Life Science Compliance Update

February 29, 2016

FDA Guidance: Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations

The FDA finalized a guidance it originally released in 2012 that is aimed to help industry collect safety data in late-stage premarket and postapproval clinical investigations. The FDA says in the guidance that selective safety data collection may be possible for some late-stage premarket and postapproval clinical investigations because "certain aspects of a drug's safety profile will be sufficiently well-established and comprehensive data collection is not needed."

Safety Databases

Safety databases collect information to accurately assess and characterize the risks of a new drug. A sponsor collects safety-related data during the course of drug development and knowledge of a drug's safety profile can change as more information comes in through its lifecycle. However, FDA notes that encouraging selective safety data collection in late-stage premarket and postapproval clinical investigations is consistent with the agency's approach to safety assessment which is focused on information that is useful and adds to current knowledge.

FDA outlines the growing interest in larger, simpler trials to obtain outcome data, data on long-term effects of drugs, and data on comparative effectiveness and safety. According to the agency, excessive safety data collection may discourage the conduct of these types of trials by increasing the resources needed to perform them and be a disincentive to investigator and patient participation in clinical trials. Therefore, FDA believes its guidance will facilitate the conduct of larger trials without compromising the integrity and the validity of trial results or losing important information, facilitate investigators' and patients' participation in clinical trials, and help contain costs by making more-efficient use of clinical trial resources.

Selective Safety Data Collection

FDA issues several examples of selective safety data collection, including no collection of certain safety data, less-frequent collection of certain safety data, and collection of certain safety data from only a fraction of the total trial enrollment. The agency writes that in general, selective data may be appropriate for certain types of safety data if:

  • The number of patients and their characteristics, the duration of exposure, and the dose range used in previous clinical investigations are sufficient to adequately characterize the safety profile of the drug for common, non-serious adverse events.
  • The occurrence of common, non-serious adverse events has been generally similar across multiple clinical investigations.
  • The drug's safety profile is established to the extent that it is reasonable to conclude that the occurrence of common, non-serious adverse events in the population to be studied will be similar to rates observed in previously conducted clinical investigations.

FDA also clarifies when selective safety data collection may be appropriate, noting the following types of clinical investigations:

  • Clinical investigations of new indications of approved drugs, if an existing safety database is relevant to such investigations.
  • Postapproval clinical studies and trials conducted to fulfill postmarketing requirements and postmarketing commitments. For example, when the study population in these types of studies is generally the same as or similar to the population from which the premarket safety database was derived, safety data collection can often be limited to the primary safety endpoint and other endpoints of interest.
  • Late-stage premarket and postapproval outcome clinical trials.
  • Premarket clinical investigations for some original applications, unless sufficient safety data already exist to adequately characterize the safety profile of a drug, comprehensive safety data collection is expected.
  • Postapproval clinical investigations in a different patient population or with different doses or other conditions of use. Selective safety data collection generally may not be appropriate in clinical investigations of marketed drugs in which there are important differences in the patient population, dose, dosage regimen, duration of use or route of administration compared with the conditions of use for the marketed indications.

Additionally, when selective safety data collection is suitable, it may be appropriate to limit collection of data or stop collection of some data, such as:

  • Non-serious adverse events not associated with dose modification, drug discontinuation, or withdrawal from the trial.
  • Routine laboratory monitoring as in many cases it may be possible to eliminate routine laboratory monitoring or to decrease the frequency of monitoring certain laboratory parameters.
  • Information on concomitant medications; if existing data satisfactorily characterize all anticipated drug-drug interactions and metabolic pathways, additional detailed information on concomitant medications may be of limited use, particularly for drugs used only short term.
  • Patient history and physical exams, where less-detailed histories and less-frequent physical exams for patients may be appropriate in some circumstances, especially in outcome clinical trials.

