft policy – Food and Drug Administration (FDA) request for

comments on masked/de-identified data

• Compensation for Injuries in India – Other related regulatory developments

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The Promise of “Open” Clinical Trials Data • Check on failure to report adverse effects

of a drug or device • Check on positive conclusions re

effectiveness • Possible new discoveries from new

analyses of same raw data • Combining data sets from multiple sources

could facilitate better science

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Risks of “Data Sharing”

– Re-identification of research subjects – Informed consent issues – Proliferation of low-quality studies that would not

advance scientific knowledge – Potential of competitive harm to sponsors whose

data have been made public – Possible effects on regulatory agency behavior

and climate

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Academic and Industry Data Sharing Initiatives

• 2012: BMJ policy – BMJ announces that starting January 2013, it will

only publish drug or device trials for which authors disclose anonymized, participant-level data upon “reasonable request”

• Late 2012: GlaxoSmithKline (GSK) – Announced that it will make anonymized participant-

level data available to researchers through an application process

– Joined by BI, Roche, Sanofi, ViiV – Pfizer has also committed to data sharing process

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Industry Initiatives

• GSK Initiative – Makes available to researchers:

• Raw data set • Analysis-ready data • Protocols with any amendments • Annotated case report forms • Reporting and analysis plan • Data set specifications • Clinical-study reports

– Data will be released through a controlled access process requiring:

• Submission of a brief research proposal • Presence of a statistician on the research team

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Industry Initiatives

• GSK Initiative (continued) – Evaluation of research proposal

• Panel of GSK-appointed experts will evaluate the analysis plan

• Unlike the EMA proposal, the panel will evaluate the qualifications of the investigators and the relevance of the research proposal to patient care

• Reasons for acceptance/rejection of research proposal will be shared with investigator

– For more information on GSK initiative, see Perry Nisen & Frank Rockhold, Access to Patient-Level Data from GlaxoSmithKline Clinical Trials, 369 N. Eng. J. Med. 475 (2013)

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EMA Draft Policy

• Background – European Medicines Agency (“EMA”) was historically opposed to

sharing of clinical trials data and clinical study reports – In 2007 a researcher requested access to clinical trials data held

by EMA regarding anti-obesity drugs – EMA denied access on the grounds that granting access to

clinical trials data would harm the commercial interests of drug manufacturers

– The European Union Ombudsman reviewed the situation and ruled that EMA should release data from the studies

– In late 2010, EMA began to release clinical study reports on request as part of its access-to-documents policy

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EMA Draft Policy

• Litigation Regarding Current Policy – The access-to-documents policy has already led to lawsuits by AbbVie

and Intermune, which are attempting to prevent the release of clinical study reports held by EMA

– AbbVie seeks to “protect [its] confidential and commercially-sensitive information” by opposing disclosure that “does not meaningfully contribute to the scientific review or evaluation of our products”

– The EU General Court issued a preliminary injunction earlier this year barring the EMA from releasing the clinical study reports at issue

– Interestingly, the clinical study reports in the AbbVie case were not requested by an academic researcher, but rather were requested by a rival pharmaceutical manufacturer (UCB)

– The EU General Court issued a preliminary injunction in 2013 barring the EMA from releasing the reports in question; however, the preliminary injunction was vacated on appeal in December 2013 and the case remanded for further proceedings

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EMA Draft Policy

• November 2012: EMA announces that as of January 2014, it will require that participant-level clinical trials data used to support a marketing authorization of a medicine be made publicly available

• EMA made clear its commitment to proactive release of data – “We are committed to proactive publication of clinical trial

data, once a marketing authorisation decision has been taken. We will deliver this project in dialogue with our stakeholders.” Introductory Presentation - November 2012 EMA Workshop on Access to Clinical Trial Data

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EMA Draft Policy

• Revised Timeline – November 2012 – Policy initiative announced – January-April 2013 – Advisory groups met – June 24, 2013 – Draft policy released – July 1-September 30, 2013 – Comment period – March 2014 – Policy and implementation plan to

be discussed at Management Board Meeting ***Note that the policy was originally to have been finalized in November 2013***

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EMA Draft Policy

• EMA draft data sharing policy provides mechanisms for release of the following clinical trials (CT) data: – Clinical summary – Clinical trial overview – Clinical study reports with line-level data listings

• The policy was available for public comment from the time of its release until September 30, 2013

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EMA Draft Policy

• Which data are subject to the draft policy? – Clinical trials (CT) data listed in the following modules

of the ICH “Common Technical Document for the Registration of Pharmaceuticals for Human Use”

