Observational / Non-Interventional Studies in Canada

New Drugs and Biologics Approved In 1996, PDUfA had just been enacted and there was a huge backlog. Therefore the 1996 and maybe 1997 high numbers are artificial.

Drugs in the R&D Pipeline 7% annual increase.

Disburse Clinical Trials Globally Half of all trials are conducted outside of North America Emerging markets have inconsistent regulatory procedures and add operating complexity.

Observational Studies Is this a possible new future for clinical trials for Canada? Is Canada well set up to do Observational Studies? What are the rules for Observational Studies?

What is an Observational Study? An Observational Study is a study in which there is no intervention between the patient and the physician. The intent of the study is simply to observe what happens. An Observational Study is also known as a Non- Interventional Study.

Non-Interventional Studies Post-authorisation Study (Post-marketing Study) Any study conducted within the conditions laid down in the Product Monograph and other conditions laid down for the marketing of the product under normal conditions of use. A post-authorisation study falls either within the definitions of a clinical trial or a non-interventional study and may also fall within the definition of a post-authorisation safety study. Post-authorisation Study Clinical Trial Non-interventional Study Either of the above could be post-authorisation safety study (PASS)

Non-Interventional Study A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.

Why Conduct an Observational Study? Observational studies may be required post authorization to monitor a safety concern, e.g., considering patients who take Drug X, how many experience problems with QT prolongation or an associated adverse reaction? For patients >75 years, is the rate of adverse events the same as for younger patients? For patients with the following comorbid condition taking Drug X, is the rate of adverse events the same as for younger patients? When taking Drug X >5 years, does the effectiveness remain? How long does effectiveness last? Europe has introduced the concept of Post Authorization Efficacy Studies Observational Studies sometimes try to get at the issue of effectiveness versus efficacy, i.e., real life data

Does an Observational Study Have a Protocol? Yes. An observational study is research and there are primary and secondary objectives. The protocol will also define how the study will be done Will it be done as a registry? Will physicians be enrolled and then all patients who take drug X from than practice be captured? Will all patients with a certain indication from a given practice be enrolled? Will all pregnant women be enrolled? How long will the observational period last?

Does an Observational Study Have Informed Consent? Yes. An Observational study must be conducted according to Good Clinical Practice (GCP), therefore an Informed Consent document must be signed by the patient/subject.

Does an Observational Study Require Ethics Review? Europe In those countries where Ethics Boards are prepared to review these studies, yes. Canada Yes, but what about retrospective studies?

Can an Observational Study Be Retrospective? Yes. A retrospective study is defined as an epidemiologic study in which participating individuals are classified as either having some outcome (cases) or lacking it (controls); the outcome may be a specific disease, and the persons' histories are examined for specific factors that might be associated with that outcome. Cases and controls are often matched with respect to certain demographic or other variables but need not be. As compared to prospective studies, retrospective studies suffer from drawbacks: certain important statistics cannot be measured, and large biases may be introduced both in the selection of controls and in the recall of past exposure to risk factors. The advantage of the retrospective study is its small scale, usually short time for completion, and its applicability to rare diseases, which would require study of very large cohorts in prospective studies. (http://medical-dictionary.thefreedictionary.com/retrospective+study)

How Are Observational Studies Regulated in Canada?

Food and Drug Regulations provide authority to HPFB. Regulatory Framework Food and Drug Regulations provide authority to HPFB. Division 5 of the Regulations define requirements for clinical trials. Regulations are consistent with ICH GCP. Division 5 of the Food and Drug regulations define CTA, clinical trial application regulations. Division 5 came into effect in 2001; Before that INDs were filed in Canada. Practically speaking, one difference between an IND filed with the FDA and a CTA is that a CTA represents one clinical protocol. An IND can have multiple protocols submitted to it. Regulations governing CTAs follow ICH GCP E6. (Good Clinical Practices). 15

What is the Definition of a Clinical Trial? An investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

Are Observational Studies Clinical Trials? Yes. All research done on human subjects are defined as clinical trials

Are Retrospective Observational Studies Clinical Trials? According to Health Canada’s definition, yes. Doesn’t really make sense, apart from privacy issue and use of a patient’s data.