 

FDA writes that other considerations for safety data collection including the collection of complete safety data in population subsets and collection of complete safety data that identifies risk factors. The guidance also specifies that sponsors should be aware of data types that are generally not appropriate for selective safety data collection and should always be collected. This includes:

  • Data on all serious adverse events.
  • Data on non-serious adverse events that lead to dose modification, drug discontinuation, or withdrawal from the trial.
  • Data on unscheduled study visits, hospitalizations, and accidental injuries because these events may reflect serious adverse events of the drug.
  • In an oncology setting, data from all Grade 3 and Grade 4 adverse events, as well as Grade 2 adverse events that affect vital organs (e.g., heart, liver).
  • In development programs for rare disease indications, complete safety data should be collected, because these trials generally have limited patient populations and are unlikely to meet the recommendations for selective safety data collection.

For these types of safety data, it is generally important to collect information on all occurrences to better understand the following:

  • Causality;
  • Incidence;
  • Severity of adverse events;
  • Populations that are at risk;
  • Dose-response;
  • Other factors that contribute to our understanding of the nature of the event and who is at risk.

In its final section, FDA added language titled, "Agreement between sponsors and FDA on a plan for selective safety data collection." FDA writes that sponsors should discuss its specified plan with the relevant FDA review division or divisions at the appropriate time (e.g., at the end-of-phase II meeting for selective safety data collection for a phase III trial). The agreement reached should be incorporated into the procedures for safety data collection in the protocol, the monitoring plan, and other appropriate trial documents, according to the agency.

February 03, 2016

ICMEJ Proposes Data Socialism – Data Utopianism Has its Cracks - Comments Due April 18

The International Committee of Medical Journal Editors (ICMJE) recently put forth a proposed set of new requirements for sharing data that was generated by interventional clinical trials. The ICJME believes there is an ethical obligation to responsibly share such data because the participants in the trials put themselves at risk.

Essentially the ICMJE is proposing that as a condition of consideration for publication of a clinical trial report in their member journals, the authors must share with others the deidentified individual patient data (IPD) that is underlying the results presented in the article, including any tables, figures, appendices, and other supplementary material, no later than six months after publication. This proposed requirement will include all data underlying the results of the article's findings, as well as any necessary metadata.

As you can imagine, there are strong opinions on both sides of this proposal. Those who are arguing for it, claim, "many funders around the world – foundations, government agencies, and industry – now mandate data sharing." You know, that whole, "everyone else is doing it, we should too," mentality that our parents warned us about when we were younger.

Those who are against it have a multitude of opinions and reasons for being against it. Some go so far as to refer to those who support data sharing as "data parasites," since they latch onto research that has already been painstakingly performed and utilize it for their own purposes.

Analysis

This new proposed rule may sound like a nice idea, having the ability to reexamine high-quality information for the possibility of new information being found, potentially resulting in higher patient satisfaction and longevity. However, as just about anyone who has ever managed clinical studies, performed data collection and analysis, or curated data sets knows, there are a litany of concerns over such a proposal. Dan L. Longo, M.D., and Jeffrey M. Drazen, M.D., penned an editorial laying out some of their concerns from that perspective.

One such concern is that someone who is not involved in the generation and the collection of the data will not understand the choices the researchers made in defining the parameters. Some specific questions raised by Longo and Drazen included, "How heterogeneous were the study populations? Were the eligibility criteria the same? Can it be assumed that the differences in study populations, data collection and analysis, and treatments, both protocol-specified and unspecified, can be ignored?"

A second, very valid, concern, is that an entirely new class of research person will emerge – someone who had nothing to do with the design and the execution of the study, but use another group's hard-earned data for their own ends. These "stealers of data" can then use the data to steal research productivity planned by the data gatherers, or even use the stolen data to disprove the original researchers analysis.

Data sharing may not be all bad, depending on how it is performed and what requirements are in place. Longo and Drazen posit, for example, that if data sharing were to work symbiotically, with collaborators whose collected data might be useful in assessing your hypothesis, it might be beneficial for all parties involved, including patients. Throughout the symbiotic relationship, the two (or more) teams of researchers work together to test a hypothesis and report new findings with coauthorship, acknowledging the group that proposed the new idea and the investigative group that pursued the data and allowed it to be tested.

