Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 34

Study phases are often hazier than the “official” schema described above. Phase I studies that go beyond the initial dose finding and escalation studies are often done throughout the phases over several years. If a drug does not go beyond phase II because of lack of efficacy (i.e., the company “kills” it), there is little point in doing drug, food, or alcohol interaction studies. Thus, these are usually not performed early in the course of development. Likewise, it is not common for the initial studies to use a formulation that is eventually approved for marketing.

Some companies have been known to try to speed up development (and lower costs) by doing somewhat larger phase II trials that, should they succeed, are submitted to the health agencies as combined phase II and III trials for approval. For critical drugs, this may be advantageous as long as it does not compromise the safety and efficacy evaluations. In general, the more patients who are studied, the more comfortable one is with the safety profile of the drug. Smaller safety databases obtained in phases I–III may require larger post-marketing safety study commitments to obtain additional information to adequately evaluate the benefit/risk profile as larger numbers of disparate patients use the drug. Obviously, the sponsor should discuss any proposed alterations of the classic drug development with the health authorities.

Phase I studies are created and supervised in most pharmaceutical companies by a dedicated phase I group (e.g., the pharmacokinetics/pharmacodynamics group) usually run by pharmacologists (PhDs, PharmDs), nurses, and physicians. The actual study is often outsourced to CROs or academic centers (clinical research units), where the patient enrollment and dosing occur. This permits close observation and continuous monitoring of subjects.

Phases II and III are usually run by “high power” clinical or medical research groups within the company led by physicians (often sub-specialists such as cardiologists, oncologists, etc.). These studies are complex and have large infrastructures supporting them in biostatistics, study-site monitoring, in-house data monitoring, clinical research, regulatory affairs, safety monitors, quality control, quality assurance, independent data monitoring committees for individual protocol oversight, a Safety Assessment Committee for development program oversight across all protocols, and so on. Many companies, particularly smaller ones, also outsource the trials (or parts of the trials) to one or more CROs and other vendors. These studies are rigorously done and are likely to be audited by the health authority before marketing approval. These studies may run into tens of millions of dollars and require complex organization, project management, and information technology support.

Phase IV studies may be done by the phase II and III group or by a separate post-marketing group. If phase IV studies are done in the clinical research department, the rigor of the earlier phases usually carries over to these phase IV studies. If the phase IV studies are done by the marketing department in isolation from the clinical research group, these studies may be somewhat more variable in quality and rigor. Some companies now have separate Safety/Epidemiology/Risk Management departments that handle PMCs and PMRs, e.g., post-marketing clinical and epidemiologic trials (but not the marketing studies). Many of these are now outsourced to CROs or firms specializing in “late phase” trials.

Some company executives have argued that small phase IV marketing studies or IIR programs are dangerous because they might discover some safety “problem” and might fail to show efficacy, thus doubly hurting the drug. Safety officers often argue just the reverse: these studies may uncover a previously unknown safety issue that represents good product stewardship, i.e., the new finding can be added to the product labeling to better inform prescribers and patients.

Clinical trial registries have been set up by health authorities and governments (clinicaltrials.gov in the United States and EudraCT in the EU), as well as by pharmaceutical companies and others in which all or almost all research trials are now posted, in detail, on a website. It has been felt by some that this will raise the standards for all trials and allow for easier data comparisons. That is not yet clear. Several things have happened, though. Patients, disease support groups, and patient advocates are now more easily able to find and track studies involving their disease by simply searching through the databases. There is also an industry that mines various databases for information on patient and investigator availability, enrollment, completion dates, and so forth.

IIR programs have traditionally posed problems. IIR is usually encouraged by companies that have roving medical liaisons. They visit academic medical centers to provide medical information and seek out new trials. These visiting medical liaisons may or may not be trained in classic clinical research methodology. They may also do “in-service” teaching or training on the company’s new products. Thus, this role combines a medical and a marketing function. In well-structured pharmaceutical companies, protocols submitted by academics are reviewed by the clinical research department, the statisticians, and the pharmacovigilance group to ensure good quality. A formal contract requiring completion, a final report within a finite period (e.g., 1 year), and SAE reporting must be done under good clinical practices. Pharmacovigilance departments in companies usually submit the SAEs to their own MAs, NDAs, and INDs, as the case may be, even if the investigator has said he or she has also done so. In less well-structured companies, the medical marketing group may be less well-connected to the other research groups and details may slip. Specifics of the contract (agreement) should be audited for compliance.

Other types of outreach programs (sometimes in combination with registries) are also used by companies for various reasons:

To help patients finish the course of therapy when they are already taking the drug;

As part of a REMS/RMP as an ETASU (an “element to assure safe use of the drug”);

To help sell the drug: In particular, for chronic therapy diseases such as cancer, hepatitis, and hypertension, companies have found that it is good medicine and good marketing to encourage patients to stay on their therapy to the end (until the cancer is in remission or cured, the viral titers drop, etc.). This means continued sales of the drug as well as successful patient treatment. The usual reasons for stopping therapy are AEs, dosing problems, or convenience reasons. Sometimes it is cost. Outreach programs that use nurses or pharmacists to contact patients every week or month on how to handle AEs and other issues are now common. These are a type of a Customer Engagement Program and must be linked to the safety department because they are often a source of safety information. When the program is well-executed, the patient’s physician is kept informed of issues and progress. The outreach team is able to work with the patient to get the patient over rough patches in the treatment regimen. AE data must be collected by the company, kept in the safety database, and reported to the health authority as required.