Life Science Compliance Update

August 15, 2016

FDA Commissioner Califf at BIO


The Biotechnology Innovation Organization (BIO) held an International Convention in San Francisco June 6 – 9, 2016. This year, the organization held two fireside chats, one of which was with Dr. Robert Califf, the Commissioner of the Food and Drug Administration (FDA). Dr. Califf discussed his commitment to strengthening programs and policies that enable the agency to carry out its mission to protect and promote the public health.

Dr. Califf noted that for the past few years, the FDA has been meeting with patients and patient advocates in an attempt to better understand their diseases and medical problems, and where regulatory efforts should be focused. Califf noted also that it is not just the regulator that should be thinking this way and increasing exposure to patient viewpoints, but also the FDA is “encourag[ing] industry to think that way” as well.

He believes that in particular, industry, patients sand the FDA ought to come together to better understand patients’ tolerance for risk. The spectrum varies widely, from rare diseases for which there are no effective treatments and for which patients are willing to take on more risk, to diseases that affect millions, where many times drugs already exist to treat aspects of the disease. However, Califf feels that there remains “a lot of work to be done about where we fall in between” those two extremes.

He discussed how in the past, the agency often spoke to small groups of representative advocates and now, they are beginning to enter this “very exciting, explosive era … with social media and broad use of the Internet, we can communicate directly.” He noted that the “best way to develop products in the future is likely going to be to involve a lot of people with diseases to have a handle on what their needs are, what their expectations are, and what their risk tolerance may be.”

Califf also touched upon FDA’s recent efforts to streamline the process by which patients can access experimental medicines under the “compassionate use” framework. He discussed the fact that FDA has been working on streamlining for years, and “not just because of a particular issue we were facing.” It was discussed that the previous system was onerous and hard to navigate, and that the new compassionate use process will likely reduce the amount of time physicians spend filling out requests for access to an investigational therapy. The FDA still doesn’t give people access, but rather the company that is developing the drug makes that decision.

Califf seemed to suggest that when it comes to off-label communications, if information was supportable and worth sharing, it should be on a drug’s label. The clinical trials construct, or “human experimentation,” as Califf referred to it, and its associated institutional review board, create a commitment to produce generalizable knowledge, “That, to me, means that if you have useful information from a human subject, you have a commitment to make that knowledge public. Then I ask what information do companies have that’s not public that they’d like to communicate properly to physicians and patients?”

Other topics discussed by Califf included: FDA staffing concerns, succession planning, new tools for evidence generation, and companies’ interest in communicating off-label information about drugs to physicians. Interestingly, Califf remarked that “I have great respect for industry, but in general, I don’t look to industry to be the least biased source of information.”

July 28, 2016

FDA Guidance Data Integrity and Compliance With CGMP

In recent years, FDA has increasingly observed current good manufacturing practice (cGMP) violations involving data integrity during cGMP inspections. This is troubling because ensuring data integrity is an important component of industry's responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA's ability to protect the public health. These data integrity-related cGMP violations have led to numerous regulatory actions, including warning letters, import alerts, and consent decrees. The underlying premise is that cGMP sets forth minimum requirements to assure that drugs meet the standards of the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding safety, identity, strength, quality, and purity. To address these concerns, FDA has recently released a guidance on data integrity.

The guidance includes 18 questions and answers on data integrity, alongside well-defined terms on data as they relate to cGMP records, as well as recommendations on when workflows on computer systems need to be validated, and how to ensure electronic master production and control records (MPCR) are monitored and can only be used by authorized personnel.

Guidance Questions and FDA Answers

Addressing whether it is permissible to exclude cGMP data from decision making, FDA states any data created as part of a CGMP record must be evaluated by the quality unit as part of release criteria and maintained for CGMP purposes. Electronic data generated to fulfill CGMP requirements should include relevant metadata. To exclude data from the release criteria decision-making process, there must be a valid, documented, scientific justification for its exclusion (see the guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production). The requirements for record retention and review do not differ depending on the data format; paper-based and electronic data record-keeping systems are subject to the same requirements.

FDA also recommends implementing appropriate controls to manage risks associated with each element of the system. Controls that are appropriately designed to validate a system for its intended use address software, hardware, personnel, and documentation.

To restrict access to CGMP computer systems, exercise appropriate controls to assure that changes to computerized MPCRs, or other records, or input of laboratory data into computerized records, can be made only by authorized personnel. FDA recommends restricting the ability to alter specifications, process parameters, or manufacturing or testing methods by technical means where possible (for example, by limiting permissions to change settings or data). FDA suggests that the system administrator role, including any rights to alter files and settings, be assigned to personnel independent from those responsible for the record content. To assist in controlling access, FDA recommends maintaining a list of authorized individuals and their access privileges for each CGMP computer system in use.

Regarding audits, FDA recommends that audit trails that capture changes to critical data be reviewed with each record and before final approval of the record. Audit trails subject to regular review should include, but are not limited to, the following: the change history of finished product test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters. FDA recommends routine scheduled audit trail review based on the complexity of the system and its intended use.