It is interesting to note that four days after jointly submitting an editorial piece with Dan Longo, M.D., Jeffrey Drazen, M.D., walked back part of it. He clarified that the New England Journal of Medicine, the forum for the initial editorial, is "committed to data sharing in the setting of clinical trials." He went on to comment that he believes "there is a moral obligation to the people who volunteer to participate in these trials to ensure that their data are widely and responsibly used" and that "researchers who analyze data collected by others can substantially improve human health."

In the walk back, he concludes by once again bringing up data sharing through collaboration, signaling that such form of data sharing may be palatable to more than just the "data socialists" who want to take your hard-researched data a mere six months after the publication of your findings.

Saurabh Jha, a radiologist in Philadelphia, summed it up nicely,

It takes a lot of effort to generate data in biomedical sciences. To expect researchers to surrender the data for the greater good is fuzzy, and lamentably boring, adolescent naivety. If we do not recognize the self-interest of researchers, data socialism, like other forms of socialism, is condemned to failure.

If you would like to provide feedback on the ICMJE proposal, you may submit your comments and concerns to the International Committee of Medical Journal Editors by April 18, 2016.

For More Background on This Controversy David Shaywitz, MD at Forbes has a great series:

Data Scientists = Research Parasites?

Biden Cancer Project: An Opportunity To Implement Data Sharing Incentives    

Do We Really Want To Separate Clinical Data Gathering And Data Analysis?

        

 

 

 

December 12, 2014

NIH Launches "ClinRegs" Website Aggregating Country-By-Country Clinical Research Regulation

 

ClinRegs


The National Institutes of Health's (NIH) National Institute for Allergy and Infectious Diseases (NIAID) has launched an online database of country-specific clinical research regulatory information “designed to save time and effort in planning and implementing clinical research.” The website, ClinRegs, provides users with useful comparison capabilities between thirteen countries. 

“By providing well-documented, up-to-date regulatory information for multiple countries in a single place, ClinRegs is intended to serve as a central resource and time-saver for persons involved in planning and implementing international clinical research,” the website states.

ClinRegs provides an overview of country-specific regulations in the following topic areas.

  • Competent Authority Oversight
  • Ethics Committee Oversight
  • Clinical Trial Lifecycle
  • Sponsorship
  • Informed Consent
  • Investigational Products
  • Specimens

The website currently asks for feedback from users, and NIAID notes that additional topics may be added based on that feedback. 

As an example, the Clinical Authority Oversight section for India states, in part:

In India, the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), is the competent authority responsible for clinical trial oversight, approval and inspections. The DCGI grants permission for clinical trials to be conducted in India in accordance with the provisions of the DCA, 1940/DCR, 1945 and Schedule Y. The DCGI is also commonly referred to as the Licensing Authority in the Indian regulations.

CDSCO is India’s central regulatory body for pharmaceuticals and medical devices. The DCGI, who directs CDSCO, handles the drug and device regulatory process; he/she is also responsible for registering all imported drugs and new drugs and for overseeing clinical trials. CDSCO functions under the Directorate of General Health Services (DGHS) which is part of the Ministry of Health and Family Welfare (MOHFW).

NIAID has aggregated information from Brazil, China, India, Kenya, Liberia, Malawi, Peru, South Africa, Tanzania, Thailand, Uganda, the United Kingdom, and the United States. Mali, Mexico, Haiti, and Vietnam will be possible additions to the programs, according to NIAID.  

The comparator tool provides side-by-side comparisons with countries on your chosen topic. For example, this shows a look at the "informed consent" requirements of both the United Kingdom and the United States. 

ClinRegs


Given the fact that large pharmaceutical companies operate internationally and must navigate a wide variety of complex clinical regulation, this website is very helpful. Having one master resource such as this can serve to both clarify a company's obligations, and expedite their understanding of responsibility in one country verses another. 

 

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