For clinical trials in Phases 1 through 3 When Is a CTA Required? For clinical trials in Phases 1 through 3 Includes trials involving marketed products where the proposed use is outside of the NOC or DIN application Applies to companies and researchers/physicians Give me an example of a Phase 1 study: (PK, Bioequivalence) Are you all comfortable with what PK (Pharmacokinetics means)?—If not Ask what kinds of things would be measured in a PK trial? (ADME=absorption, distribution, metabolism, elimination of the drug and calculations are made) What kind of pt population is a Phase 1 study done in? (Healthy volunteers, unless not ethical, e.g., cancer drugs are studied in patients). Generally a Phase 1 study is open label and involve about 20 people. What do you know about Phase 2 and 3 studies? (Patients with disease). E.g., Phase 3 is more controlled, blinded, both are randomized and multicentre. Phase 3 generally involves a few thousand patients). Phase 4 efficacy and safety trials involve a study for a use/indication outside of the Noc. These require a CTA. (Could provide an example of an off-label use where sponsor wants to invest in getting the new indication on the label such that the use can be advertised). 19

Is a CTA Required for an Observational Study? If the study is looking at a drug according to its approved monograph, then no. If unlabelled indications are being observed, then yes. Same applies to unlabeled populations (e.g., pediatrics, pregnancy) Same applies to unlabeled dosage Once a CTA is required, then according to Canadian regulations, the study is no longer observational Clinical trial supplies have to be provided and labelled according to Canadian regulations.

Labelling Requirements Investigational Drug. To be used by Qualified Investigator Only. Research Drug. Reserved only for the use of qualified researchers Name, number or identifying mark of drug Expiry date Storage conditions Lot number Name and address of sponsor Protocol Number Radiopharm requirement All clinical trial supplies must be labeled according to the above as spelled out in the guideline. The labeling requirements for a Pharmaceutical or Biological are these. There are additional requirements for a Radiopharmaceutical that include the Radiation warning symbol and a “Caution –radioactive material” in English and French. For Natural Health Products, the label would read: Investigational Natural Health Product. 21

Is an Investigational Brochure Required for an Observational Study? If the study is being done is an Observational Study in Canada, then the current Product Monograph can replace the Investigational Brochure, if one drug is being studied. Investigational Brochures are required for CTAs. Unclear what the situation is for observational studies that do not involve CTAs, especially retrospective studies.

Who Reviews CTAs for Observational Studies Who Reviews CTAs for Observational Studies? Drugs - Therapeutic Products Directorate Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD) Bureau of Pharmaceutical Sciences (BPS) Bureau of Policy, Science, and International Programs Medical Devices Bureau Office of Clinical Trials Office of Risk Management Litigation Support and Document Management Services Office of Business Transformation Office of Submissions and Intellectual Property Within each of the Directorates, there are various bureaus representing different specialized areas. The specialties are further divided up as seen here for the BMORs bureau. 23

Who Reviews CTAs for Observational Studies? Biologics - BGTD Centre for Blood and Tissues Evaluation Blood Products Division Blood, Cells, Tissues and Organs Division Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Clinical Trials Division Centre for Vaccine Evaluation Bacterial and Combination Vaccines Division Viral Vaccines Division

Canadian Good Clinical Practice Regulations

Good Clinical Practices The clinical trial is scientifically sound and clearly described in the protocol The clinical trial is conducted, and the drug is used, in accordance with the protocol and Drug Regulations Systems and procedures that assure the quality of every aspect of the clinical trial are implemented For each clinical trial site, the approval of a research ethics board is obtained before the clinical trial begins at the site At each clinical trial site, there is no more than one qualified investigator At each clinical trial site, medical care and medical decisions, in respect of the clinical trial, are under the supervision of the qualified investigator Each individual involved in the conduct of the clinical trial is qualified by education, training and experience to perform his or her respective tasks

Good Clinical Practice Written informed consent, given in accordance with the applicable laws governing consent, is obtained from every person before that person participates in the clinical trial but only after that person has been informed of The risks and anticipated benefits to his or her health arising from participation in the clinical trial and All other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial The requirements respecting information and records set out in Section C.05.012 are met The drug is manufactured, handled and stored in accordance with the applicable good manufacturing practices referred to in Divisions 2 to 4 except sections C.02.019, C.02.025 and C.02.026.

