Regulatory news - December 2016

Keep up to date with regulatory news from around the world with the Cell and Gene Therapy Catapult regulatory newsletter.


European Medicines Agency (EMA)

EMA hosts workshop on adaptive pathways

On 8th December 2016, EMA hosted a workshop to discuss adaptive pathways with relevant stakeholders in London. Adaptive pathways is a product development concept aimed at providing timely access to promising medicines that address an unmet medical need. It makes use of existing approval tools, in particular those implemented during conditional marketing authorisation and post-marketing pharmacovigilance monitoring. Critically, it also involves cooperation between various stakeholders involved throughout the life-span of a medicine including Health Technology Assessment (HTA) bodies, with a view to incorporating these requirements at an early stage of development.

This EMA workshop follows its publication of a final report on the adaptive pathways pilot in July. Key topics covered during this meeting included the generation of ‘appropriate’ real world data to aid medicine evaluation and how this can be harnessed in cases where further data is necessary (which cannot be obtained from clinical trials). The importance of collaboration with HTA bodies and payers, which traditionally evaluate medicines post-authorisation, was also discussed.

The workshop was attended by representatives from patients’ and healthcare professionals’ organisations, pharmaceutical companies, HTA bodies and payers, national competent authorities (NCAs) and the European Commission. A full report of the event is under preparation.

Click here to view the slide presentations from the workshop.

Revision to clinical data publication guidance

EMA has published updated guidance on its new policy for publication of clinical data for medicinal products for human use.

This revision is an update to the version released in March. It includes a number of clarifications, including information on how sponsors should handle removing "out of scope" individual patient data from clinical study reports, how EMA will handle incomplete redaction proposals and how sponsors should distinguish between redacted Commercially Confidential Information and Protected Personal Data.

Click here to view the revised guidance.


EU directive integrates latest Good Practice Guidelines for EU blood establishments

New Good Practice Guidelines for EU blood establishments have been adopted by the European Committee (Partial Agreement) on Blood Transfusion (CD-P-TS) of the Council of Europe. These guidelines have been jointly developed by the EC and the European Directorate for the Quality of Medicines and Healthcare of the Council of Europe (EDQM). The document is an integral part of the 19th Edition of the Council of Europe Guide to the Preparation, Use and Quality Assurance of Blood Components, Appendix to Recommendation No. R (95) 15.

Eurpean blood establishments must take into account the standards and specifications set out in these guidelines when implementing their quality system by February 2018, in line with the new Commission Directive (EU) 2016/1214.

Click here to view the Good Practice Guidelines.


European Pharmacopoeia Commission adopts new texts aimed to reduce animal testing in quality control of vaccines

At the 156th session held on 22-24 November, the Ph. Eur. commission adopted a new general chapter on the substitution of in vivo methods by in vitro methods for the quality control of vaccines (5.2.14). This chapter aims to faciliate the transition from in vivo methods by providing guidance on how to validate alternative in vitro methods in scenarios where a direct head-to-head comparison to an existing in vivo method is not possible.

Furthermore, technical revisions of the general texts on tests for extraneous agents in viral vaccines for human use (2.6.16) and cell substrates for the production of vaccines for human use (5.2.3) were adopted. As part of the revisions, the tests in adult mice and guinea pigs were deleted as they were considered redundant due to the presence of other tests providing risk mitigation. In addition, the tests in suckling mice and control eggs are to be used only if a risk assessment indicates that the tests provide risk mitigation.

Theses texts will be published in the Supplement 9.3 of the European Pharmacopoeia and will become effective on 1st January 2018.



MHRA and HTA sign partnership agreement

In early December, the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Human Tissue Authority (HTA) signed a partnership agreement strengthening a collaboration beginning in 2005. The MHRA is responsible for regulating all medicines and medical devices in the UK. The HTA is the regulator for human tissues, cells and organs and amongst other roles, is responsible for licensure and inspection of organisations that remove, store and use human tissue for research.

The main areas of cooperation between the two agencies are joint advice through the ‘One Stop Shop’ regulatory advice service for regenerative medicine (RASRM), joint inspections of Tissue Establishments and advanced therapy medicinal product (ATMP) manufacturing sites, and a joint position on the use of blood for ATMP manufacture.


Obama signs the 21st Century Cures Act

Advocates have described the 21st Century Cures Act as a bill to help modernize and personalize healthcare in the USA, encourage greater innovation, streamline the system and support the gap between research and the way new therapies are regulated.

The act creates an accelerated approval pathway for regenerative treatments stating that “the sponsor of a regenerative advanced therapy shall be eligible for the actions to expedite development and review of such therapy […] including early interactions to discuss any potential surrogate or intermediate endpoint to be used to support the accelerated approval of an application for the product...”

There may also be further potential changes in the approval process as FDA will be required to “establish processes under which patient experience data and real world evidence may be considered in the risk-benefit assessment of a new drug”.

The bill goes onto say that patient experience includes data:

“collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers); and are intended to provide information about patients’ experiences with a disease or condition, including the impact of such disease or condition, or a related therapy, on patients’ lives and preferences with respect to treatment of such disease or condition.

The term real world evidence refers to data from sources outside of traditional clinical trials. This is typically derived from electronic systems used in health care delivery, data contained within medical devices, and/or in tracking patient experience during care, including in home-use settings.

It is still unclear to what extent these types of data will contribute to the overall risk/benefit profile of a therapy however it is plausible that these legislative actions could translate into new approval processes at the FDA.


FDA approves first autologous cellularized scaffold for the repair of cartilage defects of the knee

On December 13th 2016, the FDA approved the first tissue-engineered autologous cellularized scaffold product. Maci® consists of cultured chondrocytes on a porcine collagen membrane and is now approved for the repair of symptomatic, full-thickness cartilage defects of the knee in adult patients.

