Guidance bonanza: FDA, EMA, MHRA, Health Canada and PIC/S offer new advice on a range of pharma issues

Guidance bonanza: FDA, EMA, MHRA, Health Canada and PIC/S offer new advice on a range of pharma issues
From data management to evaluating new drugs for CNS metastases, a bevy of drug regulators offered up new guidance documents over the past week.Like most guidance from drug regulators, the information contained within the documents reinforces much of what’s already known for those working in these areas. But the guidance also offers a window into what each of these agencies considers to be pertinent to this moment, in addition to all of the Covid-19-related work that they’re dealing with.PIC/SThe Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-Operation Scheme (PIC/S) offered up itsguidance on on-site inspections for biopharma companies performing manufacturing (GMP) and distribution (GDP) activities on July 1. As data integrity concerns continue to make their way into warning letters, the guidance is the culmination of more than five years’ worth of work, and although it’s primarily for biopharma inspectors, PIC/S notes how it also serves as a valuable resource for industry to provide more clarity on areas of greatest risk and regulatory expectations.“An effective ‘quality culture’ and data governance maybe different in its implementation from one location to another. However, where it is apparent that cultural approaches have led to data integrity concerns; these concerns should be effectively and objectively reported by the inspector to the organisation for rectification,” the 63-page guidance says. “The company’s Pharmaceutical Quality System should be able to prevent, detect and correct weaknesses in the system or their processes that may lead to data integrity lapses.”And while PIC/S notes that it may not be appropriate or possible to report an inspection deficiency related to an organization’s overall behavior, inspectors should understand how certain behaviors influence “the incentive to amend, delete or falsify data and the effectiveness of procedural controls designed to ensure data integrity, can provide the inspector with useful indicators of risk which can be investigated further.”FDA on drugs for CNS metastasesSolid tumors that most often metastasize to the central nervous system are small cell and non-small cell lung cancers, breast cancer, melanoma, and renal cancers, the FDA notes in itsnew final guidanceon clinical trials for the systemic drugs that attack these cancers.Among the more unique considerations for any such drug is circumventing the blood-brain barrier, although the agency said it will evaluate effects of systemic drugs on CNS metastases in the context of the entire burden of metastatic disease, regardless of whether the trial was conducted exclusively in patients with CNS metastases or in a population where only a subset of patients has CNS metastases.“Therefore, efficacy claims based on endpoints measuring CNS activity alone may not be appropriate. For example, evaluation of the clinical significance of overall response rates (ORR) or progression-free survival (PFS) that considers only CNS disease sites (CNS-ORR or CNS-PFS, respectively) is difficult to interpret as it does not take into account extra-CNS metastatic disease. Likewise, a labeling indication specifically for treatment of CNS metastases alone may not be appropriate. Where anti-tumor activity has been demonstrated in both the CNS and extra-CNS sites of disease, treatment effects on CNS metastases may be described in Section 14 (‘Clinical Studies’) of the product label,” the guidance says.While it’s rare to see the FDA call out specific drugs in its guidance documents, the agency does so here, using the example of Roche’s Alecensa, which is approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, and which the FDA also notes is an available therapy for the treatment of patients with CNS metastases from ALK-positive NSCLC.“Showing comparability to available therapy for treatment of overall metastases and demonstrating superiority for treatment of CNS metastases activity may be sufficient for expedited review consideration of a given drug,” FDA says.The guidance also discusses endpoints and leptomeningeal disease, which occurs when cancer cells migrate from a part of the body to the cerebrospinal fluid.MHRA and Health Canada joint guidance on DSURsThe UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and Health Canada on Tuesdaypublished guidanceto improve the safety of patients in clinical trials through the improved quality of periodic safety reports, known as Development Safety Update Reports.Building off the ICH’s E2F guideline, the joint UK-Canadian documentoffers adviceon how sponsors can disclose in the DSUR the way they have recorded safety data during the reporting period and reviewed it in the context of the cumulative safety profile for an investigational drug.“At present, even though trial sponsors will have conducted assessments regarding safety concerns, these detailed safety assessments are not always included in the DSUR. This makes it difficult for some regulators to find out if all safety concerns have been thoroughly investigated and whether appropriate measures have been taken to mitigate the risks associated with the use of the investigational medicinal products during a trial,” MHRA said in explaining why the guidance is necessary.Medsafe, New Zealand’s drug regulator, said it is also in agreement with the guidance and will take it into consideration when reviewing its national legislation.EMA on chemical and pharmaceutical quality documentation in trialsThe European Medicines Agency last week released a new,42-page draft guideline, open for consultation until the end of August, which deals with EU-wide harmonized requirements on the quality of biologics in clinical trials.“Assuring the quality of biological medicinal products is challenging, as they often consist of a number of product variants and process related impurities whose safety and efficacy profiles are difficult to predict. However, unlike chemical entities, toxic impurities are generally not an issue, and the safety issues of biological/biotechnological products are more often related to the mechanism of action of the biological product or to immunogenicity,” the guideline says.Before getting into the details on everything from drug substance to placebo, the EMA notes that it is the responsibility of the sponsor to ensure the protection of the clinical trial subjects using a high-quality investigational medicinal product (IMP) that is suitable for its intended purpose, and to appropriately address those quality attributes that may impair patients’ safety (e.g. microbiological aspects, viral contamination, dose)....read more