Additionally, audit trails are considered part of the associated records. Personnel responsible for record review under CGMP should review the audit trails that capture changes to critical data associated with the record as they review the rest of the record. For example, all production and control records, which includes audit trails, must be reviewed and approved by the quality unit. This is similar to the expectation that cross-outs on paper be assessed when reviewing data.

FDA explains that an electronic data becomes a CGMP record when it is generated to satisfy a CGMP requirement. Document or save the data at the time of performance to create a record in compliance with CGMP requirements. FDA expects processes to be designed so that quality data required to be created and maintained cannot be modified. For example, chromatograms should be sent to long-term storage (archiving or a permanent record) upon run completion instead of at the end of a day's runs.

FDA says it is not acceptable to record data on pieces of paper that will be discarded after the data are transcribed to a permanent laboratory notebook. Similarly, it is not acceptable to store data electronically in temporary memory, in a manner that allows for manipulation, before creating a permanent record. Electronic data that are automatically saved into temporary memory do not meet CGMP documentation or retention requirements.

A combination of technical and procedural controls can also be employed to meet CGMP documentation practices for electronic systems. For example, a computer system, such as a Laboratory Information Management System (LIMS) or an Electronic Batch Record (EBR) system, can be designed to automatically save after each separate entry. This would be similar to recording each entry contemporaneously on a paper batch record to satisfy CGMP requirements. The computer system could be combined with a procedure requiring data be entered immediately when generated. For PET drugs, see the "Laboratory Controls" section of the guidance for industry PET Drugs — Current Good Manufacturing Practice (CGMP).

Finally, FDA addresses recommendations regarding data integrity problems identified during inspections, in warning letters, or in other regulatory actions. FDA encourages demonstrations of effectively remedied problems by: hiring a third party auditor, determining the scope of the problem, implementing a corrective action plan (globally), and removing at all levels individuals responsible for problems from CGMP positions. FDA may conduct an inspection to decide whether CGMP violations involving data integrity have been remedied.

These expectations mirror those developed for the Application Integrity Policy. For more detailed guidance, see the "Points to Consider for Internal Reviews and Corrective Action Operating Plans" public document available on the FDA website.

July 26, 2016

FDA: Draft Guidance - Procedures for Evaluating Appearance Issues and Granting Authorizations for Participation in FDA Advisory Committees

FDA released draft guidance to deal with what it describes as "appearance issues" that make advisory committee members appear to lack impartiality. This applies even to those who do not have financial interests and relationships that are conflicts of interests. If an appearance issue exists, FDA will weigh the member's participation against the concern that a reasonable person may question the integrity of the FDA's decision. This is a troubling development for the constitutional freedom of association, especially if professionals are going to be forced to recuse themselves for merely the appearance of a conflict.

The guidance comes after Public Citizen filed a Freedom of Information Act lawsuit against FDA in a bid to get unredacted copies of advisory committee members' curriculum vitae -- which describe their education, qualifications and previous experience -- posted on the agency's website.

Michael Ortwerth, FDA's director of the Advisory Committee Oversight and Management Staff, said in an FDA Voice blog post that a lack of understanding about the agency's selection and evaluation process has resulted in public confusion and misunderstanding. He explains the guidance contains: "the circumstances that FDA considers when determining whether an appearance issue may exist. We evaluate the circumstances and assess whether the interests, relationships, or circumstances would cause a reasonable person with knowledge of the relevant facts to question the advisory committee member's impartiality in the matter before the committee."

As an example: "if an advisory committee member serves on the board of directors of a nonprofit organization and that organization receives donations from the sponsor that is presenting before the committee, we review the details of the donation to determine whether the member should be cleared for service on the advisory committee."

He notes this is not finalized, however: "The draft guidance is being issued for public comment before we issue a final guidance. Under Federal law, FDA is not permitted to disclose confidential information provided by advisory committee members related to appearance issues. But we are specifically requesting comments on whether the agency should request that advisory committee members voluntarily disclose if they have been granted an appearance authorization."


Members of FDA's advisory committees are subject to Government-wide standards of ethical conduct regulations in addition to Federal conflict of interest laws. Even where a member has no financial interests that would require her to refrain from participating in an advisory committee meeting ("recuse" herself) under Federal conflict of interest laws, the member may be disqualified from participation under the Government-wide Federal regulation at 5 CFR § 2635.502 ("section 502") if she has interests or relationships that may create the appearance that she lacks impartiality on the issue before the advisory committee.

Section 502 gives FDA and other agencies significant flexibility and discretion in deciding whether a member with an appearance issue should participate in a particular matter. Under section 502, when a member has an appearance issue, FDA may authorize the member to participate in the advisory committee meeting based on a determination, made in light of all relevant circumstances, that the interest of the Government in the member's participation outweighs the concern that a reasonable person may question the integrity of the agency's programs and operations. If FDA does not issue an authorization, the individual may not participate in the meeting or the portion of the meeting involving the particular matter relevant to the appearance issue.