• Module 2.5: Clinical Overview • Module 2.7: Clinical Summary • Module 5: Clinical Study Reports (CSR)

– Policy only applies to data submitted to the EMA on or after March 1, 2014

• Earlier submitted data available via Policy on Access to Documents, but different procedures apply

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EMA Draft Policy

• Which types of clinical trials are included? – Conventional randomized controlled trials – Large simple trials – Cohort studies – Case control studies – Registry data

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EMA Draft Policy

• How are data to be released? – Some data are “open access” and will be downloadable from

the EMA website, whereas others are subject to a “controlled access” policy

– Method of access depends on type of data – EMA policy places data into three categories:

• Category 1: Data containing commercially confidential information (CCI)

• Category 2: Data without protection of personal data (PPD) concerns

• Category 3: Data with PPD concerns; essentially “raw CT data”

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EMA Draft Policy

• Category 1 – data containing CCI – Documents containing CCI will not be made available

(but may be available under the Policy on Access to Documents)

– CCI is defined as information: • That is not in the public domain; and • Disclosure of which may undermine the legitimate economic interest

of the information’s owner

– EMA takes the position that only a “small number of CT data/documents” contain CCI

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EMA Draft Policy

• Category 2 – data without Protection of Personal Data (PPD) concerns – Classified as “open access” data – Data will be available as downloads from the EMA

website – Subcategories:

• Documents that lack personal data (e.g., summary tables presenting only aggregate data)

• Documents in which personal data have been “adequately de-identified”

• Instances where public health needs override PPD considerations

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EMA Draft Policy

• Category 3 – data with PPD concerns – Available only upon request – Requesters must identify themselves; EMA will verify their

identity – Requesters must be “established” in the EU – Data must be de-identified – Requesters must enter a legally binding data-sharing

agreement requiring the requester to, among other things: • Access data for the sole purpose of addressing a question or

conducting analyses in the interest of public health • Refrain from any attempt to retroactively identify participants • Refrain from using data for any purposes outside the boundaries of

the patients’ informed consent

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EMA Draft Policy

• EMA draft policy leaves several questions unanswered – Level of de-identification required for Category 2 vs.

Category 3 data – Method and nature of evaluation of informed consent

from studies for which data are shared – Extent to which secondary analyses will be placed in

the public domain – Which types of documents will be deemed to contain

CCI and thus unavailable for release

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EMA Draft Policy

• Summary of EMA data sharing categories

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EMA Draft Policy

• Conflict between EMA draft policy and current FDAAA requirements – As a result of regulations promulgated under FDAAA, the

following language must be inserted in all informed consent forms for trials subject to ClinicalTrials.gov registration requirements:

“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.” 21 C.F.R. § 50.25(c).

– EMA’s draft policy allowing for data sharing of participant-level data is directly at odds with this language

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FDA Request for Comments

• New FDA Initiative – FDA request for comments of June 4, 2013 (78

Fed. Reg. 33,421) • Proposal to make available for research participant-

level data from medical product applications • FDA recognizes a “potential to further advance

regulatory science” by allowing non-FDA experts to analyze data submitted to FDA

• Commercially confidential information and trade secrets would be excluded from any data release

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FDA Request for Comments

• Data under consideration would be both masked and de-identified – “Masked data” = data stripped of information that

could link them to a specific product or application – “De-identified data” = data that do not identify an

individual nor provide a reasonable basis to believe that the individual could be identified

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MRCT Proposed Models

• For more information on the above models and other work of MRCT, see Michelle M. Mello, Jeffrey K. Francer, Marc Wilenzick, Patricia Teden, Barbara E. Bierer & Mark Barnes, Preparing for Responsible Sharing of Clinical Trial Data, 369 THE NEW ENGLAND JOURNAL OF MEDICINE 1651 (2013)

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Compensation for Injuries— India • Early 2011: Standing committee formed by Indian

Parliament to report on functioning of Central Drugs Standard Control Organization (CDSCO) – Indicated that subjects who died while in a clinical trial were not

adequately compensated – Recommended that compensation be paid to the next of kin of

subjects who died while in trials – Noted that Office of Drugs Controller General (DCGI) lacked

expertise to judge scientific rationale of specific trials

• Mid-2011: Ministry of Health & Family Welfare (MoH) appointed 12 committees of clinicians and pharmacologists to assist DCGI in reviewing applications for clinical trials

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Compensation for Injuries— India • January 2012: Petition filed before the Supreme