Maci is the first FDA-approved product that applies the process of tissue engineering to grow cells on scaffolds using healthy cartilage tissue from the patient’s own knee. Autologous cells are expanded and placed onto a bio-resorbable porcine-derived collagen membrane that is implanted over the area where the defective or damaged tissue was removed. Each Maci implant consists of a small cellular sheet containing 500,000 to 1,000,000 cells per cm2.

The safety and efficacy of Maci were shown in a two-year clinical trial designed to demonstrate reduced pain and improved function in comparison to microfracture, an alternative surgical procedure for cartilage repair. The trial included 144 patients (72 in each treatment group). A majority of the patients who completed the two-year clinical trial also participated in a three year follow-up study and overall efficacy data supports a long-term clinical benefit from the use of the Maci implant in patients with cartilage defects.

Maci is manufactured by Vericel Corporation, headquartered in Cambridge, Massachusetts.

FDA issues draft guidance on physiologically based pharmacokinetic (PBPK) analyses

The FDA outlines PBPK analyses as models and simulations that combine physiology, population, and drug characteristics to mechanistically describe the PK and/or pharmacodynamic (PD) behaviors of a drug. The draft guidance, entitled “Physiologically Based Pharmacokinetic Analyses—Format and Content” has been produced in response to a lack of regulatory guidance on the topic.

This type of analysis is often used to support investigational new drug applications (INDs), new drug applications (NDAs) and biologics license applications (BLAs) as it can inform decisions about future clinical pharmacology studies and dosing recommendations.

The FDA has proposed a six-part format for PBPK study reports that includes a section for an executive summary, introduction, materials and methods, results, discussion and appendices, in an effort to standardise reporting and review. It is out for industry comments until the end of January.

Click here to view the draft guidance.

FDA, NIH Unveil an initial framework for biomarker qualification

A framework for the proposed criteria to support regulatory acceptance of biomarker use in drug development programs was published on 6th December 2016 by the Biomarkers Consortium Evidentiary Standards Writing Group.

This document, authored by representatives from FDA, NIH, industry and academia, outlines a general framework based on five key biomarker components including:

1) Describing the drug development need

2) Defining the context of use (COU) and clinical question being answered

3) Considering the potential benefits including potentially improved sensitivity, selectivity and the mechanistic context

4) Considering the risks associated with the intended use of the biomarker in a drug development program (consequence/frequency of false negatives/positives)

5) Determining the evidentiary criteria to support the COU based on the benefits and risks

This framework is expected to support FDA in the development of relevant guidances for evidentiary criteria in biomarker qualification. Criteria to support biomarkers as part of diagnostic tests are outside the scope of this guidance.

Click here to view the intial framework.

Use of electronic Informed Consent (eIC); Q&A guidance document

This guidance is intended for institutional review boards in the US, investigators and sponsors engaged in or responsible for oversight of human subject research under HHS and/or FDA regulations.

As detailed by the FDA in the original draft in March 2015, "electronic informed consent refers to using electronic systems and processes that may employ multiple electronic media (e.g., text, graphics, audio, video, podcasts and interactive websites, biological recognition devices, and card readers) to convey information related to the study and to obtain and document informed consent”. Advantages of this type of consent can relate to patients (or subjects) as well as investigators and study staff.

Since this draft was issued, further clarity has been added to the 16 questions and answers originally contained in the document including how to present information, steps to improve understanding of the research, how to verify a subject’s identity who electronically signs, how to use eIC for pediatric studies, what eIC documentation is required for FDA submissions, steps to ensure that eIC materials are archived appropriately and what eIC documents would be required during an inspection.

Click here to view the final guidance.

FDA releases new material on 3D Printing

In March 2016, the FDA approved the first 3D printed drug, Aprecia's epilepsy drug Spritam. To create Spritam, all the elements are assembled layer-by-layer without compression. Thin layers of powdered medication are then repeatedly spread on top of one another as patterns of liquid droplets are printed onto selected regions of each powder layer. These interactions between powder and liquid contribute to bonding the materials together at a microscopic level.

The FDA has already approved around 85 3D-printed medical devices, mostly via the 510(k) or emergency use pathways. Researchers are considering the potential of 3D printing to better manufacture biological cell and tissue products.

In May 2016, the FDA published some initial thoughts on the topic in the form of ‘leap frog guidance’, a mechanism by which the agency can share preliminary views on emerging technologies that are likely to be of public health importance, early in product development. The guidance broadly covers design & manufacturing considerations and device testing considerations.

In late December, the agency released a short video on its role in supporting the field and how it is engaging with stakeholders to advance the technology towards new therapies.



Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice (GCP) advances to implementation phase

This GCP guideline first published in 1996, is central to the international ICH process and it’s latest amendment represents the biggest revision since it’s inception.

As described in the update, “when the original ICH E6(R1) text was prepared, clinical trials were performed in a largely paper-based process. Advances in use of electronic data recording and reporting facilitate implementation of other approaches. For example, centralized monitoring can now offer a greater advantage, to a broader range of trials than is suggested in the original text”.

The changes encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial results. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated.

Click here to view the guidance.

Public consultations




Consultation Period



Strategy for pharmacopoeial public quality standards for biological medicines

9 Jan 2017


10 April 2017

Draft for public consultation



Consultation Period



Labeling of Red Blood Cell Units with Historical Antigen Typing Results Draft Guidance for Industry

3 Jan 2017


3 Apr 2017

Draft guidance for public consultation



Consultation Period



ICH guideline E17 on general principles for planning and design of multi-regional clinical trials




Draft for public consultation