In determining whether to grant an authorization under section 502 to a member with an appearance issue, FDA balances the agency's interest in access to the advice of qualified experts to make important public health decisions with the need to avoid serious questions about the member's impartiality. Section 502 places the initial burden of identifying potential appearance issues on the member. It also gives the member the initial responsibility to recuse herself where she determines that the circumstances would cause a reasonable person with knowledge of the relevant facts to question her impartiality in the matter, unless she informs FDA of the issue and receives authorization from FDA to participate. FDA has the discretion to make independent determinations about whether a member has an appearance issue and to decide whether to grant her an authorization to participate once an appearance issue is identified.

Screening to Identify Possible Appearance Issue

In preparation for an advisory committee meeting involving a particular matter, members report to FDA any interests related to the subject matter of the meeting. These interests are reported on the Confidential Financial Disclosure Report. Although the Confidential Financial Disclosure Report Form primarily focuses on current financial interests, it also asks for information about past financial interests that directly relate to the products or issues to be considered at the meeting, and any other interests or relationships that might give rise to an appearance issue.

A member may seek assistance from FDA in completing this form. In completing this form, a member is required to report anything that would create an appearance issue not otherwise disclosed on the Form. The member may make a threshold judgment as to whether the information would cause a reasonable person to question her participation, and so inform the agency. FDA reviews the completed Confidential Financial Disclosure Report for each member in advance of every committee meeting to determine whether an appearance issue exists. As part of this review, FDA may ask for clarification about reported interests or about interests not reported but of which FDA may otherwise be aware.

What Circumstances May Create Appearance Issue?

Section 502 specifically lists certain interests and relationships that could create an appearance issue. It also includes a "catch-all" provision, which covers any other circumstances that may cause a reasonable person to question the member's impartiality. Once these circumstances raise a concern regarding the impartiality of the member, FDA considers the totality of the circumstances when determining to grant an authorization.

  • "Direct and Predictable Effect" on the Current Financial Interest of a Member of the Advisory Committee Member's Household

Under section 502, the following scenario would raise a potential appearance issue: where the particular matter coming before the advisory committee is likely to have a "direct and predictable effect" on the current financial interest of a member of the advisory committee member's household.

  • A Person or Entity with Whom the Member has a "Covered Relationship" is or Represents a "Party to the Matter"

Under section 502, the following scenario would also raise a potential appearance issue: where a person (or entity) with whom the advisory committee member has a "covered relationship" is or represents a "party to the matter" coming before the advisory committee. Both "covered relationship" and "party to the matter" are described in the guidance document.

  • Other Circumstances that May Raise a Question about the Member's Impartiality

Examples include broadly stated, "matters of general applicability". "Particular matters of general applicability" involve potential changes to regulations or agency guidance, or other broad topics such as policy-making and decisions that affect an entire class of products, such as reviewing labeling changes for an entire class of products. Particular matters of general applicability tend to raise fewer appearance issues than particular matters involving specific parties. However, the agency may require members to recuse from particular matters that do not involve specific parties, based on the concern that the member's impartiality reasonably may be questioned under the circumstances.

Other listed examples include relationships that are not technically "covered relationships" such as social relationships. Past financial interests ending more than one year before the meeting that suggest a close relationship with the sponsor or involvement with the product(s) before the committee was also a part of the "catch-all" provision.

Example from FDA Guidance

Scenario: The advisory committee is reviewing the safety and efficacy of a product. The meeting is a particular matter involving specific parties with one party to the matter ("the sponsor").

Example: The member's primary employment is as a dean of the medical school at a large university. The member reported that her employer has a multi-year grant from the product sponsor (i.e., the sponsor of the product that will be reviewed and evaluated at the advisory committee meeting) and the grant is not related to the product before the committee. This is an interest or relationship that could cause a reasonable person to question the member's impartiality.

Factors FDA Would Consider in Determining Whether or Not to Grant a Section 502 Authorization For the Member to Participate in the Meeting:

  • Whether the member receives any personal funding or remuneration from the grant (if not, this would weigh in favor of a section 502 authorization);
  • Size and diversity of the range of products made or under development by the sponsor providing the grant funding to the employer (the larger and more diverse the range of products the more this would weigh in favor of a section 502 authorization);
  • Whether the member's employer relies solely, or principally, on this grant from the sponsor (if not, this would weigh in favor of a section 502 authorization);
  • Whether the matter before the committee is considered sensitive or controversial (matters that are typical and routine without controversy would weigh in favor of a section 502 authorization);
  • Whether the member has expertise that is important to the committee's work and others with comparable expertise have conflicts or appearance issues more extensive than the member's (if so, this would weigh in favor of a section 502 authorization);
  • If there is a need for multiple experts in a field (if so, this would weigh in favor of a section 502 authorization).


It comes to a point, that this is becoming ridiculous. The examples FDA uses would disqualify any physician whose institution is working on a research grant for the sponsor for a different product. Good luck in finding medical school faculty. The scenarios of "appearance" could go on forever, if the FDA wants to spend their time on fruitless exercises, then this is the guidance for you. Would not their time be better evaluating products then hunting through CV's for hidden conflicts.


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