Court of India by NGO (Swasthya Adhikar Manch) against the MoH alleging several flaws in Indian clinical trials regulatory framework

• January 2013: The Supreme Court of India suspended power of CDSCO/DCGI to approve clinical trials, due to inadequate oversight and checks/balances

• January-February 2013: New regulation on clinical trials issued, presumably in response to the Supreme Court ruling

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Rule 122 DAB – Compensation in the case of injury or death during a clinical trial:

– Subject to be given, by sponsor, free medical management for injury during trial, for as long as required

– If injury related to the clinical trial, subject also entitled to financial compensation from sponsor

– If subject dies during trial, his/her nominee(s) is entitled to financial compensation “over and above any expenses incurred on the medical management of the subject.”

Drug and Cosmetics Rules: First Amendment, effective Jan. 30, 2013

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Trial related injury or death

Defined broadly as any injury during a trial due to:

– Adverse effect of investigational product(s)

– Violation of the approved protocol, scientific misconduct or negligence by sponsor, sponsor representative, or investigator

– Failure of investigational product to provide the intended therapeutic effect

– Use of placebo in a placebo-controlled trial

– Adverse effects due to concomitant medication, excluding standard care, necessitated as part of approved protocol

– Injury to child in-utero due to participation of parent in trial

– Any clinical trial procedures involved in the study

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Compensation to cover:

• Payment for medical management

• Compensation for trial related injury

• Compensation to nominee(s) of the subject in case of death

• Compensation for child injured in-utero due to participation of parent in trial

Compensation determined by:

• For death: Expert Committee recommendation, Licensing Authority determines

• For serious adverse events other than death: Ethics Committee recommends, Licensing Authority determines

Drug and Cosmetics Rules: First Amendment, effective Jan. 30, 2013

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Penalties on non-cooperating sponsors:

If sponsor fails to provide medical management or compensation to the subject for injury; or compensation to subject nominee(s) for death, then Licensing Authority may

• Suspend/cancel the trial and/or

• Restrict the sponsor including his representative(s) from conducting any further clinical trials in India or

• Take any other action deemed necessary

Drug and Cosmetics Rules: Second Amendment, effective Feb 1st, 2013

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Ranjit Roy Chaudhury Expert Committee – July 2013 Constituted by the Ministry of Health and Family Welfare to “formulate policy, guidelines and standard operating procedures for approval of new drugs including biologics, clinical trials, and banning of drugs.”

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Ranjit Roy Chaudhury Expert Committee – Recommendations • If any adverse effect (AE) or serious adverse effect (SAE) occurs during a

clinical trial, the sponsor investigator will be responsible for providing medical treatment and care to the patient, irrespective of whether the patient is in the control group, placebo group, standard drug treatment group or the test drug administered group.

• Compensation need not be paid for injury or death due to totally proven unrelated causes.

• Any SAE arising in the group receiving the placebo in place of the standard treatment should also be compensable if the SAE is related to the use of placebo instead of the standard treatment.

• There must be strong provision for ancillary care to cater for patients suffering from any other illness during the trial.

• No compensation needs to be paid for therapeutic inefficiency, since the very purpose of a clinical trial is to determine the efficacy and safety of a given drug/vaccine/device.

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MoH Response to the Chaudhury Report

• Regarding compensation in case of injury or death due to failure of intended therapeutic effect:

Will propose an amendment to rules so such compensation is provided only “when standard care, though available, was not to be provided to the patient as per the protocol.”

• Regarding medical management of serious adverse events:

Will propose an amendment to rules specifying “that medical management should be provided as long as required or till such time it is established that the SAE is not related to Clinical Trials, whichever is earlier.”

• Regarding Compensation for use of Placebo:

Will propose an amendment to rules specifying “that compensation should be paid in cases of injury or death caused due to use of Placebo where the standard care though available was not to be provided to the subject as per the protocol.”

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• No changes to general standard for compensation.

“Compensation need not be paid for injury or death due to totally proven unrelated causes. In all other related cases of death or injury/disability, compensation should be paid to the participant or his legal heirs.”

• Ancillary Care

MoH believes Rules should be amended to provide “ancillary care to patients suffering from any other illness during the trial.”

• No changes to method of determining causation

“Ethics committees would give their opinion on the SAE to the Independent Expert Committee.”

MoH Response (cont)

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Additional Regulatory Actions Pending in India • Videotaping of informed consent

discussions required • Mandatory accreditation of research sites

and ethics committees/IRBs • Mandatory credentialing of investigators

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