Records

These records must be retained for 25 years. All versions of the IB, including records of each change with the rational for the change and documentation to support change. All ADRs including tabular summaries of Most serious Most frequent (>3%) Drop-outs Remaining (<3%) List of subjects who died Line listing of expedited reports There is a June 2006 Guidance for Records Related to Clinical Trials that I will pass around. Called Guide 0068, this is an interpretation of section C.05.012 of the Regulations. At the beginning of the Guidance, it indicates the guidance is meant to be harmonized with ICH GCP, however, there is admission that the Regulations can exceed the ICH requirements. The requirements for records, how they are to be kept, the conditions under which they are to be made available for monitoring, auditing and inspecting are included. Only the original records (copies are not required) need be retained. The 25 years is per the Regulations; not ICH. HC states that this retention period will allow for patient follow up through the subsequent stages of drug development. And marketing and provide the ability to assess impact on the 2 nd generation. Calculate from date record generated. Transfer to a second medium may be acceptable, e.g. paper to CD if the process is fully validated (available for inspection). There is some guidance in GMPs. The next 3 slides lists some of the items that are to be retained: Annex 1 of the Guidance lists all the Essential Documents for the Conduct of a Clinical Trial. 29

Retain for 25 years Records (cont’d) Enrollment records and dropouts Documentation on shipment, receipt, disposition, return and destruction of drug Qualified Investigator Undertaking Form Copies of protocol, informed consent and amendments Research Ethics Board Attestation Form 25 years is a long time. Looking back on the last 25 years, there have been many mergers, 25 years ago (when I earned my PHD) I typed my thesis on an IBM Selectric, then there were moves through DOS, MACs, MSWORD 3.1, 95, 98 etc. Things changed fast and combined with mergers, I truly wonder whether the vaults of the Novartis, Glaxo etc have all these records readily at hand. 30

How to Handle Adverse Drug Reactions

Adverse Drug Reactions ADR = response to drug that is noxious and unintended. Submit only if both serious and unexpected. Do not submit serious, but expected. Do not submit if unrelated to study product. As per slide….. Who decides if it is serious? (Doctor) What is meant by unexpected? (not in the labeling) If in doubt as to whether related, submit. 32

Adverse Drug Reactions (cont’d) Submit Canadian and International Not fatal or life-threatening – 15 days Fatal or life-threatening – immediately (7 days) Within 8 days after informing HPFB, submit complete report which includes an assessment of importance and implication of findings. Submit ADRs from the study for both the Canadian and International sites As per the slide…. The 15 or 7 days is the number of days of awareness. 33

Adverse Drug Reactions (cont’d) Submit each ADR individually. Attach ADR Expedited Reporting Summary Form to front of ADR. Submit by fax to appropriate Directorate. Do not send hard copies. If causality is unclear, submit and address issue in covering letter. As per the slide… Submit the Cover letter, ADR form, the ADR form (that I will pass around), the adverse event as received for example on a CIOMS form or Medwatch 3500A form. Submit by FAX to the appropriate directorate for your product. If physician needs to unblind: only break the code according to protocol for serious ADRs. If blinded serious ADRs are submitted, sponsor is obliged to unblind and update HC in a follow up ADR. 34

IB’s should be updated annually. ADRs and IB All expedited ADRs should be conveyed to investigators and REBs either through an updated IB or as an Addendum (e.g., safety update, Dear Investigator letter) IB’s should be updated annually. Highlight changes. How does this apply for Observational Studies? As per slide…… 35

Needed Improvement in Canada

We Need Guidelines for Observational Studies in Canada Existing Guidelines in Other Jurisdictions Europe Guidance for the format and content of the protocol of non-interventional post- authorisation safety studies Guideline on good pharmacovigilance practices (GVP). Module VIII – Post- authorisation safety studies Scientific Guidance for the conduct of non-interventional studies (NIS) in Austria US Nothing

We Need Guidelines for Observational Studies in Canada Nothing When observational studies are done in Canada, if anything is looked at beyond what is in the labelling, a CTA must be submitted and the study is no longer observational. Results in artificially defining the protocol so that nothing outside the labelling is included Maybe the intent is to look at off label use. We need to bring Canada up to date with other jurisdictions with these studies. Canada is losing studies and this particular area should not be an area of loss.